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1.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

2.
Bioengineered ; 12(1): 3398-3409, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34224316

RESUMO

Our previous study found that in nasopharyngeal carcinoma (NPC) cells, overexpression of Notch2 can inhibit epithelial-mesenchymal transition (EMT), which plays a vital role in mediating radiosensitivity. The purpose of this study was to explore the radiosensitizing efficacy of the Notch2 gene in NPC cells and its potential mechanism. We used the recombinant plasmid transfection technique to establish Notch2-overexpressing 5-8 F and CNE-2 NPC cells. Cell proliferation, radiosensitivity, apoptosis and cell cycle distribution were assessed by cell counting kit-8 (CCK-8) experiments, colony formation experiments and flow cytometry. The levels of proteins related to cell cycle, apoptosis, and the AKT/mTOR signaling pathway were evaluated by using Western blotting. The results suggested that Notch2 overexpression increased the radiosensitivity of NPC cells, with sensitizing enhancement ratios (SERs) of 1.24 (5-8 F cells) and 1.34 (CNE-2 cells). Flow cytometry indicated that the level of apoptosis and percentage of cells in G2/M-phase were highest in NPC cells overexpressing Notch2 and treated with radiotherapy compared to cells overexpressing Notch2 alone or administered radiotherapy alone. Western blotting showed that compared to that of cells treated with Notch2 overexpression or radiotherapy alone, the levels of γH2AX, Bax, Bcl-2, Cyclin D1 and AKT/mTOR signaling pathway-related proteins were modified in NPC cells overexpressing Notch2 and treated with radiotherapy. These findings showed that overexpression of Notch2 can increase the radiosensitivity of NPC cells by inhibiting the AKT/mTOR pathway.AbbreviationsNPC: Nasopharyngeal carcinoma; EMT: Epithelial-mesenchymal transition; CCK8: Cell counting kit-8; EBV: Epstein-Barr virus; FBS: Fetal bovine serum; PE: Plating efficiency; SF: Survival fraction; SER: Sensitizing enhancement ratio; DSBs: DNA double-strand breaks[Figure: see text].

3.
Semin Ophthalmol ; 36(8): 800-803, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33998380

RESUMO

Purpose: To describe the spectral-domain optical coherence tomography (SD-OCT) features of typical cystoid degeneration.Methods: This was a retrospective study of 11 eyes with typical cystoid degeneration (TCD). All patients had a complete ocular examination, ultra-widefield (UWF) pseudocolor fundus photography and SD-OCT with a 55° wide-field lens. We analyzed the cross-sectional structural information of SD-OCT imaging with TCD.Results: On SD-OCT, the TCD regions exhibited rolling hills patterns with irregularly elevated retinal surface, and multiple intraretinal hyporeflective cavities separated by irregular septums were seen in the neurosensory retina. Destructive changes were seen in the ellipsoid zone and the pigment epithelium. Consolidated vitreous with moderate to high reflectivity was seen over the lesion and there might be vitreoretinal adhesions and tractions.Results: SD-OCT shows exquisite structural features of the anatomy in vivo detail of the TCD. This imaging technique may deepen our structural understanding of TCD and may influence decision-making in clinical practice.

4.
PLoS One ; 16(3): e0248957, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33755708

RESUMO

The characteristics and evolution of pulmonary fibrosis in patients with coronavirus disease 2019 (COVID-19) have not been adequately studied. AI-assisted chest high-resolution computed tomography (HRCT) was used to investigate the proportion of COVID-19 patients with pulmonary fibrosis, the relationship between the degree of fibrosis and the clinical classification of COVID-19, the characteristics of and risk factors for pulmonary fibrosis, and the evolution of pulmonary fibrosis after discharge. The incidence of pulmonary fibrosis in patients with severe or critical COVID-19 was significantly higher than that in patients with moderate COVID-19. There were significant differences in the degree of pulmonary inflammation and the extent of the affected area among patients with mild, moderate and severe pulmonary fibrosis. The IL-6 level in the acute stage and albumin level were independent risk factors for pulmonary fibrosis. Ground-glass opacities, linear opacities, interlobular septal thickening, reticulation, honeycombing, bronchiectasis and the extent of the affected area were significantly improved 30, 60 and 90 days after discharge compared with at discharge. The more severe the clinical classification of COVID-19, the more severe the residual pulmonary fibrosis was; however, in most patients, pulmonary fibrosis was improved or even resolved within 90 days after discharge.


