PEDF-34 attenuates neurological deficit and suppresses astrocyte-dependent neuroinflammation by modulating astrocyte polarization via 67LR/JNK/STAT1 signaling pathway after subarachnoid hemorrhage in rats.

BACKGROUND: Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH), including neuroinflammation, glymphatic-lymphatic system dysfunction, brain edema, BBB disruption, and cell death. Astrocytes transform into two new reactive phenotypes with changed morphology, altered gene expression, and secretion profiles, termed detrimental A1 and beneficial A2. This study investigates the effect of 67LR activation by PEDF-34, a PEDF peptide, on neuroinflammation and astrocyte polarization after the experimental SAH. METHODS: A total of 318 male adult Sprague-Dawley rats were used in experiments in vivo, of which 272 rats were subjected to the endovascular perforation model of SAH and 46 rats underwent sham surgery. 67LR agonist (PEDF-34) was administrated intranasally 1 h after SAH. 67LR-specific inhibitor (NSC-47924) and STAT1 transcriptional activator (2-NP) were injected intracerebroventricularly 48 h before SAH. Short- and long-term neurological tests, brain water content, immunostaining, Nissl staining, western blot, and ELISA assay were performed. In experiments in vitro, primary astrocyte culture with hemoglobin (Hb) stimulation was used to mimic SAH. The expression of the PEDF-34/67LR signaling pathway and neuro-inflammatory cytokines were assessed using Western blot, ELISA, and immunohistochemistry assays both in vivo and in vitro. RESULTS: Endogenous PEDF and 67LR expressions were significantly reduced at 6 h after SAH. 67LR was expressed in astrocytes and neurons. Intranasal administration of PEDF-34 significantly reduced brain water content, pro-inflammatory cytokines, and short-term and long-term neurological deficits after SAH. The ratio of p-JNK/JNK and p-STAT1/STAT1 and the expression of CFB and C3 (A1 astrocytes marker), significantly decreased after PEDF-34 treatment, along with fewer expression of TNF-α and IL-1ß at 24 h after SAH. However, 2-NP (STAT1 transcriptional activator) and NSC-47924 (67LR inhibitor) reversed the protective effects of PEDF-34 in vivo and in vitro by promoting A1 astrocyte polarization with increased inflammatory cytokines. CONCLUSION: PEDF-34 activated 67LR, attenuating neuroinflammation and inhibiting astrocyte A1 polarization partly via the JNK/STAT1 pathway, suggesting that PEDF-34 might be a potential treatment for SAH patients.

Comparison of a covered stent and pipeline embolization device in intracranial aneurysm: a propensity score matching analysis.

BACKGROUND: The Willis covered stent (WCS) and pipeline embolization device (PED) have partly overlapping therapeutic indications. However, the differences of effect between these two treatments remain unclear. OBJECTIVE: To compare clinical outcome, angiographic outcome, and complications following treatment with a WCS versus PED. METHODS: Patients with intracranial aneurysms treated by a WCS or PED between January 2015 and December 2020 were included. The primary outcomes were complications, clinical outcome (modified Rankin Scale score >2), and angiographic outcome (incomplete aneurysm occlusion). Propensity score matching was conducted to adjust for potential confounding factors. RESULTS: A total of 94 aneurysms treated by WCS and 698 aneurysms by PED were included. Compared with the PED group, patients in the WCS group are younger, a greater number have a poor condition at admission, a larger proportion of ruptured, non-saccular, and anterior circulation aneurysms, a smaller aneurysm neck width, and less coiling assistance is required. A total of 42 (44.7%) branches were covered by WCS. After adjustment for age, sex, aneurysm type, rupture status, neck size, aneurysm location, and coiling, 50 WCS and PED pairs were examined for internal carotid artery aneurysms. No significant differences were observed in clinical (10.4% vs 2.1%, P=0.206) and angiographic outcomes (12.8% vs 18.2%, P=0.713). However, 27 branches covered by WCS, including 22 ophthalmic arteries and five posterior communicating arteries. Patients in the WCS group had a higher intraoperative complication rate than those in the PED group (28% vs 6%, P=0.008), especially in the occlusion rate of covered branches (51.9% vs 11.1%, P<0.001). CONCLUSION: The comparable clinical and angiographic outcomes of WCS or PED demonstrate the therapeutic potential of WCS as a viable alternative for aneurysms. However, the complication of occlusion of covered branches might not be negligible.

Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl2 injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl2 injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH.

Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH.

