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1.
Am J Physiol Cell Physiol ; 326(3): C684-C697, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38145297

RESUMO

Chromatin instability plays a crucial role in multiple myeloma (MM) relapse and progression, but its mechanism remains obscure. Here, we uncovered that m6A-demethylase ALKBH5 upregulated and stabilized long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15), which was elevated in MM and positively correlated with unfavorable clinical prognosis factors. ALKBH5-SNHG15 axis participated in viability and migration/invasion of myeloma cell lines and MM-xenografted SCID/NOD mice. Mechanically, ALKBH5 promoted the expression of trimethylated histone H3 at lysine 36 (H3K36me3) methyltransferase SETD2 through lncRNA SNHG15-mediated protein stability. ALKBH5-SNHG15 axis increased chromatin accessibility and altered the H3K36me3 enrichment at the gene body, which is responsible for transcription elongation. Our study suggested a novel epigenetically interaction of N6-methyladenosine (m6A) methylation, lncRNA SNHG15, and histone SETD2/H3K36me3 modifications in myeloma progression, indicating that ALKBH5 and lncRNA SNHG15 could serve as potential novel therapeutic targets for MM treatment.NEW & NOTEWORTHY To our knowledge, this study first demonstrated the prognostic significance and biological function of long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15) in multiple myeloma (MM), and indicated a novel revelation on the effect of N6-methyladenosine (m6A)-regulated lncRNA on MM tumorigenicity. Moreover, the novel chromatin-regulatory mechanism of lncRNA by interacting with epigenetic modifiers including m6A demethylase ALKBH5 and H3K36me3 methyltransferase SETD2 in myeloma progression elucidated intricate mechanism of tumor pathogenesis.


Assuntos
Mieloma Múltiplo , RNA Longo não Codificante , Animais , Camundongos , Cromatina/genética , RNA Longo não Codificante/genética , Mieloma Múltiplo/genética , RNA Nucleolar Pequeno , Camundongos Endogâmicos NOD , Camundongos SCID , Histona-Lisina N-Metiltransferase/genética
2.
Anticancer Drugs ; 35(5): 440-444, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38386312

RESUMO

Venetoclax, in combination with hypomethylation agents (HMAs), is a novel treatment for leukemia patients with low chemotherapy tolerance. However, it has been reported to be a risk of causing tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL) and elderly acute myeloid leukemia (AML) patients. Here we report a rare case of a young adult AML patient who induced TLS after receiving a combination therapy of venetoclax with decitabine (DEC). A 36-year-old male patient presented with an unexplained fever and was diagnosed with AML-M5a. The patient was first treated with a combination of antibiotics, including voriconazole 300 mg Q12h. After the infection was relieved, he was treated with 100 mg venetoclax in combination with 75 mg/m 2 DEC. However, 12 h after the first treatment, he developed diarrhea, fatigue and other symptoms, and the laboratory results were consistent with the laboratory TLS. The patient stopped chemotherapy immediately, and TLS gradually improved after receiving rehydration, diuresis, dialysis and other treatments. Finally, the patient achieved complete remission. Based on the experience of this case and related studies, we recommend the prevention of TLS should not be limited to elderly patients taking venetoclax, and it is equally important in young patients. And reduce the dosage of venetoclax when using azole antifungal drugs.


Assuntos
Leucemia Mieloide Aguda , Sulfonamidas , Síndrome de Lise Tumoral , Masculino , Adulto Jovem , Humanos , Idoso , Adulto , Decitabina/efeitos adversos , Síndrome de Lise Tumoral/etiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
3.
Cell Mol Life Sci ; 80(11): 330, 2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37856006

