Neutrophil extracellular traps promote acetaminophen-induced acute liver injury in mice via AIM2.

Excessive acetaminophen (APAP) can induce neutrophil activation and hepatocyte death. Along with hepatocyte dysfunction and death, NETosis (a form of neutrophil-associated inflammation) plays a vital role in the progression of acute liver injury (ALI) induced by APAP overdose. It has been shown that activated neutrophils tend to migrate towards the site of injury and participate in inflammatory processes via formation of neutrophil extracellular traps (NETs). In this study we investigated whether NETs were involved in hepatocyte injury and contributed to APAP-induced ALI progression. ALI mouse model was established by injecting overdose (350 mg/kg) of APAP. After 24 h, blood and livers were harvested for analyses. We showed that excessive APAP induced multiple programmed cell deaths of hepatocytes including pyroptosis, apoptosis and necroptosis, accompanied by significantly increased NETs markers (MPO, citH3) in the liver tissue and serum. Preinjection of DNase1 (10 U, i.p.) for two consecutive days significantly inhibited NETs formation, reduced PANoptosis and consequently alleviated excessive APAP-induced ALI. In order to clarify the communication between hepatocytes and neutrophils, we induced NETs formation in isolated neutrophils, and treated HepaRG cells with NETs. We found that NETs treatment markedly increased the activation of GSDMD, caspase-3 and MLKL, while pre-treatment with DNase1 down-regulated the expression of these proteins. Knockdown of AIM2 (a cytosolic innate immune receptor) abolished NETs-induced PANoptosis in HepaRG cells. Furthermore, excessive APAP-associated ALI was significantly attenuated in AIM2KO mice, and PANoptosis occurred less frequently. Upon restoring AIM2 expression in AIM2KO mice using AAV9 virus, both hepatic injury and PANoptosis was aggravated. In addition, we demonstrated that excessive APAP stimulated mtROS production and mitochondrial DNA (mtDNA) leakage, and mtDNA activated the TLR9 pathway to promote NETs formation. Our results uncover a novel mechanism of NETs and PANoptosis in APAP-associated ALI, which might serve as a therapeutic target.

One/Two-Photon-Excited ESIPT-Attributed Coordination Polymers with Wide Temperature Range and Color-Tunable Long Persistent Luminescence.

The multiple metastable excited states provided by excited-state intramolecular proton transfer (ESIPT) molecules are beneficial to bring temperature-dependent and color-tunable long persistent luminescence (LPL). Meanwhile, ESIPT molecules are intrinsically suitable to be modulated as D-π-A structure to obtain both one/two-photon excitation and LPL emission simultaneously. Herein, we report the rational design of a dynamic CdII coordination polymer (LIFM-106) from ESIPT ligand to achieve the above goals. By comparing LIFM-106 with the counterparts, we established a temperature-regulated competitive relationship between singlet excimer and triplet LPL emission. The optimization of ligand aggregation mode effectively boost the competitiveness of the latter. In result, LIFM-106 shows outstanding one/two-photon excited LPL performance with wide temperature range (100-380 K) and tunable color (green to red). The multichannel radiation process was further elucidated by transient absorption and theoretical calculations, benefiting for the application in anti-counterfeiting systems.

Defects and asymmetries in the visual pathway of non-human primates with natural strabismus and amblyopia.

Strabismus and amblyopia are common ophthalmologic developmental diseases caused by abnormal visual experiences. However, the underlying pathogenesis and visual defects are still not fully understood. Most studies have used experimental interference to establish disease-associated animal models, while ignoring the natural pathophysiological mechanisms. This study was designed to investigate whether natural strabismus and amblyopia are associated with abnormal neurological defects. We screened one natural strabismic monkey ( Macaca fascicularis) and one natural amblyopic monkey from hundreds of monkeys, and retrospectively analyzed one human strabismus case. Neuroimaging, behavioral, neurophysiological, neurostructural, and genovariation features were systematically evaluated using magnetic resonance imaging (MRI), behavioral tasks, flash visual evoked potentials (FVEP), electroretinogram (ERG), optical coherence tomography (OCT), and whole-genome sequencing (WGS), respectively. Results showed that the strabismic patient and natural strabismic and amblyopic monkeys exhibited similar abnormal asymmetries in brain structure, i.e., ipsilateral impaired right hemisphere. Visual behavior, visual function, retinal structure, and fundus of the monkeys were impaired. Aberrant asymmetry in binocular visual function and structure between the strabismic and amblyopic monkeys was closely related, with greater impairment of the left visual pathway. Several similar known mutant genes for strabismus and amblyopia were also identified. In conclusion, natural strabismus and amblyopia are accompanied by abnormal asymmetries of the visual system, especially visual neurophysiological and neurostructural defects. Our results suggest that future therapeutic and mechanistic studies should consider defects and asymmetries throughout the entire visual system.

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment.

Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells.Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204-16. ©2018 AACR.

[Outcome comparison of open versus endovascular techniques in the treatment of abdominal aortic aneurysms].