Assuntos
Inteligência Artificial , COVID-19/patologia , Fibrose Pulmonar/diagnóstico , Tórax/diagnóstico por imagem , COVID-19/complicações , COVID-19/virologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Fibrose Pulmonar/etiologia , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
5.
J Control Release ; 331: 460-471, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33545218

RESUMO

Cisplatin is one of the most used first-line anticancer drugs for various solid tumor therapies. However, cisplatin-based chemotherapy can induce tumor cells to secrete excessive prostaglandin E2 (PGE2) catalyzed by cyclooxygenase-2 (COX-2), which, in turn, counteracts its chemotherapeutic effect and further accelerates tumor metastasis. Here, we report a carrier-free self-delivered nanoprodrug based on platinum (II) coordination bonding coupled with tolfenamic acid (Tolf) (named Tolfplatin). Tolfplatin can spontaneously assemble into uniformly sized nanoparticles (NPs) with a high drug-loading capacity. Compared with cisplatin, Tolfplatin NPs can facilitate cellular uptake, significantly decrease PGE2 secretion by COX-2 inhibition, which further downregulate tumorous anti-apoptotic and metastasis-associated proteins, thereby efficiently inducing apoptotic cell death and significantly inhibit tumor metastasis in vitro and in vivo. Therefore, as the carrier-free nanoprodrug, Tolfplatin NPs are promising anti-tumoral agents to inhibit tumor proliferation and metastasis by enriching the function and promoting the anti-tumor activity of cisplatin.


Assuntos
Antineoplásicos , Neoplasias da Mama , Nanopartículas , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Feminino , Humanos , Platina
7.
J Infect Dis ; 222(11): 1784-1788, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-32491178

RESUMO

The current discharge criteria for COVID-19 require that patients have 2 consecutive negative results for reverse transcription polymerase chain reaction (RT-PCR) detection. Here, we observed that recurrent positive RT-PCR test results in patients with 3 consecutive negative results (5.4%) were significantly decreased compared with those in patients with 2 consecutive negative results (20.6%); such patients reported positive RT-PCR test results within 1 to 12 days after meeting the discharge criteria. These results confirmed that many recovered patients could show a positive RT-PCR test result, and most of these patients could be identified by an additional RT-PCR test prior to discharge.


Assuntos
COVID-19/terapia , Alta do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/virologia , Teste de Ácido Nucleico para COVID-19/métodos , Teste para COVID-19/métodos , China/epidemiologia , Técnicas de Laboratório Clínico/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Testes Sorológicos , Adulto Jovem
8.
Cell Metab ; 31(5): 892-908.e11, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32375062

RESUMO

Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib's benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP-activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.

9.
Nanoscale ; 12(16): 8664-8678, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227023

RESUMO

Effective treatment in clinic for idiopathic pulmonary fibrosis (IPF) remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-inflammatory macrophages (M1/M2 macrophages). Herein, a novel endogenous cell-targeting nanoplatform (PNCE) is developed for enhanced IPF treatment efficacy through modulating M1/M2 macrophages into the balanced status to suppress fibroblast over-activation. Notably, PNCE loaded with nintedanib (NIN) and colchicine (COL) can firstly target endogenous monocyte-derived multipotent cells (MOMCs) and then be effectively delivered into IPF lungs due to the homing ability of MOMCs, and detached sensitively from MOMCs by matrix metalloproteinases-2 (MMP-2) over-expressed in IPF lungs. After PNCE selectively accumulated within fibrosis foci, COL can mildly modulate the polarization of M1 macrophages into M2 macrophages to balance innate immune responses, which can enhance the suppressing effect of NIN on fibroblast activation, further improving the IPF therapy. Altogether, PNCE has two collaborative steps including the inhibition of innate immune responses accompanied by the decrease of fibroblast populations in IPF lungs, achieving a stronger and excellent anti-fibrotic efficacy both in vitro and in vivo. This endogenous cell-based engineered liposomal nanoplatform not only allows therapeutic drugs to take effect selectively in vivo, but also provides an alternative strategy for an enhanced curative effect by modulating innate immune responses in IPF therapy.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Imunossupressores/administração & dosagem , Macrófagos/efeitos dos fármacos , Animais , Colchicina/administração & dosagem , Colchicina/química , Colchicina/farmacocinética , Sistemas de Liberação de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose Pulmonar Idiopática/imunologia , Imunossupressores/química , Imunossupressores/farmacocinética , Indóis/administração & dosagem , Indóis/química , Indóis/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Células-Tronco Multipotentes/efeitos dos fármacos , Células-Tronco Multipotentes/metabolismo , Nanomedicina
10.
Int J Biol Macromol ; 141: 85-97, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31473314

