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1.
Foods ; 11(7)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35407131

RESUMO

Crohn's disease (CD) is a chronic inflammatory gastrointestinal disorder requiring lifelong medications. The currently approved drugs for CD are associated with relevant side effects and several studies suggest an increased use of nutraceuticals among CD patients, seeking for what is perceived as a more "natural" approach in controlling this highly morbid condition. Nutraceuticals are foods or foods' components with beneficial health properties that could aid in CD treatment for their anti-inflammatory, analgesic and immunoregulatory activities that come along with safety, high tolerability, easy availability and affordability. Depending on their biological effect, nutraceuticals' support could be employed in different subsets of CD patients, both those with active disease, as adjunctive immunomodulatory therapies, and/or in quiescent disease to provide symptomatic relief in patients with residual functional symptoms. Despite the increasing interest of the general public, both limited research and lack of education from healthcare professionals regarding their real clinical effectiveness account for the increasing number of patients turning to unconventional sources. Professionals should recognize their widespread use and the evidence base for or against their efficacy to properly counsel IBD patients. Overall, nutraceuticals appear to be safe complements to conventional therapies; nonetheless, little quality evidence supports a positive impact on underlying inflammatory activity.

2.
Nutrients ; 14(7)2022 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-35406010

RESUMO

Obese children are at high risk of developing vitamin D deficiency. Omega-3 polyunsaturated fatty acids and their derivatives might have a beneficial effect on vitamin D status of obese children, due to their anti-inflammatory action, and increasing its absorption. This multicenter, randomized, double-blind controlled study aims to investigate the effect of vitamin D and docosahexaenoic acid (DHA) co-supplementation for six months on vitamin D status, body composition, and metabolic markers of obese children with vitamin D deficiency. A total of 108 children were enrolled and 73 children completed the study: 33 were supplemented with an oral dose of 500 mg of DHA and 1200 IU/day of vitamin D3 and 41 were supplemented with 1200 IU/day of vitamin D3 + wheat germ oil. At the end of the study, more than 50% of the subjects improved their vitamin D status. However, co-supplementation was not more effective than vitamin D plus wheat germ oil. Fat mass percentage was significantly reduced, and body mass index improved in both groups, even if all the subjects were still obese at the end of the study. Children receiving both vitamin D and DHA presented a higher increase of DHA levels that could be relevant to prevent inflammatory-associated complications of obesity, but they had no effect on vitamin D levels.


Assuntos
Obesidade Pediátrica , Deficiência de Vitamina D , Composição Corporal , Criança , Colecalciferol , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos , Método Duplo-Cego , Humanos , Obesidade Pediátrica/complicações , Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/uso terapêutico
3.
Ann Hematol ; 101(6): 1227-1237, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35380239

RESUMO

Therapy-related myeloid neoplasm (t-MN) is a threatening complication of autologous stem cell transplantation (ASCT). Detecting clonal hematopoiesis (CH) mutations in cryopreserved cells before ASCT has been associated with a higher risk of t-MN, but the evolution of molecular abnormalities from pre-ASCT to t-MN, within the same patient, remains to be elucidated. We evaluated the mutational profile of 19 lymphoma/myeloma patients, at both pre-ASCT and t-MN diagnosis, using a targeted NGS approach; 26 non-developing t-MN control patients were also studied pre-ASCT. At ASCT, we found a higher frequency of CH in patients developing t-MN (58%) than in those who did not (23%) (P = 0.029); mutations in epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (PPM1D, RAD21, TP53, and STAG2) were the most represented. At t-MN, CH increased to 82% of patients. Cumulative mutational burden and variant allele frequency (VAF) also increased at t-MN. CH clones detected at ASCT were found at t-MN in eight out of 16 patients, mainly with stable VAF. Among the new driver mutations appeared at t-MN, TP53 increased from one to 13 mutations, in nine patients; being associated with complex karyotype. Mutations in transcription factor (RUNX1, CEBPA) and intracellular signaling genes (FLT3, RAS genes) also increased from three to 17 mutations in eight patients, presenting with a normal karyotype. Overall, we found that preexisting CH at ASCT rarely causes t-MN directly, but may rather facilitate the appearance of new mutations, especially those involving TP53, RUNX1, and RAS, that can drive the evolution to t-MN of at least two distinct types.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Hematopoiese Clonal/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Hematopoese/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mutação , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Segunda Neoplasia Primária/genética , Transplante Autólogo/efeitos adversos
4.
J Sch Health ; 92(6): 570-580, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35259777

