RESUMO
BACKGROUND: Colorectal cancer (CRC) represents the third most common type of cancer and the third leading cause of death from cancer around the world. M701 is a CD3/EpCAM bispecific antibody that shows promising cytotoxicity toward CRC cells. AIM: To investigate the influence of immuno-related gene polymorphisms on M701 mediated cytotoxicity to CRC cell HCT116. METHOD: We analyzed the influence of the effect of M701 on the activation and cytotoxicity of peripheral mononuclear blood cells from 129 healthy volunteers with different genotypes. RESULT: When incubated with M701, peripheral mononuclear blood cells from CD247 rs2949655 AA homozygotes showed significantly lower cytotoxicity than those from AG/GG heterozygotes. CONCLUSION: CD247 rs2949655 was significantly associated with the cytotoxicity of M701 to HCT116, which might contribute to personalized medicine of M701.
Assuntos
Anticorpos Biespecíficos/farmacologia , Complexo CD3/genética , Neoplasias Colorretais/genética , Variantes Farmacogenômicos , Complexo CD3/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Molécula de Adesão da Célula Epitelial/imunologia , Genótipo , Células HCT116 , Voluntários Saudáveis , Humanos , Medicina de PrecisãoRESUMO
Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies.
Assuntos
Neoplasias da Mama/terapia , Imunoterapia/métodos , Anticorpos Biespecíficos/imunologia , Neoplasias da Mama/imunologia , Vacinas Anticâncer , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Terapia de Alvo Molecular/métodosRESUMO
Colorectal cancer (CRC) represents the third most common type of cancer in developed countries and one of the leading causes of cancer deaths worldwide. Personalized management of CRC has gained increasing attention since there are large inter-individual variations in the prognosis and response to drugs used to treat CRC owing to molecular heterogeneity. Approximately 15% of CRCs are caused by deficient mismatch repair (dMMR) characterized by microsatellite instability (MSI) phenotype. The present review is aimed at highlighting the role of MMR status in informing prognosis and personalized treatment of CRC including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy to guide the individualized therapy of CRC.
Assuntos
Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Medicina de Precisão , Animais , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Humanos , PrognósticoRESUMO
OBJECTIVE: To investigate whether microRNA (miRNA) miR-21 regulates dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression through binding 3'-UTR region directly in human umbilical venous endothelial cells (HUVECs) and to explore whether DDAH1-V2/V3 transcripts can function as microRNA sponge, thereby modulating DDAH1-V1 expression. METHODS: The DDAH1 3'-UTR containing miR-21 recognizing sequence was cloned into PmirGLO dual-luciferase miRNA target expression plasmid to construct PmirGLO-miR-21. The plasmid and miR-21 (at concentrations of 25, 50, 100 nM, respectively) or negative control (100 nM) were co-transfected into HUVECs, luciferase activity was detected at 24 h. HUVECs were incubated with 2 µg/ml Actinomycin D for the indicated time after miR-21 (25 nM) transfection, half-lives of DDAH1 mRNA were determined. HUVECs were transfected with PmirGLO-miR-21 alone or co-transfected with miR-21 for 24 h, DDAH1 transcripts mRNA, eNOS activity and DDAH1 protein expression were determined. RESULTS: MiR-21 decreased luciferase activity of PmirGLO-miR-21 in a dose-dependent manner (P < 0.05 for 25 nM miR-21, P < 0.01 for 50 nM and 100 nM miR-21), and miR-21 inhibitor increased reporter activity of PmirGLO-miR-21 and mRNA expression of all three DDAH1 transcript variants significantly (P < 0.05, respectively). The degree of increase in endogenous DDAH1 mRNA expression by miR-21 inhibitor was more obvious for DDAH1-V3. Overexpression of miR-21 decreased mRNA expression and mRNA half-life time of all DDAH1 transcripts significantly (P < 0.05), and DDAH1-V2 displayed significantly decreased half-life time than DDAH1-V1 and -V3 with or without miR-21 transfection (P < 0.05, respectively). MiR-21 (100 nM) decreased DDAH1 protein expression and eNOS activity significantly (P < 0.05), which was reversed by PmirGLO-miR-21 transfection (P < 0.05). Transfection of PmirGLO-miR-21 alone increased intracellular miR-21 expression by approximately 5.6-fold, but only showed a trend of increase in DDAH1 protein expression. CONCLUSION: Our results confirmed DDAH1 3'-UTR as a target for miR-21, and endogenous miR-21 showed increased inhibitory effect on DDAH1-V3 transcript. DDAH1 3'-UTR, especially for DDAH1-V3, may function as miR-21 sponge to regulate DDAH1 protein expression. Modulation of miR-21-DDAH1 interaction may provide a new approach for tackling cardiovascular diseases.
