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1.
Mol Biol Rep ; 50(5): 4551-4564, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36877352

RESUMO

The thorough degeneration of organelles in the core of the lens is certainly a hallmark event during the lens development. Organelles degradation in the terminal differentiation process of lens fiber cells to form an organelle-free zone is critical for lens maturation and transparency. Several mechanisms have been proposed to expand our understanding of lens organelles degradation, including apoptotic pathways, the participation of ribozyme, proteolytic enzyme and phospholipase A and acyltransferase, and the newly discovered roles for autophagy. Autophagy is a lysosome-dependent degradation reaction during which the "useless" cellular components are degraded and recycled. These cellular components, such as incorrectly folded proteins, damaged organelles and other macromolecules, are first engulfed by the autophagosome before being further delivered to lysosomes for degradation. Although autophagy has been recognized involving in organelle degradation of the lens, the detailed functions remain to be discovered. Recent advances have revealed that autophagy not only plays a vital role in the intracellular quality control of the lens but is also involved in the degradation of nonnuclear organelles in the process of lens fiber cell differentiation. Herein, we first review the potential mechanisms of organelle-free zone formation, then discuss the roles of autophagy in intracellular quality control and cataract formation, and finally substantially summarize the potential involvement of autophagy in the development of organelle-free zone formation.


Assuntos
Catarata , Cristalino , Humanos , Organelas/metabolismo , Cristalino/metabolismo , Autofagia , Catarata/metabolismo , Lisossomos , Proteínas/metabolismo
2.
BMC Med ; 20(1): 155, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35513832

RESUMO

BACKGROUND: Anlotinib, an oral small molecule tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR a/ß, and c-kit, had demonstrated prolonged progression-free survival (PFS) in refractory metastatic colorectal cancer (mCRC). This multicenter, single-arm, phase II, exploratory study was conducted to evaluate the efficacy and safety of anlotinib combined with capecitabine and oxaliplatin as first-line treatment for unresectable RAS/BRAF wild-type mCRC. METHODS: Patients aged 18-75 with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment, and ECOG performance status ≤1 were enrolled. Eligible patients received capecitabine (850 mg/m2, p.o., bid, on day 1-14 every 21 days), oxaliplatin (130 mg/m2, i.v., on day 1 every 21 days), and anlotinib (12 mg, p.o., qd, on days 1-14 every 21 days) as induction therapy. Following 6 cycles of therapy, patients who achieved response or stable disease received capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint was objective response rate (ORR) according to RECIST (version: 1.1), and the secondary endpoints were PFS, disease control rate (DCR), duration of response (DOR), and safety. RESULTS: Between November 2019 and February 2021, 31 patients were enrolled. One patient was excluded for refusing treatment. The primary endpoint of ORR was 76.7% (95% CI, 57.7-90.1) with 1 patient achieving a complete response and 22 patients partial response. DCR was 93.3% (95% CI, 77.9-99.2). At a median follow-up of 14.1 months (95% CI, 9.9-18.3), median PFS was 11.3 months (95% CI, 7.1-14.1), and DOR was 7.9 months (95% CI, 5.5-12.7). Twenty-five (83.3%) patients experienced grade 3 or 4 treatment-emergent adverse events (TEAEs). No grade 5 TEAE was reported. The most common grade 3 or 4 TEAEs (>10%) were hypertension (15/30; 50%), neutrophil count decreased (8/30; 26.7%), and diarrhea (4/30; 13.3%). A total of 18 (60%) patients had TEAEs that resulted in dose reduction, interruptions, or delays. CONCLUSIONS: Anlotinib combined with capecitabine and oxaliplatin showed considerable ORR, DCR, PFS, and DOR in the first-line therapy of mCRC with manageable toxicity profiles. TRIAL REGISTRATION: ClinicalTrials.gov : NCT04080843.


