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1.
J Am Chem Soc ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32240585

RESUMO

Axially chiral tetra-ortho-substituted biaryl skeleton exists in numerous biologically important natural products, pharmaceutical molecules, chiral catalysts and ligands. The efficient synthesis of chiral tetra-ortho-substituted biaryl structures remains a challenging but unsolved problem. Among various asymmetric synthetic protocols, enantioselective Suzuki-Miyaura cross-coupling represents one of the most straightforward and versatile approaches. Herein we describe a powerful Suzuki-Miyaura coupling enabled by a P-chiral monophosphorus ligand BaryPhos, providing a broad range of synthetically challenging chiral tetra-ortho-substituted biaryls in excellent enantioselectivities and yields. In addition to the enhanced reactivity for sterically hindered cross-coupling, the rational design of BaryPhos also enabled a new catalysis mode of asymmetric cross-coupling involving noncovalent interactions between the ligand and two coupling partners, to effect efficient stereoinduction. This protocol is robust and practical, allowing for a concise enantioselective synthesis of therapeutically valuable male contraceptive and antitumor agent gossypol.

2.
Science ; 368(6486): 85-89, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32241947

RESUMO

Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC - is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC - subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

3.
Eur J Obstet Gynecol Reprod Biol ; 248: 156-163, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32217429

RESUMO

OBJECTIVES: To evaluate the preventive effects of low-dose aspirin on the incidence of preeclampsia and pregnancy outcomes of women at high-risk for preeclampsia. STUDY DESIGN: This prospective randomized clinical trial was conducted at the Obstetrics Department of The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, China. It analyzed data from 1105 high-risk women who were divided into the control group (placebo group) and the aspirin group (including three subgroups: 25 mg, 50 mg and 75 mg). The aspirin group in this study was instructed to take aspirin daily before bedtime beginning in the 12th week of pregnancy. MAIN OUTCOME MEASURES: The primary outcome is the occurrence of preeclampsia. The secondary outcomes included maternal and neonatal outcomes (such as premature delivery, FGR etc.), maternal serum biomarkers (including d-dimers, platelet aggregation rates, etc.) and uterine arterial blood flow resistance. The onset of preeclampsia and pregnancy outcomes were recorded after all participants delivered. RESULTS: Low-dose aspirin significantly reduced the incidence of preeclampsia and early-onset preeclampsia. Aspirin also showed significant dose dependence in preeclampsia prevention. The results of Mantel-Haenszel trend test showed that there was a linear relationship between the dosage and the incidence of preeclampsia and early preeclampsia (P < 0.05). Pearson's results showed that the incidence of preeclampsia and early preeclampsia was negatively correlated with aspirin dosage. There was also a linear relationship between the dosage and the rates of postpartum hemorrhage, fetal growth restriction, premature births and cesarean section (P < 0.05). There was no evidence to suggest differences in the incidence of fetal distress, miscarriage and placental abruption among the four groups. The blood resistance S/D value of uterine artery in early pregnancy was the only independent factor affecting the efficacy of aspirin (OR = 1.405; 95 %CI,1.058-1.867; P = 0.019). CONCLUSION: Low-dose aspirin can prevent preeclampsia and early-preeclampsia. Its efficacy is dose-dependent. It can reduce the rates of postpartum hemorrhage, fetal growth restriction, premature births and cesarean section. The prophylactic effect of aspirin on preeclampsia seemed to be greater in patients with higher blood resistance S/D value of uterine artery during early pregnancy.

4.
Trends Immunol ; 41(4): 327-340, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32139316

RESUMO

Deubiquitinases are enzymes that remove ubiquitin moieties from the vast majority of cellular proteins, controlling their stability, interactions, and localization. The expression and activity of deubiquitinases are critical for physiology and can go awry in various diseases, including cancer. Based on recent findings in human blood cancers, we discuss the functions of selected deubiquitinases in acute leukemia and efforts to target these enzymes with the aim of blocking leukemia growth and improving disease outcomes. We focus on the emergence of the newest generation of preclinical inhibitors by discussing their modes of inhibition and their effects on leukemia biology.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32215739

