RESUMEN
Nanomedicine has emerged as a promising avenue for advancing cancer treatment, but the challenge of mitigating its in vivo side effects necessitates the development of innovative structures and materials. Recent investigation has unveiled nanogels as particularly compelling candidates, characterized by a porous, three-dimensional network architecture that exhibits exceptional drug loading capacity. Beyond this, nanogels boast a substantial specific surface area and can be tailored with specific chemical functionalities. Consequently, nanogels are frequently engineered as a multi-modal synergistic platform for combating cancer, wherein photothermal therapy stands out due to its capacity to penetrate deep tissues and achieve localized tumor eradication through the application of elevated temperatures. In this review, we delve into the synthesis of diverse varieties of photothermal nanogels capable of controlled drug release triggered by either chemical or physical stimuli. It also summarizes their potential for synergistic integration with photothermal therapy alongside other therapeutic modalities to realize effective tumor ablation. Moreover, we analyze the primary mechanisms underlying the contribution of photothermal nanogels to cancer treatment while underscoring their adeptness in regulating therapeutic temperatures for repairing bone defects resulting from tumor-associated trauma. Envisioned as an auspicious strategy in the realm of cancer therapy, photothermal nanogels hold promise for furnishing controlled drug delivery and precise thermal ablation capabilities.
RESUMEN
BACKGROUND: Upregulation of SMC1A (Structural maintenance of chromosomes 1A) is linked with many types of cancer and its oncogenic function, which has been associated with crucial cellular mechanisms (cell division, cell cycle checkpoints regulation and DNA repair). Recent studies have shown that SMC1A was involved in breast cancer, although the exact mechanisms of SMC1A remain to be determined. METHODS: Using The Cancer Genome Atlas (TCGA) database, we examined SMC1A expression and its relation to other genes, including FOXM1 and STMN1. Short hairpin RNA was used to subsequently examine the biological roles of SMC1A in MDA-MB-231 and MDA-MB-468 cell lines. Bioinformatics were performed to identify the SMC1A-related gene FOXM1. RESULTS: Here, we used the TCGA database to show that SMC1A is overexpressed in breast cancer. Later investigations showed SMC1A's role in breast cancer cell survival, apoptosis and invasion. Using bioinformatics and western blot assays, we confirmed that FOXM1 acted as the downstream of SMC1A, and SMC1A knockdown significantly downregulated the FOXM1 expression via the AKT signal pathway. Interestingly, the inhibition effects induced by SMC1A downregulation could be reversed by FOXM1 overexpression. In the clinic, SMC1A expression is favorably linked with FOXM1 expression in breast cancer tumor tissues. CONCLUSIONS: Collectively, our results not only enhance our knowledge of SMC1A's molecular pathways in breast cancer, but also suggest a potential new therapeutic target.
Asunto(s)
Neoplasias de la Mama , Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona , Transducción de Señal , Femenino , Humanos , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/genética , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estatmina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Ciclo Celular/genéticaRESUMEN
The options for treating metastatic colorectal cancer are limited after failure of second-line chemotherapy. In this case report, we present the outcome of a 59-year-old male patient who underwent radical resection for rectal cancer in November 2018 and hepatectomy for liver metastasis in January 2021. His metastatic rectal cancer presented a remarkable response to the combination of fruquintinib and toripalimab after the failure of multiline chemotherapies. The patient achieved partial response within 3 months and clinical complete response of pulmonary masses within 12 months. As of now, the patient maintains a good quality of life, and the progression-free survival has been more than 17 months. In conclusion, the combination of fruquintinib and PD-1 inhibitors can improve the prognosis of metastatic colorectal cancer.
The available antitumor treatment options are very limited for patients with advanced colorectal cancer (a type of colon cancer), especially after multiple treatments have already failed. Often for patients in this situation, the available treatments do not work very well and the patients are not predicted to live very long. However, in this paper we report a case of successful treatment of this condition. A 59-year-old male patient with advanced colorectal cancer was treated with the combination therapy of two different immunotherapy drugs, fruquintinib and toripalimab, after multiple other treatments had failed. Currently, the survival time of this patient is over 17 months, and he has a satisfactory quality of life.