Assuntos
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Indóis , Oxaliplatina/uso terapêutico , Proteínas Proto-Oncogênicas B-raf , Quinolinas , Resultado do Tratamento
3.
J Transl Med ; 20(1): 89, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35164782

RESUMO

BACKGROUND: Adiponectin is an adipocyte-secreted cytokine that enhances insulin sensitivity and attenuates inflammation. Although circulating adiponectin level is often inversely associated with several malignancies, its role in the development of nasopharyngeal carcinoma (NPC) remains unclear. Here, we investigated the clinical association between circulating adiponectin level and NPC, and examined the impact of adiponectin, as well as the underlying mechanisms, on NPC growth both in vitro and in vivo. METHODS: The association between circulating adiponectin level and the risk of developing NPC was assessed in two different cohorts, including a hospital-based case-control study with 152 cases and 132 controls, and a nested case-control study with 71 cases and 142 controls within a community-based NPC screening cohort. Tumor xenograft model, cell proliferation and cycle assays were applied to confirm the effects of adiponectin on NPC growth in cultured cells and in xenograft models. We also investigated the underlying signaling mechanisms with various specific pharmacological inhibitors and biochemistry analysis. RESULTS: High adiponectin levels were associated with a monotonic decreased trend of NPC risk among males in both the hospital-based case-control study and a nested case-control study. In vitro, recombinant human full-length adiponectin significantly inhibited NPC cell growth and arrested cell cycle, which were dependent on AMPK signaling pathway. The growth of xenograft of NPC tumor was sharply accelerated in the nude mice carrying genetic adiponectin deficiency. An adiponectin receptor agonist, AdipoRon, displayed strong anti-tumor activity in human xenograft models. CONCLUSIONS: These findings demonstrated for the first time that circulating adiponectin is not only inversely associated with NPC, but also controls the development of NPC via AMPK signaling pathway. Stimulation of adiponectin function may become a novel therapeutic modality for NPC.


Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias Nasofaríngeas , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/farmacologia , Animais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int J Clin Oncol ; 27(7): 1145-1153, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35397755

RESUMO

BACKGROUND: The single progesterone receptor (PR)-positive phenotype (estrogen receptor (ER)-/PR + , sPR positive) is an infrequent and independent biological entity. However, the prognosis of patients with sPR-positive and her-2-negative phenotype is still controversial, and it is not always easy to decide treatment strategies for them. METHODS: Patients during 2010-2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was used to evaluate cancer-specific survival (CSS). The propensity score matching (PSM) method was used to balance differences of characteristics in groups. The Life-Table method was used to calculate 5-year CSS rates and the annual hazard rate of death (HRD). RESULTS: A total of 97,527 patients were included, and only 745 (0.76%) patients were sPR-positive phenotype. The majority of sPR-positive breast cancer were basal-like subtype. Survival analysis showed that the sPR-positive breast cancer had similar prognosis comparing to double hormonal receptor-negative (ER-/PR-, dHoR-negative) breast cancer, and had the highest HRD during the initial 1-2 years of follow-up, then maintained the HRD of almost zero during the late years of follow-up. CONCLUSIONS: The patients with sPR-positive and her-2-negative breast cancer, similar to dHoR-negative breast cancer, had a worse survival, and could benefit from chemotherapy significantly. However, the escalating endocrine therapy was not recommended for sPR-positive patients. The patients with sPR positive should be excluded from future clinical trials concerning endocrine therapy.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio , Receptores de Progesterona , Análise de Sobrevida
5.
BMC Public Health ; 22(1): 2183, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434572

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a pandemic infectious disease and become a serious public health crisis. As the COVID-19 pandemic continues to spread, it is of vital importance to detect COVID-19 clusters to better distribute resources and optimizing measures. This study helps the surveillance of the COVID-19 pandemic and discovers major space-time clusters of reported cases in European countries. Prospective space-time scan statistics are particularly valuable because it has detected active and emerging COVID-19 clusters. It can prompt public health decision makers when and where to improve targeted interventions, testing locations, and necessary isolation measures, and the allocation of medical resources to reduce further spread. METHODS: Using the daily case data of various countries provided by the European Centers for Disease Control and Prevention, we used SaTScan™ 9.6 to conduct a prospective space-time scan statistics analysis. We detected statistically significant space-time clusters of COVID-19 at the European country level between March 1st to October 2nd, 2020 and March 1st to October 2nd, 2021. Using ArcGIS to draw the spatial distribution map of COVID-19 in Europe, showing the emerging clusters that appeared at the end of our study period detected by Poisson prospective space-time scan statistics. RESULTS: The results show that among the 49 countries studied, the regions with the largest number of reported cases of COVID-19 are Western Europe, Central Europe, and Eastern Europe. Among the 49 countries studied, the country with the largest cumulative number of reported cases is the United Kingdom, followed by Russia, Turkey, France, and Spain. The country (or region) with the lowest cumulative number of reported cases is the Faroe Islands. We discovered 9 emerging clusters, including 21 risky countries. CONCLUSION: This result can provide timely information to national public health decision makers. For example, a country needs to improve the allocation of medical resources and epidemic detection points, or a country needs to strengthen entry and exit testing, or a country needs to strengthen the implementation of protective isolation measures. As the data is updated daily, new data can be re-analyzed to achieve real-time monitoring of COVID-19 in Europe. This study uses Poisson prospective space-time scan statistics to monitor COVID-19 in Europe.