RESUMO

PURPOSE: Styloidectomy is the mainstream treatment for Eagle's syndrome when conservative treatment fails. However, the clinical efficacy of tonsil-sparing styloidectomy remains controversial. This study aimed to evaluate postoperative pain after tonsil-sparing styloidectomy in patients with Eagle's syndrome. METHODS: This retrospective study enrolled 14 patients who underwent tonsil-sparing styloidectomy (TSS group) and 22 patients who underwent traditional tonsillect-styloidectomy (TTS group). Pain was evaluated using the 11-point numeric rating scale (NRS-11) at the following time points: on admission, 1 day after the operation, 3 days, postoperatively, 1 week postoperatively, 2 weeks, postoperatively, and 3 months, postoperatively. RESULTS: The postoperative course was uneventful in both groups. Pain with movement was significantly reduced 3 months, postoperatively (1.28 ± 1.1), compared with the preoperative baseline level (4.78 ± 0.9) (P < 0.001). There was no significant difference in the rate at which pain decreased between the TSS group (n = 9/14; 64.3%) and the TTS group (n = 17/22; 77.3%) (P = 0.396). One week postoperatively, resting pain in the TSS group (4.36 ± 0.7) was significantly lower than that in the TTS group (5.41 ± 0.8) (P = 0.001); pain with movement in the TSS group (5.00 ± 0.8) was significantly lower than that in the TTS group (5.86 ± 0.7) (P = 0.002). Two weeks postoperatively, resting pain in the TSS group (1.14 ± 0.4) was also significantly lower than that in the TTS group (1.73 ± 0.6) (P = 0.003). CONCLUSIONS: Tonsil-sparing styloidectomy is a safe and effective modality for treating Eagle's syndrome. Although there was no significant difference in surgical risk or long-term outcomes between tonsil-sparing styloidectomy and traditional tonsillect-styloidectomy, tonsil-sparing styloidectomy can alleviate perioperative pain.

6.
Fitoterapia ; 143: 104550, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32173424

RESUMO

Six new polycyclic polyprenylated acylphloroglucinols, hyperfols CH (1-6), along with seven known ones (7-13), were isolated from the aerial parts of Hypericum perforatum. The structures were identified on the basis of comprehensive spectroscopic data analysis including 1D and 2D NMR, and the absolute configurations of the new compounds were determined by quantum chemical electronic circular dichroism (ECD) calculations. In addition, compounds 4 and 12 exhibited moderate acetylcholinesterase (AChE) inhibitory activities, with IC50 values of 20.32 and 27.37 µM, respectively.

7.
Phytother Res ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32185841

RESUMO

Microcirculation, which connects macrocirculation and cells between arterioles and venules, plays a major role in the early onset of a variety of diseases. In this article, a dextran-induced microcirculation dysfunction (MCDF) model rats were adopted to evaluate the effects and mechanism of Salvia miltiorrhiza stem-leaf extracts based on plasma and urine metabonomics. The results showed the effective components of S. miltiorrhiza stem-leaf could significantly improve the hemorheology and coagulation index of MCDF rats and callback the expression of endothelin-1 (ET-1), induciblenitric oxide synthase (iNOS), vascularendothelial growth factor (VEGF), P-Selectin, thromboxane A2, 6-keto-PGF1α , TNF-α, and interleukin-1ß to control group in MCDF rats. The decrease of microvessel density (MVD) in lung and thymus caused by MCDF was upgraded by Salvia miltiorrhiza stem-leaf. Based on the plasma and urine metabolic data, 20 potential biomarkers were identified. These biomarkers are mainly related to linoleic acid metabolism, glutathione metabolism, pantothenate and coenzyme A biosynthesis, pentose and glucuronate interconversions, pyruvate metabolism, glyoxylate and dicarboxylate metabolism, beta-alanine metabolism, and citrate cycle. The results indicated that the effective components of S. miltiorrhiza stem-leaf can improve the hemorheological disorder and vascular endothelial function. Meanwhile, the effective components can regulate potential biomarkers and correlated metabolic pathway, which can provide guidance for the research and development of new drugs for MCDF.