Asunto(s)
Neoplasias Colorrectales , Neoplasias del Recto , Masculino , Humanos , Persona de Mediana Edad , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Calidad de VidaRESUMEN
The management of root caries remains a challenge for clinicians due to its unique anatomical location and structure. There is increasing interest in utilising artificial root caries lesions to develop new strategies for remineralisation. An ideal protocol has not yet been agreed upon. The aim of this review is to provide a structured overview of previously reported in vitro root caries models. The literature was screened and mined for information mainly on substrate selection, model systems utilised, and variables used in the models. Human roots (60%) were the most frequently used substrates, followed by bovine roots (40%). Chemical models (69%) were the most frequently utilised model systems, followed by microbiological models (27%), to form root caries lesions. Acetate buffer solution (80%), pH 5.0 or above (40%), and a demineralisation time of five days (25%) were the common variables used in the chemical systems, while mono-species biofilm was most frequently used (73%) in microbiological models and Streptococcus mutans was the most common bacterial strain utilised in these models (80%). This review highlights the variability amongst the experimental approaches, discusses the advantages and limitations of these approaches, and emphasises that standardisation of experimental conditions along with sustained research will benefit root caries research.
RESUMEN
Neutrophil extracellular traps (NETs) play a crucial role in breast cancer metastasis. However, the therapeutic target of NETs in breast cancer metastasis is still unknown. Using a natural metabolite library and single-cell sequencing data analysis, we identified resveratrol (RES), a polyphenolic natural phytoalexin, and agonist of silent information regulator-1 (SIRT1) that suppressed NETs formation after cathepsin C (CTSC) treatment. In vivo, RES significantly hindered breast cancer metastasis in a murine orthotopic 4T1 breast cancer model. Serum levels of myeloperoxidase-DNA and neutrophil elastase-DNA in mouse breast cancer model were significantly lower after RES treatment. Correspondingly, the tumour infiltrated CD8+T cells in the lungs increased after the treatment. Mechanistically, RES targets SIRT1 in neutrophils and significantly inhibits the citrullination of histones H3, which is essential for chromatin decondensation and NETs formation. Furthermore, we identified that the NETs were suppressed by RES in bone marrow neutrophils after CTSC treatment, while specific deficiency of SIRT1 in neutrophils promoted NETs formation and breast cancer to lung metastasis. Thus, our results revealed that RES could be potentially identified as a viable therapeutic drug to prevent neutrophil cell death and breast cancer metastasis.
Asunto(s)
Trampas Extracelulares , Neoplasias Pulmonares , Animales , Ratones , Trampas Extracelulares/metabolismo , Resveratrol/farmacología , Sirtuina 1/metabolismo , Pulmón , Neoplasias Pulmonares/patología , ADNRESUMEN
BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a neoplasm of the salivary gland that causes 3.6% of salivary gland tumors and 12% of salivary gland malignancies. Its prognosis is determined by the histological progression beyond the adenoma capsule. CXPA is thought to be a malignant transformation of a primary or recurrent pleomorphic adenoma and is associated with both benign and malignant lesions. Salivary gland cancers represent a rare heterogeneous group of neoplasms with complex clinicopathological characteristics and distinct biological behavior. CASE DESCRIPTION: This case report summarizes the treatment of a 57-year-old male patient with CXPA of the left parotid gland, harboring HER2 amplification with poor prognosis. The overall survival of the patient has been > 3.5 years. The application and outcome of an immune checkpoint inhibitor and targeted therapy combination regimens in the treatment of CXPA carcinoma are discussed. CONCLUSION: Targeted therapy combined with immunotherapy has long-term clinical benefits and targeted therapy which has a high clinical response rate (immunotherapy + dual-targeting three-drug regimens) may present an ideal choice for the treatment of patients with rare and/or refractory tumors without compromising patient safety.