Assuntos
COVID-19 , Estados Unidos , Humanos , COVID-19/epidemiologia , Pandemias , Europa (Continente)/epidemiologia , Espanha , Saúde Pública
6.
Ecotoxicol Environ Saf ; 232: 113259, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121258

RESUMO

Hydroquinone (HQ), a key metabolite of benzene, affects cell cycle and apoptosis. Poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in DNA damage repair. To explore whether PARP-1 is involved in HQ-induced cell cycle and apoptosis, we assessed the effect of PARP-1 suppression and overexpression on induction of cell cycle and apoptosis analyzed by flow cytometry analysis. We observed that HQ induced aberrant cell cycle progression and apoptosis. We further confirmed that PARP-1 suppression accelerated the cell cycle progression and inhibited cell apoptosis via inhibiting p16/pRb signal pathway after acute HQ exposure, while overexpression of PARP-1 displayed the opposite results. Therefore, we concluded that HQ-induced cell cycle and apoptosis were regulated by PARP-1 through activation of p16/pRb signaling pathway.


Assuntos
Hidroquinonas , Ribose , Difosfato de Adenosina/farmacologia , Apoptose , Ciclo Celular , Hidroquinonas/toxicidade , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ribose/farmacologia , Transdução de Sinais
7.
Int J Mol Sci ; 23(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36361525

RESUMO

Adiponectin is an adipocytokine with anti-inflammatory and anticancer properties. Our previous study has shown that blood adiponectin levels were inversely correlated to the risk of nasopharyngeal carcinoma (NPC), and that adiponectin could directly suppress the proliferation of NPC cells. However, the effect of adiponectin on NPC metastasis remains unknown. Here, we revealed in clinical studies that serum adiponectin level was inversely correlated with tumor stage, recurrence, and metastasis in NPC patients, and that low serum adiponectin level also correlates with poor metastasis-free survival. Coculture with recombinant adiponectin suppressed the migration and invasion of NPC cells as well as epithelial-mesenchymal transition (EMT). In addition, recombinant adiponectin dampened the activation of NF-κB and STAT3 signaling pathways induced by adipocyte-derived proinflammatory factors such as leptin, IL-6, and TNF-α. Pharmacological activation of adiponectin receptor through its specific agonist, AdipoRon, largely stalled the metastasis of NPC cells. Taken together, these findings demonstrated that adiponectin could not only regulate metabolism and inhibit cancer growth, but also suppress the metastasis of NPC. Pharmacological activation of adiponectin receptor may be a promising therapeutic strategy to stall NPC metastasis and extend patients' survival.


Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/patologia , Adiponectina/metabolismo , Receptores de Adiponectina/metabolismo , Transição Epitelial-Mesenquimal , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Invasividade Neoplásica , Fator de Transcrição STAT3/metabolismo
8.
Int Ophthalmol ; 42(6): 1939-1956, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35080690