RESUMO

Nanogels have been recently attracted attentions because they exhibit significantly different behaviors compared with nanoparticles. Among them, chitosan (CS) nanogels have gained considerable attentions from researchers for in vivo applications due to bioactivity, biodegradability, mucoadhesiveness, and biocompatibility of CS. In this review, we have summarized the applications of CS nanogels for efficient drug delivery. Specifically, CS nanogels can be modified by pH-sensitive groups or specific ligands to obtain the corresponding functions. These functional CS nanogels have been used to deliver therapeutic agents, such as anti-cancer drugs, genes, and vaccines. By reviewing the recent research progress on CS nanogels in pharmaceutical applications, it will provide biomaterial researchers potential help for the development of CS nanogel delivery system to meet clinical needs.


Assuntos
Antineoplásicos , Quitosana , Portadores de Fármacos , Técnicas de Transferência de Genes , Nanogéis , Vacinas , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Quitosana/química , Quitosana/uso terapêutico , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Nanogéis/química , Nanogéis/uso terapêutico , Vacinas/química , Vacinas/uso terapêutico
11.
Ann Transl Med ; 7(23): 726, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32042742

RESUMO

Background: Closure of traumatic macular hole (TMH) can be achieved spontaneously or by surgical intervention. Thus far, there exist no prospective comparative studies that have analyzed the difference between the two modalities. This study aimed to compare the anatomical and visual recovery of eyes with TMH following either an immediate vitrectomy or six-month observation. Methods: This was a multicenter prospective comparative study. Eight centers participated in the study. Patient data from 40 eyes with a recent history of blunt ocular trauma and newly formed full-thickness TMH were recruited in this study. The participating patients selected between an early vitrectomy or a six-month observation after a doctor explained the potential benefits and risks of both strategies in an unbiased manner. Twenty-five patients underwent an immediate vitrectomy, and 15 patients received six-month observation. Patients were assessed by spectral-domain optical coherence tomography (SD-OCT) and best-corrected visual acuity (BCVA). Results: Closure rates were 66.7% for the observational group, and 100% for the surgical group (P=0.002). There were no vision-threatening ocular complications in both groups. For the observational group, the mean closure time was 2.5±1.6 months, and 80% of the hole closure occurred within 3 months; cystic edema on the edge of the hole at baseline was significantly more frequent in the non-closed subgroup than in the closed subgroup (P=0.03). There were no significant differences in the foveal microstructure and in the final visual outcome between the spontaneously closed cases and the surgically closed cases. Conclusions: TMH had a moderately high incidence of spontaneous closure, but an immediate vitrectomy achieved an even higher closure rate. Vitrectomy was effective and safe to treat TMH, while a 3-month observation for spontaneous closure may be an alternative modality for TMH management. Cystic edema on the edge of the hole may be an unfavorable factor for the spontaneous closure of TMH.