RESUMO

Dramatic alterations in epigenetic landscapes are known to impact genome accessibility and transcription. Extensive evidence demonstrates that senescent cells undergo significant changes in chromatin structure; however, the mechanisms underlying the crosstalk between epigenetic parameters and gene expression profiles have not been fully elucidated. In the present study, we delineate the genome-wide redistribution of accessible chromatin regions that lead to broad transcriptome effects during senescence. We report that distinct senescence-activated accessibility regions (SAAs) are always distributed in H3K27ac-occupied enhancer regions, where they are responsible for elevated flanking senescence-associated secretory phenotype (SASP) expression and aberrant cellular signaling relevant to SASP secretion. Mechanistically, a single transcription factor, TEAD4, moves away from H3K27ac-labled SAAs to allow for prominent chromatin accessibility reconstruction during senescence. The enhanced SAAs signal driven by TEAD4 suppression subsequently induces a robust increase in the expression of adjacent SASP genes and the secretion of downstream factors, which contribute to the progression of senescence. Our findings illustrate a dynamic landscape of chromatin accessibility following senescence entry, and further reveal an insightful function for TEAD4 in regulating the broad chromatin state that modulates the overall transcriptional program of SASP genes.


Assuntos
Senescência Celular , Cromatina , Cromatina/genética , Senescência Celular/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sequências Reguladoras de Ácido Nucleico , Regulação da Expressão Gênica
4.
BMC Womens Health ; 24(1): 345, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38877551

RESUMO

BACKGROUND: The prognosis of advanced ovarian cancer is often poor. Although there are several treatment options for stage IV epithelial ovarian cancer, it is not clear which treatment will benefit the patient's prognosis.We conducted an analysis using the SEER database to compare the impact of different treatment modalities on the prognosis of advanced ovarian cancer. METHODS: The present study conducts a retrospective analysis of relevant data from the SEER database pertaining to patients diagnosed with stage IV epithelial ovarian cancer between 2011 and 2020 (n = 5345). Statistical methods including Kaplan-Meier curves, log-rank tests, and Cox regression analysis are employed to ascertain the impact of different treatment regimens on the prognosis of patients with stage IV epithelial ovarian cancer. RESULTS: Among patients with stage IV epithelial ovarian cancer, age ≥ 60 and the presence of lung metastases or multiple metastases were identified as poor prognostic factors. Conversely, being Asian or Pacific Islander, married, and testing negative for CA125 were associated with favorable prognoses. In terms of the choice of treatment for patients, surgery plus chemotherapy was the best treatment modality, and timely surgery could significantly improve the prognosis of patients, but there was no difference between chemoradiotherapy alone and the surgery group among patients with lung metastases. CONCLUSION: The prognosis of patients with stage IV epithelial ovarian cancer is influenced by many factors. In terms of the choice of treatment, patients with surgery plus chemotherapy have the best prognosis. In cases where lung metastases are inoperable, a combination of radiotherapy and chemotherapy can be used. In other cases, radiotherapy does not improve outcomes in patients with stage IV epithelial ovarian cancer. This study provides a basis for the choice of treatment for patients with stage IV epithelial ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário , Estadiamento de Neoplasias , Neoplasias Ovarianas , Programa de SEER , Humanos , Feminino , Carcinoma Epitelial do Ovário/terapia , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/mortalidade , Pessoa de Meia-Idade , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Prognóstico , Idoso , Adulto , Terapia Combinada , Bases de Dados Factuais , Estimativa de Kaplan-Meier , Estados Unidos/epidemiologia
5.
J Cell Physiol ; 238(8): 1788-1807, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37565630

RESUMO

Despite the initiation of tumor arises from tumorigenic transformation signaling in cancer cells, cancer cell survival, invasion, and metastasis also require a dynamic and reciprocal association with extracellular signaling from tumor microenvironment (TME). Primary cilia are the antenna-like structure that mediate signaling sensation and transduction in different tissues and cells. Recent studies have started to uncover that the heterogeneous ciliation in cancer cells and cells from the TME in tumor growth impels asymmetric paracellular signaling in the TME, indicating the essential functions of primary cilia in homeostasis maintenance of both cancer cells and the TME. In this review, we discussed recent advances in the structure and assembly of primary cilia, and the role of primary cilia in tumor and TME formation, as well as the therapeutic potentials that target ciliary dynamics and signaling from the cells in different tumors and the TME.