RESUMO

PURPOSE: Calculating the intraocular lens (IOL) power in short eyes for cataract surgery has been a challenge. A meta-analysis was conducted to identify, among several classic and new IOL power calculation formulae, which obtains the best accuracy. METHODS: All studies aiming at comparing the accuracy of IOL power calculation formulae in short eyes were searched up in the databases of PubMed, EMBASE, Web of Science and the Cochrane library from Jan. 2011 to Mar. 2021. Primary outcomes were the percentages of eyes with a refractive prediction error in ± 0.25D, ± 0.5D and ± 1.0D. RESULTS: Totally 1,476 eyes from 14 studies were enrolled in comparison of 13 formulae (Barrett Universal II, Castrop, Haigis, Hoffer Q, Holladay1, Holladay2, Kane, Ladas Super Formula, Okulix, Olsen, Pearl-DGS, SRK/T and T2). Pearl-DGS had the highest percentage within ± 0.25D. In the ± 0.5D range, Pearl-DGS obtained the highest percentage again, and it was significantly higher than Barrett Universal II, Haigis, Hoffer Q, Holladay1, Holladay2 and Olsen (P = 0.001, P = 0.02, P = 0.0003, P = 0.01, P = 0.007, P = 0.05, respectively). In the ± 1.0D range, Okulix possessed the highest percentage, and it was significantly higher than Barrett Universal II, Castrop, Hoffer Q and Holladay2 (P = 0.0005, P = 0.03, P = 0.003, P = 0.02, respectively). CONCLUSION: The new generation formulae, based on artificial intelligence or ray-tracing principle, are more accurate than the convergence formulae. Pearl-DGS and Okulix are the two most accurate formulae in short eyes.


Assuntos
Catarata , Lentes Intraoculares , Facoemulsificação , Erros de Refração , Inteligência Artificial , Comprimento Axial do Olho , Biometria , Humanos , Implante de Lente Intraocular , Óptica e Fotônica , Refração Ocular , Estudos Retrospectivos
9.
J Food Sci Technol ; 59(9): 3367-3378, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35875207

RESUMO

In this study, headspace solid-phase micro-extraction (HS-SPME) coupled with GC-MS was used to analyze the trend of volatile compounds in fresh and oxidative infant nutrition package. Among the volatile compounds, aldehydes and ketones, alcohols, lipids, cycloalkenes, alkanes, alkenes, aromatic hydrocarbons, oxygenated compound were identified. A total of 65 volatile compounds were detected in the fresh nutrition package, whereas 9 new volatile compounds were detected during the accelerated oxidation process, which was oxidized at 45 °C for 4 weeks. The main components of the rancid flavor formed and the relative content of volatile substances gradually changed during the accelerated oxidation process. The volatile substances hexanal, nonanal, and 2-pentylfuran substantially increased. Linalool, α-terpineol, d-limonene, and 1-methoxy-nonane presented an evidently downward trend. The relative content of the newly formed compound 3-hydroxy-2-methylpyran-4-one during the oxidation process was always large, its relative content initially increased, then decreased, and finally increased again. The formation of rancid flavor of the nutrient package was speculated to have been formed by the interaction of hexanal, nonanal, 2-pentylfuran, and 3-hydroxy-2-methylpyran-4-one.

10.
Cancer Sci ; 112(7): 2592-2606, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33938090

RESUMO

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre-clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient-derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre-clinical evaluation of onco-immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.


Assuntos
Modelos Animais de Doenças , Imunoterapia , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais/uso terapêutico , Citocinas/metabolismo , Desenvolvimento de Medicamentos , Engenharia Genética , Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunoterapia Adotiva/métodos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células Matadoras Naturais/imunologia , Camundongos , Camundongos SCID , Neoplasias/imunologia , Medicina de Precisão , Pesquisa Translacional Biomédica , Transplante Heterólogo
11.
Mol Pharm ; 18(3): 1026-1037, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33555197

RESUMO

As a third-generation platinum drug, oxaliplatin (OX) is widely used as the first-line chemotherapeutic agent in the treatment of colorectal cancer (CRC). CRC cells acquire resistance to chemotherapy and develop resistance, which is a major challenge for the treatment of advanced CRC. Recent studies have suggested that the therapeutic resistance of tumors is affected by the tumor microenvironment (TME). As a critical role among TME, tumor-associated macrophages (TAMs) play an important role. However, their regulatory mechanism underlying the drug resistance in CRC remains largely unknown. In the present study, we found that the density of macrophages infiltrated into the CRC tissues from OX-resistant patients was significantly higher compared with the OX-sensitive patients. Interestingly, both the total N6-methyladenosine (m6A) RNA content and the expression of its critical methyltransferase METTL3 were increased in the CRC tissues from OX-resistant patients compared with the OX-sensitive patients. Furthermore, we demonstrated that the M2-polarized TAMs enabled the OX resistance via the elevation of METTL3-mediated m6A modification in cells. Through whole-genome CRISPR screening and further validation, we found that TRAF5 contributes to the METTL3-triggered OX resistance in CRC cells. This study unveiled that M2-TAMs were important mediators for the acquisition of OX resistance. Furthermore, we provided evidence that targeting of M2-TAMs and METTL3-mediated m6A modification might be a promising adjuvant therapeutic strategy for CRC patients, especially for OX-resistant CRC patients.


