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BACKGROUND: For myeloid neoplasms with t(7;11)(p15;p15) translocation, the prognosis is quite dismal. Because these tumors are rare, most occurrences are reported as single cases. Clinical results and optimal treatment approaches remain elusive. This study endeavors to elucidate the clinical implications and prognosis of this cytogenetic aberration. METHODS: This study retrospectively analyzed 23 cases of myeloid neoplasm with t(7;11)(p15;p15). Clinicopathological characteristics, genetic alterations, and outcomes were evaluated, and the Kaplan-Meier method was employed to construct survival curves. RESULTS: Of these, nine cases were newly diagnosed acute myeloid leukemia (ND AML), seven presented with relapsed refractory AML (R/R AML), four had myelodysplastic syndrome (MDS), two had secondary AML, and one exhibited a mixed germinoma associated with MDS. Patients with t(7;11)(p15;p15) in AML were primarily younger females who preferred subtype M2. Interestingly, these patients had decreased hemoglobin and red blood cell counts, along with markedly elevated levels of lactic dehydrogenase and interleukin-6, and exhibited the expression of CD117. R/R AML patients exhibited a higher likelihood of additional chromosome abnormalities (ACAs) besides t(7;11). WT1 and FLT3-ITD were the most commonly found mutated genes, and 10 of those instances showed evidence of the NUP98::HOXA9 fusion gene. The composite complete remission rate was 66.7% (12/18), while the cumulative graft survival rate was 100% (4/4). However, the survival outcomes were dismal. Interestingly, the median overall survival for R/R AML patients was 4.0 months (95% CI: 1.7-6.4). Additionally, the type of AML diagnosis or the presence of ACAs or molecular prognostic stratification did not significantly influence clinical outcomes (p = 0.066, p = 0.585, p = 0.570, respectively). CONCLUSION: Myeloid leukemia with t(7;11) exhibits unique clinical features, cytogenetic properties, and molecular genetic characteristics. These survival outcomes were dismal. R/R AML patients have a limited lifespan. For myeloid patients with t(7;11), targeted therapy or transplantation may be an effective course of treatment.
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Cromossomos Humanos Par 11 , Translocação Genética , Humanos , Feminino , Masculino , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Prognóstico , Cromossomos Humanos Par 11/genética , Adulto Jovem , Idoso , Adolescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Cromossomos Humanos Par 7/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapiaRESUMO
Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D) culture model, closely mimics tissues or organs in vivo. Insulin-secreting islet organoid, derived from stem cells induced in vitro with 3D structures, has emerged as a potential alternative for islet transplantation and as a possible disease model that mirrors the human body's in vivo environment, eliminating species difference. This technology has gained considerable attention for its potential in diabetes treatment. Despite advances, the process of stem cell differentiation into islet organoid and its cultivation demonstrates deficiencies, prompting ongoing efforts to develop more efficient differentiation protocols and 3D biomimetic materials. At present, the constructed islet organoid exhibit limitations in their composition, structure, and functionality when compared to natural islets. Consequently, further research is imperative to achieve a multi-tissue system composition and improved insulin secretion functionality in islet organoid, while addressing transplantation-related safety concerns, such as tumorigenicity, immune rejection, infection, and thrombosis. This review delves into the methodologies and strategies for constructing the islet organoid, its application in diabetes treatment, and the pivotal scientific challenges within organoid research, offering fresh perspectives for a deeper understanding of diabetes pathogenesis and the development of therapeutic interventions.