12.
Hepatology ; 69(2): 524-544, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29381809

RESUMO

Tumor progression locus 2 (TPL2), a serine/threonine kinase, has been regarded as a potentially interesting target for the treatment of various diseases with an inflammatory component. However, the function of TPL2 in regulating hepatocyte metabolism and liver inflammation during the progression of nonalcoholic fatty liver disease (NAFLD) is poorly understood. Here, we report that TPL2 protein expression was significantly increased in fatty liver from diverse species, including humans, monkeys, and mice. Further investigations revealed that compared to wild-type (WT) littermates, hepatocyte-specific TPL2 knockout (HKO) mice exhibited improved lipid and glucose imbalance, reserved insulin sensitivity, and alleviated inflammation in response to high-fat diet (HFD) feeding. Overexpression of TPL2 in hepatocytes led to the opposite phenotype. Regarding the mechanism, we found that mitogen-activated protein kinase kinase 7 (MKK7) was the specific substrate of TPL2 for c-Jun N-terminal kinase (JNK) activation. TPL2-MKK7-JNK signaling in hepatocytes represents a promising drugable target for treating NAFLD and associated metabolic disorders. Conclusion: In hepatocytes, TPL2 acts as a key mediator that promotes both liver and systemic metabolic disturbances by specifically increasing MKK7-JNK activation.


Assuntos
Hepatócitos/metabolismo , Inflamação/metabolismo , Resistência à Insulina , MAP Quinase Quinase Quinases/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Haplorrinos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase 7/metabolismo , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Proteínas Proto-Oncogênicas/genética
13.
Int J Ophthalmol ; 11(11): 1796-1801, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30450310

RESUMO

AIM: To compare the incidence of persistent submacular fluid (SMF) and visual outcome after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) in different preoperative macular status according to optical coherence tomography (OCT). METHODS: A non-randomized, retrospective review was performed for patients who underwent successful PPV for RRD. OCT exams were taken preoperatively and 1mo after surgery, until SMF disappeared. According to the preoperative macular status on OCT, patients were divided into two groups: macula-off RRD (Group A) and macula-on RRD (Group B). In Group A, there were two subgroups: macula partly detached (Group A1) and macula totally detached (Group A2). The main outcome measures were the presence of SMF on OCT 1mo after surgery, and the preoperative and postoperative best corrected visual acuities (BCVA), among the different groups and depending on the presence or absence of persistent SMF. RESULTS: A total of 139 eyes of 139 patients were included in the study. Persistent SMF at 1mo after surgery was 15.8% (22/139), all occurring in Group A (22/101); Group B had no SMF at 1mo after surgery (0/38, P=0.002). The incidence of persistent SMF at 1mo after surgery in Group A1 was 50% (14/28), and in Group A2 was 11.0% (8/73, P<0.001). Significant differences were shown between the presence and absence of persistent SMF on foveola-off RRD, the preoperative BCVA, the 1mo postoperative BCVA, and the degree of the BCVA improvement from 1mo postoperatively to the final follow-up (P<0.05). However, there were no significant differences in the final BCVA (P>0.05). CONCLUSION: Persistent SMF after PPV for retinal detachment is associated with preoperative macular status. Macula-uninvolving RRD shows no persistent SMF after PPV. Macular partly detached RRD has a higher incidence of SMF than macula totally detached RRD after PPV. The persistence of SMF may be responsible for the delayed visual recovery, whereas there were no significant differences in the final visual acuity.

14.
Oncol Lett ; 16(2): 1863-1868, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30008877

RESUMO

Identifying patients who may or may not achieve pathologic complete response (pathCR) allows for treatment with alternative approaches in the preoperative setting. The aim of the current study was to investigate whether aneuploidy of chromosome 8 and mutations of circulating tumor cells (CTCs) could predict the response of patients with rectal cancer to preoperative chemoradiotherapy. A total of 33 patients with locally advanced rectal cancer (cT3-T4 and/or cN+) treated with neoadjuvant chemoradiotherapy between September 2014 and March 2015 were recruited. Blood samples were collected from 33 patients with pre-chemoradiotherapy rectal cancer. It was demonstrated that ≥5 copies of chromosome 8 was associated with pathCR (univariate logistic regression, P=0.042). Of the 6 patients whose CTCs had <5 copies of chromosome 8, 3 achieved pathCR (3/6, 50%), and of the 27 patients whose CTCs had ≥5 copies of chromosome 8 obtained 3 pathCR (3/27, 11.1%; Chi-square test, P=0.0255). Of the 33 patients with mutations assessed, 8 significant nonsynonymous mutations in CTCs were identified as associated with pathCR (Chi-square test, P-values range, 0.0004-0.0298; mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 and AR). These results suggest that ≥5 copies of chromosome 8 and 8 nonsynonymous mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 AR in CTCs were associated with pathCR. This conclusion should be validated further in larger prospective studies and the long-term follow-up survival data of this study will also be reported in the future.