Assuntos
Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Metiltransferases/genética , Necroptose/genética , Oxaliplatina/farmacologia , Fator 5 Associado a Receptor de TNF/genética , Macrófagos Associados a Tumor/patologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Transdução de Sinais/genética , Microambiente Tumoral/genética
12.
J Biopharm Stat ; 31(3): 339-351, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33400607

RESUMO

There has been limited research on the confidence intervals of the conditional odds ratio in matched-pairs design. This article investigates the interval estimation of the conditional odds ratio. We described several confidence intervals, which are available in some situations, and they can produce different results. We tried to determine which method(s) should be recommended for different situations. We derived four confidence intervals from the delta test, the score test, the inferential model test, and the fiducial test, and employed four exact calculation studies to compare the performances of the four methods, in order to make recommendations for small and moderate-to-large sample sizes. All of the methods are illustrated using a real example. And we offered the recommendations for different situations.


Assuntos
Projetos de Pesquisa , Intervalos de Confiança , Humanos , Razão de Chances , Tamanho da Amostra
13.
Med Sci Monit ; 26: e923664, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32759885

RESUMO

BACKGROUND Gastric cancer (GC) is a worldwide malignancy and the molecular mechanism of the GC carcinogenesis has not been fully elucidated. Our previous study suggested CDCA5 played a role in GC development via regulating cell proliferation, migration, and apoptosis in GC cells. MATERIAL AND METHODS Here, we first carried out bioinformatics analysis and found cyclin-dependent kinase 1 (CDK1) was possibly associated with CDCA5 using STRING. Then, the expression levels of CDK1 and CDCA5 in cancer tissues were estimated through Oncomine and The Cancer Genome Atlas (TCGA) database. After that, functional experiments were exerted to detect the association of CDK1 and CDCA5. Finally, cell proliferation assay, colon formation assay, cell scratch assay, transwell migration and invasion assays were applied to explore the roles of CDK1 and CDCA5 in GC cells MGC-803. RESULTS CDK1 and CDCA5 were both upregulated and co-expressed in GC tissues. The expression of CDK1 and CDCA5 in MGC-803 was positively related. CDK1 or CDCA5 inhibition can suppress the proliferation, colon formation, migration, and invasion abilities of GC cells. CONCLUSIONS Co-expression of CDK1 and CDCA5 might confer cell proliferation, migration, and invasion abilities in GC cells, and this can provide some clues for further therapies of gastric tumors.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Invasividade Neoplásica/genética , Mapas de Interação de Proteínas/genética , RNA Mensageiro/genética , Neoplasias Gástricas/patologia , Transcriptoma , Transfecção , Regulação para Cima/genética
14.
Exp Eye Res ; 175: 90-97, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29913163

RESUMO

Consistent results suggest the promoting roles of serine racemase (SR)/D-serine in retinal neurodegeneration in diabetic retinopathy (DR). However, the direct evidence connecting SR deficiency with retinal neuroprotection in genetic model of diabetes mellitus has not been reported. In this investigation, we explore the effect of absence of functional SR on the degeneration of retinal ganglion cells (RGCs) with a diabetic murine model, Ins2Akita mice. We established a murine strain with double mutation, termed Ins2Akita-Srr, by mating heterozygous Ins2Akita mice with homozygous Srrochre269 mice. Ins2Akita retained less RGC in posterior, middle, and peripheral retinae than the counterpart from non-diabetic sibling mice at the age of five or seven months. Ins2Akita-Srr mice retained more RGC in middle and peripheral--but not in posterior-- retinae than the counterpart from Ins2Akita sibling mice at the age of five months. By contrast, at the age of seven months, Ins2Akita-Srr mice contained more RGC in peripheral, middle, and posterior retinae than the counterpart from Ins2Akita. RGCs were identified with retrograde labeling in vivo or with immunolabeling against a RGC-specific transcription factor, Brn3a, in retinal flat mounts. Correspondingly, the aqueous humor of Ins2Akita-Srr contained less amount of D-serine than sibling Ins2Akita mice. Thus, SR deficiency significantly prevented RGC loss in diabetic mice. We conclude that D-serine is a critical factor in the degeneration of RGC in DR. Targeting SR expression or activity may be a strategy for ameliorating RGC loss in DR.