RESUMO

BACKGROUND: The aim of the present study was to analyze the association between course type and health among high school students. METHODS: A cross-sectional study with 675 Brazilian high school students. The independent variable was course type (general or vocational) and dependent variables were health characteristics. All information was obtained by a self-report questionnaire and the following health characteristics were analyzed: mental health, physical activity, sedentary behavior, food consumption, daytime sleepiness, tobacco use, alcohol consumption, aggression, and musculoskeletal symptoms. The prevalence ratio (PR) was estimated by Poisson regression. RESULTS: Vocational students presented a higher prevalence in 7 of the 20 mental health symptoms analyzed (PR = 1.21-1.64), daytime sleepiness (PR = 1.39-1.71), and musculoskeletal symptoms in neck, shoulders, low back, and knees (PR = 1.31-1.41), and a lower likelihood of being physically active (PR = 0.59-0.70). Conversely, vocational students showed lower sedentary behavior on TV and videogames during the week (PR = 0.35-0.46), consumption of snacks, cookies, and crackers (PR = 0.56-0.72), and experiences of aggression (PR = 0.13-0.17), all P < .05. CONCLUSIONS: High school can affect students' health distinctly, indicating that intervention programs and health monitoring should be specific to course type.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Educação Vocacional , Estudos Transversais , Humanos , Instituições Acadêmicas , Estudantes/psicologia , Inquéritos e Questionários
5.
Haematologica ; 2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35320921

RESUMO

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival (PFS) and overall survival (OS) of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. 103 patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, PFS was significantly better in the transplanted patients than in the non-transplanted group: 63% vs. 48% at 5 years (p=0.042). OS was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year OS: 70% vs. 50%, p=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged PFS (HR 0.57, 95% CI 0.35-0.93) and OS (HR 0.57, 95% CI 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.

6.
Clin Lymphoma Myeloma Leuk ; 22(2): e135-e148, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728169

RESUMO

BACKGROUND: immunotherapy (IT), including checkpoint inhibitors (CIs) and Chimeric Antigen Receptor T cell therapy (CAR-T) revolutionized the treatment of relapsing or refractory (r/r) lymphoma. Several preliminary experiences evaluated concomitant administration of radiotherapy and IT. METHODS: we performed a systematic review of current literature as of March 30, 2020. A total of 1090 records was retrieved, 42 articles were selected on the basis of title and abstract and, after the removal of analyses with no original data or insufficient clinical information, 28 papers were included in the review. RESULTS: previous studies were mostly represented by case reports/series or small cohorts. Nonetheless, combination of radiotherapy and CIs or CAR-T led to promising outcomes, resulting in extremely high rates of complete response and improving progression free and overall survival compared with data from recent clinical trials. Combination of RT and CIs had a fair toxicity profile with no reports of severe side effects. Within the limits of the small cohorts retrieved, RT seems a superior option compared with systemic treatment as a 'bridge' to CAR-T and could as well reduce severe complications rates. Radiotherapy could elicit immune response against lymphoma, as demonstrated by multiple cases of abscopal effect and its inclusion in anti-neoplastic vaccines protocols. CONCLUSION: The results of this review warrant the evaluation of combination of RT and immunotherapy in larger and preferably prospective and randomized cohorts to confirm these preliminary impressive outcomes. The optimal dose, fractionation and timing of RT still have to be clarified.


Assuntos
Linfoma , Recidiva Local de Neoplasia , Humanos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Linfoma/terapia , Estudos Prospectivos
7.
J Clin Oncol ; 40(3): 242-251, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-34843406

