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1.
Oncoimmunology ; 10(1): 1976439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721946

RESUMO

Spatial information on the tumor immune microenvironment is of clinical relevance. Here, we aimed to quantify the spatial heterogeneity of lymphocytes and cancer cells and evaluated its prognostic value in patients with nasopharyngeal carcinoma (NPC). The scanned immunohistochemistry images of 336 NPC patients from two different hospitals were used to generate cell density maps for tumor and immune cells. Then, Getis-Ord hotspot analysis, a spatial statistic method used to describe species biodiversity in ecological habitats, was applied to identify cancer, immune, and immune-cancer hotspots. The results showed that cancer hotspots were not associated with any of the studied clinical outcomes, while immune-cancer hotspots predicted worse overall survival (OS) in the training cohort. In contrast, a high immune hotspot score was significantly associated with better OS (HR 0.41, 95% CI 0.22-0.77, P = .006), disease-free survival (DFS) (HR 0.43, 95% CI 0.24-0.75, P = .003) and distant metastasis-free survival (DMFS) (HR 0.40, 95% CI 0.20-0.81, P = .011) in NPC patients in the training cohort, and similar associations were also evident in the validation cohort. Importantly, multivariate analysis revealed that the immune hotspot score remained an independent prognostic indicator for OS, DFS, and DMFS in both cohorts. We explored the spatial heterogeneity of cancer cells and lymphocytes in the tumor microenvironment of NPC patients using digital pathology and ecological analysis methods and further constructed three spatial scores. Our study demonstrates that spatial variation may aid in the identification of the clinical prognosis of NPC patients, but further investigation is needed.

3.
Brain Behav ; 11(10): e2307, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34520621

RESUMO

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH), caused by rupture of an intracranial aneurysm and bleeding into the subarachnoid space, is a life-threatening cerebrovascular disease. Because of improvements in clinical interventions, the mortality rate of aSAH is gradually decreasing. Thus, many survivors recover from aSAH but still have sequelae. Working memory (WM) deficit is one of the most common and severe sequelae after aSAH. Interestingly, the severity of WM deficit is not identical to the extent or localization of brain damage, which implies an underlying mechanism of WM deficit other than direct hemorrhagic brain damage. Previous studies have revealed altered neural activity of several brain regions during stimulus tasks. However, the behaviors and functional organization of these corresponding areas in the resting state remain unclear. Insights into the organization of the WM network could reveal novel information about the mechanism of WM deficits, which will be of great value in developing new therapeutic strategies. METHODS: In this study, we recruited 50 aSAH patients consisting of survivors with either impaired or intact WM (two groups). Independent component analysis was performed on resting state data to extract the WM network. Dynamic causal modeling was then performed to assess the intrinsic coupling between key regions of the WM network. A model describing the neural activity and functional organization of the WM network was established, although some connections were not consistent in the resting state. RESULTS: We found that effective connectivity of the precuneus (PCUN)-middle temporal gyrus (MTG), MTG-PCUN, and middle frontal gyrus-inferior parietal lobule was significantly decreased in the impaired WM group, which suggests a vital and central role of affected regions or connections and provides new targets for brain stimulation. CONCLUSIONS: The results of this study may contribute to new therapeutic or rehabilitation strategies for aSAH patients with WM deficits.

4.
Birth ; 48(3): 397-405, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33884662

RESUMO

BACKGROUND AND AIMS: The relationship between prior breastfeeding experience and the duration of exclusive breastfeeding is of significant interest, but few studies have explored the mechanisms underlying this relationship. The purpose of this study is to address two hypotheses: (a) that attitude and self-efficacy mediate the relationship between previous breastfeeding experience and the duration of exclusive breastfeeding; and (b) that attitude and self-efficacy have serial mediation functions in this relationship. METHODS: The data collection process was divided into two stages. The original stage included 394 women hospitalized after delivery who completed socio-demographic questionnaires (including previous breastfeeding experience), the Iowa Infant Feeding Attitude Scale (IIFAS), and the Breastfeeding Self-efficacy Short-Form Scale (BSES-SF). Follow-up data about duration of exclusive breastfeeding were obtained at six months postpartum. RESULTS: Mediation analysis indicated that previous breastfeeding experience directly affected the duration of exclusive breastfeeding and that the rate of the total indirect effect was 22.878%. Self-efficacy mediated previous breastfeeding experience and duration of exclusive breastfeeding, whereas attitude and self-efficacy played the series mediational role between previous breastfeeding experience and duration of exclusive breastfeeding. Cluster analysis supported these results. CONCLUSIONS: The duration of exclusive breastfeeding can be promoted by improving breastfeeding attitude and self-efficacy in women without breastfeeding experience.


