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1.
Biomater Sci ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33458722

RESUMO

Bond cleavage bioorthogonal chemistry has been widely employed to restore or activate proteins or prodrugs. Nitric oxide (NO), as a free radical molecule, has joined the clinical arena of cancer therapy, since high levels of NO could produce a cancer cell growth inhibitory effect. However, the spatiotemporal controlled release of NO remains a great challenge, and bioorthogonal chemistry may open a new window. Herein, we described a class of O2-3-isocyanopropyl diazeniumdiolates 3a-f as new bioorthogonal NO precursors, which can be effectively uncaged via tetrazine-mediated bond cleavage reactions to liberate NO and acrolein in living cancer cells, exhibiting potent antiproliferative activity. Furthermore, 3a and tetrazine BTZ were respectively encapsulated into two liposomes. It was found that simultaneous administrations of the two liposomes could specifically release large amounts of NO in the implanted cancer cells in zebrafish, thus generating potent tumor suppression activity in vivo. Our findings indicate that the TZ-labile NO precursors could serve to expand the NO-based smart therapeutics and the scope of bioorthogonal chemistry utility in vivo in the near future.

2.
J Mol Diagn ; 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33271368

RESUMO

RNA sequencing (RNA-seq) is a well-validated tool for detecting gene fusions in fresh frozen tumors, whereas it is much more challenging to use it with formalin-fixed paraffin-embedded (FFPE) tumor samples. We evaluated the performance of RNA-seq to detect gene fusions in clinical FFPE tumor samples. Our assay identified all 15 spiked-in NTRK fusions from RNA reference material and 6 known fusions from 5 cancer cell lines. Limit of detection for the assay was assessed with a series of dilutions of RNA from the cell line H2228. These fusions can be detected when the dilution is down to 10%. Good intra- and inter-assay reproducibility was observed in three specimens. For clinical validation, the assay detected 10 of 12 fusions initially identified by a DNA panel (covering 23 gene fusions) in clinical specimens (83.3% sensitivity), whereas one fusion (MET fusion) was identified in another 34 fusion-negative tumor specimens as determined by the DNA panel (negative prediction value of 94.3%). This MET fusion was confirmed by RT-PCR and Sanger sequencing, which demonstrated that this is a false negative for DNA panel. The assay also identified 26 extra fusions not covered by the DNA panel, and 20 of them (76.9%) were validated by RT-PCR and Sanger sequencing. Therefore, this RNA assay has reasonable performance and could be a complement to DNA-based next-generation sequencing assays.

3.
ACS Omega ; 5(43): 28212-28223, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33163804

RESUMO

The CuO-La2O3/ZrO2 catalysts calcined at different temperatures from 500 to 800 °C were studied for the hydrogenation of oxalates to ethylene glycol (EG). Along with the increase of calcination temperatures, the BET surface area, pore volume, and Cu dispersion decreased, whereas the crystallite sizes of Cu species increased. Interestingly, the superior performance such as a 98% selectivity of EG in dimethyl oxalate hydrogenation or a 96.5% selectivity of EG in diethyl oxalate hydrogenation was obtained over the catalyst calcined at 700 °C. Essentially, the surface synergism between Cu species and monoclinic ZrO2 was enhanced by the higher calcination temperature, resulting in the remarkable surface adsorption and activation of H2. Besides, the increase of calcination temperature significantly reduced the surface acidity and basicity, which could effectively suppress the byproduct formation.

4.
J Med Chem ; 63(22): 13899-13912, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33141588

RESUMO

Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.

5.
Chin J Nat Med ; 18(8): 633-640, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32768171

RESUMO

To search for potent anti-ischemic stroke agents, a series of tetramethylpyrazine (TMP)/resveratrol (RES) hybrids 6a-t were designed and synthesized. These hybrids inhibited adenosine diphosphate (ADP)- or arachidonic acid (AA)-induced platelet aggregation, among them, 6d, 6g-i, 6o and 6q were more active than TMP. The most active compound 6h exhibited more potent anti-platelet aggregation activity than TMP, RES, as well as positive control ticlopidine (Ticlid) and aspirin (ASP). Furthermore, 6h exerted strong antioxidative activity in a dose-dependent manner in rat pheochromocytoma PC12 cells which were treated with hydrogen peroxide (H2O2) or hydroxyl radical (·OH). Importantly, 6h significantly protected primary neuronal cells suffered from oxygen-glucose deprivation/reoxygenation (OGD/R) injury, comparable to an anti-ischemic drug edaravone (Eda). Together, our findings suggest that 6h may be a promising candidate warranting further investigation for the intervention of ischemic stroke.