Asunto(s)
Adenocarcinoma , Adenoma Pleomórfico , Neoplasias de las Glándulas Salivales , Humanos , Masculino , Persona de Mediana Edad , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/terapia , Adenoma Pleomórfico/patología , Mutación , Cuidados Paliativos , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/genética , Genes erbB-2/genéticaRESUMEN
Large oral bone defects require grafting of bone blocks rather than granules to give physically robust, biocompatible and osteoconductive regeneration. Bovine bone is widely accepted as a source of clinically appropriate xenograft material. However, the manufacturing process often results in both reduced mechanical strength and biological compatibility. The aim of this study was to assess bovine bone blocks at different sintering temperatures and measure the effects on mechanical properties and biocompatibility. Bone blocks were divided into four groups; Group 1: Control (Untreated); Group 2: Initial boil for 6 h; Group 3: Boil 6 h followed by sintering at 550 °C for 6 h; Group 4: Boil 6 h followed by sintering at 1100 °C for 6 h. Samples were assessed for their purity, crystallinity, mechanical strength, surface morphology, chemical composition, biocompatibility and clinical handling properties. Statistical analysis was performed using one-way ANOVA and post-hoc Tukey's tests for normally distributed and Friedman test for abnormally distributed quantitative data from compression tests and PrestoBlue™ metabolic activity tests. The threshold for statistical significance was set at p < 0.05. The results showed that higher temperature sintering (Group 4) removed all organic material (0.02% organic components and 0.02% residual organic components remained) and increased crystallinity (95.33%) compared to Groups 1-3. All test groups (Group 2-4) showed decreased mechanical strength (MPa: 4.21 ± 1.97, 3.07 ± 1.21, 5.14 ± 1.86, respectively) compared with raw bone (Group 1) (MPa: 23.22 ± 5.24, p <0.05), with micro-cracks seen under SEM in Groups 3 and 4. Group 4 had the highest biocompatibility (p < 0.05) with osteoblasts as compared to Group 3 at all time points in vitro. Clinical handling tests indicated that Group 4 samples could better withstand drilling and screw placement but still demonstrated brittleness compared to Group 1. Hence, bovine bone blocks sintered at 1100 °C for 6 h resulted in highly pure bone with acceptable mechanical strength and clinical handling, suggesting it is a viable option as a block grafting material.
RESUMEN
Neutrophil extracellular traps (NETs) are network structures comprised of decondensed DNA strands coated with granule proteins. There have been three types of NETs recorded. NETs have been discovered concerning the progression of some malignancies, including gastric cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, colorectal cancer, glioblastoma, diffuse large B cell lymphoma (DLBCL), and lung cancer, among others. In various methods, tumors encourage the formation of NETs, and NETs, in turn, promote tumor growth. NETs can stimulate primary tumor cell proliferation, suppress immune cells to create a tumor-friendly immune microenvironment, and stimulate epithelial-mesenchymal transition (EMT). NETs significantly promote liver and lung metastasis, possibly by altering vascular permeability, inducing cytoskeleton rearrangement and directional cell migration, and reawakening dormant cancer cells. NETs are therapeutically promising targets for cancer patients. Cancer patients may benefit from anti-NETs therapy, especially when combined with immune checkpoint inhibitors.
RESUMEN
BACKGROUND: ß-elemene is known to play a critical role in tumorigenesis as well as tyrosine kinase inhibitor (TKI) resistance in lung cancer. However, the biological function and molecular mechanism remain largely unknown. METHODS: In this study, the common genes involved in gefitinib resistance and ß-elemene were identified using bioinformatic analysis. The expression of FBP1 was examined by qRT-PCR and Western blot analysis. Cell proliferation, flow cytometry, clone formation and IC50 assays were performed to assess the effects of ß-elemene and FBP1. Western blot analysis was used to evaluate apoptosis-related gene expression. Finally, in vivo experiments were conducted to assess the crucial role of FBP1 in gefitinib-resistant HCC827/GR cells in nude mice. RESULTS: Screening analysis demonstrated that fructose-1,6-bisphosphatase (FBP1) was induced by ß-elemene and downregulated in gefitinib-resistant lung cells. Functionally, overexpression of FBP1 inhibited proliferation and gefitinib resistance and promoted apoptosis of PC9/GR and HCC827/GR cells in vitro. Mechanistically, FBP1 impeded the nuclear translocation of p-STAT3. The FBP1/STAT3 axis was required for FBP1-mediated apoptosis-related gene expression. In vivo experiments further confirmed the enhanced effects of FBP1 on lung cancer cell sensitivity to gefitinib. CONCLUSION: Our research indicated that ß-elemene suppressed proliferation and enhanced sensitivity to gefitinib by inducing apoptosis through the FBP1/STAT3 axis in gefitinib-resistant lung cancer cells.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos/genética , Gefitinib/farmacología , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones DesnudosRESUMEN