8.
Biomolecules ; 10(2)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050706

RESUMO

Multidrug resistance in Pseudomonas aeruginosa is a noticeable and ongoing major obstacle for inhibitor design. In P. aeruginosa, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) acetyltransferase (PaLpxA) is an essential enzyme of lipid A biosynthesis and an attractive drug target. PaLpxA is a homotrimer, and the binding pocket for its substrate, UDP-GlcNAc, is positioned between the monomer A-monomer B interface. The uracil moiety binds at one monomer A, the GlcNAc moiety binds at another monomer B, and a diphosphate form bonds with both monomers. The catalytic residues are conserved and display a similar catalytic mechanism across orthologs, but some distinctions exist between pocket sizes, residue differences, substrate positioning and specificity. The analysis of diversified pockets, volumes, and ligand positions was determined between orthologues that could aid in selective inhibitor development. Thenceforth, a complex-based pharmacophore model was generated and subjected to virtual screening to identify compounds with similar pharmacophoric properties. Docking and general Born-volume integral (GBVI) studies demonstrated 10 best lead compounds with selective inhibition properties with essential residues in the pocket. For biological access, these scaffolds complied with the Lipinski rule, no toxicity and drug likeness properties, and were considered as lead compounds. Hence, these scaffolds could be helpful for the development of potential selective PaLpxA inhibitors.

9.
Asian J Androl ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32031084

RESUMO

The aims of this study were to determine the prognostic value of primary tumor surgery and identify optimal candidates for such surgery among patients with seminoma and distant metastasis at diagnosis. We identified 521 patients with seminoma and distant metastasis at diagnosis between 2004 and 2014 from the Surveillance, Epidemiology, and End Results database. Among these patients, 434 had undergone surgery, whereas 87 had not. The prognostic value of primary tumor surgery was assessed by Kaplan-Meier methods, log-rank analyses, and multivariate Cox's proportional hazards model. Survival curves and forest plots were also plotted. Survival analysis indicated that patients who underwent surgery had a better 5-year overall survival and cancer-specific survival than those who did not. Multivariate analyses demonstrated that primary tumor surgery is an independent prognostic factor for overall survival and cancer-specific survival, along with age at diagnosis, M stage, and marital status. In addition, primary tumor surgery still had considerable prognostic value in the subgroup of patients with lymph node metastasis. Further, forest plots demonstrated that patients with M1a stage, N1 or N2-3 stage, and a younger age at diagnosis (<60 years) may benefit from primary tumor surgery. In conclusion, our findings indicate that primary tumor surgery is correlated with improved survival in patients with seminoma and distant metastasis. Furthermore, primary tumor surgery is an independent prognostic indicator for patients with seminoma and distant metastasis.

10.
Theranostics ; 10(5): 2374-2384, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089746

RESUMO

Liquid biopsy has emerged in the last ten years as an appealing noninvasive strategy to support early cancer diagnosis and follow-up interventions. However, conventional liquid biopsy strategies involving specified biomarkers have encountered unexpected inconsistencies stemming from the use of different analytical methodologies. Recent reports have repeatedly demonstrated that integrated detection of multiple liquid biopsy biomarkers can significantly improve diagnostic performance by eliminating the influence of intratumoral heterogeneity. Herein, we review the progress in the field of liquid biopsy and propose a novel integrated liquid biopsy framework consisting of three categories: elementary, intermediate, and advanced integration. We also summarize the merits of the integration strategy and propose a roadmap toward refining cancer diagnosis, metastasis surveillance, and prognostication.

11.
Biomed Res Int ; 2020: 4030826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32090087

RESUMO

Circular RNAs are a class of endogenous noncoding RNAs that play an important role in gene regulation. These RNAs are involved in the development and progression of various cancers, but their roles in gastric cancer have not yet been thoroughly elucidated. This study showed that hsa_circ_0000467 expression was higher in gastric cancer tissues than in corresponding adjacent tissues (P < 0.050) and that hsa_circ_0000467 expression levels were correlated with gastric cancer histological grade (P < 0.050). In addition, hsa_circ_0000467 was remarkably upregulated in gastric cancer cell lines (P < 0.001). Cell function experiments indicated that hsa_circ_0000467 downregulation decreased the proliferation and invasion ability of BGC-823 and SGC-7901 cells and the number of cells entering the G2/M phase. A direct binding interaction was detected between hsa_circ_0000467 and miR-326-3p by dual-luciferase reporter assays. In addition, the results showed that inhibition of miR-326-3p reversed the decreases in the proliferation and invasion of BGC-823 and SGC-7901 cells caused by hsa_circ_0000647 downregulation. Inhibition of miR-326-3p also decreased the number of cells entering the G2/M phase and the expression of cyclin D1. In conclusion, hsa_circ_0000467 plays a regulatory role in the development and progression of gastric cancer by regulating miR-326-3p, and this circRNA may be a potential diagnostic marker and therapeutic target of gastric cancer.