6.
J Med Chem ; 63(17): 9127-9135, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787095

RESUMO

Implantable medical device-related infections with biofilms have become a significant challenge in clinics. Based on the potential bacteria biofilm dispersing effect of nitric oxide (NO) and the unique antibacterial activity of antimicrobial peptides (AMP), we synthesized five peptides and selected the most potent one to conjugate its N-terminal with a furoxan moiety to offer a hitherto unknown NO-donating antimicrobial peptide (FOTyr-AMP), which exhibited Staphylococcus aureus and Escherichia coli biofilm dispersion and eradication, and potent antibacterial activities in vitro. In an implanted biofilm infection mice model, topical subcutaneous injection of FOTyr-AMP allowed synergetic eradication of bacterial biofilms and potent antibacterial activity, superior to the antibiotic cephalosporin C. Given the low hemolysis effect, little influence on the blood pressure, and potent in vivo efficacy of FOTyr-AMP, it is clear that subcutaneous administration of FOTyr-AMP could be a promising approach for the intervention of medical device-related biofilm infections with desirable safety.

7.
Liver Cancer ; 9(3): 308-325, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32647633

RESUMO

Introduction: The benefits of combining transarterial chemoembolization (TACE) and sorafenib (TACE-S) over TACE alone for treatment of unresectable hepatocellular carcinoma (HCC) remain controversial. Yet, such populations are heterogeneous in terms of baseline characteristics. Objective: To investigate the predictors of survival benefits from added sorafenib and identify the potential candidates for TACE-S. Methods: This multicenter observational study was conducted in 17 Chinese tertiary hospitals for patients with unresectable, liver-confined HCC. Eligible patients with performance status score of ≤1 and Child-Pugh score of ≤7 were treated with TACE or TACE-S. Interactions between treatment and baseline variables were evaluated to find indicators for survival benefits, based on which the patients were stratified. Multivariate models adjusted for baseline characteristics or propensity score were used to compare overall survival (OS) and time to tumor progression (TTP). Results: From January 2009 to December 2015, 1,719 consecutive patients received TACE (n = 1,406) or TACE-S (n = 313). Although TACE-S compared with TACE improved TTP (adjusted hazard ratio [HR] 0.75, p = 0.008), no difference in OS was observed (adjusted HR 0.87, p = 0.090). Nevertheless, the tumor burden (sum of maximum diameter of largest tumor [cm] and tumor number) and albumin-bilirubin (ALBI) score independently predicted the survival benefits from added sorafenib (interaction p< 0.001). For patients with either moderate tumor burden (7-13) or low ALBI score (no more than -2.8) defined as candidates, TACE-S prolonged OS (adjusted HR 0.73, p = 0.003) and TTP (adjusted HR 0.72, p = 0.014) compared to TACE alone, whereas its superiority disappeared in non-candidates. Conclusions: Not all unresectable HCC patients but those with moderate tumor burden or low ALBI score achieve survival benefits from TACE-S compared with TACE alone. Future randomized controlled trials focusing on the subset are warranted.