RESUMO

PURPOSE: Romidepsin, a histone deacetylase inhibitor, has demonstrated activity in relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used as first-line treatment of PTCL; however, it has limited efficacy. Results from a phase Ib and II study showed the feasibility of combining romidepsin with CHOP (Ro-CHOP). METHODS: This study is a randomized phase III study of Ro-CHOP versus CHOP in adult patients with previously untreated PTCL. All patients received CHOP in 3-week cycles for six cycles. Romidepsin, 12 mg/m2, was administered intravenously over a 4-hour period on days 1 and 8 of each 3-week cycle for six cycles. The primary end point was progression-free survival (PFS) according to International Working Group 1999 criteria. RESULTS: Between January 2013 and December 2017, 421 patients were enrolled (Ro-CHOP, n = 211; CHOP, n = 210). The median PFS for Ro-CHOP versus CHOP was 12.0 months (95% CI, 9.0 to 25.8) versus 10.2 months (95% CI, 7.4 to 13.2) with a hazard ratio of 0.81 (P = .096). In the Ro-CHOP versus CHOP arms, the median overall survival was 51.8 versus 42.9 months and the objective response rate was 63% versus 60% with complete response plus unconfirmed complete response rates of 41% versus 37% (P > .1 in all comparisons), respectively. Grade 3 or 4 treatment-emergent adverse events occurring in ≥ 30% of patients in the Ro-CHOP arm included thrombocytopenia (50% v 10% in the Ro-CHOP v CHOP arms, respectively), neutropenia (49% v 33%), anemia (47% v 17%), and leukopenia (32% v 20%). CONCLUSION: The addition of romidepsin to CHOP did not improve PFS, response rates, nor overall survival and increased the frequency for grade ≥ 3 treatment-emergent adverse events. Ro-CHOP does not represent a significant advance in the standard of care for patients with previously untreated PTCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ásia , Austrália , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Depsipeptídeos/efeitos adversos , Progressão da Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Europa (Continente) , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Fatores de Tempo , Vincristina/efeitos adversos , Vincristina/uso terapêutico
8.
Front Oncol ; 11: 789891, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34938664

RESUMO

Patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis, with an expected survival of less than 1 year using standard salvage therapies. Recent advances in our understanding of the biology of PTCL have led to identifying B-Cell Lymphoma 2 (BCL2) protein as a potential therapeutic target. BLC2 inhibitor venetoclax was investigated in a prospective phase II trial in patients with BCL2-positive R/R PTCL after at least one previous standard line of treatment (NCT03552692). Venetoclax given alone at a dosage of 800 mg/day resulted in one complete response (CR) and two stable diseases (SDs) among 17 enrolled patients. The majority of patients (88.2%) interrupted the treatment due to disease progression. No relationship with BCL2 expression was documented. At a median follow-up of 8 months, two patients are currently still on treatment (one CR and one SD). No case of tumor lysis syndrome was registered. Therefore, venetoclax monotherapy shows activity in a minority of patients whose biological characteristics have not yet been identified. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03552692, EudraCT number 2017-004630-29).

9.
Biomedicines ; 9(11)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34829900

RESUMO

Acute inflammation is particularly relevant in the pathogenesis of visceral hypersensitivity associated with inflammatory bowel diseases. Glia within the enteric nervous system, as well as within the central nervous system, contributes to neuroplasticity during inflammation, but whether enteric glia has the potential to modify visceral sensitivity following colitis is still unknown. This work aimed to investigate the occurrence of changes in the neuron-glial networks controlling visceral perception along the gut-brain axis during colitis, and to assess the effects of peripheral glial manipulation. Enteric glia activity was altered by the poison fluorocitrate (FC; 10 µmol kg-1 i.p.) before inducing colitis in animals (2,4-dinitrobenzenesulfonic acid, DNBS; 30 mg in 0.25 mL EtOH 50%), and visceral sensitivity, colon damage, and glia activation along the pain pathway were studied. FC injection significantly reduced the visceral hyperalgesia, the histological damage, and the immune activation caused by DNBS. Intestinal inflammation is associated with a parallel overexpression of TRPV1 and S100ß along the gut-brain axis (colonic myenteric plexuses, dorsal root ganglion, and periaqueductal grey area). This effect was prevented by FC. Peripheral glia activity modulation emerges as a promising strategy for counteracting visceral pain induced by colitis.

10.
J Imaging ; 7(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34821860

RESUMO

Diagnostic physical methods are increasingly applied to Cultural Heritage both for scientific investigations and conservation purposes. In particular, the X-ray imaging techniques of computed tomography (CT) and digital radiography (DR) are non-destructive investigation methods to study an object, being able to give information on its inner structure. In this paper, we present the results of the X-ray imaging study on an ancient Egyptian statuette (Late Period 722-30 BCE) belonging to the collection of Museo Egizio in Torino and representing an Egyptian goddess called Taweret, carved on wood and gilded with some colored details. Since few specific studies have been focused on materials and techniques used in Ancient Egypt for gilding, a detailed investigation was started in order to verify the technical features of the decoration in this sculpture. Specifically, DR and CT analyses have been performed at the Centro Conservazione e Restauro "La Venaria Reale" (CCR), with a new high resolution flat-panel detector, that allowed us to perform tomographic analysis reaching a final resolution better than the one achievable with the previous apparatus operating in the CCR.

