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1.
Lancet ; 401(10373): 269-280, 2023 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-36709073

RESUMO

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. FUNDING: Sierra Oncology.


Assuntos
Anemia , Inibidores de Janus Quinases , Mielofibrose Primária , Humanos , Mielofibrose Primária/complicações , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/diagnóstico , Danazol/efeitos adversos , Resultado do Tratamento , Anemia/tratamento farmacológico , Anemia/etiologia , Inibidores de Janus Quinases/uso terapêutico , Método Duplo-Cego
2.
Blood ; 139(11): 1646-1658, 2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35007323

RESUMO

Given that there are only a few prospective studies with conflicting results, we investigated the prognostic value of multiparameter geriatric assessment (GA) domains on tolerance and outcomes after intensive chemotherapy in older adults with acute myeloid leukemia (AML). In all, 105 newly diagnosed patients with AML who were older than age 60 years and who received intensive chemotherapy consisting of cytarabine and idarubicin were enrolled prospectively. Pretreatment GA included evaluations for social and nutritional support, cognition, depression, distress, and physical function. The median age was 64 years (range, 60-75 years), and 93% had an Eastern Cooperative Oncology Group performance score <2. Between 32.4% and 69.5% of patients met the criteria for impairment for each domain of GA. Physical impairment by the Short Physical Performance Battery (SPPB) and cognitive dysfunction by the Mini-Mental State Examination in the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Assessment Packet (MMSE-KC) were significantly associated with nonfatal toxicities, including grade 3 to 4 infections (SPPB, P = .024; MMSE-KC, P = .044), acute renal failure (SPPB, P = .013), and/or prolonged hospitalization (≥40 days) during induction chemotherapy (MMSE-KC, P = .005). Reduced physical function by SPPB and depressive symptoms by the Korean version of the short form of geriatric depression scales (SGDS-K) were significantly associated with inferior survival (SPPB, P = .027; SGDS-K, P = .048). Gait speed and sit-and-stand speed were the most powerful measurements for predicting survival outcomes. Notably, the addition of SPPB and SGDS-K, gait speed and SGDS-K, or sit-and-stand speed and SGDS-K significantly improved the power of existing survival prediction models. In conclusion, GA improved risk stratification for treatment decisions and may inform interventions to improve outcomes for older adults with AML. This study was registered at the Clinical Research Information Service as #KCT0002172.


Assuntos
Avaliação Geriátrica , Leucemia Mieloide Aguda , Idoso , Avaliação Geriátrica/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos
3.
Haematologica ; 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39385733

RESUMO

Primary myelofibrosis (PMF) is a myeloid proliferative neoplasm (MPN) characterized by bone marrow (BM) fibrosis. Pre-fibrotic PMF (pre-PMF) progresses to overt PMF. Megakaryocytes (MKs) play a primary role in PMF; however, the functions of MK subsets and those of other hematopoietic cells during PMF progression remain unclarified. Therefore, we analyzed BM aspirates in pre-PMFs, overt PMFs, and other MPNs using single-cell RNA sequencing (scRNA-seq). We identified 14 cell types with subsets, including hematopoietic stem and progenitor cells (HSPCs) and MKs. HSPCs in overt PMF were MK-biased and inflammation/fibrosis-enriched. Among MKs, the epithelial-mesenchymal transition (EMT)-enriched subset was abruptly increased in overt PMF. MKs in non-fibrotic/non-PMF MPN were MK differentiation-enriched, whereas those in fibrotic/non-PMF MPN were inflammation/fibrosis-enriched. Overall, the inflammation/fibrosis signatures of the HSPC, MK, and CD14+ monocyte subsets increased from pre-PMF to overt PMF. Cytotoxic and dysfunctional scores also increased in T and NK cells. Clinically, MK and HSPC subsets with high inflammation/fibrosis signatures were frequent in the patients with peripheral blood blasts ≥1%. scRNA-seq predicted higher cellular communications of MK differentiation, inflammation/fibrosis, immunologic effector/dysfunction, and tumor-associated signaling in overt PMF than pre-PMF. However, no decisive subset emerged during PMF progression. Our study demonstrated that HSPCs, monocytes, and lymphoid cells contribute to PMF progression, and subset specificity existed regarding inflammation/fibrosis and immunologic dysfunction. PMF progression may depend on multiple cell types' alterations, and EMTenriched MKs may be potential targets for the diagnosis and therapy of the progression.