Assuntos
Aleitamento Materno , Autoeficácia , Análise por Conglomerados , Feminino , Humanos , Período Pós-Parto , Inquéritos e Questionários
5.
Vet Parasitol ; 291: 109326, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33545560

RESUMO

Parabronemosis is a disease that severely threatens camel health, causing huge economic losses to industries involved in camel husbandry. Previous studies have reported that horn flies (Haematobia irritans) act as intermediate hosts of Parabronema skrjabini; however, the infection and developmental processes of P. skrjabini in horn flies remain unclear. In the present study, the infection rates of P. skrjabini were determined in morphologically and molecularly identified horn flies collected from Bactrian camels (Camelus bactrianus) producing regions in Inner Mongolia, China that have high P. skrjabini infection rates. The horn flies were dissected to obtain the nematode larvae at various instar stages. The P. skrjabini found in the different instar stages of horn fly instars were counted and identified to assess the infection and developmental status. Nematode larvae at different developmental stages were obtained from the horn fly instars for further molecular analysis. Sequencing results confirmed that the nematode larvae were P. skrjabini. Furthermore, we found that the mean growth rate of the nematode larva increased as the horn fly instars develops. The results suggested that P. skrjabini infected the horn flies at the larval instar stage, and that the nematode larvae developed simultaneously with the horn fly instars stages. Our findings provide useful information into the elucidation of P. skrjabini infection and life history by studying horn fly development.


Assuntos
Muscidae/parasitologia , Nematoides/crescimento & desenvolvimento , Animais , China , Interações Hospedeiro-Parasita , Estágios do Ciclo de Vida
6.
Mol Cancer ; 20(1): 27, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541368

RESUMO

The development of immune checkpoint blockade (ICB)-based immunotherapy has dramatically changed methods of cancer treatment. This approach triggers a durable treatment response and prolongs patients' survival; however, not all patients can benefit. Accumulating evidence demonstrated that the efficacy of ICB is dependent on a robust antitumor immune response that is usually damaged in most tumors. Conventional chemotherapy and targeted therapy promote the antitumor immune response by increasing the immunogenicity of tumor cells, improving CD8+ T cell infiltration, or inhibiting immunosuppressive cells in the tumor microenvironment. Such immunomodulation provides a convincing rationale for the combination therapy of chemotherapeutics and ICBs, and both preclinical and clinical investigations have shown encouraging results. However, the optimal drug combinations, doses, timing, and sequence of administration, all of which affect the immunomodulatory effect of chemotherapeutics, as well as the benefit of combination therapy, are not yet determined. Future studies should focus on these issues and help to develop the optimal combination regimen for each cancer.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Terapia de Alvo Molecular , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Sinergismo Farmacológico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunomodulação/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia
7.
Mol Cancer ; 20(1): 14, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430876

RESUMO

Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.


Assuntos
Heterogeneidade Genética , Imunoterapia , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/terapia , Microambiente Tumoral , Estudos de Coortes , Genoma Humano , Humanos , Carcinoma Nasofaríngeo/genética , Prognóstico , Reprodutibilidade dos Testes , Microambiente Tumoral/genética
8.
J Natl Cancer Inst ; 113(4): 471-480, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33094348

RESUMO

BACKGROUND: Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the mainstay treatment for patients with locoregionally advanced nasopharyngeal carcinoma. However, some patients obtain little benefit and experience unnecessary toxicities from IC. We intended to develop a gene-expression signature that can identify beneficiaries of IC. METHODS: We screened chemosensitivity-related genes by comparing gene-expression profiles of patients with short-term tumor response or nonresponse to IC (n = 95) using microarray analysis. Chemosensitivity-related genes were quantified by digital expression profiling in a training cohort (n = 342) to obtain a gene signature. We then validated this gene signature in the clinical trial cohort (n = 187) and an external independent cohort (n = 240). Tests of statistical significance are 2-sided. RESULTS: We identified 43 chemosensitivity-related genes associated with the short-term tumor response to IC. In the training cohort, a 6-gene signature was developed that was highly accurate at predicting the short-term tumor response to IC (area under the curve [AUC] = 0.87, sensitivity = 87.5%, specificity = 75.6%). We further found that IC conferred failure-free survival benefits only in patients in the benefit group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.34 to 0.87; P = .01) and not on those in the no-benefit group (HR = 1.25, 95% CI = 0.62 to 2.51; P = .53). In the clinical trial cohort, the 6-gene signature was also highly accurate at predicting the tumor response (AUC = 0.82, sensitivity = 87.5%, specificity = 71.8%) and indicated failure-free survival benefits. In the external independent cohort, similar results were observed. CONCLUSIONS: The 6-gene signature can help select beneficiaries of IC and lay a foundation for a more individualized therapeutic strategy for locoregionally advanced nasopharyngeal carcinoma patients.