The translation of nanoparticles in cancer treatment is limited by their low drug-loading capacity, poor colloidal stability, insufficient tumor penetration, and uncontrolled drug release. Herein, gelatin/nanochitosan/doxorubicin nanoparticles (GND) are developed by crosslinking nanochitosan (NCT) with gelatin for doxorubicin delivery. The hydrophilicity and stability properties of GND allow it to be protected and have a long circulation time in blood. The GND formulation exhibited shedding and triggered release effects as well as improved colloidal stability. When reaching the tumor site, matrix metallopeptidase-2 (MMP-2) from the tumor environment degrades gelatin from 178-nm GND to release smaller 4 nm nanochitosan/doxorubicin (ND) nanoparticles for deep tumor penetration and efficient tumor cell endocytosis. Following endocytosis by tumor cells, the intracellular low pH and MMP-2 further trigger doxorubicin release, resulting in superior inhibitory capacity against cancer cells. Using a mouse tumor-bearing model, the superior anticancer activity and good in vivo biocompatibility of GND were verified. The rational design of tumor-penetrating GND enables MMP-2/pH sequentially triggered intelligent drug delivery, providing a practical approach for anticancer therapy.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Liberación de Fármacos , Gelatina/química , Metaloproteinasa 2 de la Matriz/metabolismo , Doxorrubicina , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/patología , Portadores de Fármacos/uso terapéutico , Línea Celular Tumoral , Concentración de Iones de HidrógenoRESUMEN
Nanoparticles can promote the accumulation of drugs in tumors. However, they find limited clinical applications because they cannot easily penetrate the stroma of cancer tissues, and it is difficult to control drug release. We developed a multiresponse multistage drug-delivery nanogel with improved tumor permeability and responsiveness to the tumor microenvironment for the controlled delivery of anticancer agents. For this purpose, â¼100 nm multistage drug delivery nanogels with pH, redox, near-infrared stimulation, and enzyme responsiveness were grown in situ using 20 nm gold nanoparticles (AuNPs) via an emulsion-aiding crosslinking technique with cysteine crosslinker. An alginate cysteine AuNP (ACA) nanocarrier can efficiently load the cationic drug doxorubicin (DOX) to produce a multistage drug delivery nanocarrier (DOX@ACA). DOX@ACA can maintain the slow release of DOX and reduce its toxicity. In cancer tissues, the high pH and reductase microenvironment combined with the in vitro delivery of alginate and near-infrared light drove drug release. The developed nanoparticles effectively inhibited cancer cells, and in vivo evaluations showed that they effectively enhanced antitumor activity while having negligible in vivo toxicity to major organs.
Asunto(s)
Antineoplásicos , Nanopartículas del Metal , Nanopartículas , Alginatos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cisteína , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Emulsiones , Oro , Concentración de Iones de Hidrógeno , Nanogeles , Sistema de Administración de Fármacos con Nanopartículas , OxidorreductasasRESUMEN
Tumor-associated macrophages (TAMs), one of the dominating constituents of tumor microenvironment, are important contributors to cancer progression and treatment resistance. Therefore, regulation of TAMs polarization from M2 phenotype towards M1 phenotype has emerged as a new strategy for tumor immunotherapy. Herein, we successfully initiated antitumor immunotherapy by inhibiting TAMs M2 polarization via autophagy intervention with polyethylene glycol-conjugated gold nanoparticles (PEG-AuNPs). PEG-AuNPs suppressed TAMs M2 polarization in both in vitro and in vivo models, elicited antitumor immunotherapy and inhibited subcutaneous tumor growth in mice. As demonstrated by the mRFP-GFP-LC3 assay and analyzing the autophagy-related proteins (LC3, beclin1 and P62), PEG-AuNPs induced autophagic flux inhibition in TAMs, which is attributed to the PEG-AuNPs induced lysosome alkalization and membrane permeabilization. Besides, TAMs were prone to polarize towards M2 phenotype following autophagy activation, whereas inhibition of autophagic flux could reduce the M2 polarization of TAMs. Our results revealed a mechanism underlying PEG-AuNPs induced antitumor immunotherapy, where PEG-AuNPs reduce TAMs M2 polarization via induction of lysosome dysfunction and autophagic flux inhibition. This study elucidated the biological effects of nanomaterials on TAMs polarization and provided insight into harnessing the intrinsic immunomodulation capacity of nanomaterials for effective cancer treatment.
