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1.
Artigo em Inglês | MEDLINE | ID: mdl-39205642

RESUMO

Transcription factor 3 (TCF3), a pivotal member of the TCF/LEF family, plays a critical role in tumorigenesis. Nonetheless, its impact on the tumor microenvironment (TME) and cancer phenotypes remains elusive. We perform an exhaustive analysis of TCF3 expression, DNA variation profiles, prognostic implications, and associations with the TME and immunological aspects. This study is based on a large-scale pan-cancer cohort, encompassing over 17,000 cancer patients from multiple independent datasets, validated by in vitro assays. Our results show that TCF3/4/7 exhibits differential expression patterns between normal and tumor tissues across pan-cancer analyses. Mutational analysis of TCF3 across diverse cancer types reveals the highest alteration rates in biliary tract cancer. Additionally, mutations and single nucleotide variants in TCF3/4/7 are found to exert varied effects on patient prognosis. Importantly, TCF3 emerges as a robust predictor of survival across all cancer cohorts and among patients receiving immune checkpoint inhibitors. Elevated TCF3 expression is correlated with more aggressive cancer subtypes, as validated by immunohistochemistry and diverse cohort data. Furthermore, TCF3 expression is positively correlated with intratumoral heterogeneity and angiogenesis. In vitro investigations demonstrate that TCF3 is involved in epithelial-mesenchymal transition, migration, invasion, and angiogenesis. These effects are likely mediated through the interaction of TCF3 with the NF-κB/MMP2 pathway, which is modulated by IL-17A in human uveal melanoma MUM2B cells. This study elucidates, for the first time, the significant associations of TCF3 with DNA variation profiles, prognostic outcomes, and the TME in multiple cancer contexts. TCF3 holds promise as a molecular marker for diagnosis and as a potential target for novel therapeutic strategies, particularly in uveal melanoma.

2.
Mol Med ; 28(1): 78, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35836112

RESUMO

Angiogenesis plays the critical roles in promoting tumor progression, aggressiveness, and metastasis. Although few studies have revealed some angiogenesis-related genes (ARGs) could serve as prognosis-related biomarkers for the prostate cancer (PCa), the integrated role of ARGs has not been systematically studied. The RNA-sequencing data and clinical information of prostate adenocarcinoma (PRAD) were downloaded from The Cancer Genome Atlas (TCGA) as discovery dataset. Twenty-three ARGs in total were identified to be correlated with prognosis of PRAD by the univariate Cox regression analysis, and a 19-ARG signature was further developed with significant correlation with the disease-free survival (DFS) of PRAD by the least absolute shrinkage and selection operator (LASSO) Cox regression with tenfold cross-validation. The signature stratified PRAD patients into high- and low-ARGs signature score groups, and those with high ARGs signature score were associated with significantly poorer outcomes (median DFS: 62.71 months vs unreached, p < 0.0001). The predicting ability of ARGs signature was subsequently validated in two independent cohorts of GSE40272 & PRAD_MSKCC. Notably, the 19-ARG signature outperformed the typical clinical features or each involved ARG in predicting the DFS of PRAD. Furthermore, a prognostic nomogram was constructed with three independent prognostic factors, including the ARGs signature, T stage and Gleason score. The predicted results from the nomogram (C-index = 0.799, 95%CI = 0.744-0.854) matched well with the observed outcomes, which was verified by the calibration curves. The values of area under receiver operating characteristic curve (AUC) for DFS at 1-, 3-, 5-year for the nomogram were 0.82, 0.83, and 0.83, respectively, indicating the performance of nomogram model is of reasonably high accuracy and robustness. Moreover, functional enrichment analysis demonstrated the potential targets of E2F targets, G2M checkpoint pathways, and cell cycle pathways to suppress the PRAD progression. Of note, the high-risk PRAD patients were more sensitive to immune therapies, but Treg might hinder benefits from immunotherapies. Additionally, this established tool also could predict response to neoadjuvant androgen deprivation therapy (ADT) and some chemotherapy drugs, such as cisplatin, paclitaxel, and docetaxel, etc. The novel ARGs signature, with prognostic significance, can further promote the application of targeted therapies in different stratifications of PCa patients.