4.
J Clin Lab Anal ; 38(7): e25034, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38525919

RESUMO

BACKGROUND: Accurate quantification of the BCR::ABL1 transcripts is essential for measurable residual disease (MRD) monitoring in chronic myeloid leukemia (CML) after tyrosine kinase inhibitor (TKI) treatment. This study evaluated the newly developed digital real-time PCR method, Dr. PCR, as an alternative reverse transcription-PCR (qRT-PCR) for MRD detection. METHODS: The performance of Dr. PCR was assessed using reference and clinical materials. Precision, linearity, and correlation with qRT-PCR were evaluated. MRD levels detected by Dr. PCR were compared with qRT-PCR, and practical advantages were investigated. RESULTS: Dr. PCR detected MRD up to 0.0032%IS (MR4.5) with excellent precision and linearity and showed a strong correlation with qRT-PCR results. Notably, Dr. PCR identified higher levels of MRD in 12.7% (29/229) of patients than qRT-PCR, including six cases of MR4, which is a critical level for TKI discontinuation. Dr. PCR also allowed for sufficient ABL1 copies in all cases, while qRT-PCR necessitated multiple repeat tests in 3.5% (8/229) of cases. CONCLUSION: Our study provides a body of evidence supporting the clinical application of Dr. PCR as a rapid and efficient method for assessing MRD in patients with CML under the current treatment regimen.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Neoplasia Residual , Reação em Cadeia da Polimerase em Tempo Real , Humanos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Neoplasia Residual/genética , Reprodutibilidade dos Testes
5.
Proc Natl Acad Sci U S A ; 118(32)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34349022

RESUMO

The concentration of atmospheric methane (CH4) continues to increase with microbial communities controlling soil-atmosphere fluxes. While there is substantial knowledge of the diversity and function of prokaryotes regulating CH4 production and consumption, their active interactions with viruses in soil have not been identified. Metagenomic sequencing of soil microbial communities enables identification of linkages between viruses and hosts. However, this does not determine if these represent current or historical interactions nor whether a virus or host are active. In this study, we identified active interactions between individual host and virus populations in situ by following the transfer of assimilated carbon. Using DNA stable-isotope probing combined with metagenomic analyses, we characterized CH4-fueled microbial networks in acidic and neutral pH soils, specifically primary and secondary utilizers, together with the recent transfer of CH4-derived carbon to viruses. A total of 63% of viral contigs from replicated soil incubations contained homologs of genes present in known methylotrophic bacteria. Genomic sequences of 13C-enriched viruses were represented in over one-third of spacers in CRISPR arrays of multiple closely related Methylocystis populations and revealed differences in their history of viral interaction. Viruses infecting nonmethanotrophic methylotrophs and heterotrophic predatory bacteria were also identified through the analysis of shared homologous genes, demonstrating that carbon is transferred to a diverse range of viruses associated with CH4-fueled microbial food networks.


Assuntos
Bactérias/virologia , Carbono/metabolismo , Vírus de DNA/genética , Metano/metabolismo , Solo/química , Bactérias/genética , Bactérias/metabolismo , Radioisótopos de Carbono/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Genoma Bacteriano , Genoma Viral , Metagenômica , Metano/química , Microbiota , Microbiologia do Solo
6.
J Korean Med Sci ; 39(3): e24, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38258361

RESUMO

BACKGROUND: Previous studies have suggested that patients with polycythemia vera (PV) who exhibit hydroxyurea-resistance (HU-R) and -intolerance (HU-I) may have distinct characteristics and clinical outcomes. However, to date, no studies have reported a comparison between these two groups or assessed prognostic factors in these patients. METHODS: The objective of this study was to evaluate clinical outcomes and identify prognostic factors among PV patients with HU-R or HU-I. We conducted a review of PV patients who received frontline treatment with HU from nine centers and identified 90 patients with HU-R or HU-I. RESULTS: The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio, 6.27, 95% confidence interval, 1.83-21.47, P = 0.003). Additionally, higher lactate dehydrogenase levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. CONCLUSION: These findings suggest that patients with HU-R face a higher risk of hematological transformation, but have a comparable risk of thrombosis to patients with HU intolerance. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.