12.
J Obstet Gynaecol Res ; 46(4): 646-653, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32045956

RESUMO

AIM: To investigate the clinicopathologic characteristic and fertility results of patients with mucinous borderline ovarian tumors (MBOTs), and the effects of intraepithelial carcinoma (IECA) on them. METHODS: Fifty-two patients treated for MBOTs with or without IECA were retrospectively analyzed. RESULTS: Patients with IECA were more frequently observed at stage Ic (3/12 vs 1/40, P = 0.034) and accompanied by microinvasive carcinoma (3/12 vs 1/40, P = 0.034). The detected rate of IECA by intraoperative frozen section (5/12, 41.7%) was much lower than that of MBOTs (82.5%, P = 0.010). About 61.5% patients in our study underwent fertility-sparing surgery. Follow-up information was retained completely in 41 patients. And all four tumor recurrences were observed (9.8%) in conservative surgery group in 66 months, though there was no statistical association (P = 0.280). There were three patients who recurred more than once, even one occurred tumor-related death. Only one recurrent patient was in IECA group (P > 0.05). However, patients with IECA were more likely to receive adjuvant chemotherapy (3 of 12 vs 0 of 40, P = 0.010) and surgical staging (75% vs 52.5%, P = 0.200). As for fertility results, nine patients wished to be pregnant and seven of them (77.8%) were successful. CONCLUSION: For young patients with MBOTs, fertility results are satisfactory after conservative surgery. But patients should be fully informed about the relative high recurrent rate. And IECA has no statistical negative effects on MBOTs till now, but a long-term follow-up is required.

13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 34-39, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027250

RESUMO

OBJECTIVE: To explore the expression of miR-155 in patients with chronic lymphocytic leukemia (CLL) and its correlation with the clinical and biological features in CLL. METHODS: The expression of miR-155 was detected by quantitative real time polymerase chain reaction (qRT-PCR) in the peripheral mononuclear cells collected from 73 CLL patients and CD19 positive B cells collected from 60 healthy controls, respectively. The expression of miR-155 in CLL patients was compared with the healthy controls, and the correlation of miR-155 expression with the clinical characteristics of CLL patients such as age, sex, Binet stage, cytogenetic and molecular genetic, as well as the relationship of miR-155 expression level with time to treatment (TTT) and overall survival (OS) was further analysed. RESULTS: The expression of miR-155 was significantly elevated in CLL patients compared with the healthy controls. Further analysis showed that miR-155 expression decreased in the patients with the mutated immunoglobulin heavy chian variable region (IGHV) as compared with the patients unmutated (P<0.05), and its expression was significant higher in the IGHV-39 family (P<0.05). Fluorescence in situ hybridization (FISH) showed that the expression of miR-155 increased in patients with P53 mmutation/deletion and ATM deletion (P<0.05). However, OS and TTT were not different between the patients with high and low expression of miR-155. CONCLUSION: MiR-155 is increasingly expresses in CLL patients and correlates with poor prognosis, suggesting its important role in the genesis and progress of CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B , MicroRNAs/genética , Humanos , Região Variável de Imunoglobulina , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Prognóstico
14.
Respir Med ; 163: 105881, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32056835

RESUMO

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular disease (CVD). As a new inflammatory biomarker of CVD, rare attention has been paid to the roles of lipoprotein-associated phospholipase (Lp-PLA2) in OSAS studies. In this study, we aimed to investigate the correlation between Lp-PLA2 and concomitant CVD in OSAS patients. METHODS: In this prospective study, 152 OSAS patients were further divided into mild, moderate, and severe OSAS subgroups. They presented heart failure, coronary artery disease, or arrhythmia were confirmed with CVD. Thirty-one subjects without OSAS were recruited for the control group. The relationship between Lp-PLA2 and concomitant CVD in OSAS patients was analyzed. RESULTS: Serum Lp-PLA2 values were significantly higher in the severe and moderate OSAS group compared with mild OSAS and OSAS negative groups (P = 0.025). Significant increase was noticed in serum Lp-PLA2 levels in CVD patients compared with those without in severe-moderate-mild OSAS (P < 0.05). In logistic regression analysis, the level of Lp-PLA2 was proved as a significant independent predictor for CVD (OR = 1.117, P = 0.008). The ROC analysis indicated that the best cut-off value of Lp-PLA2 for predicting CVD in OSAS patients was 238.09 ng/ml. The positive and negative predictive values were 72.5% and 70.5%, respectively. The sensitivity was 46.8% and the specificity was 87.8%. CONCLUSIONS: Lp-PLA2 might be associated with the severity of OSAS and the occurrence of CVD in OSAS patients. Lp-PLA2 is expected to be a promising biomarker candidate in predicting CVD in patients with OSAS due to test convenience.