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Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Organoides , Humanos , Organoides/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/citologia , Animais , Transplante das Ilhotas Pancreáticas/métodos , Diabetes Mellitus/terapia , Diabetes Mellitus/patologia , Diferenciação CelularRESUMO
As an autoimmune-mediated inflammatory demyelinating disease of the central nervous system, multiple sclerosis (MS) is often confused with cerebral small vessel disease (cSVD), which is a regional pathological change in brain tissue with unknown pathogenesis. This is due to their similar clinical presentations and imaging manifestations. That misdiagnosis can significantly increase the occurrence of adverse events. Delayed or incorrect treatment is one of the most important causes of MS progression. Therefore, the development of a practical diagnostic imaging aid could significantly reduce the risk of misdiagnosis and improve patient prognosis. We propose an interpretable deep learning (DL) model that differentiates MS and cSVD using T2-weighted fluid-attenuated inversion recovery (FLAIR) images. Transfer learning (TL) was utilized to extract features from the ImageNet dataset. This pioneering model marks the first of its kind in neuroimaging, showing great potential in enhancing differential diagnostic capabilities within the field of neurological disorders. Our model extracts the texture features of the images and achieves more robust feature learning through two attention modules. The attention maps provided by the attention modules provide model interpretation to validate model learning and reveal more information to physicians. Finally, the proposed model is trained end-to-end using focal loss to reduce the influence of class imbalance. The model was validated using clinically diagnosed MS (n=112) and cSVD (n=321) patients from the Beijing Tiantan Hospital. The performance of the proposed model was better than that of two commonly used DL approaches, with a mean balanced accuracy of 86.06 % and a mean area under the receiver operating characteristic curve of 98.78 %. Moreover, the generated attention heat maps showed that the proposed model could focus on the lesion signatures in the image. The proposed model provides a practical diagnostic imaging aid for the use of routinely available imaging techniques such as magnetic resonance imaging to classify MS and cSVD by linking DL to human brain disease. We anticipate a substantial improvement in accurately distinguishing between various neurological conditions through this novel model.
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Doenças de Pequenos Vasos Cerebrais , Aprendizado Profundo , Esclerose Múltipla , Humanos , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Masculino , Imageamento por Ressonância Magnética/métodos , Feminino , Redes Neurais de Computação , Interpretação de Imagem Assistida por Computador/métodos , Pessoa de Meia-Idade , Adulto , Neuroimagem/métodosRESUMO
Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/farmacologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Reparo do DNA , Dano ao DNA , Transaminases/genéticaRESUMO
OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has demonstrated efficacy against multiple types of dystonia, but only a few case reports and small-sample studies have investigated the clinical utility of STN-DBS for Meige syndrome, a rare but distressing form of craniofacial dystonia. Furthermore, the effects of DBS on critical neuropsychological sequelae, such as depression and anxiety, are rarely examined. In this study, the authors investigated the therapeutic efficacy of STN-DBS for both motor and psychiatric symptoms of Meige syndrome. METHODS: The authors retrospectively reviewed consecutive patients with Meige syndrome receiving bilateral STN-DBS at their institution from January 2016 to June 2023. Motor performance and nonmotor features including mood, cognitive function, and quality of life (QOL) were evaluated using standardized rating scales at baseline and at final postoperative follow-up. Clinical and demographic factors influencing postoperative motor outcome were evaluated by uni- and multivariable linear regression models. RESULTS: Fifty-one patients were ultimately included, with a mean ± SD follow-up duration of 27.3 ± 18.0 months. The mean Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) movement score improved from 12.9 ± 5.2 before surgery to 5.3 ± 4.2 at the last follow-up (mean improvement 58.9%, p < 0.001) and the mean BFMDRS disability score improved from 5.6 ± 3.3 to 2.9 ± 2.9 (mean improvement 44.6%, p < 0.001). Hamilton Depression and Anxiety Rating Scale scores also improved by 35.3% and 34.2%, respectively, and the postoperative 36-item Short-Form Health Survey score indicated substantial QOL enhancement. Global cognition remained stable after treatment. Multiple linear regression analysis identified disease duration (ß = -0.241, p = 0.027), preoperative anxiety severity (ß = -0.386, p = 0.001), and volume of activated tissue within the dorsolateral (sensorimotor) STN (ß = 0.483, p < 0.001) as independent predictors of motor outcome. CONCLUSIONS: These findings support STN-DBS as an effective and promising therapy for both motor and nonmotor symptoms of Meige syndrome. Timely diagnosis, treatment of preoperative anxiety, and precise electrode placement within the dorsolateral STN are essential for optimal clinical outcome.