Assuntos
Hidroxiureia , Policitemia Vera , Humanos , Progressão da Doença , Fatores de Risco de Doenças Cardíacas , Hidroxiureia/farmacologia , Policitemia Vera/tratamento farmacológico , Trombose/epidemiologia , Estudos Retrospectivos
7.
Molecules ; 29(17)2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39274884

RESUMO

Prion diseases, known as a group of fatal neurodegenerative disorders caused by prions, remain incurable despite extensive research efforts. In a recent study, crude extract from Curcuma phaeocaulis Valeton (Cp) showed promising anti-prion efficacy in in vitro and in vivo models, prompting further investigation into their active compounds. We endeavored to identify the chemical constituents of the Cp extract and discover potential anti-prion agents. With the use of centrifugal partition chromatography (CPC), major constituents were isolated from the n-hexane (HX) fraction of the extract in a single step. Spectroscopic analysis confirmed the presence of curcumenone, curcumenol, and furanodienone. Subsequent efficacy testing in a cell culture model of prion disease identified curcumenol and furanodienone as active compounds. This study underscores the potential of natural products in the search for effective treatments against prion diseases.


Assuntos
Curcuma , Extratos Vegetais , Curcuma/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Príons/antagonistas & inibidores , Doenças Priônicas/tratamento farmacológico , Camundongos , Humanos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação
8.
Haematologica ; 108(11): 2933-2945, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37317880

RESUMO

Treating patients with refractory acute myeloid leukemia (AML) remains challenging. Currently there is no effective treatment for refractory AML. Increasing evidence has demonstrated that refractory/relapsed AML is associated with leukemic blasts which can confer resistance to anticancer drugs. We have previously reported that high expression of Fms-related tyrosine kinase 4 (FLT4) is associated with increased cancer activity in AML. However, the functional role of FLT4 in leukemic blasts remains unknown. Here, we explored the significance of FLT4 expression in leukemic blasts of refractory patients and mechanisms involved in the survival of AML blasts. Inhibition or absence of FLT4 in AML blasts suppressed homing to bone marrow of immunocompromised mice and blocked engraftment of AML blasts. Moreover, FLT4 inhibition by MAZ51, an antagonist, effectively reduced the number of leukemic cell-derived colony-forming units and increased apoptosis of blasts derived from refractory patients when it was co-treated with cytosine arabinoside under vascular endothelial growth factor C, its ligand. AML patients who expressed high cytosolic FLT4 were linked to an AML-refractory status by internalization mechanism. In conclusion, FLT4 has a biological function in leukemogenesis and refractoriness. This novel insight will be useful for targeted therapy and prognostic stratification of AML.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Animais , Camundongos , Fator C de Crescimento do Endotélio Vascular/uso terapêutico , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Medula Óssea/metabolismo , Antineoplásicos/uso terapêutico , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/uso terapêutico
9.
Cytotherapy ; 25(12): 1307-1316, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37542512

RESUMO

BACKGROUND AIMS: Peripheral T-cell lymphomas (PTCLs) are rare and aggressive tumors with uncertain optimal treatment. This study investigated the clinical outcomes of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) after CD34+ selective purging in PTCL patients. METHODS: Retrospective analysis included 67 PTCL patients who achieved remission and underwent HDT/ASCT. CD34+ selective purging was performed using CliniMACS® (Miltenyi Biotec, Bergisch Gladbach, Germany). Survival outcomes, engraftment, lymphocyte subsets and viral infections were evaluated. RESULTS: CD34+ selective purged autografts were associated with significantly improved overall survival (OS) and disease-free survival (DFS) compared with unpurged autografts (5-year OS, 73.3% versus 37.8%, 5-year DFS, 73.8% versus 33.4%). The cumulative incidence of relapse was also lower in the purged group (31.5% versus 73.3%). Subgroup analysis revealed significant survival benefits in the high-risk group receiving purged autografts. Lymphocyte subset analysis showed increased natural killer (NK) cell counts in the purged group after ASCT. Higher post-ASCT lymphocyte-to-monocyte ratio (LMR) was associated with improved OS and DFS. CONCLUSIONS: CD34+ selective purging in PTCL patients undergoing HDT/ASCT improved survival outcomes and reduced relapse risk. The procedure increased NK cell counts and post-ASCT LMR. CD34+ selective purging may minimize autograft tumor cell contamination and enhance efficacy in T-cell lymphomas.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/terapia , Transplante Autólogo , Estudos Retrospectivos , Recidiva Local de Neoplasia , Antígenos CD34 , Moléculas de Adesão Celular , Recidiva
10.
Eur J Haematol ; 110(2): 137-148, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36217591