Assuntos
Amidoidrolases/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , HumanosRESUMO
Excess fluoride and iodide coexist in drinking water in many regions, but few studies have investigated the single or interactive effects on thyroid in vivo. In our study, Wistar rats were exposed to excess fluoride and/or iodide through drinking water for 2 or 8 months. The structure and function of the thyroid, cells apoptosis and the expression of inositol-requiring enzyme 1 (IRE1) pathway-related factors were analyzed. Results demonstrated that excess fluoride and/or iodide could change thyroid follicular morphology and alter thyroid hormone levels in rats. After 8 months treatment, both single and co-exposure of the two microelements could raise the thyroid cells apoptosis. However, the expressions of IRE1-related factors were only increased in fluoride-alone and the combined groups. In conclusion, thyroid structure and thyroid function were both affected by excess fluoride and/or iodide. IRE1-induced apoptosis were involved in this cytotoxic process caused by fluoride or the combination of two microelements.
Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Iodatos/toxicidade , Compostos de Potássio/toxicidade , Fluoreto de Sódio/toxicidade , Glândula Tireoide/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Iodatos/administração & dosagem , Proteínas de Membrana/metabolismo , Compostos de Potássio/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Wistar , Fluoreto de Sódio/administração & dosagem , Testes de Função Tireóidea , Glândula Tireoide/metabolismo , Glândula Tireoide/patologiaRESUMO
Cumulative fluoride exposure has adverse influences on children's intelligence quotient (IQ). In addition, catechol-O-methyltransferase (COMT) gene Val158Met polymorphism (rs4680) is associated with cognitive performance. This study aimed to evaluate the associations of COMT polymorphism and alterations of protein profiles with children's intelligence in endemic fluorosis area. We recruited 180 schoolchildren (10-12 years old) from high fluoride exposure (1.40 mg/l) and control areas (0.63 mg/l) in Tianjin City, China. The children's IQ, fluoride contents in drinking water (W-F), serum (S-F), and urine (U-F); serum thyroid hormone levels, COMT Val158Met polymorphism, and plasma proteomic profiling were determined. Significant high levels of W-F, S-F, U-F, along with poor IQ scores were observed in the high fluoride exposure group compared with those in control (all P < 0.05). S-F and U-F were inversely related with IQ (r(s) = -0.47, P < 0.01; r(s) = -0.45, P = 0.002). Importantly, higher fluoride exposure was associated with steeper cognitive decline among children with the reference allele Val compared with those homozygous or heterozygous for the variant allele Met (95% CI, -16.80 to 2.55; P interaction < 0.01). Additionally, 5 up-regulated protein spots related to cell immunity and metabolism were detected in children with high fluoride exposure compared with the control. In conclusion, fluoride exposure was adversely associated with children's intelligence, whereas the COMT polymorphism may increase the susceptibility to the deficits in IQ due to fluoride exposure. Moreover, the proteomic analysis can provide certain basis for identifying the early biological markers of fluorosis among children.
Assuntos
Catecol O-Metiltransferase/genética , Fluorose Dentária/epidemiologia , Inteligência/genética , Polimorfismo Genético , Proteômica , Criança , China/epidemiologia , Doenças Endêmicas , Feminino , Humanos , MasculinoRESUMO
In many regions, excessive fluoride and excessive iodide coexist in groundwater, which may lead to biphasic hazards to human thyroid. To explore fluoride-induced thyroid cytotoxicity and the mechanism underlying the effects of excessive iodide on fluoride-induced cytotoxicity, a thyroid cell line (Nthy-ori 3-1) was exposed to excessive fluoride and/or excessive iodide. Cell viability, lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) formation, apoptosis, and the expression levels of inositol-requiring enzyme 1 (IRE1) pathway-related molecules were detected. Fluoride and/or iodide decreased cell viability and increased LDH leakage and apoptosis. ROS, the expression levels of glucose-regulated protein 78 (GRP78), IRE1, C/EBP homologous protein (CHOP), and spliced X-box-binding protein-1 (sXBP-1) were enhanced by fluoride or the combination of the two elements. Collectively, excessive fluoride and excessive iodide have detrimental influences on human thyroid cells. Furthermore, an antagonistic interaction between fluoride and excessive iodide exists, and cytotoxicity may be related to IRE1 pathway-induced apoptosis.