15.
Int J Ophthalmol ; 11(7): 1217-1221, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30046542

RESUMO

AIM: To evaluate the safety and efficacy of intravitreal conbercept (IVC) injections as pretreatment for pars plana vitrectomy (PPV) in severe proliferative diabetic retinopathy (PDR). METHODS: This was a retrospective chart review of all patients who underwent PPV for PDR from January 2014 to October 2016. Patients who underwent IVC injection before PPV were assigned to the IVC group; the others were assigned to the control group. The IVC was performed 3-7d before surgery in the IVC group. All the eyes in the two groups were operated by the same doctor to complete the vitrectomy. Intraoperative complications and the changes in best-corrected visual acuity (BCVA) before and after surgery were compared between the two groups. RESULTS: A total of 68 eyes of 63 patients (22 eyes in the IVC group and 46 eyes in the control group) were examined. The risk of intraoperative bleeding was lower in the IVC group (2/22) than in the control group (25/46, P=0.000). Furthermore, the use of endodiathermy was significantly lower in the IVC group (1/22) than in the control group (12/46, P=0.047). The surgical time in the IVC group (112.64±34.52min) was significantly shorter than in the control group (132.85±40.04min, P<0.05). Compared to the BCVA before surgery, the mean BCVA was significantly improved after surgery for both groups (P<0.05). CONCLUSION: PPV is an effective treatment and can improve vision in patients with PDR. Preoperative intravitreal injection of conbercept could reduce the chances of intraoperative bleeding and the use of endodiathermy and shorten the operative time, which are beneficial in the management of PDR.

16.
Br J Radiol ; 91(1089): 20170594, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29927628

RESUMO

OBJECTIVE:   The goal of the study was to analyze the incidence and patterns of failure in patients with gastric cancer who received D2 dissection and adjuvant chemoradiotherapy (CRT). METHODS:   From January 2004 to October 2015, 324 patients with gastric cancer who underwent radical D2 resection followed by postoperative CRT were enrolled. Clinicopathological characteristics and patterns of failure were retrospectively reviewed to identify factors associated with survival and recurrence. RESULTS:   After a median follow-up of 30 months, the 3-year overall survival and 3-year disease-free survival rates of these patients were 60.3 and 51.1%, respectively. 117 patients had recurrence or metastasis, with peritoneal recurrence as the most frequent (20.7%), followed by distant metastasis (14.2%). The most commonly involved distant organs were the liver (5.9%) and bone (4.9%). Locoregional failure occurred in 39 patients (12.0%), with isolated regional failure occurring in only 23 (7.1%). Further multivariate Cox regression analysis revealed N stage to be an independent risk factor for distant failure-free survival (p = 0.012). Independent risk factors for peritoneal metastasis were tumor differentiation (p = 0.022), T stage (p =0.035) and vascular invasion (p = 0.016). CONCLUSION: Postoperative CRT has a potential effect on optimizing locoregional control, resulting in only 12.0% of locoregional failure. In patients after D2 resection and adjuvant CRT, peritoneal metastasis was the leading pattern of failure, followed by distant metastasis. Advances in knowledge: Peritoneal recurrence was the most common pattern of failure after D2 dissection and adjuvant CRT, followed by distant metastasis, whereas locoregional relapse was relatively rare. Selection of patients based on the predicted risk of each recurrence pattern may be a reasonable approach to the optimization of treatment strategies.