Assuntos
Retinopatia Diabética/prevenção & controle , Modelos Animais de Doenças , Mutação com Perda de Função/genética , Racemases e Epimerases/genética , Degeneração Retiniana/prevenção & controle , Células Ganglionares da Retina/metabolismo , Animais , Glicemia/metabolismo , Contagem de Células , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/prevenção & controle , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Técnica Indireta de Fluorescência para Anticorpo , Técnicas de Genotipagem , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Marcação In Situ das Extremidades Cortadas , Insulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Reação em Cadeia da Polimerase , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/patologia
15.
Cancer ; 123(13): 2432-2443, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28267199

RESUMO

BACKGROUND: The real-world occurrence rate of non-breast cancer-specific death (non-BCSD) and its impact on patients with breast cancer are poorly recognized. METHODS: Women with resectable breast cancer from 1990 to 2007 in the Surveillance, Epidemiology, and End Results database (n = 199,963) were analyzed. The outcome events of breast cancer were classified as breast cancer-specific death (BCSD), non-BCSD, or survival. Binary logistics was used to estimate the occurrence rates of non-BCSD and BCSD with different clinicopathological factors. The Gray method was used to measure the cumulative incidence of non-BCSD and BCSD. The ratio of non-BCSDs to all causes of death and stacked cumulative incidence function plots were used to present the impact of non-BCSD on overall survival (OS). Models of Cox proportional hazards regression and competing risk regression were compared to highlight the suitable model. RESULTS: There were 12,879 non-BCSDs (6.44%) and 28,784 BCSDs (14.39%). The oldest age group (>62 years), black race, and a single or divorced marital status were associated with more non-BCSDs. With adjustments for age, a hormone receptor-positive (HoR+) status was no longer related to increased non-BCSDs. In patients with grade 1, stage I disease and an HoR+ status as well as the oldest subgroup, a great dilution of non-BCSD on all causes of death could be observed, and this led to incorrect interpretations. The inaccuracy, caused by the commonly used Cox proportional hazards model, could be corrected by a competing risk model. CONCLUSIONS: OS was largely impaired by non-BCSD during early breast cancer. For some future clinical trial planning, especially for the oldest patients and those with HoR+ breast cancer, non-BCSD should be considered a competing risk event. Cancer 2017;123:2432-43. © 2017 American Cancer Society.


Assuntos
Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Taxa de Sobrevida , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Fatores Etários , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Causas de Morte , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Modelos Logísticos , Estado Civil , Mastectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Programa de SEER , Estados Unidos
16.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 46(1): 36-43, 2017 Jan 25.
Artigo em Zh | MEDLINE | ID: mdl-28436629

RESUMO

Objective: To investigate the expression of hypoxia-inducible factor 1α (HIF-1α) and CD133 in predicting pathologic remission and survival of patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy. Methods: One hundred and fourteen patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy from January 2010 to December 2015 in Jinhua Municipal Central Hospital were enrolled in the study. RT-PCR and immunohistochemistry methods were used to detect the mRNA and protein expression of HIF-1α and CD133 before and after chemoradiotherapy. Spearman rank correlation was used to analyze the correlation between HIF-1α and CD133 mRNA expression. Univariate and logistic multivariate analyses were used to determine the factors related to pathological complete response (pCR). Logistic regression analysis and Cox's proportional hazard model were used to determine factors related to overall survival and recurrence-free survival. Results: The expression of HIF-1α and CD133 mRNA was correlated with pT, ypTNM, pCR, recurrence and metastasis of rectal cancer, while not correlated with sex, age and BMI of patients. HIF-1α mRNA expression was positively correlated with CD133 mRNA expression ( α=0.579, P=0.000). Immunohistochemistry analysis showed that residual cancer cells strongly expressing HIF-1α also expressed CD133 strongly. Univariate analysis showed that HIF-1α mRNA and CD133 mRNA were significantly correlated with pCR ( P=0.001, P=0.022, respectively). Multivariate analysis showed that HIF-1α and CD133 mRNA expression were independent prognostic factors of pCR ( P=0.012, P=0.047, respectively). Cox regression analysis showed that the expression of HIF-1α mRNA and CD133 mRNA were independent predictors of recurrence-free survival and overall survival ( P=0.025, P=0.033, respectively). Conclusion: The study indicates that HIF-1α and CD133 can predict pathological complete remission and survival of patients with locally advanced rectal cancer.