Assuntos
Estimulação Encefálica Profunda , Síndrome de Meige , Núcleo Subtalâmico , Humanos , Estimulação Encefálica Profunda/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome de Meige/terapia , Resultado do Tratamento , Adulto , Qualidade de Vida , Idoso , Seguimentos , Ansiedade/terapia , Ansiedade/etiologiaRESUMO
OBJECTIVES: In patients with acute promyelocytic leukemia (APL), additional chromosomal abnormalities (ACAs) are prognostic indicators. However, the clinical features of ACAs were not systematically reported in Chinese patients. Therefore, we enrolled a large cohort of APLs to demonstrate the clinical characteristics and prognostic value of ACAs. METHODS: 268 patients with newly diagnosed APL with t(15;17)(q24;q21) were retrospectively enrolled, and their clinical characteristics and the predictive value of ACAs were assessed between patients with the presence and absence of ACAs. RESULTS: APL patients with and without ACAs did not differ significantly in their clinical features or treatment response and clinical outcomes like overall survival (OS) and disease-free survival (DFS). It appeared to be substantially associated with worse OS in APL patients with trisomy 8, which was the most common ACA, although DFS was unaffected. Interestingly, the presence of ACAs or trisomy 8 affected OS and DFS in the subgroup of patients aged ≥60 years; by contrast, ACAs had no effect on OS or DFS in any treatment subgroup (ATRA + ATO/RIF or ATRA + ATO/RIF + CH or ATRA + CH), except for the ATRA + ATO/RIF + CH treatment subgroup, where their impact on DFS was less favorable. CONCLUSIONS: Our results suggested that OS and DFS were unaffected by ACAs. Nonetheless, in the subgroup of patients older than 60, the existence of ACAs or trisomy 8 appeared to impact OS and DFS negatively. Individuals with t(15;17) alone had a higher DFS and were more susceptible to ATRA + ATO/RIF + CH than individuals with t(15;17) ACAs.
Assuntos
Arsenicais , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína , Estudos Retrospectivos , Prognóstico , Aberrações Cromossômicas , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Ferroptosis induction through the suppression of glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2) has proven to be an effective approach in eliminating chemotherapy-resistant cells of various types. However, a comprehensive understanding of the roles of GPX4 and AIFM2 in acute myeloid leukemia (AML) has not yet been achieved. Using cBioPortal, DepMap, GEPIA, Metascape, and ONCOMINE, we compared the transcriptional expression, survival data, gene mutation, methylation, and network analyses of GPX4- and AIFM2-associated signaling pathways in AML. The results revealed that high expression levels of GPX4 and AIFM2 are associated with an adverse prognosis for AML patients. Overexpression of AIFM2 correlated with elevated mutation frequencies in NPM1 and DNMT3A. GPX4 upregulation modulated the following pathways: GO:0045333, cellular respiration; R-HSA-5389840, mitochondrial translation elongation; GO:0009060, aerobic respiration; R-HSA-9609507, protein localization; and R-HSA-8953854, metabolism of RNA. On the other hand, the overexpression of AIFM2 influenced the following processes: GO:0048704, embryonic skeletal system morphogenesis; GO:0021546, rhombomere development; GO:0009954, proximal/distal pattern formation; and GO:0048732, gland development. This study identifies the high expression of GPX4 and AIFM2 as novel biomarkers predicting a poor prognosis for AML patients. Furthermore, ferroptosis induction may improve the stratified treatment of AML.
Assuntos
Ferroptose , Leucemia Mieloide Aguda , Humanos , Ferroptose/genética , Leucemia Mieloide Aguda/genética , Prognóstico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , MutaçãoRESUMO
Circular RNAs (circRNAs), a type of endogenous noncoding RNA (ncRNA), exert vital roles in leukemia progression and are promising prognostic factors. Here, we report a novel circRNA, circSLC25A13 (hsa_circ_0081188), which was increased in acute myeloid leukemia (AML) patients with poor overall survival (OS) comparing to patients with good prognosis. Knockdown of circSLC25A13 in AML cells inhibited proliferation and increased cell apoptosis in vitro and in vivo. Enhanced circSLC25A13 expression promoted the survival of AML cells. Mechanistically, circSLC25A13 played as a microRNA sponge of miR-616-3p, which inhibited the expression of adenylate cyclase 2 (ADCY2). Downregulation of miR-616-3p and overexpression of ADCY2 partially rescued circSLC25A13 deficient induced cell growth arrest. In summary, through competitive absorption of miR-616-3p and thereby upregulating ADCY2 expression, circSLC25A13 promoted AML progression. Moreover, circSLC25A13 may represent a potential novel biomarker for the prognosis of AML and offer a potential therapeutic target for AML treatment.
Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Humanos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genéticaRESUMO
Medulloblastoma (MB) is one of the most common malignant childhood brain tumors (WHO grade IV). Its high degree of malignancy leads to an unsatisfactory prognosis, requiring more precise and personalized treatment in the near future. Multi-omics and artificial intelligence have been playing a significant role in precise medical research, but their implementation needs a large amount of clinical information and biomaterials. For these reasons, it is urgent for current MB researchers to establish a large sample-size database of MB that contains complete clinical data and sufficient biomaterials such as blood, cerebrospinal fluid (CSF), cancer tissue, and urine. Unfortunately, there are few biobanks of pediatric central nervous system (CNS) tumors throughout the world for limited specimens, scarce funds, different standards collecting methods and et cl. Even though, China falls behind western countries in this area. The present research set up a standard workflow to construct the Beijing Children's Hospital Medulloblastoma (BCH-MB) biobank. Clinical data from children with MB and for collecting and storing biomaterials, along with regular follow-up has been collected and recorded in this database. In the future, the BCH-MB biobank could make it possible to validate the promising biomarkers already identified, discover unrevealed MB biomarkers, develop novel therapies, and establish personalized prognostic models for children with MB upon the support of its sufficient data and biomaterials, laying the foundation for individualized therapies of children with MB.
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Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Humanos , Criança , Meduloblastoma/diagnóstico , Meduloblastoma/terapia , Meduloblastoma/patologia , Inteligência Artificial , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Prognóstico , Neoplasias Encefálicas/diagnóstico , HospitaisRESUMO
Glutamine metabolic reprogramming in acute myeloid leukaemia (AML) cells contributes to the decreased sensitivity to antileukemic drugs. Leukaemic cells, but not their myeloid counterparts, largely depend on glutamine. Glutamate dehydrogenase 1 (GDH1) is a regulation enzyme in glutaminolysis. However, its role in AML remains unknown. Here, we reported that GDH1 was highly expressed in AML: high GDH1 was one of the independent negative prognostic factors in AML cohort. The dependence of leukaemic cells on GDH1 was proved both in vitro and in vivo. High GDH1 promoted cell proliferation and reduced survival time of leukaemic mice. Targeting GDH1 eliminated the blast cells and delayed AML progression. Mechanistically, GDH1 knockdown inhibited glutamine uptake by downregulating SLC1A5. Moreover, GDH1 invalidation also inhibited SLC3A2 and abrogated the cystine-glutamate antiporter system Xc- . The reduced cystine and glutamine disrupted the synthesis of glutathione (GSH) and led to the dysfunction of glutathione peroxidase-4 (GPX4), which maintains the lipid peroxidation homeostasis by using GSH as a co-factor. Collectively, triggering ferroptosis in AML cells in a GSH depletion manner, GDH1 inhibition was synthetically lethal with the chemotherapy drug cytarabine. Ferroptosis induced by inhibiting GDH1 provides an actionable therapeutic opportunity and a unique target for synthetic lethality to facilitate the elimination of malignant AML cells.
Assuntos
Glutamato Desidrogenase , Leucemia Mieloide Aguda , Camundongos , Animais , Glutamina/metabolismo , Cistina , Citarabina , Glutationa/metabolismoRESUMO
Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/ß-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.
