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1.
Cytokine ; 179: 156636, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38718489

RESUMO

BACKGROUND: Interleukin-2 (IL-2) is one of the most important cytokines that regulate the activation and proliferation of T cells and natural killer cells. The production of IL-2 may be affected by polymorphisms in the promoter region of the IL-2 gene (rs2069762). In allogeneic hematopoietic cell transplantation (HCT) from adult donors, rs2069762 has been associated with the incidence of acute and chronic graft-versus-host disease (GVHD). However, the impacts of IL-2 polymorphism on cord blood transplantation (CBT) outcomes remain unclear. OBJECTIVE: The objective of this study was to assess the impact of IL-2 polymorphism rs2069762 on transplant outcomes, such as hematopoietic recovery, GVHD, overall survival, relapse, and non-relapse mortality (NRM) after CBT. STUDY DESIGN: We conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from November 2005 to March 2023 for whom DNA samples from recipients and donors were available. IL-2 genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2069762. RESULTS: A total of 143 recipient and donor pairs were included in this study. The proportion of recipient IL-2 polymorphism rs2069762 was 48 % (n = 69) for AA, 42 % (n = 60) for CA, and 10 % (n = 14) for CC. The proportion of donor IL-2 polymorphism rs2069762 was 43 % (n = 61) for AA, 48 % (n = 69) for CA, and 9 % (n = 13) for CC. In the multivariate analysis, the use of an rs2069762 CA + CC donor was associated with lower neutrophil recovery compared to an rs2069762 AA donor (hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.50-0.88; P = 0.004). Furthermore, recipients of rs2069762 CA + CC were associated with higher NRM compared to recipients of rs2069762 AA (HR, 2.32; 95 % CI, 1.01-5.34; P = 0.047). Serum IL-2 levels at 8 weeks were significantly higher in rs2069762 CA + CC recipients compared to those with rs2069762 AA recipients (P = 0.014). CONCLUSION: Our data showed that donor IL-2 polymorphism affects neutrophil recovery and recipient IL-2 polymorphism affects NRM in adults undergoing single-unit CBT. The polymorphism of IL-2 rs2069762 in recipients and donors might be associated with the clinical outcomes of single-unit CBT.

2.
3.
Artigo em Inglês | MEDLINE | ID: mdl-38740951

RESUMO

We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.

5.
Mol Cell ; 84(8): 1475-1495.e18, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38521065

RESUMO

Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.


Assuntos
Cromatina , Neoplasias , Animais , Humanos , Camundongos , Cromatina/genética , Mutação , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Splicing de RNA/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo
6.
Int J Hematol ; 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38523199

RESUMO

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is not a standard therapy for solid cancer because of its high toxicity and insufficient evidence levels. However, the potential graft-versus-solid-tumor (GVT) effect of this therapy has been discussed. Many case reports have also described treatment effects of allo-HSCT in patients with hematologic malignancies and active solid tumors. A 38-year-old woman treated with fulvestrant and abemaciclib for recurrent breast cancer with multiple lung metastases was diagnosed with myelodysplastic syndrome (MDS) with increased blasts 2. She was classified as adverse risk by the 2017 European LeukemiaNet risk stratification and as very high risk by the Molecular International Prognostic Scoring System. Breast cancer treatment was interrupted and venetoclax and azacitidine therapy was started. Complete hematologic response was achieved after three cycles. However, multiple lung metastases from the breast cancer remained. The patient then underwent umbilical cord blood transplantation. She has maintained complete remission of MDS as of 1 year post-transplantation, without serious complications. Lung metastatic activity on FDG-PET/CT scan also completely disappeared by half a year post-transplantation, and this response has continued as of 1 year post-transplantation. This favorable treatment course suggests the existence of a GVT effect.