Assuntos
Expressão Gênica , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Adulto , Idoso , Área Sob a Curva , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Sensibilidade e Especificidade , Resultado do Tratamento
9.
Cancer Commun (Lond) ; 40(12): 721-737, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33038291

RESUMO

BACKGROUND: Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC). However, the epigenetic mechanisms underlying NPC metastasis remains poorly understood. We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment. METHODS: Bisulfite pyrosequencing was used to analyze zinc finger protein 582 (ZNF582) methylation in NPC tissues and cell lines. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting were used to determine the expression of ZNF582. In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC. ZNF582-targeting genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) and were confirmed by ChIP-qPCR and luciferase assay. RESULTS: ZNF582 promoter was hypermethylated in NPC, and both the mRNA and protein levels of ZNF582 were down-regulated in NPC tissues and cell lines. The restoration of ZNF582 inhibited NPC migration, invasion, and metastasis, while the knockdown of ZNF582 promoted NPC migration, invasion, and metastasis in vitro and in vivo. ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin-3 and NRXN3. Both Nectin-3 and NRXN3 were identified as functional targets of ZNF582, and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis. CONCLUSIONS: ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin-3 and NRXN3, which may provide novel therapeutic targets for NPC treatment.


Assuntos
Metilação de DNA , Fatores de Transcrição Kruppel-Like/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Nectinas/genética , Proteínas do Tecido Nervoso/genética , Linhagem Celular Tumoral , Epigênese Genética , Células HEK293 , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Regiões Promotoras Genéticas
10.
Cancer Res ; 80(23): 5174-5188, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33067266

RESUMO

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)-MAPK-MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR-ACLY-PADI1-MAPK-MMP2/9 axis as a potential therapeutic target in NPC. SIGNIFICANCE: TINCR-mediated regulation of a PADI1-MAPK-MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.


Assuntos
Acetilcoenzima A/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Carcinoma Nasofaríngeo/patologia , RNA Longo não Codificante/genética , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Acetilcoenzima A/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/mortalidade , Prognóstico , Proteína-Arginina Desiminase do Tipo 1/genética , Proteína-Arginina Desiminase do Tipo 1/metabolismo , Estabilidade de RNA , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Midwifery ; 91: 102837, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32916595

RESUMO

BACKGROUND: Breast milk is the optimal method of human nutrition, and donor human milk is often needed to reduce the incidence of necrotizing enterocolitis and septicemia in preterm infants and improve their survival rate. Donor human milk is recommended as the first alternative when mothers' milk is not available. The establishment of human milk banks is of great significance to promote the breastfeeding of preterm infants. However, there are insufficient studies on human milk banks and milk donation in China. OBJECTIVES: (1) To investigate postpartum women's knowledge, attitude and practice regarding human milk banks and milk donation and to analyze the influencing factors. (2) To explore reasons why postpartum women reject milk donation and donor milk. DESIGN AND SETTINGS: A cross-sectional survey was conducted from February 2019 to July 2019 at two hospitals in Wuhan, a large city in central China. PARTICIPANTS: Mothers who returned to hospital for postpartum follow-up within six months participated in this survey (N = 1078). METHODS: Questionnaires were used to obtain sociodemographic data and to determine participants' knowledge, attitude and practice regarding human milk banks and milk donation. FINDINGS: Of the respondents, 216 (20%) had prior knowledge of human milk banks and milk donation. For the sub-domain of knowledge, the item with the highest correct response rate was the benefit of breast milk, and the item with the lowest correct rate was the acceptance of donor human milk. For the sub-domain of attitude, 811(75.3%) of participants held a supportive attitude for the establishment of human milk banks, and 877(81.3%) were supportive of donating breast milk while 412 (38.3%) were supportive of accepting donor human milk. For the sub-domain of practice, the practice of milk donation was not optimistic as participants lacked interest in donating breast milk and spreading knowledge of breast milk banks, and only 28.3% of participants indicated that they would donate breast milk continuously. Participants' age, educational background, weight of the newborn and having prior knowledge of human milk banks were factors that could positively predict their knowledge, attitude and practice associated with human milk banks and milk donation; medication usage during pregnancy or lactation was a factor negatively predicting their knowledge about human milk banks and milk donation. CONCLUSION: This study reveals that a majority of postpartum women are supportive of human milk banks and more willing to donate breast milk than receive donor milk. Lack of knowledge about human milk banks and safety concerns are the main factors hindering postpartum women from donating or accepting donor milk. Findings suggest that it is important to enhance public awareness regarding human milk banks as potential resources for life-saving therapy for preterm infants.This information should be disseminated during the early stage of the establishment of human milk banks. Moreover, health education of pregnant women should include the importance of human milk as well as the alternative and safety of donor milk from milk banks, especially for promoting the health of preterm infants and infants who are unable to receive mothers' breastmilk.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Bancos de Leite , Leite Humano , Período Pós-Parto/psicologia , Adulto , China , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Pesquisa Qualitativa , Inquéritos e Questionários
12.
Prev Vet Med ; 183: 105080, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32919319