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Leucemia Mieloide Aguda , Humanos , Antineoplásicos/uso terapêutico , Apoptose , beta Catenina/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Lipoilação , Prognóstico , Via de Sinalização WntRESUMO
BACKGROUND: Fatty acid oxidation has been considered as an important energy source for tumorigenesis and development. Several studies have investigated the role of CPT1A, a kind of fatty acid oxidation rate-limiting enzyme, in AML. However, prognostic value and regulatory network of another subtype, CPT1B in AML remains elusive. This study aims to clarify the independent prognostic role of CPT1B in CN-AML based on clinical data and molecular level data (mRNA, miRNA and lncRNA). OBJECTIVE: The aim of this study is to investigate the prognostic value of CPT1B in AML patients. METHODS: First, we analyzed the CPT1B expression in AML cohort via the online database "GEPIA". Subsequently, miRNA-mRNA and ceRNA networks were constructed to help predict the role of CPT1B in AML. Several molecules which showed the prognostic value and metabolic function of CPT1B were identified. Finally, the expression of CPT1B in our own cohort of 324 CN-AML patients was analyzed to clarify the results. RESULTS: It was found that CPT1B was markedly higher in AML patients compared to normal people and this upregulation was associated with the poor clinical outcome. Several molecules revealed the possible regulatory mechanism of CPT1B in AML. CONCLUSION: CPT1B is a potential prognostic factor and a therapeutic target for AML treatment.
Assuntos
Leucemia Mieloide Aguda , MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/genética , Leucemia Mieloide Aguda/genética , Fatores de Risco , RNA Mensageiro/genética , Ácidos Graxos , RNA Longo não Codificante/genética , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismoRESUMO
Integrins are heterodimeric receptors comprising α and ß subunits. They are expressed on the cell surface and play key roles in cell adhesion, migration, and growth. Several types of integrins are expressed on the platelets, including αvß3, αIIbß3, α2ß1, α5ß1, and α6ß1. Among these, physically αIIbß3 is exclusively expressed on the platelet surface and their precursor cells, megakaryocytes. αIIbß3 adopts at least three conformations: i) bent-closed, ii) extended-closed, and iii) extended-open. The transition from conformation i) to iii) occurs when αIIbß3 is activated by stimulants. Conformation iii) possesses a high ligand affinity, which triggers integrin clustering and platelet aggregation. Platelets are indispensable for maintaining vascular system integrity and preventing bleeding. However, excessive platelet activation can result in myocardial infarction (MI) and stroke. Therefore, finding a novel strategy to stop bleeding without accelerating the risk of thrombosis is important. Regulation of αIIbß3 activation is vital for this strategy. There are a large number of molecules that facilitate or inhibit αIIbß3 activation. The interference of these molecules can accurately control the balance between hemostasis and thrombosis. This review describes the structure and signal transduction of αIIbß3, summarizes the molecules that directly or indirectly affect integrin αIIbß3 activation, and discusses some novel antiαIIbß3 drugs. This will advance our understanding of the activation of αIIbß3 and its essential role in platelet function and tumor development.
RESUMO
BACKGROUND: Spermatogenesis associated serine rich 2 like (SPATS2L) was highly expressed in homoharringtonine (HHT) resistant acute myeloid leukemia (AML) cell lines. However, its role is little known in AML. The present study aimed to investigate the function of SPATS2L in AML pathogenesis and elucidate the underlying molecular mechanisms. METHODS: Overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) were used to evaluate the prognostic impact of SPATS2L for AML from TCGA database and ourcohort. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. The changes of proteins were assessed by Western blot(WB). A xenotransplantation mice model was used to evaluate in vivo growth and survival. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML. RESULTS: SPATS2L expression increased with increasing resistance indexes(RI) in HHT-resistant cell lines we had constructed. Higher SPATS2L expression was observed in intermediate/high-risk patients than in favorable patients. Meanwhile, decreased SPATS2L expression was observed in AML patients achieving complete remission (CR). Multivariate analysis showed high SPATS2L expression was an independent poor predictor of OS, EFS, RFS in AML. SPATS2L knock down (KD) suppressed cell growth, induced apoptosis, and suppressed key proteins of JAK/STAT pathway, such as JAK2, STAT3, STAT5 in AML cells. Inhibiting SPATS2L expression markedly enhanced the pro-apoptotic effects of traditional chemotherapeutics (Ara-c, IDA, and HHT). CONCLUSIONS: High expression of SPATS2L is a poor prognostic factor in AML, and targeting SPATS2L may be a promising therapeutic strategy for AML patients.