11.
Rev Saude Publica ; 55: 57, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34706035

RESUMO

OBJECTIVE: To synthesize evidence from studies that analyzed the associations between sedentary behavior and motor competence in children and adolescents. METHODS: Systematic review of original articles that analyzed possible associations between sedentary behavior and motor competence in children and adolescents (3-18 years of age), without restrictions on study design, instruments and analysis protocols. The articles were identified through searches in the PubMed, Web of Science, Academic Search Premier, Cinahl, Medline and SPORTDiscus databases, as well as in reference lists. The level of evidence was evaluated according to the amount of studies that reported statistical significance in the associations between the variables and the quality of the articles (risk of bias). RESULTS: Of 2,462 initial studies, 22 composed the synthesis (two interventions, nine longitudinal and eleven cross-sectional studies). Of these, in 13, we observed negative associations between the variables, more often in the age group of seven to fourteen years. In the analysis of risk of bias, the main limitations of the studies were "convenience sampling" and "no description of sample sizing". CONCLUSIONS: The available evidence suggests that sedentary behavior is negatively associated with motor competence in elementary school children, although the evidence is uncertain in the preschool years; the synthesis of results from longitudinal studies suggests that sedentary behavior negatively affects the development of motor competence. It is important that future studies have greater control over sociocultural determinants and deepen knowledge regarding sex and age, as well as the methods and indicators used to evaluate the two variables.


Assuntos
Comportamento Sedentário , Adolescente , Brasil , Criança , Pré-Escolar , Estudos Transversais , Escolaridade , Humanos
12.
Phytother Res ; 35(12): 6893-6903, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34643000

RESUMO

Given the abundancy of angiotensin converting enzyme 2 (ACE-2) receptors density, beyond the lung, the intestine is considered as an alternative site of infection and replication for severe acute respiratory syndrome by coronavirus type 2 (SARS-CoV-2). Cannabidiol (CBD) has recently been proposed in the management of coronavirus disease 2019 (COVID-19) respiratory symptoms because of its anti-inflammatory and immunomodulatory activity exerted in the lung. In this study, we demonstrated the in vitro PPAR-γ-dependent efficacy of CBD (10-9 -10-7  M) in preventing epithelial damage and hyperinflammatory response triggered by SARS-CoV-2 spike protein (SP) in a Caco-2 cells. Immunoblot analysis revealed that CBD was able to reduce all the analyzed proinflammatory markers triggered by SP incubation, such as tool-like receptor 4 (TLR-4), ACE-2, family members of Ras homologues A-GTPase (RhoA-GTPase), inflammasome complex (NLRP3), and Caspase-1. CBD caused a parallel inhibition of interleukin 1 beta (IL-1ß), IL-6, tumor necrosis factor alpha (TNF-α), and IL-18 by enzyme-linked immunosorbent assay (ELISA) assay. By immunofluorescence analysis, we observed increased expression of tight-junction proteins and restoration of transepithelial electrical resistance (TEER) following CBD treatment, as well as the rescue of fluorescein isothiocyanate (FITC)-dextran permeability induced by SP. Our data indicate, in conclusion, that CBD is a powerful inhibitor of SP protein enterotoxicity in vitro.


Assuntos
Canabidiol , SARS-CoV-2/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/imunologia , COVID-19 , Células CACO-2 , Canabidiol/farmacologia , Caspase 1 , Citocinas , Humanos , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR , PPAR gama , Receptor 4 Toll-Like
13.
Blood Adv ; 5(21): 4504-4514, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34597375

RESUMO

The role of consolidation radiotherapy (RT) for bulky lesions is controversial in patients with advanced-stage Hodgkin lymphoma who achieve complete metabolic response (CMR) after doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)-based chemotherapy. We present the final results of the Fondazione Italiana Linfomi HD0801 trial, which investigated the potential benefit of RT in that setting. In this phase 3 randomized study, patients with a bulky lesion at baseline (a mass with largest diameter ≥5 cm) who have CMR after 2 and 6 ABVD cycles were randomly assigned 1:1 to RT vs observation (OBS) with a primary endpoint of event-free survival (EFS) at 2 years. The sample size was calculated estimating an EFS improvement for RT of 20% (from 60% to 80%). The secondary end point was progression-free survival (PFS). One hundred sixteen patients met the inclusion criteria and were randomly assigned to RT or OBS. Intention-to-treat (ITT) analysis showed a 2-year EFS of 87.8% vs 85.8% for RT vs OBS (hazard ratio [HR], 1.5; 95% confidence interval [CI], 0.6-3.5; P = .34). At 2 years, ITT-PFS was 91.3% vs 85.8% (HR, 1.2; 95% CI, 0.5-3; P = .7). Patients in CMR randomly assigned to OBS had a good outcome, and the primary end point of a 20% benefit in EFS for RT was not met. However, the sample size was underpowered to detect a benefit of 10% or less, keeping open the question of a potential, more limited role of RT in this setting. This trial was registered at www.clinicaltrials.gov as #NCT00784537.