Assuntos
Adenocarcinoma , Neoplasias da Próstata , Adenocarcinoma/genética , Adenocarcinoma/terapia , Antagonistas de Androgênios , Humanos , Masculino , Próstata , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Transcriptoma , Microambiente Tumoral/genética
3.
BMC Med ; 20(1): 84, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35241087

RESUMO

BACKGROUND: Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC. METHODS: This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12. RESULTS: A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients. CONCLUSION: SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study. TRIAL REGISTRATION: Clinical trials.gov NCT02691975; registered February 25, 2016.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/farmacocinética , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Humanos , Masculino , Dose Máxima Tolerável , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia
4.
J Natl Compr Canc Netw ; 20(1): 54-62, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34653963

RESUMO

BACKGROUND: Although China accounts for 7.8% of worldwide new prostate cancer (PCa) cases and 14.5% of new deaths according to GLOBOCAN 2020, the risk of PCa associated with germline mutations is poorly defined, hampered in part by lack of nationwide evidence. Here, we sequenced 19 PCa predisposition genes in 1,836 Chinese patients with PCa and estimated disease risk associated with inherited mutations. PATIENTS AND METHODS: Patients were recruited from 4 tertiary cancer centers (n=1,160) and a commercial laboratory (n=676). Germline DNA was sequenced using a multigene panel, and pathogenic/likely pathogenic (P/LP) mutation frequencies in patients with PCa were compared with populations from the gnomAD (Genome Aggregation Database) and ChinaMAP (China Metabolic Analytics Project) databases. Clinical characteristics and progression-free survival were assessed by mutation status. RESULTS: Of 1,160 patients from hospitals, 89.7% had Gleason scores ≥8, and 65.6% had metastases. P/LP mutations were identified in 8.49% of Chinese patients with PCa. Association with PCa risk was significant for mutations in ATM (odds ratio [OR], 5.9; 95% CI, 3.1-11.1), BRCA2 (OR, 15.3; 95% CI, 10.0-23.2), MSH2 (OR, 15.8; 95% CI, 4.2-59.6), and PALB2 (OR, 5.9; 95% CI, 2.7-13.2). Compared with those without mutations, patients with mutations in ATM, BRCA2, MSH2, or PALB2 showed a poor outcome with treatment using androgen deprivation therapy and abiraterone (hazard ratio, 2.19 [95% CI, 1.34-3.58] and 2.47 [95% CI, 1.23-4.96], respectively) but similar benefit from docetaxel. CONCLUSIONS: The present multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata , Antagonistas de Androgênios , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Gradação de Tumores , Neoplasias da Próstata/patologia
5.
Curr Ther Res Clin Exp ; 95: 100653, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34917218

RESUMO

BACKGROUND: Both National Comprehensive Cancer Network and Chinese guidelines recommend beginning prostate-specific antigen (PSA) screening for men aged 50 years or 45 years with a family history because they were at a higher risk of developing prostate cancer. Several model-based economic evaluations of PSA screening studies have been conducted, but with little evidence from China. OBJECTIVE: The aim of this study was to conduct an economic evaluation of the cost-utility of PSA-based prostate cancer screening in Chinese men. METHODS: We developed a decision-tree and Markov model in Excel (Microsoft Corp, Redmond, Washington) to compare 2 strategies that can be used to detect prostate cancer: PSA-based screening followed by a biopsy, and non-PSA screening. We assumed that the patients would repeat screening in subsequent years if their first-year PSA value was higher than 4.0 ng/mL. The model adopted health care system perspective and lifetime horizon. Screening efficacy, cost, utility, and long-term survival of prostate cancer were retrieved from published literature and physician surveys. Both quality-adjusted life year and costs were discounted at an annual rate of 3.5%. Uncertainty was assessed by 1-way and probabilistic sensitivity analyses. Our model also calculated the risk-to-benefit ratio as the ratio of overdiagnosis (biopsy without diagnosed) to prostate cancer-related deaths prevented in different age groups. RESULTS: The results suggested that PSA-based screening was cost-effective compared with no PSA screening, with an incremental cost-utility ratio of ¥11,381 ($1821/€1480) per quality-adjusted life year. This value was less than the threshold of 1-time gross domestic product per capita in China (ie, ¥70,892 [$11,343/€9216]). Sensitivity analyses confirmed the robustness of the results. The risk-to-benefit ratios of the 50 to 65 years and the 65 to 80 years age groups were 1.3 and 2.8, respectively. CONCLUSIONS: PSA-based prostate cancer screening appears to be cost-effective in some high-risk Chinese men. PSA screening (PSA testing followed by magnetic resonance imaging and biopsy if positive) can be recommended for Chinese men aged 50 to 65 years because this approach had the lowest risk-to-benefit ratio. The approach should be further adapted based on future updated data. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX)© 2022 Elsevier HS Journals, Inc.