Assuntos
Cílios , Neoplasias , Humanos , Cílios/patologia , Microambiente Tumoral , Neoplasias/patologia , Transdução de Sinais
6.
Hum Mol Genet ; 30(7): 525-535, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33575778

RESUMO

Oogenesis is a highly regulated process and its basic cellular events are evolutionarily conserved. However, the time spans of oogenesis differ substantially among species. To explore these interspecies differences in oogenesis, we performed single-cell RNA-sequencing on mouse and monkey female germ cells and downloaded the single-cell RNA-sequencing data of human female germ cells. The cell cycle analyses indicate that the period and extent of cell cycle transitions are significantly different between the species. Moreover, hierarchical clustering of critical cell cycle genes and the interacting network of cell cycle regulators also exhibit distinguished patterns across species. We propose that differences in the regulation of cell cycle transitions may underlie female germ cell developmental allochrony between species. A better understanding of the cell cycle transition machinery will provide new insights into the interspecies differences in female germ cell developmental time spans.


Assuntos
Ciclo Celular/genética , Oócitos/metabolismo , Oogênese/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Animais , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Humanos , Macaca fascicularis , Camundongos , Oócitos/citologia , Especificidade da Espécie , Fatores de Tempo
7.
FASEB J ; 36(3): e22210, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35167144

RESUMO

Precise regulation of chromosome separation through spindle assembly checkpoint (SAC) during oocyte meiosis is critical for mammalian reproduction. The kinetochore plays an important role in the regulation of SAC through sensing microtubule tension imbalance or missing microtubule connections. Here, we report that kinetochore scaffold 1 (KNL1, also known as CASC5), an outer kinetochore protein, plays a critical role in the SAC function of mouse oocytes. KNL1 localized at kinetochores from GVBD to the MII stage, and microinjection of KNL1-siRNA caused accelerated metaphase-anaphase transition and premature first meiosis completion, producing aneuploid eggs. The SAC was prematurely silenced in the presence of unstable kinetochore-microtubule attachments and misaligned chromosomes in KNL1-depleted oocytes. Additionally, KNL1 and MPS1 had a synergistic effect on the activation and maintenance of SAC. Taken together, our results suggest that KNL1, as a kinetochore platform protein, stabilizes SAC to ensure timely anaphase entry and accurate chromosome segregation during oocyte meiotic maturation.


Assuntos
Pontos de Checagem da Fase M do Ciclo Celular , Meiose , Proteínas Associadas aos Microtúbulos/metabolismo , Oócitos/metabolismo , Oogênese , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Associadas aos Microtúbulos/genética , Oócitos/citologia
8.
Support Care Cancer ; 31(5): 282, 2023 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-37074462

RESUMO

PURPOSE: Mucositis is a frequent and severe complication in haematopoietic stem cell transplantation (HSCT). The effectiveness of probiotics in mucositis has been indicated by several clinical trials, but the results are still controversial. To date, studies on the influence of probiotics in HSCT are limited. Therefore, we conducted this retrospective study to evaluate the impact of viable Bifidobacterium tablets on the incidence and duration of chemotherapy-/radiation-induced mucositis in patients undergoing HSCT. METHODS: Clinical data of 278 patients who underwent HSCT between May 2020 and November 2021 were retrospectively analysed. They were divided into a control group (138) and a probiotic group (140) according to whether they took viable Bifidobacterium tablets. First, we analysed the baseline data of the two groups. Then, we compared the incidence, severity and duration of mucositis between the two groups by using Mann-Whitney U test, chi-square test and Fisher's exact test according to the type of data. In order to exclude the influence of confounding factors, we further evaluated the efficacy of oral probiotics in preventing oral mucositis by Binary logistic regression analysis. RESULTS: The use of viable Bifidobacterium tablets markedly reduced the incidence of oral mucositis (OM) (62.9% vs. 81.2%, p = 0.001) and mainly reduced the incidence of grades 1-2 OM (74.6% vs. 58.6%, p = 0.005). There was no significant difference in the incidence of severe (grades 3-4) OM between the two groups (6.5% vs. 4.3%, p = 0.409). The median duration of OM was shorter in the probiotic group (10 vs. 12 days, p = 0.037). The incidence and duration of diarrhoea did not differ between the two groups. Moreover, the use of viable Bifidobacterium tablets had no influence on engraftment. CONCLUSIONS: Our results suggested that viable Bifidobacterium tablets could effectively reduce the incidence of grades 1-2 OM and duration of OM during the transplant process without affecting the outcome of HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucosite , Estomatite , Humanos , Estudos Retrospectivos , Mucosite/etiologia , Mucosite/prevenção & controle , Bifidobacterium , Estomatite/epidemiologia , Estomatite/etiologia , Estomatite/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos
9.
Nano Lett ; 22(17): 6866-6876, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-35926215