Assuntos
Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Humanos , Estadiamento de Neoplasias , Vimblastina/uso terapêutico
14.
Metabolites ; 11(9)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34564408

RESUMO

Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-κB (NF-κB) signalling pathway via the selective activation of the PPARα receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-α, Il-1ß) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-α) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in proinflammatory markers (TLR4, p-p38 MAPK, NF-κB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1ß, TNF-α over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in angiotensin-converting enzyme-2 (ACE-2) following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-α, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19.

15.
Haematologica ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34289655

RESUMO

Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (Double Expressor Lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (Double/Triple-Hit Lymphomas, DH/TH). TP53 mutations are detected in 20-25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or High-Grade Lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven pts (55%) had high-intermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progressionfree survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, p=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, p=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (p=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; p= 0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

16.
Front Pharmacol ; 12: 639728, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986673

RESUMO

Genetically engineered probiotics, able to in situ deliver therapeutically active compounds while restoring gut eubiosis, could represent an attractive therapeutic alternative in Clostridium difficile infection (CDI). Palmitoylethanolamide is an endogenous lipid able to exert immunomodulatory activities and restore epithelial barrier integrity in human models of colitis, by binding the peroxisome proliferator-activated receptor-α (PPARα). The aim of this study was to explore the efficacy of a newly designed PEA-producing probiotic (pNAPE-LP) in a mice model of C. difficile toxin A (TcdA)-induced colitis. The human N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), a key enzyme involved in the synthesis of PEA, was cloned and expressed in a Lactobacillus paracasei that was intragastrically administered to mice 7 days prior the induction of the colitis. Bacteria carrying the empty vector served as negative controls (pLP).In the presence of palmitate, pNAPE-LP was able to significantly increase PEA production by 27,900%, in a time- and concentration-dependent fashion. Mice treated with pNAPE-LP showed a significant improvement of colitis in terms of histological damage score, macrophage count, and myeloperoxidase levels (-53, -82, and -70.4%, respectively). This was paralleled by a significant decrease both in the expression of toll-like receptor-4 (-71%), phospho-p38 mitogen-activated protein kinase (-72%), hypoxia-inducible factor-1-alpha (-53%), p50 (-74%), and p65 (-60%) and in the plasmatic levels of interleukin-6 (-86%), nitric oxide (-59%), and vascular endothelial growth factor (-71%). Finally, tight junction protein expression was significantly improved by pNAPE-LP treatment as witnessed by the rescue of zonula occludens-1 (+304%), Ras homolog family member A-GTP (+649%), and occludin expression (+160%). These protective effects were mediated by the specific release of PEA by the engineered probiotic as they were abolished in PPARα knockout mice and in wild-type mice treated with pLP. Herein, we demonstrated that pNAPE-LP has therapeutic potential in CDI by inhibiting colonic inflammation and restoring tight junction protein expression in mice, paving the way to next generation probiotics as a promising strategy in CDI prevention.