RESUMEN
This study aimed to comprehensively analyze the effect of empty-nest on mental health and behaviors of the older population and explore the urban-rural differences. Data from the Cohort of Older People Health and Environment Controllable Factors were used, including 1071 older people aged 60 or over from a rural and an urban. Mental health, daily life behaviors, chronic physical diseases, and activities of daily living were evaluated. Logistic regression was used. The prevalence of empty-nest in older people was 55.0% in urban and 58.7% in rural. The empty-nest older people in urban were more likely to participate in physical exercise (OR[95%CI]: 1.55[1.03-2.31]), while the empty-nest older people in rural had lower rate of smoking (OR[95%CI]: 0.46[0.28-0.76]) and religious belief (OR[95%CI]: 1.61[1.01-2.58]), and higher prevalence of depression (OR[95%CI]: 1.55[1.03-2.35]) and higher level of total cholesterol (OR[95%CI]: 1.51[1.03-2.19]) compared with the non-empty-nest older people. In conclusion, the prevalence of empty-nest in older people was high both in rural and urban in China. Empty-nest exerts greater influences on the older people in rural than in urban, which should be given more attention, especially the depression and high total cholesterol.
Asunto(s)
Actividades Cotidianas , Salud Mental , Anciano , China/epidemiología , Colesterol , Enfermedad Crónica , Depresión/epidemiología , Conductas Relacionadas con la Salud , Humanos , Población Rural , Encuestas y CuestionariosRESUMEN
AIMS: Dipeptidyl peptidase-4 inhibitor (DPP4i), a new antidiabetic agent, is reported to affect the progression of chronic liver diseases. The study aims to investigate the effects of DPP4i on contractile response, splanchnic hemodynamics, and portal pressure in cirrhotic rats. MATERIALS AND METHODS: A rat model of carbon tetrachloride-induced cirrhosis was used in this study. Sixteen rats with cirrhosis were treated with DDP4i sitagliptin for 5 consecutive days. Portal and systemic pressures and portal blood flow were measured. Mesenteric arterioles were isolated, and concentration-response curves to norepinephrine (NE) were evaluated. The expression of NADPH oxidase (Nox)1, Nox2, Nox4, and soluble epoxide hydrolase (sEH) were detected. Reactive oxygen species (ROS) and epoxyeicosatrienoic acid (EET) levels in mesenteric arteries were also measured. KEY FINDINGS: In cirrhotic rats, sitagliptin significantly reduced portal blood flow and portal pressure without effects on systemic pressure and reversed the decreased response of mesenteric arterioles to NE in an endothelium-dependent manner. Sitagliptin suppressed the increased Nox4 expression and ROS production. In vitro studies showed that Nox4 inhibitor enhanced arteriolar response to NE and reduced hydrogen peroxide (H2O2) level in cirrhotic rats. Sitagliptin also reduced EET levels and increased sEH expression of mesenteric vessels. Pre-incubation with sEH inhibitor in vitro reversed sitagliptin-induced augmentation of response to NE in cirrhotic rats. SIGNIFICANCE: DPP4 inhibition by sitagliptin in vivo has beneficial effects on portal hypertension in cirrhotic rats through normalizing arterial hypocontractility. DDP4 inhibitor may be a novel strategy in the treatment of patients with cirrhosis and portal hypertension.
Asunto(s)
Arterias/fisiopatología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipertensión Portal/complicaciones , Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Cirrosis Hepática/fisiopatología , Vasoconstricción , Animales , Arterias/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hemodinámica/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Hipertensión Portal/fisiopatología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiopatología , NADPH Oxidasa 4/metabolismo , Norepinefrina/farmacología , Ratas Sprague-Dawley , Fosfato de Sitagliptina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
OBJECTIVE: On May 2, 2017, an outbreak of unexplained fever with rashes was reported in Lu'an, China. In this study, we aimed to identify the possible pathogens, epidemiological characteristics, and risk factors of this outbreak. METHODS: We conducted descriptive field epidemiological studies. Blood samples were tested using an indirect immunofluorescence assay for Rickettsia rickettsii antibody, and nested polymerase chain reaction and gene sequencing assays were performed. RESULTS: We recruited 39 cases who had symptomatic onset from April 20 to June 8, 2017. Among these, 9 were suspected cases, 18 were probable cases, and 12 were confirmed cases. No one died. The main clinical manifestations were fever (100%), rash (100%), fatigue (97.3%), myalgia (83.8%), and anorexia (83.8%). None of the patients died. Thirty-seven patients who were treated with antibiotics during hospitalization showed significant improvement. The cases were distributed across 14 townships in 2 counties. The median age was 59 (43.0-81.0) years, of which 93.3% had a history of tea picking (28/30), and 77.3% (17/22) had a history of tick bites. The mean incubation period was 5.0 days (2.0-13.0 days). Serum IgG titers were higher in convalescent patients than in the general population (p = 0.016). Phylogenetic analysis revealed that the ompA sequences of Rickettsia sp. Lu'an-2018 had an 86.8%-99.0% sequence identity with the 23 strains of Rickettsia found worldwide. CONCLUSIONS: This was the first reported outbreak of an undetermined species of a human infection with the spotted fever group of Rickettsia in China, which might be caused by ticks biting local residents when picking tea.