8.
Postepy Dermatol Alergol ; 37(2): 250-254, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32489362

RESUMO

Introduction: Previous studies found that vitamin D receptor (VDR) TaqI, BsmI, FokI and ApaI gene polymorphisms are associated with several inflammatory diseases. However, the relationship between VDR gene polymorphisms and chronic spontaneous urticaria (CSU) is not clear. Aim: The purpose of our study was to explore the relationship between the polymorphism of VDR and the incidence of chronic spontaneous urticaria in the Chinese Han population. Meanwhile, the vitamin D levels in patients with chronic spontaneous urticaria were also detected and the effects of VDR gene polymorphism on vitamin D levels were detected. Material and methods: The genotypes of four VDR polymorphisms (TaqI, BsmI, ApaI, and FokI) were studied using allele-specific PCR analysis in 90 CSU patients and 90 healthy controls. Results: Compared to the control group, the mutant allele (C) of FokI were more common in patients with CSU (57.2% vs. 45%, p = 0.020, odds ratio (OR) = 0.612, 95% confidence interval (CI): 0.403-0.928). We found that serum vitamin D levels were significantly lower in CSU patients than in healthy controls (p = 0.023). However, the effect of VDR gene polymorphism on vitamin D levels was not found in patients of CSU. Conclusions: We first reported the effect of VDR gene FokI (rs2228570) polymorphism on the incidence of chronic spontaneous urticaria in the Chinese Han population.

9.
Chin J Nat Med ; 18(4): 275-283, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32402405

RESUMO

Glaucoma is a disease that causes irreversible blindness. Reducing intraocular pressure (IOP) is the main treatment at present. Nitric oxide (NO), an endogenous gas signaling molecule, can increase aqueous humor outflow facility, inhibit aqueous humor production thereby reducing IOP, as well as regulate eye blood flow and protect the optic nerve. Therefore, NO donating anti-glaucoma drugs have broad research prospects. In this review, we summarize NO-mediated therapy for glaucoma, and the state of the art of some NO donating molecules, including latanoprostene bunod in market and some other candidate compounds, for the intervention of glaucoma, as well as prospects and challenges ahead in this field.

10.
Chem Commun (Camb) ; 56(29): 4130-4131, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32236266

RESUMO

Correction for 'O2-(6-Oxocyclohex-1-en-1-yl)methyl diazen-1-ium-1,2-diolates: a new class of nitric oxide donors activatable by GSH/GSTπ with both anti-proliferative and anti-metastatic activities against melanoma' by Chengfeng Bai et al., Chem. Commun., 2017, 53, 5059-5062.

11.
World J Gastroenterol ; 26(6): 657-669, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32103874

RESUMO

BACKGROUND: The treatment outcome of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) varies greatly due to the clinical heterogeneity of the patients. Therefore, several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE (re-TACE). AIM: To investigate the correlations between prognostic systems and radiological response, compare the predictive abilities, and integrate them in sequence for outcome prediction. METHODS: This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016. The Hepatoma Arterial-embolization Prognostic (HAP) score system and its modified versions (mHAP, mHAP2 and mHAP3), as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival (OS) prediction for first TACE. The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART (assessment for re-treatment with TACE) and ABCR (alpha-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh and Response) systems for post re-TACE survival (PRTS). RESULTS: All the prognostic systems were correlated with radiological response achieved by first TACE, and the six-and-twelve criteria exhibited the highest correlation (Spearman R = 0.39, P = 0.026) and consistency (Kappa = 0.14, P = 0.019), with optimal performance by area under the receiver operating characteristic curve of 0.71 [95% confidence interval (CI): 0.68-0.74]. With regard to the prediction of OS, the mHAP3 system identified patients with a favorable outcome with the highest concordance (C)-index of 0.60 (95%CI: 0.57-0.62) and the best area under the receiver operating characteristic curve at any time point during follow-up; whereas, PRTS was well-predicted by the ABCR system with a C-index of 0.61 (95%CI: 0.59-0.63), rather than ART. Finally, combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo, compared with non-candidates with a median PRTS of 20.0 mo (log-rank test P < 0.001). CONCLUSION: Radiological response to TACE is closely associated with tumor burden, but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.