OBJECTIVE: To compare the efficacy, cost and safety of endovascular aortic repair (EVAR) versus open surgery in the treatment of infrarenal abdominal aortic aneurysms. METHODS: Retrospective analyses were conducted for the clinical data and follow-up information of 218 cases from January 2002 to December 2011 at our hospital. Open surgery group included 86 patients with an mean age of 65.5 years and a mean aneurysm diameter of 5.4 cm. In EVAR group, there were 132 cases with an average age of 76.8 years and a mean aneurysm diameter of 5.6 cm. RESULTS: Among 86 open cases, there were inverted "Y" type artificial graft (n = 83) and straight artificial graft (n = 3). The surgical success rate was 98.8%, perioperative period mortality rate was 2.3%, a mean volume of blood loss 450 ml and a mean transfusion volume 320 ml. The mean operative duration was 230 min, a mean hospitalization time (30 ± 3) days and a mean hospitalization cost RMB yuan 58 000. In EVAR group, the surgical success rate was 100% and perioperative period mortality rate 0.8%. Separating stent graft (n = 121, 91.7%), straight stent graft (n = 4, 3%) and one-stent-graft (n = 7, 5.3%). The mean operative duration was 150 min, a mean volume of blood loss 140 ml, a mean hospitalization time 15.5 days and a mean hospitalization cost RMB yuan 104 800. The operative duration, volume of blood loss and length of hospital stay of EVAR group were superior to those of open surgery group (P < 0.05). But the cost of group EVAR was significantly higher than that of group open surgery (P < 0.05). In group open surgery, 80 cases (94.1%) received a mean follow-up period of 46 months. And 79 artificial grafts maintained patency (98.8%) and 8 cases died (10%). There were 125 cases in group EVAR (94.7%) with a mean time of 32.5 months; stent graft patency in 120 cases (96%), 10 death; 8 complication cases (5.6%) involved stent migration (n = 2) and iliac artery branch occlusion (n = 6). Long-term effects had no significant difference between two groups (P > 0.05). In terms of the incidence of complications, group EVAR was significantly more than group open surgery (P < 0.05). CONCLUSION: In terms of operative duration, volume of blood loss and length of hospital stay, EVAR and open surgery treatment for infrarenal abdominal aortic aneurysms group EVAR is significantly better than group open surgery. As far hospitalization cost, group EVAR is significantly higher than group open surgery. But, in terms of incidence of long-term complications, group EVAR is significantly higher than group open surgery while the latter often requires further interventions.

[Detection of the anterior segment configuration of primary angle-closure glaucoma by anterior segment optical coherence tomography].

OBJECTIVE: To quantitatively measure and evaluate the ocular anterior segment parameters in different subtypes of primary angle-closure glaucoma (PACG) using anterior segment optical coherence tomography (AS-OCT). METHODS: This retrospective study collected Fifty-five subjects (55 eyes) with APACG, 63 (63 eyes) with chronic primary angle-closure glaucoma (CPACG) and 90 (90 eyes) normal controls from December 2009 to December 2010 in Zhongshan Ophthalmic Center. AS-OCT examination was performed on all patients and the anterior segment parameters were recorded including: central anterior chamber depth (ACD), anterior chamber width (ACW), anterior chamber volume (ACV), angle opening distance (AOD), trabecular iris area (TISA), angle recess area (ARA), lens thickness (LT) and crystalline lens rise (CLR). The differences of parameters between APACG, CPACG and normal controls were compared. RESULTS: The anterior segment parameters of APACG and CPACG were significantly (P ≤ 0.001) smaller, respectively, than those of normal controls (PACG: ACD 1.81 ± 0.25 mm, ACW 11.30 ± 0.43 mm, AOD 0.039 mm, ARA 0.038 mm(2), ACV 72.8 ± 16.04 mm(3), TISA 0.017 mm(2), Mean ± SD, and CPACG: ACD 2.02 ± 0.25, ACW 11.49 ± 0.45, AOD 0.042, ARA 0.053, ACV 83.60 ± 19.49, TISA 0.022 vs. normal: ACD 2.70 ± 0.35, ACW 11.81 ± 0.47, AOD 0.260, ARA 0.197, ACV 148.52 ± 31.89, TISA 0.100). The LT and CLR of PACG were significantly (P < 0.001) larger, respectively, than that of normal controls (LT: APACG 5.22 ± 0.38, CPACG 5.06 ± 0.36 mm, CLR: APACG 1.07 ± 0.26, CPACG 0.94 ± 0.21 mm vs. normal: LT 4.57 ± 0.42, CLR 0.39 ± 0.33 mm). Compared with CPACG, the anterior segment parameters of APACG were significantly (P < 0.001 - 0.015) decreased, but the LT (P = 0.003) and CLR were significantly (P < 0.001) increased. Compared with APACG-fellow eyes, the anterior segment parameters of APACG-attacked eyes were significantly (P < 0.001 - 0.041) decreased (Fellow-eye: ACD 1.90 ± 0.23 mm, AOD 0.045 mm, TISA 0.037 mm(2), ARA 0.047 mm(2) vs. attached-eye: ACD 1.81 ± 0.25, AOD 0.039, TISA 0.017 and ARA 0.038), while CLR was significantly (t = 1.349, P = 0.043) increased (fellow-eye: 1.01 ± 0.23 mm vs. Attached-eye: 1.07 ± 0.26). There was no significant difference in the other AS-OCT parameters between APACG-attacked eyes and fellow eyes (t = 0.574 - 1.147, P = 0.257 - 0.567). CONCLUSIONS: Our results indicated a more crowding anterior segment configuration in PACG than that in normal controls and a more anterior located and thicker lensing APACG than that in CPACG, which constitute a morphological basis of acute attack.