RESUMO

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (Teff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/Teff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α3ß1 integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures Teff cells via the activatable α4ß1 integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.


Assuntos
Neoplasias , Microambiente Tumoral , Animais , Imunomodulação , Integrinas , Camundongos , Neoplasias/tratamento farmacológico , Linfócitos T
10.
J Cell Physiol ; 237(9): 3661-3670, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35853150

RESUMO

AZD1208, a pan-inhibitor that can effectively inhibit PIM kinase, is used for the treatment of advanced solid tumors and malignant lymphomas. Numerous studies have proved its curative effects while its potential cellular toxicity on reproduction was still little known. In this study, we investigated the toxic effects of AZD1208 on mouse oocytes. The results showed that AZD1208 treatment did not affect meiotic resumption, but postponed oocyte maturation as indicated by delayed first polar body extrusion. Further mechanistic study showed that AZD1208 treatment delayed spindle assembly. In addition, we found that oocytes treated with AZD1208 showed mitochondrial dysfunction. Abnormal mitochondrial clusters with decreased mitochondrial membrane potential were observed in oocytes during incubation in vitro. Moreover, increased oxidative stress was observed by testing the level of reactive oxygen species. In summary, our results suggest that AZD1208 treatment influences oocyte meiotic progression by causing mitochondrial dysfunctions and subsequent delayed spindle assembly.


Assuntos
Compostos de Bifenilo , Oócitos , Animais , Compostos de Bifenilo/farmacologia , Meiose , Camundongos , Mitocôndrias , Oócitos/metabolismo , Tiazolidinas/metabolismo
11.
Sensors (Basel) ; 22(10)2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35632177

RESUMO

Tests for SARS-CoV-2 are crucial for the mass surveillance of the incidence of infection. The long waiting time for classic nucleic acid test results highlights the importance of developing alternative rapid biosensing methods. Herein, we propose a fiber-optic biolayer interferometry-based biosensor (FO-BLI) to detect SARS-CoV-2 spike proteins, extracellular domain (ECD), and receptor-binding domain (RBD) in artificial samples in 13 min. The FO-BLI biosensor utilized an antibody pair to capture and detect the spike proteins. The secondary antibody conjugated with horseradish peroxidase (HRP) reacted with the enzyme substrate for signal amplification. Two types of substrates, 3,3'-diaminobenzidine (DAB) and an advanced 3-Amino-9-ethylcarbazole (i.e., AMEC), were applied to evaluate their capabilities in enhancing signals and reaching high sensitivity. After careful comparison, the AMEC-based FO-BLI biosensor showed better assay performance, which detected ECD at a concentration of 32-720 pM and RBD of 12.5-400 pM in artificial saliva and serum, respectively. The limit of detection (LoD) for SARS-CoV-2 ECD and RBD was defined to be 36 pM and 12.5 pM, respectively. Morphology of the metal precipitates generated by the AMEC-HRP reaction in the fiber tips was observed using field emission scanning electron microscopy (SEM). Collectively, the developed FO-BLI biosensor has the potential to rapidly detect SARS-CoV-2 antigens and provide guidance for "sample-collect and result-out on-site" mode.