RESUMO

Although the prevalence of brucellosis in Inner Mongolia Autonomous Region currently remains high, data available on the epidemiological of circulating Brucella abortus strains were limited. A total of 75 isolates obtained from cattle, sheep, and humans were analysed using both the classical method and multiple locus variable-number tandem repeat analysis (MLVA). There are at least three B. abortus biovars (1, 3 and 6) in this region, and B. abortus biovar 3 is the predominant one. Ten known MLVA-11 genotypes were identified, of which five genotypes (72, 75, 78, 82 and 210) were shared among strains from this study and others previously collected in two to seven different nations, suggesting that this population has multiple geographic origins. An MLVA-16 assay sorted the 75 B. abortus strains into two groups (I and II), 5 clusters (A-E) and 44 genotypes (GT1-44), with 26 unique genotypes represented by single isolates, indicating that these B. abortus brucellosis cases were not directly epidemiologically related. The remaining 18 shared genotypes (among a total of 47 isolates) were represented by two to eight isolates, suggesting that there were epidemiologically related pathogens from each shared genotype among the cases. Importantly, the cluster B1 branch including 22 cluster isolates with identical or similar genotypes confirmed the occurrence of a concentrated outbreak epidemic in the eastern region during 1988-1995. This work will contribute to better understanding of B. abortus brucellosis epidemiology in Inner Mongolia.


Assuntos
Brucella abortus/genética , Brucelose Bovina/epidemiologia , Brucelose/epidemiologia , Brucelose/veterinária , Genótipo , Doenças das Cabras/epidemiologia , Repetições Minissatélites , Doenças dos Ovinos/epidemiologia , Animais , Bovinos , China/epidemiologia , Feminino , Cabras , Humanos , Epidemiologia Molecular , Tipagem de Sequências Multilocus/veterinária , Filogenia , Ovinos , Carneiro Doméstico
13.
Breastfeed Med ; 15(12): 789-797, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32945686

RESUMO

Background/Objective: Many studies have focused on the effects of previous breastfeeding experience (PBE) on subsequent breastfeeding, but few have explored their specific relationships. To explain the relationship between PBE and subsequent breastfeeding behavior based on a follow-up study. Materials and Methods: After delivery, 394 participants who had no PBE completed a demographic questionnaire, breastfeeding knowledge questionnaire, the breastfeeding self-efficacy short-form scale (BSES-SF), and the Iowa infant feeding attitudes scale (IIFAS). Multiparas with PBE also completed the maternal breastfeeding evaluation scale (MBFES) in addition to the aforementioned four questionnaires. On the 42nd day after delivery, participants completed the breastfeeding experience scale (BES) through social networking platforms (QQ, WeChat: both are Chinese social medias). At 4 and 6 months postpartum, researchers contacted participants by phone or a social network regarding their exclusive and partial breastfeeding experiences. Results: In this study, exclusive breastfeeding rates were 58.6% and 30.5% at 4 and 6 months. PBE affected breastfeeding attitudes (p < 0.05), self-efficacy (p < 0.01), and difficulties (p < 0.05). Breastfeeding knowledge, attitude, self-efficacy, and difficulties were relevant to exclusive and partial breastfeeding at 4 and 6 months (p < 0.05). Multivariate logistic regression analysis showed that compared with women without PBE, the probability of exclusive breastfeeding of multiparas with PBE at 4 and 6 months increased by 275% and 369%, respectively. Conclusions: The rate of breastfeeding remains low among Chinese women, but PBE is associated with a higher probability of breastfeeding at 4 and 6 months postpartum. Multiparas, especially those having PBE were more likely to breastfeed for an extended period based on their knowledge, attitude, self-efficacy, and ability to manage difficulties.