Asunto(s)
Rickettsia , Fiebre Maculosa de las Montañas Rocosas , Adulto , Anciano , Anciano de 80 o más Años , Animales , Mordeduras y Picaduras , China/epidemiología , Brotes de Enfermedades , Humanos , Persona de Mediana Edad , Filogenia , Rickettsia/genética , Fiebre Maculosa de las Montañas Rocosas/epidemiología , GarrapatasRESUMEN
Metabolism negotiates cell-endogenous requirements of energy, nutrients and building blocks with the immediate environment to enable various processes, including growth and differentiation. While there is an increasing number of examples of crosstalk between metabolism and chromatin, few involve uptake of exogenous metabolites. Solute carriers (SLCs) represent the largest group of transporters in the human genome and are responsible for the transport of a wide variety of substrates, including nutrients and metabolites. We aimed to investigate the possible involvement of SLC-mediated solutes uptake and cellular metabolism in regulating cellular epigenetic states. Here, we perform a CRISPR-Cas9 transporter-focused genetic screen and a metabolic compound library screen for the regulation of BRD4-dependent chromatin states in human myeloid leukaemia cells. Intersection of the two orthogonal approaches reveal that loss of transporters involved with purine transport or inhibition of de novo purine synthesis lead to dysfunction of BRD4-dependent transcriptional regulation. Through mechanistic characterization of the metabolic circuitry, we elucidate the convergence of SLC-mediated purine uptake and de novo purine synthesis on BRD4-chromatin occupancy. Moreover, adenine-related metabolite supplementation effectively restores BRD4 functionality on purine impairment. Our study highlights the specific role of purine/adenine metabolism in modulating BRD4-dependent epigenetic states.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas de Transporte de Nucleósidos/metabolismo , Purinas/metabolismo , Proteínas Transportadoras de Solutos/metabolismo , Factores de Transcripción/metabolismo , Adenina/metabolismo , Vías Biosintéticas , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular , Cromatina/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Proteínas de Transporte de Membrana , Modelos Biológicos , Proteínas Transportadoras de Solutos/genética , Factores de Transcripción/antagonistas & inhibidores , Transcripción GenéticaRESUMEN
Salinomycin (Sal) is a potent inhibitor with effective anti-breast cancer properties in clinical therapy. The occurrence of various side effect of Sal greatly limits its application. The epidermal growth factor receptor (EGFR) family is a family of receptors highly expressed in most breast cancer cells. GE11 is a dodecapeptide which shows excellent EGFR affinity. A series of nanoparticles derivatives with GE11 peptide conjugated PLGA/TPGS were synthesized. Nanoprecipitation method was used to prepare the Sal loaded nanoparticles at the optimized concentration. The characterization, targeting efficacy, and antitumor activity were detected both in vitro and in vivo. Encapsulation of Sal in GE11 modified PLGA/TPGS nanoparticles shows an improved therapy efficacy and lower systemic side effect. This represents the delivery system a promising strategy to enhance the therapeutic effect against EGFR highly expressed breast cancer.