Assuntos
Técnicas Biossensoriais , COVID-19 , Glicoproteína da Espícula de Coronavírus , COVID-19/diagnóstico , Humanos , Glicoproteínas de Membrana/química , SARS-CoV-2 , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
12.
Cancer Immunol Immunother ; 69(11): 2305-2317, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32506263

RESUMO

BACKGROUND: Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy. RESULTS: Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. CONCLUSIONS: The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Neoplasias da Bexiga Urinária , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Humanos , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
13.
Proc Natl Acad Sci U S A ; 114(45): E9474-E9482, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29078316

RESUMO

Uncoupling protein 1 (UCP1) is localized on the inner mitochondrial membrane and generates heat by uncoupling ATP synthesis from proton transit across the inner membrane. UCP1 is a key element of nonshivering thermogenesis and is most likely important in the regulation of body adiposity. Pigs (Artiodactyl family Suidae) lack a functional UCP1 gene, resulting in poor thermoregulation and susceptibility to cold, which is an economic and pig welfare issue owing to neonatal mortality. Pigs also have a tendency toward fat accumulation, which may be linked to their lack of UCP1, and thus influences the efficiency of pig production. Here, we report application of a CRISPR/Cas9-mediated, homologous recombination (HR)-independent approach to efficiently insert mouse adiponectin-UCP1 into the porcine endogenous UCP1 locus. The resultant UCP1 knock-in (KI) pigs showed an improved ability to maintain body temperature during acute cold exposure, but they did not have alterations in physical activity levels or total daily energy expenditure (DEE). Furthermore, ectopic UCP1 expression in white adipose tissue (WAT) dramatically decreased fat deposition by 4.89% (P < 0.01), consequently increasing carcass lean percentage (CLP; P < 0.05). Mechanism studies indicated that the loss of fat upon UCP1 activation in WAT was linked to elevated lipolysis. UCP1 KI pigs are a potentially valuable resource for agricultural production through their combination of cold adaptation, which improves pig welfare and reduces economic losses, with reduced fat deposition and increased lean meat production.


Assuntos
Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiologia , Sistemas CRISPR-Cas/fisiologia , Termogênese/fisiologia , Proteína Desacopladora 1/metabolismo , Adiposidade/fisiologia , Animais , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/fisiologia , Temperatura Baixa , Metabolismo Energético/fisiologia , Feminino , Lipólise/fisiologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Suínos
14.
Nanomedicine ; 20: 102004, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31055076

RESUMO

Patients with acute myeloid leukemia have a very poor prognosis related to a high rate of relapse and drug-related toxicity. The ability of leukemia stem cells (LSCs) to survive chemotherapy is primarily responsible for relapse, and eliminating LSCs is ultimately essential for cure. We developed novel disulfide-crosslinked CLL1-targeting micelles (DC-CTM), which can deliver high concentrations of daunorubicin (DNR) into both bulk leukemia cells and LSCs. Compared to free DNR, DC-CTM-DNR had a longer half-life, increased DNR area under the curve concentration by 11-fold, and exhibited a superior toxicity profile. In patient-derived AML xenograft models, DC-CTM-DNR treatment led to significant decreases in AML engraftment and impairment of secondary transplantation compared to control groups. Collectively, we demonstrate superior anti-LSC/AML efficacy, and preferable pharmacokinetic and toxicity profiles of DC-CTM-DNR compared to free DNR. DC-CTM-DNR has the potential to significantly improve treatment outcomes and reduce therapy-related morbidity and mortality for patients with AML.