Assuntos
Aleitamento Materno/psicologia , Mães/psicologia , Adolescente , Adulto , Aleitamento Materno/estatística & dados numéricos , Estudos de Coortes , Feminino , Seguimentos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Lactente , Período Pós-Parto , Estudos Prospectivos , Autoeficácia , Inquéritos e Questionários , Adulto Jovem
14.
Cell Res ; 30(11): 1024-1042, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32686767

RESUMO

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A+ dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell-cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A+ DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.


Assuntos
Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Análise de Célula Única , Transcriptoma/genética , Linfócitos B/imunologia , Comunicação Celular , Diferenciação Celular , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Células Matadoras Naturais/imunologia , Macrófagos/metabolismo , Monócitos/metabolismo , Células Mieloides/metabolismo , Carcinoma Nasofaríngeo/patologia , Fenótipo , Prognóstico , Processos Estocásticos , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
Oncogene ; 39(34): 5616-5632, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32661324

RESUMO

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in the tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in nasopharyngeal carcinoma (NPC) are still largely unknown. Our previous lncRNA expression profiles identified that LINC01503 was overexpressed in NPC. Here, we verified that LINC01503 was highly expressed in NPC and correlated with poor prognosis. LINC01503 promoted NPC cell proliferation, migration, and invasion in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, LINC01503 recruited splicing factor proline-and glutamine-rich (SFPQ) to activate Fos like 1 (FOSL1) transcription, and ectopic expression of FOSL1 reversed the suppressive effect of LINC01503 knockdown on NPC progression. Moreover, androgen receptor (AR)-mediated transcription activation was responsible for the overexpression of LINC01503, and AR ligand-dependent cell growth, migration, and invasion in NPC cells. Taken together, our findings reveal that AR-induced LINC01503 can promote NPC progression through the SFPQ-FOSL1 axis, which represents a novel prognostic biomarker and therapeutic target for NPC patients.


Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fator de Processamento Associado a PTB/genética , Proteínas Proto-Oncogênicas c-fos/genética , RNA Longo não Codificante/genética , Receptores Androgênicos/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/terapia , Fator de Processamento Associado a PTB/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Interferência de RNA , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Ther Adv Med Oncol ; 12: 1758835920937424, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32647541

RESUMO

Background: The treatment effects of cumulative cisplatin dose (CCD) during radiotherapy (RT) following induction chemotherapy (IC) have not been determined for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: A total of 3460 patients with locoregionally advanced NPC who were treated with IC plus cisplatin-based concurrent chemoradiotherapy or RT alone were included in this retrospective study. Three CCD groups (0 mg/m2 ⩽ CCD <100 mg/m2, 100 mg/m2 ⩽ CCD <200 mg/m2, CCD ⩾200 mg/m2) were balanced through the inverse probability of treatment weighting based on propensity scores estimated by a general boosted model. The primary endpoint was overall survival (OS); the secondary endpoints were distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS). Results: CCD ⩾200 mg/m2 and <200 mg/m2 exhibited similar treatment effects for OS and DMFS, and were both superior to CCD <100 mg/m2 for OS and DMFS in patients with stage IVa NPC. The three CCD groups achieved similar treatment effects for patients with stage II-III NPC. After IC, CCD during RT appeared to exert little treatment effect on LRFS. Conclusion: The CCD during RT exerts treatment effects and improves OS by reducing the risk of distant metastasis for patients with stage IVa NPC following IC, and CCD <200 mg/m2 (mainly 160 mg/m2 in this group) is recommended. However, RT alone may be sufficient after IC in patients with stage II-III NPC.