12.
Mol Ther Nucleic Acids ; 19: 482-497, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-31902747

RESUMO

Hepatocellular carcinoma (HCC) accounts for approximately 85%-90% of primary liver cancers. Based on in silico analysis, differentially expressed long non-coding RNA (lncRNA) LINC01224 in HCC, the downstream microRNA (miRNA) miR-330-5p, and its target gene checkpoint kinase 1 (CHEK1) were selected as research subjects. Herein, this study was designed to evaluate their interaction effects on the malignant phenotypes of HCC cells. LINC01224 and CHEK1 were upregulated and miR-330-5p was downregulated in HCC cells. miR-330-5p shared negative correlations with LINC01224 and CHEK1, and LINC01224 shared a positive correlation with CHEK1. Notably, LINC01224 could specifically bind to miR-330-5p, and CHEK1 was identified as a target gene of miR-330-5p. When LINC01224 was silenced or miR-330-5p was elevated, the sphere and colony formation abilities and proliferative, migrative, and invasive potentials of HCC cells were diminished, while cell cycle arrest and apoptosis were enhanced. Moreover, LINC01224 induced HCC progression in vitro and accelerated tumor formation in nude mice by increasing CHEK1 expression. The key findings of the present study demonstrated that silencing LINC01224 could downregulate the expression of CHEK1 by competitively binding to miR-330-5p, thus inhibiting HCC progression. This result highlights the LINC01224/miR-330-5p/CHEK1 axis as a novel molecular mechanism involved in the pathology of HCC.

13.
Stem Cell Res Ther ; 10(1): 237, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387619

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common tumors globally, with varying prevalence based on endemic risk factors. Bone morphogenetic protein (BMP) exhibits a broad spectrum of biological activities in various tissues including angiogenesis. Here, this study aimed to investigate the mechanism of BMP2 in HCC by mediating the mitogen-activated protein kinase (MAPK)/p38 signaling pathway. METHODS: BMP2 expression was quantified in HCC and adjacent tissues. BMP2 gain- and loss-of-function experiments were conducted by infection with lentivirus over-expressing BMP2 or expressing shRNA against BMP2. The angiogenesis was evaluated with HepG2 cells co-cultured with ECV304 cells. SB-239063 was applied to inhibit the activation of the MAPK/p38 signaling pathway so as to identify the significance of this pathway in HCC progression. Finally, in vivo experiments were conducted to identify the role of BMP2 and the MAPK/p38 signaling pathway in tumor growth and angiogenesis. RESULTS: BMP2 was highly expressed in HCC. Over-expression of BMP2 was found to accelerate cell proliferation, migration, invasion, microvascular density, and angiogenesis and decrease cell apoptosis in vitro and in vivo. BMP2 silencing exhibited inhibitory effects on HCC cell invasion and angiogenesis. The co-culture system illustrated that HepG2 cells secreted BMP2 in ECV304, and silenced BMP2 in HepG2 cells resulted in the inactivation of the MAPK/p38 signaling pathway, thus suppressing cancer progression, tumor growth, and angiogenesis in HCC. CONCLUSION: Taken together, the key findings of this study propose that silencing of BMP2 inhibits angiogenesis and tumor growth in HCC, highlighting BMP2 silencing as a potential strategy for the treatment of HCC.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Carcinoma Hepatocelular/patologia , Células Endoteliais/metabolismo , Neoplasias Hepáticas/patologia , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Proteína Morfogenética Óssea 2/antagonistas & inibidores , Proteína Morfogenética Óssea 2/genética , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Endoteliais/citologia , Feminino , Células Hep G2 , Humanos , Imidazóis/farmacologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica , Pirimidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Nanomaterials (Basel) ; 9(9)2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31450756

RESUMO

A series of zeolites with different topology structures, including SAPO-34, SUZ-4, ZSM-5, USY, MOR, and beta, were used to synthesize polyoxymethylene dimethyl ethers (PODEn) from dimethoxymethane (DMM) and trioxymethylene (TOM). The influence of acidic properties and channel systems were studied by activity evaluation, characterization, and theoretical calculation. The results confirmed that pore mouth diameter larger than a TOM molecule was an essential prerequisite for the synthesis of PODEn over zeolites, and the synergistic effect between medium-strong Brønsted acid sites (Brønsted MAS) and the maximal space of zeolites available determined the catalytic performance of all studied zeolites. DMM and TOM were firstly decomposed into methoxymethoxy groups (MMZ) and monomer CH2O over Brønsted MAS. Subsequently, the steric constraint of the maximum included sphere, with an appropriate size in zeolite channels, can promote the combination of CH2O and MMZ to form transition species ZO(CH2O)nCH3, which reacted with the methyl-end group to form PODEn over Brønsted MAS. Moreover, the reaction temperature showed different effects on the product selectivity and distribution, which also mainly depends on the size of the maximum space available in zeolite channels.