Assuntos
Daunorrubicina/uso terapêutico , Lectinas Tipo C/química , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Micelas , Nanopartículas/química , Células-Tronco Neoplásicas/patologia , Animais , Reagentes de Ligações Cruzadas/química , Daunorrubicina/farmacocinética , Daunorrubicina/toxicidade , Dissulfetos/química , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Células-Tronco Neoplásicas/efeitos dos fármacos , Ratos Sprague-Dawley
15.
Nanomedicine ; 14(3): 789-799, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29317342

RESUMO

Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days. PDX tumors could be synergistically eradicated with a single intravenous injection of NP-AAG followed by multiple light treatments within 7 days. NP-AAG mediated treatment could not only specifically deliver 17AAG and produce heat and reactive oxygen species, but also more effectively inhibit essential bladder cancer essential signaling molecules like Akt, Src, and Erk, as well as HIF-1α induced by photo-therapy. This multifunctional nanoplatform has high clinical relevance and could dramatically improve management for bladder cancers with minimal toxicity.


Assuntos
Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Imagem Molecular/métodos , Nanopartículas/administração & dosagem , Fotoquimioterapia , Porfirinas/administração & dosagem , Neoplasias da Bexiga Urinária/terapia , Idoso de 80 Anos ou mais , Animais , Benzoquinonas/administração & dosagem , Benzoquinonas/química , Sobrevivência Celular , Terapia Combinada , Feminino , Humanos , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/química , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , Nanopartículas/química , Porfirinas/química , Porfirinas/efeitos da radiação , Espécies Reativas de Oxigênio , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Cancer ; 141(3): 604-613, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28437852

RESUMO

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts-the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [14 C]carboplatin-DNA monoadduct levels in the cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R2 = 0.95, p < 0.0001) and correlated with IC50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p = 0.02 and p = 0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK) and [14 C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [14 C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [14 C]carboplatin formulation for the microdose was 107 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Additional accruals are required to significantly correlate adduct levels with response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina , Carcinoma Pulmonar de Células não Pequenas/patologia , Adutos de DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Idoso , Radioisótopos de Carbono/farmacocinética , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Distribuição Tecidual
17.
Hum Genet ; 136(11-12): 1463-1475, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29094203

RESUMO

Human Waardenburg syndrome 2A (WS2A) is a dominant hearing loss (HL) syndrome caused by mutations in the microphthalmia-associated transcription factor (MITF) gene. In mouse models with MITF mutations, WS2A is transmitted in a recessive pattern, which limits the study of hearing loss (HL) pathology. In the current study, we performed ENU (ethylnitrosourea) mutagenesis that resulted in substituting a conserved lysine with a serine (p. L247S) in the DNA-binding domain of the MITF gene to generate a novel miniature pig model of WS2A. The heterozygous mutant pig (MITF +/L247S) exhibits a dominant form of profound HL and hypopigmentation in skin, hair, and iris, accompanied by degeneration of stria vascularis (SV), fused hair cells, and the absence of endocochlear potential, which indicate the pathology of human WS2A. Besides hypopigmentation and bilateral HL, the homozygous mutant pig (MITF L247S/L247S) and CRISPR/Cas9-mediated MITF bi-allelic knockout pigs both exhibited anophthalmia. Three WS2 patients carrying MITF mutations adjacent to the corresponding region were also identified. The pig models resemble the clinical symptom and molecular pathology of human WS2A patients perfectly, which will provide new clues for better understanding the etiology and development of novel treatment strategies for human HL.


Assuntos
Modelos Animais de Doenças , Etilnitrosoureia/toxicidade , Perda Auditiva/genética , Fator de Transcrição Associado à Microftalmia/genética , Mutação , Síndrome de Waardenburg/genética , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Feminino , Perda Auditiva/induzido quimicamente , Perda Auditiva/patologia , Humanos , Masculino , Fator de Transcrição Associado à Microftalmia/antagonistas & inibidores , Mutagênese , Mutagênicos/toxicidade , Homologia de Sequência , Suínos , Porco Miniatura , Síndrome de Waardenburg/induzido quimicamente , Síndrome de Waardenburg/patologia
18.
Reproduction ; 151(1): 39-49, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26604326