6.
Zhonghua Nan Ke Xue ; 27(6): 522-525, 2021 Jun.
Artigo em Zh | MEDLINE | ID: mdl-34914292

RESUMO

OBJECTIVE: To investigate the changes in the size of the penis after radical prostatectomy (RP) and the possible influencing factors. METHODS: This study included 45 cases of RP for PCa performed by the same surgeon from January to June 2019. Before and at 2 weeks after surgery, we measured the stretched penile length (SPL), flaccid penile length (FPL) and penile circumference of the patients. We conducted an IIEF-5 questionnaire investigation on the preoperative characteristics of the patients and their attitudes towards postoperative penile rehabilitation. We also analyzed the factors associated with the postoperative changes in the size of the penis. RESULTS: Compared with the baseline, the postoperative SPL (ï¼»9.72 ± 1.87ï¼½ vs ï¼»7.80 ± 1.57ï¼½ cm, P = 0), FPL (ï¼»6.26 ± 1.14ï¼½ vs ï¼»5.13 ± 1.10ï¼½ cm, P = 0) and penile circumference (ï¼»7.69 ± 0.83ï¼½ vs ï¼»7.26 ± 0.78ï¼½ cm, P = 0.012) were decreased significantly, by (1.92 ± 0.12) cm, (1.13 ± 0.09) cm and (0.43 ± 0.08) cm, respectively. The age of the patients was significantly correlated with the change of the FPL (P = 0.042), but not the other factors with the change of the penile size. Twenty-six (57.7%) cases of severe and moderate ED were observed in the patients postoperatively. Those with better preoperative sexual function took a more positive attitude towards penile rehabilitation and treatment postoperatively (n = 3, 75.0%). CONCLUSIONS: The penile size of the PCa patient is decreased markedly after radical prostatectomy, with a significant correlation between the patient's age and the postoperative change of the flaccid penile length. The patients with better preoperative sexual function are more likely to seek penile rehabilitation and treatment postoperatively.


Assuntos
Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Pênis , Período Pós-Operatório , Neoplasias da Próstata/cirurgia
7.
Oncologist ; 25(7): e1042-e1050, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32190957

RESUMO

BACKGROUND: Germline DNA damage repair gene mutations (gDDRm) have been found in approximately 12% of patients with metastatic prostate cancer (mPCa). Previous studies of the clinical impact of gDDRm have mainly been in the setting of metastatic castration-resistant prostate cancer (mCRPC). This study aimed to determine the prognostic value of gDDRm in de novo metastatic and castration-sensitive prostate cancer (mCSPC). MATERIALS AND METHODS: We retrospectively collected the records of 139 consecutive men with de novo mCSPC who initially received systemic therapies following guidelines. This included 128 patients who underwent genetic testing at our center and 11 patients referred to our center after being identified as gDDRm carriers. Time to mCRPC was collected. Kaplan-Meier and log-rank analysis were used to analyze the association between gDDRm and clinical outcomes. Survival outcomes were adjusted using multivariable Cox regression models. RESULTS: Of the 139 patients with de novo mCSPC, 28 gDDRm carriers were identified. Median time progressing to mCRPC was significantly shorter in patients carrying gDDRm than in those without mutations (8.3 vs 13.2 months; hazard ratio [HR], 2.37; p < .001). Moreover, median progression time was almost halved in BRCA2 carriers (6.3 vs. 13.2 months; HR, 3.73; p < .001). Subgroup analysis revealed that the presence of gDDRm indicated poor therapy response regardless of disease volume and prostate-specific antigen nadir within the first 7 months. Presence of gDDRm remained independently associated with increased risk of progression to mCRPC in multivariate analysis (adjusted HR, 1.98; p = .006). CONCLUSION: Our study suggested that positive gDDRm status predicted rapid progression to castration resistance in patients with de novo mCSPC. We propose identifying gDDRm status at the time of diagnosis for mCSPC patients, considering it is the first step of tailoring individualized treatment. In addition, DNA repair genes were a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and our results call for more frontline targeted therapy trials in gDDRm carriers to prolong the progression time. IMPLICATIONS FOR PRACTICE: Results of this study suggested that positive germline DNA damage repair gene mutation (gDDRm) status predicted earlier progression to castration resistance in patients with de novo metastatic and castration-sensitive prostate cancer (mCSPC). These findings indicated the importance of intense therapy for some subgroups of mCSPC, especially for mCSPC harboring gDDRm with low-volume disease. Moreover, gDDRm was a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and these findings call for more molecular marker driven trials moving to the mTNPC setting.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Castração , Reparo do DNA/genética , Células Germinativas , Humanos , Masculino , Mutação , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Estudos Retrospectivos
8.
Genome ; 63(4): 239-251, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32053407

RESUMO

Segregation distortion is a common phenomenon that has been observed in genetics and plant breeding; however, the mechanism of segregation distortion is unknown. In the present study, three half-sib F2 populations derived from three japonica overwinter (perennial) rice varieties (W1, W2, and W3) crossed to the indica rice variety Minghui725 (MH725) were developed to construct three half-sib linkage maps. We established linkage map lengths of 2032.8, 2317.4, and 2108.7 cM with average intervals of 20.1, 20.5, and 19.7 cM using 101, 113, and 107 SSR markers in W1/MH725, W2/MH725, and W3/MH725, respectively. Discrepancies in marker order and genetic linkage distance occurred in the three half-sib linkage maps due to segregation distortion. A total of 88 markers exhibited segregation distortion across the three linkage maps at P < 0.01 level, 42 segregation distortion loci (SDLs) were detected across the three half-sib populations and exhibited variable LOD value that ranged from 3.2 (SDL2f) to 30.1 (SDL5d), and 13 of the 42 SDLs were repeatedly located at the same chromosomal regions of the previously published hybrid sterility quantitative trait loci. Data from this study provide an extensive archive for investigating the genetic characteristic of overwintering cultivated rice and the future exploration and innovation of overwintering rice breeding.