17.
J Neuroinflammation ; 18(1): 115, 2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-33993886

RESUMO

BACKGROUND: Mood and metabolic disorders are interrelated and may share common pathological processes. Autonomic neurons link the brain with the gastrointestinal tract and constitute a likely pathway for peripheral metabolic challenges to affect behaviors controlled by the brain. The activities of neurons along these pathways are regulated by glia, which exhibit phenotypic shifts in response to changes in their microenvironment. How glial changes might contribute to the behavioral effects of consuming a high-fat diet (HFD) is uncertain. Here, we tested the hypothesis that anxiogenic and depressive-like behaviors driven by consuming a HFD involve compromised duodenal barrier integrity and subsequent phenotypic changes to glia and neurons along the gut-brain axis. METHODS: C57Bl/6 male mice were exposed to a standard diet or HFD for 20 weeks. Bodyweight was monitored weekly and correlated with mucosa histological damage and duodenal expression of tight junction proteins ZO-1 and occludin at 0, 6, and 20 weeks. The expression of GFAP, TLR-4, BDNF, and DCX were investigated in duodenal myenteric plexus, nodose ganglia, and dentate gyrus of the hippocampus at the same time points. Dendritic spine number was measured in cultured neurons isolated from duodenal myenteric plexuses and hippocampi at weeks 0, 6, and 20. Depressive and anxiety behaviors were also assessed by tail suspension, forced swimming, and open field tests. RESULTS: HFD mice exhibited duodenal mucosa damage with marked infiltration of immune cells and decreased expression of ZO-1 and occludin that coincided with increasing body weight. Glial expression of GFAP and TLR4 increased in parallel in the duodenal myenteric plexuses, nodose ganglia, and hippocampus in a time-dependent manner. Glial changes were associated with a progressive decrease in BDNF, and DCX expression, fewer neuronal dendritic spines, and anxiogenic/depressive symptoms in HFD-treated mice. Fluorocitrate (FC), a glial metabolic poison, abolished these effects both in the enteric and central nervous systems and prevented behavioral alterations at week 20. CONCLUSIONS: HFD impairs duodenal barrier integrity and produces behavioral changes consistent with depressive and anxiety phenotypes. HFD-driven changes in both peripheral and central nervous systems are glial-dependent, suggesting a potential glial role in the alteration of the gut-brain signaling that occurs during metabolic disorders and psychiatric co-morbidity.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Depressão/etiologia , Dieta Hiperlipídica/efeitos adversos , Duodeno/patologia , Transtornos Mentais/etiologia , Neuroglia/metabolismo , Animais , Peso Corporal , Duodeno/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plexo Mientérico/metabolismo , Plexo Mientérico/patologia , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Gânglio Nodoso/metabolismo , Gânglio Nodoso/patologia
18.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799405

RESUMO

Palmitoylethanolamide (PEA) is an N-acylethanolamide produced on-demand by the enzyme N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD). Being a key member of the larger family of bioactive autacoid local injury antagonist amides (ALIAmides), PEA significantly improves the clinical and histopathological stigmata in models of ulcerative colitis (UC). Despite its safety profile, high PEA doses are required in vivo to exert its therapeutic activity; therefore, PEA has been tested only in animals or human biopsy samples, to date. To overcome these limitations, we developed an NAPE-PLD-expressing Lactobacillus paracasei F19 (pNAPE-LP), able to produce PEA under the boost of ultra-low palmitate supply, and investigated its therapeutic potential in a murine model of UC. The coadministration of pNAPE-LP and palmitate led to a time-dependent release of PEA, resulting in a significant amelioration of the clinical and histological damage score, with a significantly reduced neutrophil infiltration, lower expression and release of pro-inflammatory cytokines and oxidative stress markers, and a markedly improved epithelial barrier integrity. We concluded that pNAPE-LP with ultra-low palmitate supply stands as a new method to increase the in situ intestinal delivery of PEA and as a new therapeutic able of controlling intestinal inflammation in inflammatory bowel disease.


Assuntos
Amidas/metabolismo , Colite/tratamento farmacológico , Etanolaminas/metabolismo , Inflamação/tratamento farmacológico , Lactobacillus paracasei/genética , Ácidos Palmíticos/metabolismo , Amidas/farmacologia , Animais , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Etanolaminas/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Lactobacillus paracasei/metabolismo , Engenharia Metabólica , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Ácidos Palmíticos/farmacologia
19.
J Clin Oncol ; 39(11): 1214-1222, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33577377

RESUMO

PURPOSE: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050). RESULTS: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases. CONCLUSION: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Avaliação Geriátrica , Humanos , Estudos Prospectivos
20.
Cancers (Basel) ; 13(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466784

RESUMO

MCL is an uncommon lymphoproliferative disorder that has been regarded as incurable since its identification as a distinct entity. Allogeneic transplantation for two decades has represented the only option capable of ensuring prolonged remissions and possibly cure. Despite its efficacy, its application has been limited by feasibility limitations and substantial toxicity, particularly in elderly patients. Nevertheless, the experience accumulated over time has been wide though often scattered among retrospective and small prospective studies. In this review, we aimed at critically revise and discuss available evidence on allogeneic transplantation in MCL, trying to put available evidence into the 2020 perspective, characterized by unprecedented development of novel promising therapeutic agents and regimens.

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