15.
Mater Sci Eng C Mater Biol Appl ; 102: 820-828, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147054

RESUMO

Poly(d,l-lactide-co-glycolide) (PLGA) microspheres have been used as an injectable depot for prolonged release of octreotide (Sandostatin LAR®), a peptide drug for the treatment of acromegaly and gastrointestinal tumors. However, acylation and incomplete release of the encapsulated octreotide, as well as acidic degradation product-induced inflammation are the major challenges hampering widespread clinical applications of this delivery system. The purpose of this study was to develop a novel octreotide-delivering system utilizing naturally derived biodegradable material, silk fibroin (SF). Octreotide acetate was encapsulated in the SF microspheres with a high loading (8-10 wt%) using polyethylene glycol (PEG)-assisted emulsification method. The octreotide-SF microspheres exhibited a silk I structure (low crystallinity) and burst release in in vitro release studies. Ethanol treatment after microsphere formation significantly increased ß-sheet and silk II structure (high crystallinity) of the microspheres, significantly reducing the burst release and resulting in zero-order sustained release of octreotide over 102 days, and the data could be fit to the diffusion-driven release model. After the ethanol-treated microspheres were intramuscularly injected into rats at low (2 mg/kg) and high (8 mg/kg) octreotide doses, the plasma concentration of octreotide in the high dose group remained high (>50 pg/mL) at day 28 when compared to that of the control (pure drug at low dose) and low dose microsphere group. Interestingly, the plasma concentration for the high dose group at day 56 dramatically increased to >280 pg/mL observed at day 28. The low dose microsphere group showed a similar increase, but at a much lower level. The rebound octreotide level likely reflected degradation of the SF matrix which released tightly bound/trapped octreotide. Therefore, SF microspheres can deliver octreotide over a long period of time with release kinetics and the mechanism different from PLGA microsphere system.


Assuntos
Liberação Controlada de Fármacos , Fibroínas/química , Microesferas , Octreotida/farmacocinética , Animais , Bombyx , Etanol/química , Feminino , Metanol/química , Octreotida/sangue , Tamanho da Partícula , Ratos Sprague-Dawley
16.
Am J Transl Res ; 11(2): 983-990, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30899397

RESUMO

The apoptosis machinery is compromised in liver cancer (LC). The underlying mechanism needs to be further investigated. Histone deacetylases (HDAC) have multiple and strong biochemical activities. This study tests a hypothesis that HDAC11 prevents LC cell (LCC) apoptosis via modulating the p53 gene transcription. In this study, the LC tissues were collected from patients with LC. The LCCs were purified by magnetic cell sorting. The gene transcription activities of the LCCs were analyzed by immunoprecipitation (IP) and chromatin IP. We observed that the LCCs expressed high levels of HDAC11, which was negatively correlated with the expression of p53 in LCCs. Further findings indicated that HDAC11 formed a complex with Egr1, the transcription factor of p53. HDAC11 induced Egr1 deacetylation and thus prevented the p53 gene transcription. Over expression of HDAC11 in liver cells inhibited the cell apoptosis. Inhibition of the expression of HDAC11 in LCCs promoted the LCC apoptosis. In conclusion, HDAC11 plays a critical role in the compromising the expression p53 in LCC, which can be reversed by the inhibition of HDAC11. To regulate HDAC11 may have therapeutic potential for LC treatment.