Assuntos
Ligação Genética , Oryza/genética , Locos de Características Quantitativas/genética , Mapeamento Cromossômico , Marcadores Genéticos/genética , Genótipo
9.
Prostate ; 79(13): 1563-1571, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31376193

RESUMO

BACKGROUND: The rarities of primary neuroendocrine prostate cancer (NEPC) and primary adenocarcinoma with neuroendocrine differentiation (NE differentiation) mean that their clinical characteristics have not been fully elucidated. MATERIALS AND METHODS: A total of 449 patients with NEPC, including 352 cases of pure NEPC and 97 cases of NE differentiation, together with 408 629 cases of prostate adenocarcinoma at diagnosis were retrieved from the Surveillance, Epidemiology, and End Results program (2010-2015). Clinical parameters and prognoses were compared between patients with different histological types of NEPC using the χ2 test and Kaplan-Meier analysis, respectively. The prognostic value of prostate-specific antigen (PSA) in NEPC and adenocarcinoma was evaluated using Cox regression and the Kaplan-Meier method. RESULTS: Pure NEPC had higher rates of visceral metastases (brain, lung, and liver: 4.58%, 26.72%, and 36.64%, respectively) but a lower rate of bone metastasis (65.65%) compared with NE differentiation and prostate adenocarcinoma. Moreover, patients diagnosed with pure NEPC had a poorer outcome (median survival time: 10 months) compared with patients with NE differentiation (26 months) and prostate adenocarcinoma (median survival time not reached). Using PSA 4.1 to 10 ng/mL as the reference, the adjusted hazard ratios (HRs) for PSA lower than or equal to 4.0 ng/mL were 2.24 (95% confidence interval [CI]: 1.11-4.55, P = .025) in the NE differentiation group and 1.57 (95% CI: 1.11-2.23, P = .011) in the pure NEPC group. CONCLUSIONS: Patients with NE differentiation had different clinical characteristics and a better prognosis than patients with pure NEPC. In addition, low-serum PSA levels were associated with a poorer prognosis in patients with either NEPC or NE differentiation.


Assuntos
Adenocarcinoma/sangue , Antígenos de Neoplasias/sangue , Carcinoma Neuroendócrino/sangue , Proteínas de Neoplasias/sangue , Neoplasias da Próstata/sangue , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Carcinoma Neuroendócrino/epidemiologia , Carcinoma Neuroendócrino/patologia , Diferenciação Celular/fisiologia , Estudos de Coortes , Proteínas Ligadas por GPI/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Programa de SEER , Estados Unidos/epidemiologia , Adulto Jovem
10.
Zhonghua Nan Ke Xue ; 25(5): 329-332, 2019 Apr.
Artigo em Zh | MEDLINE | ID: mdl-32216214

RESUMO

OBJECTIVE: To investigate the attitudes of prostate cancer (PCa) patients towards postoperative penile rehabilitation and their influencing factors. METHODS: Seventy-nine PCa patients underwent radical prostatectomy from January through June 2017 and all received a questionnaire investigation before surgery on IIEF-5 and their attitudes towards postoperative penile rehabilitation. We analyzed the reasons for the patients' rejection of postoperative penile rehabilitation. RESULTS: Totally 56 (71%) of the patients accepted and the other 23 (29%) refused postoperative penile rehabilitation. The factors influencing their attitudes towards penile rehabilitation mainly included age (P = 0.023), income (P = 0.040), tumor stage (P = 0.044), and preoperative sexual activity (P = 0.004). The patients who accepted penile rehabilitation had significantly higher IIEF-5 scores than those who refused it (14.75 ± 0.88 vs 8.48 ± 1.16, P = 0.000 2). During the follow-up period, only 29 (36.7%) of the patients bought the vacuum erection device but not the other 50 (63.3%). The tumor stage (P = 0.004), income (P < 0.01) and preoperative androgen-deprivation therapy (P = 0.039) significantly influenced the patients' decision on the purchase of the device. Relevant admission education achieved a 45% decrease in the number of the patients unwilling to accept penile rehabilitation for worrying about its negative effect on cancer treatment, a 25% decrease in those rejecting penile rehabilitation because of age, and a 20% decrease in those refusing it due to the tumor stage. The cost of treatment was an important reason for the patients' rejection of postoperative penile rehabilitation. CONCLUSIONS: The tumor stage and income are the main factors influencing PCa patients' decision on postoperative penile rehabilitation. Relevant admission education and reduced cost of rehabilitation are important for popularization of postoperative penile rehabilitation in PCa patients.