Assuntos
Antígeno AC133/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Recidiva Local de Neoplasia/genética , Neoplasias Retais/química , Neoplasias Retais/epidemiologia , Neoplasias Retais/genética , Antígeno AC133/genética , Biomarcadores Tumorais/análise , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Terapia Neoadjuvante , Gradação de Tumores , Metástase Neoplásica/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Neoplasia Residual/genética , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Retais/terapia , Taxa de Sobrevida
17.
J Surg Oncol ; 114(8): 1004-1008, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27891617

RESUMO

BACKGROUND AND OBJECTIVES: Signet ring cell carcinoma (SRCC) is a uniquely separated subgroup in metastatic colorectal cancer (mCRC). The aims are to investigate the value of resection in patients with resectable metastatic signet ring cell colorectal cancer. METHODS: Patients with mCRC who underwent resection in Surveillance, Epidemiology, and End Results database during 1998-2010 were retrospectively analyzed. Kaplan-Meier and COX models were used to analyze the differences in the survival. Logistic regression models were used to evaluate the relationship between SRCC and other clinicopathological factors. RESULTS: Among the 3,568 patients, 94 (2.63%) patients had SRCC. The median survival time of patients with SRCC and non-SRCC were 17 and 29 months, respectively (P < 0.001). Multivariate analysis indicated that SRCC was an independent prognostic factor for poor overall survival. Logistic regression model based on variables identified by univariate analysis indicated that younger age (≤50 years old) (P = 0.005), female (P < 0.001), location in colon (P = 0.012), and N positive status (P = 0.003) were independent variables correlated with the SRCC subgroup. SRCC had a dramatically higher invalid surgical outcome rate than non-SRCC (P = 0.001). CONCLUSION: SRCC patients might benefit little from the resection of primary and metastatic lesions with a high rate of undergoing invalid operations. J. Surg. Oncol. 2016;114:1004-1008. © 2016 Wiley Periodicals, Inc.


Assuntos
Carcinoma de Células em Anel de Sinete/secundário , Carcinoma de Células em Anel de Sinete/cirurgia , Neoplasias Colorretais/cirurgia , Futilidade Médica , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células em Anel de Sinete/mortalidade , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Programa de SEER , Análise de Sobrevida
18.
Chin J Cancer ; 34(8): 365-72, 2015 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-26227634

RESUMO

BACKGROUND: With industrial and econom ic development in recent decades in South China, cancer incidence may have changed due to the changing lifestyle and environment. However, the trends of lung cancer and the roles of smoking and other environmental risk factors in the development of lung cancer in rural areas of South China remain unclear. The purpose of this study was to explore the lung cancer incidence trends and the possible causes of these trends. METHODS: Joinpoint regression analysis and the age-period-cohort (APC) model were used to analyze the lung cancer incidence trends in Sihui, Guangdong province, China between 1987 and 2011, and explore the possible causes of these trends. RESULTS: A total of 2,397 lung cancer patients were involved in this study. A 3-fold increase in the incidence of lung cancer in both sexes was observed over the 25-year period. Joinpoint regression analysis showed that while the incidence continued to increase steadily in females during the entire period, a sharp acceleration was observed in males starting in 2005. The full APC model was selected to describe age, period, and birth cohort effects on lung cancer incidence trends in Sihui. The age cohorts in both sexes showed a continuously significant increase in the relative risk (RR) of lung cancer, with a peak in the eldest age group (80-84 years). The RR of lung cancer showed a fluctuating curve in both sexes. The birth cohorts identified an increased trend in both males and females; however, males had a plateau in the youngest cohorts who were born during 1955-1969. CONCLUSIONS: Increasing trends of the incidence of lung cancer in Sihui were dominated by the effects of age and birth cohorts. Social aging, smoking, and environmental changes may play important roles in such trends.