RESUMO

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently identified high-risk subgroup of T-cell ALL in children. However, there have been conflicting reports and limited data have been reported in adult patients. We retrospectively analyzed the cytogenetic and molecular characteristics and long-term survival outcomes of adult patients with ETP-ALL versus non-ETP-ALL. We analyzed 58 patients (median age, 35 years [range, 18-76 years]) with newly diagnosed T-cell ALL who received a uniform remission induction and consolidation chemotherapy with suitable samples for genetic analyses. If a donor was available, all patients were recommended allogeneic hematopoietic cell transplantation (allo-HCT) for post-remission therapy. Out of 58 patients, 21 (36.2%) had ETP-ALL. Patients with ETP-ALL were older and had a higher proportion of complex karyotype than non-ETP-ALL. Additionally, more DNMT3A mutations were detected in ETP-ALL, whereas FBXW7 mutations and CDKN2A/CDKN2B deletions were found nearly exclusively in non-ETP-ALL. The overall complete remission (CR) rates were not different between ETP-ALL (95.2%) and non-ETP-ALL (81.1%) and subsequent allo-HCT proceeding rates in CR1 were 61.9% for ETP-ALL and 43.2% for non-ETP-ALL, respectively. The overall prognosis of patients with T-ALL was poor that estimated 5-year overall survival (OS) was 33.3% for ETP-ALL and 29.5% for non-ETP-ALL. In a subgroup analysis of patients treated with allo-HCT in CR1 (n = 29), 5-year OS was 53.8% for ETP-ALL and 55.4% for non-ETP-ALL. Our data showed molecular characteristics of ETP-ALL and non-ETP-ALL and revealed that intensive chemotherapy followed by allo-HCT for post-remission therapy can contribute to preserved survival outcome of adult patients with ETP-ALL.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células Precursoras de Linfócitos T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , Humanos , Adulto , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Estudos Retrospectivos , Prognóstico , Indução de Remissão , Análise Citogenética
11.
Mol Biol Rep ; 50(5): 4029-4038, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36848005

RESUMO

INTRODUCTION: Osteosarcoma (OS) is the most common form of bone malignancy. Although contemporary chemotherapy and surgery have improved the prognosis of those with OS, developing new OS therapies has proven difficult for some time. The activation of the matrix metalloproteinase (MMP) and mitogen-activated protein kinase (MAPK) signaling pathways can induce metastasis, which is an obstacle to OS treatment. Ursonic acid (UNA) is a phytochemical with the potential to cure a variety of human ailments, including cancer. METHODS AND RESULTS: In this study, we investigated the anti-tumor properties of UNA in MG63 cells. We conducted colony formation assay, wound healing assay, and Boyden chamber assays to investigate the anti-OS effects of UNA. UNA was found to significantly inhibit the proliferative, migratory, and invasive abilities of MG63 cells. This bioactivity of UNA was mediated by the inhibition of extracellular signal-regulated kinase (ERK) and p38 and reduction of MMP-2 transcriptional expression as observed in western blot analysis, gelatin zymography and RT-PCR. Anti-OS activities of UNA were also observed in Saos2 and U2OS cells, indicating that its anti-cancer properties are not specific to cell types. CONCLUSION: Our findings suggest that UNA has the potential for use in anti-metastatic drugs in the treatment of OS.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Linhagem Celular Tumoral , Movimento Celular , Sistema de Sinalização das MAP Quinases , Metaloproteinases da Matriz/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Neoplasias Ósseas/metabolismo , Invasividade Neoplásica
12.
Am J Emerg Med ; 68: 175-178, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37030085