Assuntos
Atitude , Disfunção Erétil/reabilitação , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Neoplasias da Próstata/reabilitação , Neoplasias da Próstata/cirurgia , Antagonistas de Androgênios/uso terapêutico , Humanos , Masculino , Ereção Peniana , Prostatectomia
11.
Mol Genet Genomics ; 293(1): 81-93, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28879498

RESUMO

Overwintering (OW) is the process by which rice passes through the winter season and germinates in the following spring. OW is also a typical quantitative inheritance trait. Currently, the molecular genetic basis of OW trait in Chinese perennial Dongxiang wild rice (DXWR) still remains to be known. In this study, a linkage map consisting of 139 simple sequence repeat (SSR) markers was constructed using an F2 population derived from a cross between DXWR and 93-11. This map covered the rice genome by approximately 1778.72 cM with approximately 12.80 cM average interval. The phenotype data of OW trait were investigated for QTL analysis in the following spring of 2017. The gene ontology (GO) annotation of the M-QTL was performed through the rice genome annotation project system. A major QTL-qOW6 was flanked by RM20069 (16,542,428 bp) and RM3498 (20,982,059 bp) on chromosome 6 and detected repeatedly by both inclusive composite interval and single-marker analysis mapping with an LOD score of 9.45 and explained 22.22% of phenotypic variance. In addition, two small QTLs (qOW2 and qOW3) controlling OW trait were detected on the second and third chromosomes, respectively. No epistatic interaction was detected between these QTLs, suggesting their unique genetic model. A total of 183 candidate genes at qOW6 locus were involved in 887 GO terms. Among them, 52 candidate genes were involved in response to stress. The other 28 candidate genes were related to cell membrane, which might affect the OW trait in perennial DXWR. These results may establish the foundation for understanding the genetic mechanism about OW trait and provide a novel gene resource for OW rice variety improvement.


Assuntos
Ligação Genética , Oryza/genética , Locos de Características Quantitativas/genética , Estresse Fisiológico/genética , Mapeamento Cromossômico , Cromossomos de Plantas/genética , Temperatura Baixa , Genes de Plantas/genética , Repetições de Microssatélites/genética , Oryza/crescimento & desenvolvimento , Fenótipo
12.
New Phytol ; 220(3): 878-892, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30019754

RESUMO

The pentatricopeptide repeat (PPR) protein family is a large family characterized by tandem arrays of a degenerate 35-amino-acid motif whose members function as important regulators of organelle gene expression at the post-transcriptional level. Despite the roles of PPRs in RNA editing in organelles, their editing activities and the underlying mechanism remain obscure. Here, we show that a novel DYW motif-containing PPR protein, PPS1, is associated with five conserved RNA-editing sites of nad3 located in close proximity to each other in mitochondria, all of which involve conversion from proline to leucine in rice. Both pps1 RNAi and heterozygous plants are characterized by delayed development and partial pollen sterility at vegetative stages and reproductive stage. RNA electrophoresis mobility shift assays (REMSAs) and reciprocal competition assays using different versions of nad3 probes confirm that PPS1 can bind to cis-elements near the five affected sites, which is distinct from the existing mode of PPR-RNA binding because of the continuity of the editing sites. Loss of editing at nad3 in pps1 reduces the activity of several complexes in the mitochondrial electron transport chain and affects mitochondrial morphology. Taken together, our results indicate that PPS1 is required for specific editing sites in nad3 in rice.


Assuntos
Mitocôndrias/metabolismo , Oryza/genética , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Edição de RNA/genética , Motivos de Aminoácidos , Sequência de Bases , Núcleo Celular/metabolismo , Sequência Conservada , Transporte de Elétrons , Evolução Molecular , Regulação da Expressão Gênica de Plantas , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Oryza/ultraestrutura , Fenótipo , Pólen/metabolismo , Pólen/ultraestrutura , Ligação Proteica , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo
13.
New Phytol ; 210(3): 934-45, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26781807

RESUMO

Cytoplasmic male sterility (CMS) and restoration of fertility (Rf) are widely distributed in plant species utilized by humans. RF5 and GRP162 are subunits of the restoration of fertility complex (RFC) in Hong-Lian rice. Despite the fact that the RFC is 400-500 kDa in size, the other proteins or factors in the complex still remain unknown. Here, we identified RFC subunit 3, which encodes a DUF1620-containing and WD40-like repeat protein (RFC3) that is present in all tissues but highly expressed in leaves. We established that RFC3 interacts with both RF5 and GRP162 in vitro and in vivo, and is transported into the mitochondria as a membrane protein. Furthermore, CMS RNA (atp6-orfH79) and CMS cytotoxic protein (ORFH79) accumulate when RFC3 is silenced in restorer lines. We presented the analysis with blue-native polyacrylamide gel electrophoresis, indicating that RFC is disrupted in the RNAi line. We concluded that RCF3 is indispensable as a scaffold protein for the assembly of the RFC complex. We unveil a new molecular player of the RFC in the Rf pathway in rice and propose the model of RFC based on these data.