Assuntos
Incidência , Neoplasias Pulmonares , Fatores de Risco , Envelhecimento , China , Feminino , Humanos , Masculino , Fumar
19.
Clin Exp Ophthalmol ; 42(9): 841-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24645972

RESUMO

BACKGROUND: The objective of this clinical study is to examine the association between D-serine and diabetic retinopathy (DR). DESIGN: Retrospective, case-control study was performed in the affiliated Eye Hospital of Wenzhou Medical University. PARTICIPANTS: This study included 25 patients with proliferative diabetic retinopathy (PDR), and 25 sex- and age-matched control subjects, i.e. patients with idiopathic macular hole and idiopathic epiretinal membrane. METHODS: Clinical diagnoses were made by the senior ophthalmologists in the Eye Hospital; the aqueous and vitreous humour specimens were collected from these patients undergoing pars plana vitrectomy for treating complications. MAIN OUTCOME MEASURES: The aqueous and vitreous levels of D-serine and glutamate were measured with reverse-phase high-performance liquid chromatography (HPLC); the contents of haemoglobin in the blood and in the vitreous specimens from PDR were measured with spectrophotometry to correct possible introduction of amino acids from PDR haemorrhage. RESULTS: The concentrations of D-serine in the aqueous or vitreous humour were significantly higher in patients with PDR compared with control subjects. The vitreous concentrations of D-serine in PDR were 25.55 ± 0.63 µmol/L compared with control subjects at 22.76 ± 0.36 µmol/L (P = 0.002); the levels of D-serine in the aqueous humour from patients with PDR were 29.08 ± 1.31 µmol/L compared with control subjects at 24.22 ± 0.65 µmol/L (P = 0.006). Correction from possible introduction of D-serine from the vitreous haemorrhage in PDR did not significantly alter the findings. CONCLUSIONS: Increased D-serine in the aqueous and vitreous humour was found in patients with PDR compared with control subjects.


Assuntos
Humor Aquoso/metabolismo , Retinopatia Diabética/metabolismo , Neovascularização Retiniana/metabolismo , Serina/metabolismo , Corpo Vítreo/metabolismo , Idoso , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Retinopatia Diabética/patologia , Feminino , Ácido Glutâmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Retiniana/patologia , Estudos Retrospectivos
20.
J Ovarian Res ; 17(1): 116, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38807145

RESUMO

BACKGROUND: PCOS patients with unexpectedly low oocyte yield following conventional ovarian stimulation are referred to as suboptimal responders. However, identifying suboptimal responders presents a significant challenge within reproductive medicine and limited research exists on the occurrence of suboptimal response. This analysis aimed to develop a predictive model of suboptimal response during in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatments in PCOS patients. METHODS: This retrospective study involved a cohort of 313 PCOS patients undergoing their first IVF/ICSI cycle from 2019 to 2022. Univariate logistic regression analyses, least absolute shrinkage, selection operator regression analysis, and recursive feature elimination were employed to identify relevant characteristics and construct predictive models. Moreover, a nomogram was constructed based on the best model. Receiver operating characteristic curves, decision curve analysis (DCA), and calibration curves were used to evaluate the model. RESULTS: The predictors included in the model were age, Anti-Mullerian hormone, antral follicle count, and basal follicle-stimulating hormone. The area under the receiver operating characteristic curve (AUC) was 0.7702 (95% confidence interval 0.7157-0.8191). The AUC, along with the DCA curve and calibration curve, demonstrated a satisfactory level of congruence and discrimination ability. CONCLUSION: The nomogram effectively predicted the probability of suboptimal response in PCOS patients undergoing gonadotropin-releasing hormone antagonist protocol during IVF/ICSI treatment.


Assuntos
Fertilização in vitro , Hormônio Liberador de Gonadotropina , Indução da Ovulação , Síndrome do Ovário Policístico , Injeções de Esperma Intracitoplásmicas , Adulto , Feminino , Humanos , Gravidez , Fertilização in vitro/métodos , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Nomogramas , Indução da Ovulação/métodos , Síndrome do Ovário Policístico/tratamento farmacológico , Estudos Retrospectivos , Curva ROC
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