Assuntos
Iodeto de Potássio/toxicidade , Fluoreto de Sódio/toxicidade , Glândula Tireoide/citologia , Poluentes Químicos da Água/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Chaperona BiP do Retículo Endoplasmático , Endorribonucleases/genética , Proteínas de Choque Térmico/genética , Humanos , Proteínas Serina-Treonina Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição de Fator Regulador X , Fator de Transcrição CHOP/genética , Fatores de Transcrição/genéticaRESUMO
Fluorine, a toxic and reactive element, is widely prevalent throughout the environment and can induce toxicity when absorbed into the body. This study was to explore the possible mechanisms of developmental neurotoxicity in rats treated with different levels of sodium fluoride (NaF). The rats' intelligence, as well as changes in neuronal morphology, glucose absorption, and functional gene expression within the brain were determined using the Morris water maze test, transmission electron microscopy, small-animal magnetic resonance imaging and Positron emission tomography and computed tomography, and Western blotting techniques. We found that NaF treatment-impaired learning and memory in these rats. Furthermore, NaF caused neuronal degeneration, decreased brain glucose utilization, decreased the protein expression of glucose transporter 1 and glial fibrillary acidic protein, and increased levels of brain-derived neurotrophic factor in the rat brains. The developmental neurotoxicity of fluoride may be closely associated with low glucose utilization and neurodegenerative changes.
Assuntos
Encéfalo/efeitos dos fármacos , Glucose/metabolismo , Degeneração Neural/induzido quimicamente , Fluoreto de Sódio/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/ultraestrutura , Feminino , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Transportador de Glucose Tipo 1/biossíntese , Transportador de Glucose Tipo 1/genética , Deficiências da Aprendizagem/induzido quimicamente , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Imagem Multimodal , Tamanho do Órgão/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tomografia Computadorizada por Raios XRESUMO
Excessive iodide and fluoride coexist in the groundwater in many regions, causing a potential risk to the human thyroid. To investigate the mechanism of iodide- and fluoride-induced thyroid cytotoxicity, human thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with different concentrations of potassium iodide (KI), with or without sodium fluoride (NaF). Cell morphology, viability, lactate dehydrogenase (LDH) leakage, apoptosis, and expression of inositol-requiring enzyme 1 (IRE1) pathway-related molecules were assessed. Results showed 50 mM of KI, 1 mM of NaF, and 50 mM of KI +1 mM of NaF changed cellular morphology, decreased viability, and increased LDH leakage and apoptosis. Elevated expression of binding protein (BiP), IRE1, and C/EBP homologous protein (CHOP) mRNA and protein, as well as spliced X-box-binding protein-1 (sXBP-1) mRNA, were observed in the 1 mM NaF and 50 mM KI +1 mM NaF groups. Collectively, excessive iodide and/or fluoride is cytotoxic to the human thyroid. Although these data do not manifest iodide could induce the IRE1 pathway, the cytotoxicity followed by exposure to fluoride alone or in combination with iodide may be related to IRE1 pathway-induced apoptosis. Furthermore, exposure to the combination of excessive iodide and fluoride may cause interactive effects on thyroid cytotoxicity.
Assuntos
Apoptose/efeitos dos fármacos , Endorribonucleases/biossíntese , Fluoretos/toxicidade , Iodetos/toxicidade , Proteínas de Membrana/biossíntese , Proteínas Serina-Treonina Quinases/biossíntese , Actinas/antagonistas & inibidores , Actinas/biossíntese , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Sobrevivência Celular/efeitos dos fármacos , Primers do DNA , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Endorribonucleases/genética , Endorribonucleases/fisiologia , Humanos , L-Lactato Desidrogenase/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fatores de Transcrição de Fator Regulador X , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição CHOP/biossíntese , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genéticaRESUMO
Long-term excessive fluoride intake is known to be toxic and can damage a variety of organs and tissues in the human body. However, the molecular mechanisms underlying fluoride-induced male reproductive toxicity are not well understood. In this study, we used a rat model to simulate the situations of human exposure and aimed to evaluate the roles of endoplasmic reticulum (ER) stress and inflammatory response in fluoride-induced testicular injury. Sprague-Dawley rats were administered with sodium fluoride (NaF) at 25, 50 and 100mg/L via drinking water from pre-pregnancy to gestation, birth and finally to post-puberty. And then the testes of male offspring were studied at 8weeks of age. Our results demonstrated that fluoride treatment increased MDA accumulation, decreased SOD activity, and enhanced germ cell apoptosis. In addition, fluoride elevated mRNA and protein levels of glucose-regulated protein 78 (GRP78), inositol requiring ER-to-nucleus signal kinase 1 (IRE1), and C/EBP homologous protein (CHOP), indicating activation of ER stress signaling. Furthermore, fluoride also induced testicular inflammation, as manifested by gene up-regulation of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in a nuclear factor-κB (NF-κB)-dependent manner. These were associated with marked histopathological lesions including injury of spermatogonia, decrease of spermatocytes and absence of elongated spermatids, as well as severe ultrastructural abnormalities in testes. Taken together, our results provide compelling evidence that ER stress and inflammation would be novel and significant mechanisms responsible for fluoride-induced disturbance of spermatogenesis and germ cell loss in addition to oxidative stress.