Assuntos
Oryza/fisiologia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Sequências Repetitivas de Aminoácidos , Sequência de Aminoácidos , Sequência Conservada , Fertilidade , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Membranas Mitocondriais/metabolismo , Oryza/genética , Infertilidade das Plantas/genética , Plantas Geneticamente Modificadas , Ligação Proteica , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de Sequência
14.
World J Surg Oncol ; 14(1): 163, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27329038

RESUMO

BACKGROUND: Laparoscopic partial nephrectomy (LPN) is not a novel but a relatively technically challenging surgical procedure. Off-clamp LPN with zero ischemia can completely eliminate ischemic reperfusion injury to the kidney. The purpose of this study was to evaluate the safety and functional outcome of nephrometry score-guided off-clamp technique in LPN. METHODS: A total of 44 patients underwent LPN between January 2015 and July 2015 for renal mass with radius, exophytic/endophytic, nearness to sinus, anterior/posterior location (RENAL) score 4 were enrolled. Twenty-two of them underwent off-clamp LPN with zero ischemia, and the other 22 received standard LPN with common renal artery clamp. Estimate blood loss (EBL), total operation time, resection time, renorrhaphy time, preoperative estimated glomerular filtration rate (eGFR), postoperative eGFR, eGFR change, and drainage after surgery were compared between these two groups using t test. RESULTS: Patients' characteristics including gender, age, BMI, tumor size, and RENAL score were balanced between the two groups. Average EBL was more in the off-clamp group than in the on-clamp group (134.32 versus 70.23 ml, p = 0.001). Average eGFR change was less in the off-clamp group than in the on-clamp group (-1.56 versus -6.45, p < 0.001). Average drainage after surgery was 203.41 ml for the off-clamp group and 145.46 ml for the on-clamp group, p = 0.062. No urinary leakage and hematuria occurred in both groups. There were no statistical difference in total operation time, resection time, renorrhaphy time, preoperative eGFR, and postoperative eGFR between the two groups. CONCLUSIONS: Off-clamp LPN is a safe and feasible approach to excise certain kidney tumors with RENAL score 4. This technique can better preserve kidney function without ischemic reperfusion injury.


Assuntos
Carcinoma Papilar/cirurgia , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Laparoscopia/métodos , Nefrectomia/métodos , Tratamentos com Preservação do Órgão/métodos , Seleção de Pacientes , Carcinoma Papilar/patologia , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Duração da Cirurgia , Fatores de Tempo , Resultado do Tratamento
15.
Plant Cell ; 24(1): 109-22, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22247252

RESUMO

The cytoplasmic male sterility (CMS) phenotype in plants can be reversed by the action of nuclear-encoded fertility restorer (Rf) genes. The molecular mechanism involved in Rf gene-mediated processing of CMS-associated transcripts is unclear, as are the identities of other proteins that may be involved in the CMS-Rf interaction. In this study, we cloned the restorer gene Rf5 for Hong-Lian CMS in rice and studied its fertility restoration mechanism with respect to the processing of the CMS-associated transcript atp6-orfH79. RF5, a pentatricopeptide repeat (PPR) protein, was unable to bind to this CMS-associated transcript; however, a partner protein of RF5 (GRP162, a Gly-rich protein encoding 162 amino acids) was identified to bind to atp6-orfH79. GRP162 was found to physically interact with RF5 and to bind to atp6-orfH79 via an RNA recognition motif. Furthermore, we found that RF5 and GRP162 are both components of a restoration of fertility complex (RFC) that is 400 to 500 kD in size and can cleave CMS-associated transcripts in vitro. Evidence that a PPR protein interacts directly with a Gly-rich protein to form a subunit of the RFC provides a new perspective on the molecular mechanisms underlying fertility restoration.