Assuntos
Leucemia Mieloide Aguda , Fator de Transcrição STAT5 , Animais , Camundongos , Mepesuccinato de Omacetaxina/farmacologia , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Janus Quinases/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Prognóstico , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Fatores de Transcrição STAT/uso terapêutico , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Fator de Transcrição STAT5/farmacologia , HumanosRESUMO
Acute myeloid leukemia (AML) is a group of hematological malignancies characterized by clonal proliferation of immature myeloid cells. Lipid rafts are highly organized membrane subdomains enriched in cholesterol, sphingolipids, and gangliosides and play roles in regulating apoptosis through subcellular redistribution. Flotillin1 (FLOT1) is a component and also a marker of lipid rafts and had been reported to be involved in the progression of cancers and played important roles in cell death. However, the role of FLOT1 in AML remains to be explored. In this study, we found that increased expression of FLOT1 was correlated with poor clinical outcome in AML patients. Knockdown of FLOT1 in AML cells not only promoted cell death in vitro but also inhibited malignant cells engraftment in vivo. Mechanically, FLOT1 knockdown triggered apoptosis and pyroptosis. FLOT1 overexpression promoted AML cell growth and apoptosis resistance. Our findings indicate that FLOT1 is a prognostic factor of AML and may be a potential target for AML treatment.
Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Humanos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Leucemia Mieloide Aguda/patologia , PiroptoseRESUMO
Bromodomain-containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/ß-catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/ß-catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co-treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010-resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3-inhibitor-resistant FLT3-ITD/tyrosine kinase domain mutations and AML cells without FLT3-ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3-ITD.
Assuntos
Leucemia Mieloide Aguda , beta Catenina , Animais , Camundongos , Apoptose , beta Catenina/genética , Linhagem Celular Tumoral , Tirosina Quinase 3 Semelhante a fms/genética , Mepesuccinato de Omacetaxina/farmacologia , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas Nucleares/genética , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/genética , HumanosRESUMO
Somatosensory neurons are highly heterogeneous with distinct types of neural cells responding to specific stimuli. However, the distribution and roles of cell-type-specific long intergenic noncoding RNAs (lincRNAs) in somatosensory neurons remain largely unexplored. Here, by utilizing droplet-based single-cell RNA-seq (scRNA-seq) and full-length Smart-seq2, we show that lincRNAs, but not coding mRNAs, are enriched in specific types of mouse somatosensory neurons. Profiling of lincRNAs from single neurons located in dorsal root ganglia (DRG) identifies 200 lincRNAs localized in specific types or subtypes of somatosensory neurons. Among them, the conserved cell-type-specific lincRNA CLAP associates with pruritus and is abundantly expressed in somatostatin (SST)-positive neurons. CLAP knockdown reduces histamine-induced Ca2+ influx in cultured SST-positive neurons and in vivo reduces histamine-induced scratching in mice. In vivo knockdown of CLAP also decreases the expression of neuron-type-specific and itch-related genes in somatosensory neurons, and this partially depends on the RNA binding protein MSI2. Our data reveal a cell-type-specific landscape of lincRNAs and a function for CLAP in somatosensory neurons in sensory transmission.
Assuntos
Prurido , RNA Longo não Codificante , Células Receptoras Sensoriais , Animais , Camundongos , Histamina , Prurido/genética , RNA Longo não Codificante/genética , SensaçãoRESUMO
Long intergenic noncoding RNAs (lincRNAs) are crucial regulators in numerous biological processes. However, the functions and mechanisms of m6A-modified lincRNAs in neuronal development remain unclear. Here, we report an m6A-modified lincRNA, Dppa2 upstream binding RNA (Dubr), abundantly expressed at the early developmental stage of dorsal root ganglion (DRG) and cerebral cortex. Silencing Dubr impairs axon elongation of DRG neurons and axon projection and migration of cortical neurons, whereas lacking m6A modification of Dubr fully loses its functions. Mechanically, Dubr interacts with m6A-binding proteins, the YTHDF1/3 complex, through its m6A motifs to protect YTHDF1/3 from degradation via the proteasome pathway. Furthermore, Tau and Calmodulin are regulated by YTHDF1/3 and m6A-modified Dubr. Overexpression of YTHDF1/3 not only rescues the reduced Tau and Calmodulin but also restores axon elongation of DRG neurons by Dubr knockdown. This study uncovers a critical role of m6A-modified lincRNA in neuronal development by regulating the degradation of RNA-binding protein.