RESUMO

BACKGROUND: This study aimed to investigate the association between traumatic tap and the incidence of post-dural puncture headache (PDPH) following lumbar puncture (LP) among patients who underwent LP with a primary discharge diagnosis of primary headache in the emergency department (ED). METHODS: We retrospectively reviewed the medical records of patients who visited a single tertiary ED with the symptom of a headache and underwent LP for cerebrospinal fluid (CSF) analysis between January 2012 and January 2022. Patients who met the definition of PDPH and revisited the ED or outpatient clinic within 2 weeks of discharge were included. For comparative analysis, we divided the groups according to CSF RBC counts (group 1, CSF RBC <10 cells/µL; group 2, 10-100 cells/µL; group 3, ≥100 cells/µL). The primary outcome was the difference in CSF RBC counts between the ED or outpatient clinic revisiting patients who underwent LP within 2 weeks after discharge from the ED. The secondary outcomes were the admission rate and risk factors for PDPH; sex, age, needle size, and CSF pressure. RESULTS: Data from 112 patients were collected; PDPH was reported in 39 patients (34.8%), and 40 (35.7%) patients were admitted. The median (interquartile range) CSF RBC count was 10 [2-100.8] cells/µL. One-way analysis of variance test of the mean differences among the three groups showed no differences in age, the duration of headache before LP, PLT counts, PT, or aPTT among the groups. There were differences in the number of admitted patients (30 vs. 7 vs. 3, P < 0.001) and the incidence of PDPH (29 vs. 6 vs. 4, P < 0.003). In the comparison of the PDPH and non-PDPH groups, there were differences in age (28.7 ± 8.4 years vs. 36.9 ± 18.4 years, P = 0.01) and the admission rate (85% vs. 9%, P < 0.001). CONCLUSIONS: Notably, our results suggest that traumatic LP may be an unexpected factor in reducing the occurrence rate of PDPH. Consequently, the admission rate for PDPH was significantly reduced among patients with traumatic LP and those with primary headaches. In this study, we collected and analyzed the data from a relatively small sample size of 112 patients. Further studies are needed to evaluate the relationship between traumatic LP and PDPH.


Assuntos
Cefaleia Pós-Punção Dural , Punção Espinal , Humanos , Adulto Jovem , Adulto , Punção Espinal/efeitos adversos , Estudos Retrospectivos , Cefaleia/epidemiologia , Cefaleia/etiologia , Cefaleia Pós-Punção Dural/epidemiologia , Serviço Hospitalar de Emergência
13.
J Enzyme Inhib Med Chem ; 38(1): 2191164, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36950944

RESUMO

Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.


Assuntos
Doenças Priônicas , Príons , Humanos , Príons/metabolismo , Proteínas Priônicas/metabolismo , Encéfalo , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Células Cultivadas
14.
Ecotoxicol Environ Saf ; 249: 114352, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36508815

RESUMO

Chlorpyrifos-methyl (CPM) is one of the thiophosphate insecticides, and it is mainly metabolized to 3,5,6-trichloro-2-pyridinol (TCP) in the environment. As CPM is a strongly toxic and TCP is persistent in the environment, CPM and TCP need to be evaluate their toxicities using animal model organisms. With this regard, CPM and TCP were treated on zebrafish (Danio rerio) embryos and LC50 values were determined as over 2000 µg/L and 612.5 µg/L, respectively. For the hatchability, CPM did not exhibit any interference, while TCP showed weak inhibition. In the CPM-treated embryos, pericardial edema and bleeding were observed at 48 hpf, but recovered afterwards. The pericardial edema and yolk sac edema were observed in TCP-treated zebrafish embryos at the concentration of 500 µg/L after 72 hpf. TCP induced abnormal heart development and the heartbeat was dramatically decreased in Tg(cmlc2:EGFP) embryos at the level of 500 µg/L. The expression level of heart development-related genes such as gata, myl7, and cacna1c was significantly decreased in the TCP 500 µg/L-treated embryos at the 96 hpf. Taken together, TCP appears to be more toxic than the parent compound towards the zebrafish embryos. It is highly requested that TCP needs to be monitored with a strong public concern because it affects presumably heart development in early-stage aquatic vertebrates.


Assuntos
Clorpirifos , Embrião não Mamífero , Poluentes Químicos da Água , Animais , Edema/induzido quimicamente , Embrião não Mamífero/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Clorpirifos/toxicidade
15.
Ecotoxicol Environ Saf ; 253: 114654, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36801540