Assuntos
Oryza/metabolismo , Oryza/fisiologia , Infertilidade das Plantas/fisiologia , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Dados de Sequência Molecular , Oryza/genética , Infertilidade das Plantas/genética , Proteínas de Plantas/genética
16.
Tumour Biol ; 36(5): 3573-82, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25566960

RESUMO

Clinical and epidemiological data suggest coronary artery disease shares etiology with prostate cancer (PCa). The aim of this work was to assess the effects of several serum markers reported in cardiovascular disease on PCa. Serum markers (oxidized low-density lipoprotein [ox-LDL], apolipoprotein [apo] B100, and apoB48) in peripheral blood samples from 50 patients from Fudan University Shanghai Cancer Center (FUSCC) with localized or lymph node metastatic PCa were investigated in this study. Twenty-five samples from normal individuals were set as controls. We first conducted enzyme-linked immunosorbent assay analysis to select candidate markers that were significantly different between these patients and controls. Then, the clinical relevance between OLR1 (the ox-LDL receptor) expression and PCa was analyzed in The Cancer Genome Atlas (TCGA) cohort. We also investigated the function of ox-LDL in PCa cell lines in vitro. Phosphorylation protein chips were used to analyze cell signaling pathways in ox-LDL-treated PC-3 cells. The ox-LDL level was found to be significantly correlated with N stage of prostate cancer. OLR1 expression was correlated with lymph node metastasis in the TCGA cohort. In vitro, ox-LDL stimulated the proliferation, migration, and invasion of LNCaP and PC-3 in a dose-dependent manner. The results of phosphoprotein microarray illustrated that ox-LDL could influence multiple signaling pathways of PC-3. Activation of proliferation promoting signaling pathways (including ß-catenin, cMyc, NF-κB, STAT1, STAT3) as well as apoptosis-associating signaling pathways (including p27, caspase-3) demonstrated that ox-LDL had complicated effects on prostate cancer. Increased serum ox-LDL level and OLR1 expression may indicate advanced-stage PCa and lymph node metastasis. Moreover, ox-LDL could stimulate PCa proliferation, migration, and invasion in vitro.


Assuntos
Lipoproteínas LDL/sangue , Neoplasias da Próstata/genética , Receptores Depuradores Classe E/biossíntese , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Lipoproteínas LDL/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Receptores Depuradores Classe E/sangue
17.
World J Surg Oncol ; 13: 132, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25886313

RESUMO

BACKGROUND: Bladder cancer is the second most common genitourinary malignancy. Our study was to introduce a standardized surgical procedure of retrograde radical cystectomy and consequent peritoneal cavity reconstruction in localized male bladder cancer. METHODS: Eighty-four consecutive male patients with localized bladder cancer (clinical stage T2 or lower) underwent surgery in our institute with the proposed procedure between May 2012 and April 2013. Median age was 65 years (range, 35 to 83 years); patient characteristics, surgical parameters, perioperative complications, pathology, and short-term prognosis were analyzed. Median follow-up was 24 months (range, 18 to 30 months). RESULTS: The complete procedure including urinary diversion took 4.0 h (2.2 to 5.0 h), with a median exposed peritoneal cavity of 45 min (0 to 75 min); the median blood loss was 140 ml (50 to 600 ml), and 2 patients needed transfusion; neurovascular bundles were reserved in 76 cases; the median abdominal and pelvic drainage was 9.0 days (6 to 15 days), the median gastrointestinal recovery was 2.5 days (1 to 12 days), and the median postoperative hospital stay was 13.0 days (10 to 21 days). Four patients had severe surgical complications, and two had mild to moderate ileus, with recovery in 1 and 2 weeks with supportive treatment. No perioperative deaths or postoperative recurrence were reported. CONCLUSIONS: The surgical procedure in male localized bladder cancer described in the present study provided surgical facilities, with limited abdominal organ disturbance and satisfactory tumor control. The procedure was associated with good gastrointestinal recovery, few postoperative complications, and a short hospital stay.


Assuntos
Cistectomia , Cavidade Peritoneal/cirurgia , Procedimentos de Cirurgia Plástica , Complicações Pós-Operatórias , Neoplasias da Bexiga Urinária/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Seguimentos , Humanos , Laparoscopia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Cavidade Peritoneal/patologia , Prognóstico , Neoplasias da Bexiga Urinária/patologia
18.
World J Surg Oncol ; 13: 172, 2015 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-25943443