[The correlative factors of darkroom provocative test in anterior segment parameters].

OBJECTIVE: To investigate the correlative anterior segment parameters of positive darkroom provocative test in patients with narrow anterior chamber angles. METHODS: It was a retrospective case series study. Two hundred and sixty patients [36 males and 224 females, mean age (59.6 ± 9.3) years] with narrow anterior chamber angles underwent darkroom provocative test and UBM scan were analyzed retrospectively. Anterior segment parameters including anterior chamber depth (ACD), pupil diameter (PD), lens vault (LV), peripheral iris thickness (IT), iris convex (IC), anterior chamber angle open distance (AOD), trabecular-meshwork ciliary process angle (TCPA) and the number of appositional angle closure (NPAC) were quantitatively analyzed. Correlative factors of positive results were analysis by both single factor and multiple-factor analysis. RESULTS: Seventy-one (27.3%) of the 260 patients had positive results in the darkroom provocative test. Males (15 out of 36) had statistically higher positive result rate than females (56 out of 224) (M: 41.7% vs. F:25.0%, χ(2) = 4.340, P = 0.037). In single factor analysis, male (OR = 2.14), AOD (OR = 0.98), IT (OR = 1.68) and NPAC (OR = 2.24) were correlative factors for positive results. In multiple-factor analysis, only IT (OR = 1.47) and NPAC (OR = 1.70) were independent risk factors of positive results. CONCLUSIONS: Positive darkroom provocative test is correlated to parameters of anterior chamber angle and iris, while IT and NPAC are independent correlative factors in patients with narrow anterior chamber angle.

[Management strategies of arterial prosthetic graft infection in lower extremity:a report of 5 cases].

OBJECTIVE: To explore the management strategies of pyogenic vascular prosthetic graft infection. METHODS: The clinical data of 5 cases of prosthetic vascular graft infection in lower extremity between 2003 and 2010 were retrospectively analyzed. RESULTS: All of them were treated by antibiotics, debridement and drainage. One patient died from acute myocardial infarction and septic shock. Two patients were cured by extra-anatomic arterial bypass and removal of infected graft after a basic control of infections. And another two patients had the diseased limb amputated after the removal of infected vascular graft without blood reconstruction. CONCLUSION: Pyogenic infection of vascular graft is hard to treat with conservative measures. Revascularization prior to removal of infected graft is recommended for a better outcome.

[Efficacies of carotid endarterectomy in the treatment of atherosclerotic carotid artery stenosis].

OBJECTIVE: To explore the feasibility and efficacy of carotid endarterectomy (CEA) in the treatment of atherosclerotic carotid artery stenosis (ACAS). METHODS: From January 2002 to December 2010, 126 ACAS patients undergoing carotid endarterectomy at our hospital were retrospectively analyzed. There were 92 males and 34 females with an average age of 65.5 years old (range: 48 - 75). Among them, 25 had sequelae of cerebral infarction, 69 symptomatic cerebral ischemia and 32 asymptomatic. Sixty-two patients were monitored intra-operatively with transcranial Doppler (TCD). Among them, 5 patients underwent arterial shunt due to a reduced of blood flow in middle cerebral artery for over 50%. The other 64 patients without TCD monitoring underwent intra-operative arterial shunt. And 22 patients underwent patch angioplasty with autologous or prosthetic vascular patch. Intracranial hyperperfusion was prevented by a compression of common carotid artery or control was successful without perioperative mortality. All patients with cerebral ischemic symptoms and some patients with cerebral infarction sequelae had much post-operative improvement. Deviated tongue protrusion occurred in 10 patients and 8 of them recovered at Week 2 post-operation. And 118 patients were followed up for a mean period of 46.5 months (range: 6 - 96). Two patients with deviated tongue protrusion had slight improvements; 2 patients with severe carotid artery stenosis underwent stent angioplasty; 4 patients with moderate carotid artery stenosis received conservative treatment; among 7 deceased patients, two died of cerebral infarction. CONCLUSION: CEA is effective in the treatment of carotid artery stenosis with a high success rate. TCD monitoring during CEA is valuable for preventing cerebral ischemia and intracranial hyperperfusion. Arterial shunt and arterial patch angioplasty should be considered according to certain conditions during CEA.