RESUMO

Pymetrozine (PYM) is worldwide used to control sucking insect pests in rice-cultivated fields and it is degraded into various metabolites including 3-pyridinecarboxaldehyde (3-PCA). These two pyridine compounds were used to determine their impacts on aquatic environments, particularly on the aquatic animal model zebrafish (Danio rerio). PYM did not show acute toxicities in terms of lethality, hatching rate, and phenotypic changes in zebrafish embryos in the tested ranges up to a concentration of 20 mg/L. 3-PCA exhibited acute toxicity with LC50 and EC50 values of 10.7 and 2.07 mg/L, respectively. 3-PCA treatment caused phenotypic changes including pericardial edema, yolk sac edema, hyperemia, and curved spine, at a concentration of 10 mg/L after 48 h of exposure. Abnormal cardiac development was observed in 3-PCA-treated zebrafish embryos at a concentration of 5 mg/L with reduced heart function. In a molecular analysis, cacna1c, encoding a voltage-dependent calcium channel, was significantly down-regulated in the 3-PCA-treated embryos, indicating synaptic and behavioral defects. Hyperemia and incomplete intersegmental vessels were observed in 3-PCA-treated embryos. Based on these results, it is necessary to generate scientific information on the acute and chronic toxicity of PYM and its metabolites with regular monitoring of their residues in aquatic environments.


Assuntos
Hiperemia , Poluentes Químicos da Água , Animais , Peixe-Zebra/metabolismo , Embrião não Mamífero/metabolismo , Hiperemia/metabolismo , Coração , Poluentes Químicos da Água/análise
16.
Ecotoxicol Environ Saf ; 258: 114995, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37167734

RESUMO

Piperlongumine (PL) and piperine (PP) are alkaloids presented in long pepper (Piper longum), and they exhibit various biological activities, especially anti-cancer properties. With these regards, they are considered as future medicines with high potential. Even they are exposed to humans such a long time, their potential toxicities in the environment have not been studied. Therefore, their ecological toxicities were assessed using zebrafish embryos. PP showed low mortality and no abnormal phenotype up to 10 µM. However, PL exhibited strong acute toxicity at the concentration of 5-10 µM ranges, and abnormal development were frequently found in the range of 1-2.5 µM with pericardial and yolk sac edemas. In transgenic zebrafish embryos, PL induced an increase in the number of intersegmental vessels and delayed the early-stage development. PL treatment affected heart formation and heart rate. The presence of PL induced the expression of cytokines, inflammatory markers, and inflammasome in the embryos. The PL treatment changed the mRNA levels of the ER stress and apoptosis-related genes. In addition, ROS production was observed during early-stage development of PL-treated zebrafish embryos. These results indicate that developing PL as a medicine would require extremely meticulous strategies to prevent potential toxicity.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Humanos , Animais , Peixe-Zebra/metabolismo , Embrião não Mamífero , Pericárdio , Fígado , Poluentes Químicos da Água/metabolismo
17.
J Exp Bot ; 73(3): 817-834, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-34698829

RESUMO

Protein storage vacuoles (PSVs) in aleurone cells coalesce during germination, and this process is highly coupled with mobilization of PSV reserves, allowing de novo synthesis of various hydrolases in aleurone cells for endosperm degradation. Here we show that in barley (Hordeum vulgare L.) oleosins, the major integral proteins of oleosomes are encoded by four genes (HvOle1 to 4), and the expression of HvOle1 and HvOle3 is strongly up-regulated by abscisic acid (ABA), which shows antagonism to gibberellic acid. In aleurone cells, all HvOLEs were subcellularly targeted to the tonoplast of PSVs. Gain-of-function analyses revealed that HvOLE3 effectively delayed PSV coalescence, whereas HvOLE1 only had a moderate effect, with no notable effect of HvOLE2 and 4. With regard to longevity, HvOLE3 chiefly outperformed other HvOLEs, followed by HvOLE1. Experiments swapping the N- and C-terminal domain between HvOLE3 and other HvOLEs showed that the N-terminal region of HvOLE3 is mainly responsible, with some positive effect by the C-terminal region, for mediating the specific preventive effect of HvOLE3 on PSV coalescence. Three ACGT-core elements and the RY-motif were responsible for ABA induction of HvOle3 promoter activity. Transient expression assays using aleurone protoplasts demonstrated that transcriptional activation of the HvOle3 promoter was mediated by transcription factors HvABI3 and HvABI5, which acted downstream of protein kinase HvPKABA1.