15.
HPB (Oxford) ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31980306

RESUMO

BACKGROUND: Aging of the population and prolonged life expectancy have significantly increased the number of elderly patients undergoing hepatectomy for hepatocellular carcinoma (HCC). However, potential benefits, especially long-term oncologic outcomes of hepatectomy for elderly patients with HCC remain unclear. METHOD: Patients treated with curative-intent hepatectomy for HCC in 8 Chinese hospitals were enrolled. Patients were divided into the elderly (≥70 years old) and younger (<70 years old) groups. Overall survival (OS), cancer-specific survival (CSS), and time-to-recurrence (TTR) were compared. Risk factors of CSS and TTR were evaluated by univariable and multivariable competing-risk regression analyses. RESULTS: Of 2134 patients, 259 (12.1%) and 1875 (87.9%) were elderly and younger aged, respectively. Postoperative 30-day and 90-day mortality was comparable among elderly and younger patients. Compared with younger patients, the elderly had a worse 5-year OS (49.4% vs. 55.3%, P = 0.032), yet a better 5-year CCS (74.5% vs. 61.0%, P = 0.005) and a lower 5-year TTR (33.7% vs. 44.9%, P < 0.001), respectively. Multivariable analyses identified that elder age was independently associated with more favorable CSS (HR 0.74, 95%CI 0.58-0.90, P = 0.011) and TTR (0.69, 0.53-0.88, P < 0.001) but was not associated with OS (P = 0.136). CONCLUSIONS: Age by itself is not a contraindication to surgery, and selected elderly patients with HCC can benefit from hepatectomy. Compared with younger patients, elderly patients have noninferior oncologic outcomes following hepatectomy for HCC.

16.
Bioorg Chem ; 95: 103527, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31911298

RESUMO

Diabetes mellitus (DM) is a serious chronic metabolic disorder which occurs due to dysfunction of insulin and therapeutic approaches are poor. It is an under estimation that 387 million people currently suffering globally with diabetic and more than 592 million people may be affected by 2030. It makes an urgent necessity to discover novel drugs to control amplified diabetic populations. In this study, amino chalcones (3a-j) were synthesized and hydroxy chalcones (3g-j) were isolated from natural source such as Sophora interrupta, Clerodendrum phlomidis and Andrographis macrobotrys. Structural elucidation was carried out using Mass, 1H and 13C NMR Spectra. In vivo studies were carried out with alloxan induced diabetic rats (100 mg/kg) which reveals compounds 3c, 3a and 3h have significant antidiabetic efficacy with decreased blood glucose levels in the diabetic rats while compared with control rats. Besides, docking studies with aldose reductase, dipeptidyl peptidase, PPAR and glucosidase were monitored which accomplishes that the compounds 3c, 3i, 3a and 3d have eloquent binding affinity (kcal/mol) with aldose reductase, besides the chalcones 3c, 3b, 3d, 3e and 3i were also showed inhibition with DPP-IV, PPAR-α and α-glucosidase. Also, these compounds explicated distinct interactions i.e., π-π, π-cationic, polar, electrostatic and hydrophobic bonds were observed with key residues of binding pockets. Bioavailability is disclosed with Lipinski rule of five and the design pharmacokinetic as well as pharmacodynamic properties are reliable. Therefore, chalcones were implied as antidiabetic leads for in further studies and could be worthwhile for the development of new classes of effective antidiabetic agents.