7.
Int J Hematol ; 119(4): 465-471, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38424413

RESUMO

While our understanding of the molecular basis of mixed phenotype acute leukemia (MPAL) has progressed over the decades, our knowledge is limited and the prognosis remains poor. Investigating cases of familial leukemia can provide insights into the role of genetic and environmental factors in leukemogenesis. Although familial cases and associated mutations have been identified in some leukemias, familial occurrence of MPAL has never been reported. Here, we report the first cases of MPAL in a family. A 68-year-old woman was diagnosed with MPAL and received haploidentical stem cell transplantation from her 44-year-old son. In four years, the son himself developed MPAL. Both cases exhibited similar characteristics such as biphenotypic leukemia with B/myeloid cell antigens, Philadelphia translocation (BCR-ABL1 mutation), and response to acute lymphoblastic leukemia-type chemotherapy. These similarities suggest the presence of hereditary factors contributing to the development of MPAL. Targeted sequencing identified shared germline variants in these cases; however, in silico analyses did not strongly support their pathogenicity. Intriguingly, when the son developed MPAL, the mother did not develop donor-derived leukemia and remained in remission. Our cases provide valuable insights to guide future research on familial MPAL.


Assuntos
Leucemia Aguda Bifenotípica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Feminino , Idoso , Adulto , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Doença Aguda , Fenótipo , Células Germinativas , Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/terapia , Leucemia Aguda Bifenotípica/diagnóstico
8.
Nature ; 627(8002): 221-228, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38383791

RESUMO

Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1-7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2-compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.


Assuntos
Histonas , Linfoma , Adulto , Humanos , Histonas/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Metilação , Cromatina/genética
10.
Sci Rep ; 14(1): 1413, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38228718

RESUMO

Although daily higher urinary sodium (Na) and potassium (K) excretion ratio is associated with the risk of cardiovascular disease in the general population, a low Na/K ratio is associated with renal dysfunction in critically ill patients. Thus, we retrospectively analyzed the impact of daily urinary Na and K excretion and their ratio on non-relapse mortality (NRM) and overall mortality in 172 adult single-unit cord blood transplantation (CBT) patients treated at our institution between 2007 and 2020. Multivariate analysis showed that a low urinary Na/K ratio at both 14 days (hazard ratio [HR], 4.82; 95% confidence interval [CI], 1.81-12.83; P = 0.001) and 28 days (HR, 4.47; 95% CI 1.32-15.12; P = 0.015) was significantly associated with higher NRM. Furthermore, a low urinary Na/K ratio at 28 days was significantly associated with higher overall mortality (HR, 2.38; 95% CI 1.15-4.91; P = 0.018). Patients with a low urinary Na/K ratio had decreased urine volume, more weight gain, experienced more grade III-IV acute graft-versus-host disease, and required corticosteroids by 28 days after CBT. These findings indicate that a low urinary Na/K ratio early after single-unit CBT is associated with poor NRM and survival in adults.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Estudos Retrospectivos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Sódio , Doença Crônica , Potássio
11.
Haematologica ; 109(4): 1107-1120, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37731380

RESUMO

Acute myeloid leukemia (AML) is a hematologic malignancy that frequently relapses, even if remission can be achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic cells from immune surveillance. Currently, there is no effective immunotherapy for AML because of the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and determine the therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 cases of AML indicated that the survival of patients with high expression of CD112 was shorter than that of patients with low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhanced the expression of cytotoxicity-related genes, thus overcoming the inhibitory activity of TIGIT. Between CD155 and CD112, CD112 is an especially important target for natural killer (NK)-cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also discovered that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, our findings suggest that the levels of expression of these molecules are potential prognostic markers in AML.