RESUMO

BACKGROUND: The aim of this study is to assess the prognosis of prostate cancer (PCa) with lymph node metastases (LNM) detected in pelvic lymph node dissection (PLND) after radical prostatectomy (RP) and adjuvant androgen deprivation therapy (ADT) in a Chinese population. METHODS: From June 2005 to September 2012, the medical histories of 67 Chinese PCa patients with LNM detected after RP and extended PLND were collected, and all these patients received continuous adjuvant ADT. Postoperative survival was estimated using the Kaplan-Meier method. The impact of various clinicopathological factors on outcome was analyzed using Cox proportional hazard regression models. All tests were two-sided with P < 0.05 considered significant. RESULTS: Median follow-up was 46.7 months, and two patients were lost to follow-up. Five-year event-free survival for patients with positive lymph nodes was 93.0%, 83.0%, and 96.0% for local recurrence, systemic progression, and cancer death, respectively. One-year, 2-year, and 3-year biochemical recurrence (BCR)-free survival was 52%, 40%, and 22%, respectively. Postoperative BCR-free survival was 25.7 months. BCR-free survival for patients with a single LNM was longer than those with two or more LNM (median 39.1 months vs. median 17.2 months, P = 0.002). In a multivariate Cox model, only two or more LNM was a significant predictor of BCR (hazard ratio 2.6, P = 0.005). CONCLUSIONS: Despite low BCR-free survival, Chinese patients with LNM can benefit from RP and adjuvant ADT. Patients with low nodal metastatic burden had a favorable prognosis.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Linfonodos/patologia , Recidiva Local de Neoplasia/terapia , Prostatectomia/mortalidade , Neoplasias da Próstata/terapia , Idoso , China , Estudos de Coortes , Terapia Combinada , Seguimentos , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Taxa de Sobrevida
19.
Zhonghua Wai Ke Za Zhi ; 53(7): 543-6, 2015 Jul 01.
Artigo em Zh | MEDLINE | ID: mdl-26359080

RESUMO

OBJECTIVE: To evaluate clinical factors affecting Gleason score upgrade in patients receiving radical prostatectomy (RP). METHODS: A total of 322 patients with prostate cancer who received RP from January 2012 to December 2013 at Department of Urology at Fudan University Shanghai Cancer Center were included, and their data of age, body mass index (BMI), prostate-specific antigen (PSA), prostate volume, percentage core, clinical staging, pathological characteristics, biopsy Gleason score and RP Gleason score were analyzed. Differences in categorical variables and continuous variables were compared using χ² tests and Student's t-test, respectively. Unconditional multiple logistic regression was used to estimate OR and 95% CI of the association of Gleason score upgrade with clinical factors. RESULTS: Gleason score upgrade occurred in 107 of 322 (33.3%) patients. There was no difference in age, BMI and clinical staging between the two groups. Compared with patients without Gleason score upgrade, higher levels of PSA (χ² =6.740, P=0.034), smaller prostate volume (t=3.481, P=0.002) and elevated percentage core (t=-2.097, P=0.037) were observed in patients with Gleason score upgrade. In addition, lymph node metastasis (χ² =4.193, P=0.041) and extracapsular extension (χ² =4.747, P=0.029) were more common in patients with Gleason score upgrade. After adjusting for potential confounders, PSA levels (OR=2.451, 95% CI: 1.290-4.660), prostate volume (OR=0.982, 95% CI: 0.969-0.995) and percentage core (OR=2.756, 95% CI: 1.033-7.357) were independent predictors for Gleason score upgrade. CONCLUSION: Gleason score upgrade happens at a relatively high rate. PSA levels, prostate volume and percentage core are important factors affecting Gleason score upgrade.


Assuntos
Gradação de Tumores , Prostatectomia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/cirurgia , Biópsia , Índice de Massa Corporal , China , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Antígeno Prostático Específico/sangue
20.
Biochem Biophys Res Commun ; 444(2): 116-20, 2014 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-24434156

RESUMO

The glycine-rich proteins (GRP) containing RNA recognition motifs (RRM) are involved in the regulation of transcriptional and/or post-transcriptional events. Previous studies have established that GRP162 plays an important role in the restoration of fertility in Honglian cytoplasmic male sterile (HL-CMS) rice. In this study, the ion binding properties of rGRP162 were tested by isothermal titration calorimetry (ITC) and electrophoretic mobility shift assay (EMSA) was performed to test the interaction. Circular dichroism (CD) was carried out to detect the alteration of secondary structure in the presence and absence of Cu(2+). Furthermore, two RRM containing proteins, AtRBP45A and AtRBP47A, were expressed to validate the interaction. Results showed Cu(2+) and Fe(3+) bound GRP162, whereas Ca(2+), Mn(2+), Mg(2+) and K(+) did not. EMSA confirmed that interaction with Cu(2+) interrupted the biological activity of GRP162 by disrupting the secondary structure of the protein based on the results of CD. Moreover, the RNA binding activities of rAtRBP45A and rAtRBP47A were also impaired in the presence of Cu(2+). Data suggest that Cu(2+) in excess may disrupt RNA-binding proteins containing RRM that are essential for post-transcriptional regulation and may impair the development of plants or animals.


Assuntos
Cobre/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Sítios de Ligação , Ligação Competitiva , Calorimetria , Dicroísmo Circular , Cobre/química , Ensaio de Desvio de Mobilidade Eletroforética , Escherichia coli/genética , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/genética , Ligação Proteica , Estrutura Secundária de Proteína , RNA/química , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
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