Assuntos
Quimiorradioterapia Adjuvante , Neoplasias Gástricas/terapia , Idoso , Análise de Variância , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Análise de Sobrevida , Falha de Tratamento
18.
Hepatology ; 67(4): 1320-1338, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29077210

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a prevalent and complex disease that confers a high risk of severe liver disorders. Despite such public and clinical health importance, very few effective therapies are currently available for NAFLD. We report a protective function and the underlying mechanism of dual-specificity phosphatase 14 (DUSP14) in NAFLD and related metabolic disorders. Insulin resistance, hepatic lipid accumulation, and concomitant inflammatory responses, key pathological processes involved in NAFLD development, were significantly ameliorated by hepatocyte-specific DUSP14 overexpression (DUSP14-HTG) in high-fat diet (HFD)-induced or genetically obese mouse models. By contrast, specific DUSP14 deficiency in hepatocytes (DUSP14-HKO) aggravated these pathological alterations. We provided mechanistic evidence that DUSP14 directly binds to and dephosphorylates transforming growth factor ß-activated kinase 1 (TAK1), resulting in the reduced activation of TAK1 and its downstream signaling molecules c-Jun N-terminal kinase 1 (JNK), p38, and nuclear factor kappa B NF-κB. This effect was further evidenced by the finding that inhibiting TAK1 activity effectively attenuated the deterioration of glucolipid metabolic phenotype in DUSP14-HKO mice challenged by HFD administration. Furthermore, we identified that both the binding domain and the phosphatase activity of DUSP14 are required for its protective role against hepatic steatosis, because interruption of the DUSP14-TAK1 interaction abolished the mitigative effects of DUSP14. CONCLUSION: Hepatocyte DUSP14 is required for maintaining hepatic metabolic homeostasis and for suppressing inflammation, a novel function that relies on constraining TAK1 hyperactivation. (Hepatology 2018;67:1320-1338).


Assuntos
Fosfatases de Especificidade Dupla/metabolismo , Hepatócitos/metabolismo , Homeostase/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Western Blotting , Humanos , Imuno-Histoquímica , Resistência à Insulina/genética , Fígado/metabolismo , Fígado/patologia , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
19.
Nat Med ; 24(1): 73-83, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29227475

RESUMO

Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.


Assuntos
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Araquidonato 12-Lipoxigenase/metabolismo , Fígado/irrigação sanguínea , Receptores Acoplados a Proteínas G/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/antagonistas & inibidores , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biossíntese , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Metabolismo dos Lipídeos , Camundongos , Traumatismo por Reperfusão/parasitologia , Suínos
20.
Int J Ophthalmol ; 10(10): 1539-1544, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29062773

RESUMO

AIM: To assess peripapillary retinal nerve fiber layer (RNFL) and choroidal thickness obtained with enhanced depth imaging (EDI) mode compared with those obtained without EDI mode using Heidelberg Spectralis optical coherence tomography (OCT). METHODS: Fifty eyes of 25 normal healthy subjects and 32 eyes of 20 patients with different eye diseases were included in the study. All subjects underwent 3.4 mm diameter peripapillary circular OCT scan centered on the optic disc using both the conventional and the EDI OCT protocols. The visualization of RNFL and choroidoscleral junction was assessed using an ordinal scoring scale. The paired t-test, intraclass correlation coefficient (ICC), 95% limits of agreement (LoA), and Bland and Altman plots were used to test the agreement of measurements. RESULTS: The visibility score of RNFL obtained with and without EDI was of no significant difference (P=0.532), the visualization of choroidoscleral junction was better using EDI protocol than conventional protocol (P<0.001). Peripapillary RNFL thickness obtained with EDI was slightly thicker than that obtained without EDI (103.25±9.42 µm vs 101.87±8.78 µm, P=0.010). The ICC of the two protocols was excellent with the value of 0.867 to 0.924, the 95% LoA of global RNFL thickness was between -10.0 to 7.4 µm. Peripapillary choroidal thickness obtained with EDI was slightly thinner than that obtained without EDI (147.23±51.04 µm vs 150.90±51.84 µm, P<0.001). The ICC was also excellent with the value of 0.960 to 0.987, the 95% LoA of global choroidal thickness was between -12.5 to 19.8 µm. CONCLUSION: Peripapillary circular OCT scan with or without EDI mode shows comparable results in the measurement of peripapillary RNFL and choroidal thickness.

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