Assuntos
Proteínas de Checkpoint Imunológico , Leucemia Mieloide Aguda , Humanos , Nectinas , Proteínas de Checkpoint Imunológico/metabolismo , Células Matadoras Naturais , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/metabolismo , Receptores Imunológicos , Terapia Baseada em Transplante de Células e Tecidos , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo
12.
Cancer Rep (Hoboken) ; 7(1): e1938, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38014499

RESUMO

BACKGROUND: Hypomethylating agents, including azacytidine (AZA), are standard therapeutics for patients with high-risk myelodysplastic syndromes (MDS), a group of myeloid neoplasms. However, treatment schedules are not unified in real-world practice; in addition to the standard 7-day (standard-dose) schedule, shortened (reduced-dose) schedules are also used. AIMS: The aim of this study was to discover the patient group(s) which show differential efficacy between standard-and reduced-dose AZA to MDS. METHODS AND RESULTS: The outcome of different AZA doses in a cohort of 151 MDS patients were retrospectively analyzed. Overall survival (OS) was not significantly different between standard- and reduced-dose AZA groups by multivariate analysis. However, an interaction was found between either the sex (female vs. male), the platelet counts (< 40 × 103 /µl vs. ≥ 40 × 103 /µl), or the karyotype risk (< poor vs. ≥ poor) and standard-dose AZA for longer OS. Subgroup analyses revealed better OS with standard- over reduced-dose AZA in female patients (HR, 0.27 [95% CI, 0.090-0.79]; p = 0.011), and those with platelet counts ≥ 40 × 103 /µl (HR, 0.51 [95% CI, 0.26-0.99]; p = 0.041). The union of female and preserved platelet count subgroups also benefited from standard-dose AZA. With this as a test cohort, we next analyzed patients registered in the JALSG MDS212 study, for whom 7-day and 5-day AZA treatment strategies were prospectively compared, as a validation cohort (N = 172). That cohort showed the same tendency as the retrospective results. CONCLUSION: We identified the union of female and preserved platelet count subgroups which benefited from standard-dose AZA, imparting crucial information to physicians planning treatment regimens in MDS patients.


Assuntos
Azacitidina , Síndromes Mielodisplásicas , Humanos , Masculino , Feminino , Azacitidina/efeitos adversos , Contagem de Plaquetas , Estudos Retrospectivos , Antimetabólitos Antineoplásicos/efeitos adversos , Resultado do Tratamento , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico
13.
Br J Haematol ; 204(3): 1086-1095, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37926112

RESUMO

By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF), raccoon eyes, dystrophic nails, rib anomalies, fragility fractures (FFs), high IgE level, extremely short telomere lengths (TLs), and skewed numbers of cytotoxic T cells with B and NK cytopenia. Haploinsufficiency in the other family members resulted in short TL and osteopenia. These patients also had the lowest bone mineral density Z-score compared to other BMF-patients. Danazol/zoledronic acid improved the outcomes of BMF and FFs. This causative TERT variant has been observed in one family afflicted with dyskeratosis congenita (DC), and thus, we also define a second report and new phenotype related to the variant which should be suspected in severe cases of DC with co-existent BMF, FFs, high IgE level and rib anomalies.


Assuntos
Disceratose Congênita , Pancitopenia , Fraturas das Costelas , Telomerase , Humanos , Telômero , Mutação , Disceratose Congênita/genética , Imunoglobulina E/genética , Telomerase/genética
14.
Blood Adv ; 8(5): 1258-1271, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38127276

RESUMO

ABSTRACT: Aberrant micro-RNA (miRNA) expression profiles have been associated with disease progression and clinical outcome in pediatric cancers. However, few studies have analyzed genome-wide dysregulation of miRNAs and messenger RNAs (mRNAs) in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). To identify novel prognostic factors, we comprehensively investigated miRNA and mRNA sequencing (miRNA-seq and mRNA-seq) data in pediatric BCP-ALL samples with poor outcome. We analyzed 180 patients, including 43 matched pairs at diagnosis and relapse. Consensus clustering of miRNA expression data revealed a distinct profile characterized by mainly downregulation of miRNAs (referred to as an miR-low cluster [MLC]). The MLC profile was not associated with any known genetic subgroups. Intriguingly, patients classified as MLC had significantly shorter event-free survival (median 21 vs 33 months; log-rank P = 3 ×10-5). Furthermore, this poor prognosis was retained even in hyperdiploid ALL. This poor prognostic MLC profiling was confirmed in the validation cohort. Notably, non-MLC profiling at diagnosis (n = 9 of 23; Fisher exact test, P = .039) often changed into MLC profiling at relapse for the same patient. Integrated analysis of miRNA-seq and mRNA-seq data revealed that the transcriptional profile of MLC was characterized by enrichment of MYC target and oxidative phosphorylation genes, reduced intron retention, and low expression of DICER1. Thus, our miRNA-mRNA integration approach yielded a truly unbiased molecular stratification of pediatric BCP-ALL cases based on a novel prognostic miRNA signature, which may lead to better clinical outcomes.