17.
Spectrochim Acta A Mol Biomol Spectrosc ; 213: 210-217, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30690304

RESUMO

The present paper reported a hybrid structure for the optical recognition of PA (picric acid). This dye-MOF structure, named as R6h@EuBTC, consisted of a supporting matrix based on rare earth MOF and a sensing probe based on rhodamine dye, which was confirmed using XRD, IR, thermal and photophysical analysis. R6h@EuBTC's rhodamine absorption in visible region was enhanced by increasing PA concentrations, showing obvious color change and consequently colorimetric sensing. R6h@EuBTC's rhodamine emission component was increased by increasing PA concentrations, while its Eu emission component was slightly quenched by increasing PA concentrations, which offered self-calibrated sensing signals for ratiometric fluorescent sensing. Linear response and good selectivity were observed for both sensing channels with LOD of 3.9 µM. R6h@EuBTC's sensing mechanism towards PA was the combination of two procedures, which were the emission turn on effect of rhodamine component triggered by PA-released protons and the emission turn off effect of Eu component caused by its electron transfer procedure to PA, respectively. R6h@EuBTC's novelty was its two sensing channels and the practicability of naked eye detection.

18.
J Hepatol ; 70(5): 893-903, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30660709

RESUMO

BACKGROUND & AIMS: Previous prognostic scores for transarterial chemoembolization (TACE) were mainly derived from real-world settings, which are beyond guideline recommendations. A robust model for outcome prediction and risk stratification of recommended TACE candidates is lacking. We aimed to develop an easy-to-use tool specifically for these patients. METHODS: Between January 2010 and May 2016, 1,604 treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh A5-B7 and performance status 0 undergoing TACE were included from 24 tertiary centres. Patients were randomly divided into training (n = 807) and validation (n = 797) cohorts. A prognostic model was developed and subsequently validated. Predictive performance and discrimination were further evaluated and compared with other prognostic models. RESULTS: The final presentation of the model was "linear predictor = largest tumour diameter (cm) + tumour number", which consistently outperformed other currently available models in both training and validation datasets as well as in different subgroups. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were further selected as cut-off values, leading to the "six-and-twelve" score which could divide patients into 3 strata with the sum of tumour size and number ≤6, >6 but ≤12, and >12 presenting significantly different median survival of 49.1 (95% CI 43.7-59.4) months, 32.0 (95% CI 29.9-37.5) months, and 15.8 (95% CI 14.1-17.7) months, respectively. CONCLUSIONS: The six-and-twelve score may prove an easy-to-use tool to stratify recommended TACE candidates (Barcelona Clinic Liver Cancer stage-A/B) and predict individual survival with favourable performance and discrimination. Moreover, the score could stratify these patients in clinical practice as well as help design clinical trials with comparable criteria involving these patients. Further external validation of the score is required. LAY SUMMARY: There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials. The six-and-twelve score provides patient survival prediction, especially in ideal candidates of TACE, outperforming other currently available models in both training and validation sets, as well as different subgroups. With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 strata with significantly different outcomes and may shed light on risk stratification of these patients in clinical practice as well as in clinical trials.


Assuntos
Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica , Neoplasias Hepáticas/mortalidade , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Carga Tumoral
19.
Chem Sci ; 9(34): 6893-6898, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30210764

RESUMO

Currently, there is no effective therapy for the treatment of highly metastatic triple-negative breast cancer (TNBC). Microvesicle (MV) formation is crucial for the metastasis of TNBC. Here we report a novel strategy to inhibit the generation of MVs for the intervention of TNBC. O2-3-Aminopropyl diazeniumdiolates 3a-f are designed and synthesized, which can be activated by lysyloxidase over-expressed in TNBC cells. The most active compound 3f is able to selectively release high levels of NO in TNBC cells, inhibit the cell proliferation, and reduce the adhesion, invasion and migration of TNBC cells in vitro. Furthermore, 3f significantly suppresses the growth and metastasis of implanted TNBC in vivo through attenuating MV formation by an epigenetic modification of miR-203/RAB22A expression in an NO-dependent manner, providing the first evidence of NO donor(s) acting as epigenetic modulators to fight highly metastatic TNBC.

20.
Bioorg Med Chem Lett ; 28(18): 3064-3066, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30119957

RESUMO

A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b exhibited excellent activity against the three tested strains. Both of them were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, and were far more potent than INH and RIF against MDR-TB 16833 and 16995 strains. Thus, both of them could act as leads for further optimization.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrocompostos/farmacologia , Oximas/farmacologia , Amidas/síntese química , Amidas/química , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Oximas/química , Relação Estrutura-Atividade
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