Assuntos
Ácido Abscísico , Hordeum , Ácido Abscísico/metabolismo , Giberelinas/metabolismo , Hordeum/metabolismo , Proteínas de Plantas/metabolismo , Vacúolos/metabolismo
18.
Acta Haematol ; 145(5): 465-475, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35016175

RESUMO

OBJECTIVES: Although splenectomy has long been second-line option for immune thrombocytopenia (ITP) patients, an indicator that reliably predicts the efficacy of splenectomy is still being explored. We investigated the treatment outcomes of splenectomy as a second-line therapy for relapsed/refractory ITP according to first-line intravenous immunoglobulin (IVIG) responses. METHODS: Fifty-two adult patients treated with splenectomy as second-line therapy for ITP between 2009 and 2019 were included, and they were classified according to first-line IVIG responses (no response to IVIG: nonresponders; only transient IVIG response shorter than 4 weeks: poor responders; IVIG response for a longer period; stable responders). The efficacy of splenectomy was analyzed in the three subgroups. RESULTS: Of the 52 patients, 10 were IVIG nonresponders, 34 were poor responders, and the remaining 8 were stable responders. Response to splenectomy was observed in 50.0% of IVIG nonresponders, 94.1% of poor responders, and 100% of stable responders (p = 0.0030). Among the 45 patients who responded to splenectomy, 51.1% relapsed subsequently, and a significantly lower relapse rate was noted in the stable IVIG responders (12.5%, p = 0.0220) than in nonresponders (60.0%) and poor responders (59.4%). CONCLUSIONS: First-line IVIG response is indicated as a useful predictive factor for response to splenectomy.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/cirurgia , Esplenectomia , Resultado do Tratamento
19.
Future Oncol ; 18(27): 2999-3009, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35924546

RESUMO

Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the disease by targeting the molecular source. Hydroxyurea is the recommended treatment, but many patients experience resistance or intolerance. Anagrelide is an approved second-line option for ET, but concerns of a higher frequency of disease transformation may affect its role as a suitable long-term option. Interferons have been evaluated in myeloproliferative neoplasms for over 30 years, but early formulations had safety and tolerability issues. SURPASS-ET (NCT04285086) is a phase III, open-label, multicenter, global, randomized, active-controlled trial that will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide as second-line therapy in high-risk ET.


Essential thrombocythemia (ET) is a condition characterized by having more platelets than normal. The high number of platelets increases the risk of a life-threatening blood clot and/or bleeding. Patients with ET and at a high risk for these events are usually treated first with hydroxyurea (HU), but some patients do not respond properly or may develop significant side effects. Anagrelide is an approved medication used in patients who do not respond to HU. Ropeginterferon alfa-2b is a disease-specific, long-acting interferon with a good safety profile approved in polycythemia vera, another type of myeloproliferative neoplasm. The SURPASS-ET clinical trial will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide in patients with ET who are resistant or cannot tolerate HU. Clinical Trial Registration: NCT04285086 (ClinicalTrials.gov).


Assuntos
Hidroxiureia , Trombocitemia Essencial , Ensaios Clínicos Fase III como Assunto , Humanos , Hidroxiureia/efeitos adversos , Estudos Multicêntricos como Assunto , Quinazolinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombocitemia Essencial/tratamento farmacológico
20.
Int J Mol Sci ; 24(1)2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36613636

RESUMO

Prion diseases are neurodegenerative disorders in humans and animals for which no therapies are currently available. Here, we report that Curcuma phaeocaulis Valeton (Zingiberaceae) (CpV) extract was partly effective in decreasing prion aggregation and propagation in both in vitro and in vivo models. CpV extract inhibited self-aggregation of recombinant prion protein (PrP) in a test tube assay and decreased the accumulation of scrapie PrP (PrPSc) in ScN2a cells, a cultured neuroblastoma cell line with chronic prion infection, in a concentration-dependent manner. CpV extract also modified the course of the disease in mice inoculated with mouse-adapted scrapie prions, completely preventing the onset of prion disease in three of eight mice. Biochemical and neuropathological analyses revealed a statistically significant reduction in PrPSc accumulation, spongiosis, astrogliosis, and microglia activation in the brains of mice that avoided disease onset. Furthermore, PrPSc accumulation in the spleen of mice was also reduced. CpV extract precluded prion infection in cultured cells as demonstrated by the modified standard scrapie cell assay. This study suggests that CpV extract could contribute to investigating the modulation of prion propagation.


Assuntos
Doenças Priônicas , Príons , Scrapie , Zingiberaceae , Animais , Camundongos , Curcuma/metabolismo , Modelos Animais , Extratos Vegetais/farmacologia , Doenças Priônicas/tratamento farmacológico , Proteínas Priônicas , Príons/metabolismo , Scrapie/metabolismo , Ovinos
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