Assuntos
Linfoma de Burkitt , MicroRNAs , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , MicroRNAs/genética , MicroRNAs/metabolismo , RNA-Seq , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Recidiva , RNA Mensageiro/genética , Ribonuclease III , RNA Helicases DEAD-box
17.
Int J Hematol ; 118(6): 718-725, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37851311

RESUMO

Augmented renal clearance (ARC) is a phenomenon characterized by increased renal functionality, which can impact the pharmacokinetics and pharmacodynamics of antimicrobial drugs eliminated by the kidneys. It is a potential concern for infection treatment. Cord blood transplantation (CBT) is primarily impeded by delayed neutrophil recovery and immune reconstitution, thereby increasing susceptibility to infection. However, the clinical implications of ARC following CBT remain unexplored. We retrospectively assessed the influence of ARC on post-transplant outcomes at various time points in 194 adult recipients of single-unit unrelated CBT between 2007 and 2022 at our institution. ARC was observed in 52.9% of patients at 1 day, 39.8% at 15 days, and 26.5% at 29 days post-CBT. ARC was not significantly associated with bloodstream infection, acute graft-versus-host disease, or veno-occlusive disease/sinusoidal obstruction syndrome at any time point. ARC at 1 day, 15 days, and 29 days post-CBT was not significantly associated  with overall survival, non-relapse mortality, or relapse rates. These findings suggest that ARC is common in adults during the early stages of CBT, but does not discernibly influence clinical outcomes or post-CBT complications.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Estudos Retrospectivos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Recidiva Local de Neoplasia
18.
Case Rep Oncol ; 16(1): 999-1006, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37900854

RESUMO

Venetoclax and azacitidine combination therapy (VEN+AZA) is a promising novel therapy for elderly or unfit patients with acute myeloid leukemia (AML). Recently, VEN+AZA with subsequent allo-hematopoietic stem cell transplantation has been reported, and human leukocyte antigen-haploidentical peripheral blood stem cell transplantation using posttransplant cyclophosphamide (PTCy-haplo-PBSCT) from related donors appears to be a suitable option. Here, we report two elderly patients with refractory AML harboring an IDH2 mutation, who were successfully treated with VEN+AZA bridged to PTCy-haplo-PBSCT. This report suggests the efficacy and safety of VEN+AZA as a bridging treatment for PTCy-haplo-PBSCT in refractory AML.

19.
Cell Rep ; 42(9): 113098, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37714156

RESUMO

Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.


Assuntos
Azacitidina , Leucemia Mieloide Aguda , Humanos , Decitabina/farmacologia , Decitabina/uso terapêutico , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/patologia , Metilação de DNA/genética , DNA , Proteínas Adaptadoras de Transdução de Sinal/genética
20.
EJHaem ; 4(3): 714-718, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37601868

RESUMO

We studied the pathophysiology of aplastic anaemia (AA) in six different pairs of relatives without a family history of hematologic disorders or congenital AA. Five and four of the six pairs shared the HLA-DRB1*15:01 and B*40:02 alleles, respectively. Glycosylphosphatidylinositol-anchored protein-deficient blood cells were detected in eight of the 10 patients evaluated. In a mother-daughter pair from one family, flow cytometry detected leukocytes lacking HLA-A2 due to loss of heterogeneity in chromosome 6p. Whole-exome sequencing of the family pair revealed a missense mutation in MYSM1. These results suggest that genetic inheritance of immune traits might underlie familial AA in some patients.

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