Asunto(s)
Antibacterianos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Péptidos/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Piranos/farmacología , Vitamina E/química , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Piranos/administración & dosificación , Piranos/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The aim of the present study was to confirm the role of Brachyury in breast cancer and to verify whether four types of machine learning models can use Brachyury expression to predict the survival of patients. METHODS: We conducted a retrospective review of the medical records to obtain patient information, and made the patient's paraffin tissue into tissue chips for staining analysis. We selected 303 patients for research and implemented four machine learning algorithms, including multivariate logistic regression model, decision tree, artificial neural network and random forest, and compared the results of these models with each other. Area under the receiver operating characteristic (ROC) curve (AUC) was used to compare the results. RESULTS: The chi-square test results of relevant data suggested that the expression of Brachyury protein in cancer tissues was significantly higher than that in paracancerous tissues (P=0.0335); patients with breast cancer with high Brachyury expression had a worse overall survival (OS) compared with patients with low Brachyury expression. We also found that Brachyury expression was associated with ER expression (P=0.0489). Subsequently, we used four machine learning models to verify the relationship between Brachyury expression and the survival of patients with breast cancer. The results showed that the decision tree model had the best performance (AUC = 0.781). CONCLUSIONS: Brachyury is highly expressed in breast cancer and indicates that patients had a poor prognosis. Compared with conventional statistical methods, decision tree model shows superior performance in predicting the survival status of patients with breast cancer.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Proteínas Fetales/metabolismo , Proteínas de Dominio T Box/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Retículo Endoplásmico/metabolismo , Femenino , Proteínas Fetales/genética , Humanos , Aprendizaje Automático , Persona de Mediana Edad , Análisis de Supervivencia , Proteínas de Dominio T Box/genéticaRESUMEN
Our objective was to evaluate the relationship of blood metal levels including strontium, cadmium, lead, vanadium, aluminum, cobalt, and manganese with dyslipidemia in the elderly Chinese population. In this study, stratified cluster sampling was adopted in the elderly in two communities of Lu'an City from June to September 2016, and 1013 participants were finally included. The inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the metals' concentrations in whole blood. After multivariable adjustment, the odds ratios (95% confidence interval [CI]) of dyslipidemia associated with the highest quartile of metal concentrations were 1.32 (0.89 ~ 1.96), 1.28 (0.83 ~ 1.97), 1.86 (1.23 ~ 2.80), 0.80 (0.55 ~ 1.16), 0.76 (0.51 ~ 1.13), 0.76 (0.53 ~ 1.11), and 1.14 (0.78 ~ 1.67) for strontium, cadmium, lead, vanadium, aluminum, cobalt, and manganese, respectively, compared with the lowest quartile. After reducing the dimensionality of metal elements by principal component analysis, we found that the combined exposure of aluminum, cobalt, and vanadium was the protective factor of non-dyslipidemia, while the combined exposure of cadmium, strontium, and lead was the risk factor of dyslipidemia.
Asunto(s)
Dislipidemias , Metales Pesados , Anciano , Cadmio , Cobre , Dislipidemias/inducido químicamente , Dislipidemias/epidemiología , Humanos , Metales Pesados/sangre , ZincRESUMEN
This study aimed to evaluate the association between aluminum (Al), arsenic (As), barium (Ba), cobalt (Co), manganese (Mn), selenium (Se), strontium (Sr), thallium (Tl), and vanadium (V) levels in whole blood and the cognitive ability of people over 60 years old. A total of 1217 eligible participants were enrolled in our study in Lu'an city, Anhui province, China. The inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the concentration of nine trace elements in the whole blood, which reflect their exposure levels. Mini-mental State Examination (MMSE) scale was employed to screen the cognitive function of the elderly. Logistic regression was applied to assess the associations of nine whole blood trace elements with cognition. In the work, it has found that high levels of whole blood As and Se are risk factors for cognitive dysfunction. As and Se quartile were correlated with increased risk of cognitive dysfunction, and with the odds ratio (OR) of 2.06 (95% CI 1.30-3.25; p-trend = 0.002), 1.947 (95% CI 1.20-3.17; p-trend = 0.007) in the highest quartile. However, high concentration of Al, V, and Ba in whole blood were protective factors for cognitive function [OR = 0.63 (95% CI 0.40-0.98; p-trend = 0.040), 0.549 (95% CI 0.36-0.85; p-trend = 0.007), 0.460 (95% CI 0.28-0.75; p-trend = 0.002) respectively]. The study suggested that the exposure of some trace elements (As, Se) were associated with the increased risk of cognitive dysfunction; on the contrary, other elements (Al, V, Ba) could be protective factor for cognitive function. These findings need to be confirmed in additional research of a large elderly population.