17.
Sci Total Environ ; 709: 136164, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31927431

RESUMO

With the backdrop of continuous global change, it is beneficial to create consistent long-term records of sea ice area on regional scales for ice disaster prevention and risk mitigation. In this study, a piecewise multiple nonlinear regression model was developed to reconstruct long-term daily sea ice area dataset in the Bohai Sea from 1958 to 2015 by linking the related meteorological data and the satellite-derived ice area. The validation analysis show that related meteorological status corresponding to physical process had stable skill of predictive ability, which was able to account for 81% of the observational variance under consideration of sea ice state, freezing and melting phases. The reconstructed daily sea ice area dataset was further used to study the interannual and seasonal variability of sea ice area. The annual maximum ice area (AMIA) and the annual average ice area (AAIA) in the Bohai Sea exhibited a decreasing trend with fluctuation of -0.33 ± 0.18% yr-1 and -0.51 ± 0.16% yr-1 over the period of 1958-2015, respectively. The most obvious change of the Bohai Sea ice area occurred in time scale of ~30 years. The whole study period could be divided into slight increasing stage (1958-1980), significant decreasing stage (1980-1995), and moderate increasing stage (1995-2015). In most years, the annual changes of sea ice area showed an unimodal variation and the freezing period (~65 days) was longer than the melting phase (~40 days) due to the relatively higher freezing rate. In addition, high correlations between AAIA and Arctic Oscillation (AO) index (r = -0.60, p < .01) and North Atlantic Oscillation (NAO) index (r = -0.69, p < .01) from 1958 to 2015 suggested AO and NAO are the primary large-scale climate factors driving the sea ice variability in the Bohai Sea.

18.
Radiology ; 294(3): 568-579, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31934830

RESUMO

Background Early stage hepatocellular carcinoma (HCC) is the ideal candidate for resection in patients with preserved liver function; however, cancer will recur in half of these patients and no reliable prognostic tool has been established. Purpose To investigate the effectiveness of radiomic features in predicting tumor recurrence after resection of early stage HCC. Materials and Methods In total, 295 patients (median age, 58 years; interquartile range, 50-65 years; 221 men) who underwent contrast material-enhanced CT and curative resection for early stage HCC that met the Milan criteria between February 2009 and December 2016 were retrospectively recruited from three independent institutions. Follow-up consisted of serum α-fetoprotein level, liver function tests, and dynamic imaging examinations every 3 months during the first 2 years and then every 6 months thereafter. In the development cohort of 177 patients from institution 1, recurrence-related radiomic features were computationally extracted from the tumor and its periphery and a radiomics signature was built with least absolute shrinkage and selection operator regression. Two models, one integrating preoperative and one integrating pre- and postoperative variables, were created by using multivariable Cox regression analysis. An independent external cohort of 118 patients from institutions 2 and 3 was used to validate the proposed models. Results The preoperative model integrated radiomics signature with serum α-fetoprotein level and tumor number; the postoperative model incorporated microvascular invasion and satellite nodules into the above-mentioned predictors. In both study cohorts, two radiomics-based models provided better predictive performance (concordance index ≥0.77, P < .05 for all), lower prediction error (integrated Brier score ≤0.14), and larger net benefits, as determined by means of decision curve analysis, than rival models without radiomics and widely adopted staging systems. The radiomics-based models gave three risk strata with high, intermediate, or low risk of recurrence and distinct profiles of recurrent tumor number. Conclusion The proposed radiomics models with pre- and postresection features helped predict tumor recurrence for early stage hepatocellular carcinoma. © RSNA, 2020 Online supplemental material is available for this article.

19.
Trends Cancer ; 6(1): 62-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31952783

RESUMO

Metastasis contributes to the vast majority of cancer-related mortality. Regulatory mechanisms of the multistep invasion-metastasis cascade are being unraveled. TP53 is the most frequently mutated gene across human cancers. Accumulating evidence has shown that mutations of TP53 not only lead to loss of function or dominant negative effects, but also promotes a gain of function. Specifically, gain of function mutant p53 promotes cancer cell motility, invasion, and metastasis. Here, we summarize the mechanisms and functions of mutant p53 that foster metastasis in different types of cancers. We also discuss the prognostic value of mutant p53 and current status of therapeutic strategies targeting mutant p53. Future studies will shed light on discovering novel mechanisms of mutant p53-driven cancer metastasis and developing innovative therapeutics to improve clinical outcomes in patients harboring p53 mutations.

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