RESUMO

Accumulating evidence suggests that faulty epigenetic reprogramming leads to the abnormal development of cloned embryos and results in the low success rates observed in all mammals produced through somatic cell nuclear transfer (SCNT). The aberrant methylation status of H3K9me and H3K9me2 has been reported in cloned mouse embryos. To explore the role of H3K9me2 and H3K9me in the porcine somatic cell nuclear reprogramming, BIX-01294, known as a specific inhibitor of G9A (histone-lysine methyltransferase of H3K9), was used to treat the nuclear-transferred (NT) oocytes for 14-16 h after activation. The results showed that the developmental competence of porcine SCNT embryos was significantly enhanced both in vitro (blastocyst rate 16.4% vs 23.2%, P<0.05) and in vivo (cloning rate 1.59% vs 2.96%) after 50 nm BIX-01294 treatment. BIX-01294 treatment significantly decreased the levels of H3K9me2 and H3K9me at the 2- and 4-cell stages, which are associated with embryo genetic activation, and increased the transcriptional expression of the pluripotency genes SOX2, NANOG and OCT4 in cloned blastocysts. Furthermore, the histone acetylation levels of H3K9, H4K8 and H4K12 in cloned embryos were decreased after BIX-01294 treatment. However, co-treatment of activated NT oocytes with BIX-01294 and Scriptaid rescued donor nuclear chromatin from decreased histone acetylation of H4K8 that resulted from exposure to BIX-01294 only and consequently improved the preimplantation development of SCNT embryos (blastocyst formation rates of 23.7% vs 21.5%). These results indicated that treatment with BIX-01294 enhanced the developmental competence of porcine SCNT embryos through improvements in epigenetic reprogramming and gene expression.


Assuntos
Azepinas/farmacologia , Reprogramação Celular/efeitos dos fármacos , Clonagem de Organismos/métodos , Epigênese Genética , Técnicas de Transferência Nuclear/veterinária , Quinazolinas/farmacologia , Sus scrofa , Animais , Blastocisto/química , Blastocisto/fisiologia , Reprogramação Celular/genética , Técnicas de Cultura Embrionária/veterinária , Transferência Embrionária/veterinária , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Fator 3 de Transcrição de Octâmero/genética , Células-Tronco Pluripotentes , RNA Mensageiro/análise , Fatores de Transcrição SOXB1/genética
19.
Tumour Biol ; 37(8): 11429-41, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27002617

RESUMO

Despite advances in the roles of long non-coding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) in cancer biology, which has been identified as a tumor suppressor by regulating cell proliferation, apoptosis, migration, invasion, cell cycle, and tumor growth, the function of TUSC7 in hepatocellular carcinoma (HCC) remains unknown. In this study, we observed that the expression of TUSC7 was immensely decreased in HCC. Clinically, the lower expression of TUSC7 predicted poorer survival and may be an independent risk factor for HCC patients. Moreover, TUSC7 inhibited cell metastasis, invasion, and epithelial-to-mesenchymal transformation (EMT) through competitively binding miR-10a. Furthermore, we found that TUSC7 could decrease the expression of Eph tyrosine kinase receptor A4 (EphA4), a downstream target of miR-10a as well as an EMT suppressor, through TUSC7-miR-10a-EphA4 axis. Taken together, we demonstrate that TUSC7 suppresses EMT through the TUSC7-miR-10a-EphA4 axis, which may be a potential target for therapeutic intervention in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Receptor EphA4/biossíntese , Receptor EphA4/genética , Transfecção
20.
Chem Res Toxicol ; 29(11): 1843-1848, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27657672

RESUMO

Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. We determined whether subtherapeutic "microdoses" of gemcitabine are incorporated into DNA at levels that correlate to drug cytotoxicity. A pair of nearly isogenic bladder cancer cell lines differing in resistance to several chemotherapy drugs were treated with various concentrations of 14C-labeled gemcitabine for 4-24 h. Drug incorporation into DNA was determined by accelerator mass spectrometry. A mechanistic analysis determined that RRM2, a DNA synthesis protein and a known resistance factor, substantially mediated gemcitabine toxicity. These results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Antineoplásicos/farmacocinética , Área Sob a Curva , Linhagem Celular Tumoral , Reparo do DNA , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Gencitabina
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