17.
Sci Rep ; 10(1): 5967, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249852

RESUMO

We have demonstrated that with e-beam deposition of a thin Al2O3 layer before atomic layer deposition, a uniform Al2O3 film can be obtained on WSe2/sapphire samples. Device performances are observed for WSe2 top-gate transistors by using oxide stacks as the gate dielectric. By using thermal evaporation, epitaxially grown multilayer antimonene can be prepared on both MoS2 and WSe2 surfaces. With multilayer antimonene as the contact metal, a significant increase in drain currents and ON/OFF ratios is observed for the device, which indicates that high contact resistance between metal/2D material interfaces is a critical issue for 2D devices. The observation of multilayer antimonene grown on different 2D material surfaces has demonstrated less dependence on the substrate lattice constant of the unique van der Waals epitaxy for 2D materials. The results have also demonstrated that stacking 2D materials with different materials plays an important role in the practical applications of 2D devices.

18.
Cells ; 9(3)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120844

RESUMO

Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo. Importantly, we found that UCHL1 interacts with CTTN, and may function as a ligase promoting CTTN degradation by increasing K48-linked ubiquitination of CTTN. Additionally, restoration of CTTN in NPC cells that overexpressed UCHL1 rescued UCHL1 suppressive effects on NPC cell migration and invasion, which indicated that CTTN is a functional target of UCHL1 in NPC. Our findings revealed that UCHL1 acts as a tumor suppressor gene in NPC and thus provided a novel therapeutic target for NPC treatment.


Assuntos
Cortactina/metabolismo , Metilação de DNA/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Proteólise , Ubiquitina Tiolesterase/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Lisina/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Regiões Promotoras Genéticas , Ligação Proteica , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação
19.
Eur Radiol ; 30(2): 816-822, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31650266

RESUMO

OBJECTIVES: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0-2 and T1-4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0-2 and T1-4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). METHODS: We included 3107 patients with stage IVa NPC disease (1871 with T4N0-2 and 1236 with T1-4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0-2 and T1-4N3 patients were compared. RESULTS: T1-4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis-free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse-free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0-2 patients. Multivariate analysis showed that T1-4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274-1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100-1.572, p = 0.003), whereas T4N0-2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158-2.158, p = 0.004). CONCLUSIONS: In terms of the OS, T4N0-2 patients had better prognosis compared with T1-4N3 patients, and the patterns of failure differed between T4N0-2 and T1-4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0-2 from T1-4N3. KEY POINTS: • In nasopharyngeal carcinoma, T4N0-2 patients tended to develop local relapse, whereas T1-4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0-2 patients had better prognosis than T1-4N3 patients. • T4N0-2 should be separated from T1-4N3 in the UICC/AJCC staging system.


Assuntos
Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Radioterapia de Intensidade Modulada/métodos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento
20.
Biol Trace Elem Res ; 197(2): 544-554, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31838737

RESUMO

Sodium para-aminosalicylic acid (PAS-Na) has been used to treat patients with manganism, a neurological disease caused by manganese (Mn) toxicity, although the exact molecular mechanisms are yet unclear. The present study aims to investigate the effect of PAS-Na on glutamate (Glu) turnover of Mn-exposed rats. The results showed that Mn concentrations in the hippocampus, thalamus, striatum, and globus pallidus were increased in Mn-exposed rats. Moreover, the results also demonstrated that subacute Mn exposure (15 mg/kg for 4 weeks) interrupted the homeostasis of Glu by increasing Glu levels but decreasing glutamine (Gln) levels in the hippocampus, thalamus, striatum, and globus pallidus in male Sprague-Dawley rats. These effects lasted even after Mn exposure had been ceased for a period of 6 weeks. Meanwhile the main Glu turnover enzymes [Gln synthetase (GS) and phosphate-activated glutaminase (PAG)] and transporters [Glu/aspartate transporter (GLAST) and Glu transporter-1 (GLT-1)] were also affected by Mn treatment. Additionally, PAS-Na treatment recovered the aforementioned changes induced by Mn. Taken together, these results indicate that Glu turnover might be involved in Mn-induced neurotoxicity. PAS-Na treatment could promote Mn excretions and recover the changes in Glu turnover induced by Mn, and a prolonged PAS-Na treatment may be more effective.


Assuntos
Ácido Aminossalicílico , Ácido Aminossalicílico/farmacologia , Animais , Ácido Glutâmico , Humanos , Masculino , Manganês/toxicidade , Ratos , Ratos Sprague-Dawley , Sódio
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