BACKGROUND: Hematoma clearance has been a proposed therapeutic strategy for hemorrhagic stroke. This study investigated the impact of CX3CR1 (CX3C chemokine receptor 1) activation mediated by r-FKN (recombinant fractalkine) on hematoma resolution, neuroinflammation, and the underlying mechanisms involving AMPK (AMP-activated protein kinase)/PPARγ (peroxisome proliferator-activated receptor gamma) pathway after experimental germinal matrix hemorrhage (GMH). METHODS: A total of 313 postnatal day 7 Sprague Dawley rat pups were used. GMH was induced using bacterial collagenase by a stereotactically guided infusion. r-FKN was administered intranasally at 1, 25, and 49 hours after GMH for short-term neurological evaluation. Long-term neurobehavioral tests (water maze, rotarod, and foot-fault test) were performed 24 to 28 days after GMH with the treatment of r-FKN once daily for 7 days. To elucidate the underlying mechanism, CX3CR1 CRISPR, or selective CX3CR1 inhibitor AZD8797, was administered intracerebroventricularly 24 hours preinduction of GMH. Selective inhibition of AMPK/PPARγ signaling in microglia via intracerebroventricularly delivery of liposome-encapsulated specific AMPK (Lipo-Dorsomorphin), PPARγ (Lipo-GW9662) inhibitor. Western blot, Immunofluorescence staining, Nissl staining, Hemoglobin assay, and ELISA assay were performed. RESULTS: The brain expression of FKN and CX3CR1 were elevated after GMH. FKN was expressed on both neurons and microglia, whereas CX3CR1 was mainly expressed on microglia after GMH. Intranasal administration of r-FKN improved the short- and long-term neurobehavioral deficits and promoted M2 microglia polarization, thereby attenuating neuroinflammation and enhancing hematoma clearance, which was accompanied by an increased ratio of p-AMPK (phosphorylation of AMPK)/AMPK, Nrf2 (nuclear factor erythroid 2-related factor 2), PPARγ, CD36 (cluster of differentiation 36), CD163 (hemoglobin scavenger receptor), CD206 (the mannose receptor), and IL (interleukin)-10 expression, and decreased CD68 (cluster of differentiation 68), IL-1ß, and TNF (tumor necrosis factor) α expression. The administration of CX3CR1 CRISPR or CX3CR1 inhibitor (AZD8797) abolished the protective effect of FKN. Furthermore, selective inhibition of microglial AMPK/PPARγ signaling abrogated the anti-inflammation effects of r-FKN after GMH. CONCLUSIONS: CX3CR1 activation by r-FKN promoted hematoma resolution, attenuated neuroinflammation, and neurological deficits partially through the AMPK/PPARγ signaling pathway, which promoted M1/M2 microglial polarization. Activating CX3CR1 by r-FKN may provide a promising therapeutic approach for treating patients with GMH.

Association between smoking and intracranial artery dissection in patients aged less than 50 years: A propensity score-matched analysis.

INTRODUCTION: Smoking is a common risk factor for stroke in the young population. Intracranial artery dissection (ICAD) is a major cause of stroke in this population. However, the association between smoking and ICAD in young patients is not well characterized. We aimed to evaluate the association between smoking and ICAD in young individuals using propensity score-matched analysis. METHODS: We conducted a retrospective study of consecutive patients aged <50 years with ICAD who were admitted to Beijing Tiantan Hospital between January 2016 and December 2020. Patients with other non-atherosclerotic/non-aneurysmal cerebrovascular diseases were selected as controls. Propensity score matching was based on age and sex. Smoking and other vascular risk factors were compared between the two groups. RESULTS: The ICAD and control group included 120 and 197 patients, respectively. Propensity score matching resulted in 70 matched pairs. Smoking was the only significant factor association with ICAD in the matched cohort (p=0.031). CONCLUSIONS: In this propensity score-matched analysis, smoking showed a positive association with ICAD in young patients with common cerebrovascular diseases that were neither atherosclerotic nor aneurysmal. Further studies are required to investigate the predictive role of smoking for ICAD in the young population.

Immunostimulant In Situ Fibrin Gel for Post-operative Glioblastoma Treatment by Macrophage Reprogramming and Photo-Chemo-Immunotherapy.

Tumor recurrence remains the leading cause of treatment failure following surgical resection of glioblastoma (GBM). M2-like tumor-associated macrophages (TAMs) infiltrating the tumor tissue promote tumor progression and seriously impair the efficacy of chemotherapy and immunotherapy. In addition, designing drugs capable of crossing the blood-brain barrier and eliciting the applicable organic response is an ambitious challenge. Here, we propose an injectable nanoparticle-hydrogel system that uses doxorubicin (DOX)-loaded mesoporous polydopamine (MPDA) nanoparticles encapsulated in M1 macrophage-derived nanovesicles (M1NVs) as effectors and fibrin hydrogels as in situ delivery vehicles. In vivo fluorescence imaging shows that the hydrogel system triggers photo-chemo-immunotherapy to destroy remaining tumor cells when delivered to the tumor cavity of a model of subtotal GBM resection. Concomitantly, the result of flow cytometry indicated that M1NVs comprehensively improved the immune microenvironment by reprogramming M2-like TAMs to M1-like TAMs. This hydrogel system combined with a near-infrared laser effectively promoted the continuous infiltration of T cells, restored T cell effector function, inhibited the infiltration of myeloid-derived suppressor cells and regulatory T cells, and thereby exhibited a strong antitumor immune response and significantly inhibited tumor growth. Hence, MPDA-DOX-NVs@Gel (MD-NVs@Gel) presents a unique clinical strategy for the treatment of GBM recurrence.

Morphological characteristics associated with ruptured intracranial vertebral artery dissecting aneurysms.

OBJECTIVE: Morphological risk factors for the rupture of intracranial vertebral artery dissecting aneurysms (IVADAs) have not been well characterized. In this study, we aim to identify morphological characteristics associated with IVADA rupture. METHODS: We conducted a retrospective study of 249 consecutive patients with single IVADAs (31 ruptured and 218 unruptured) admitted to Beijing Tiantan Hospital between January 2016 and December 2020. Various morphological parameters were measured using three-dimensional digital subtraction angiography images. Univariate and multivariate logistic regression analyses were performed to identify morphological characteristics associated with IVADA rupture. RESULTS: Univariate regression analysis revealed that the coexistence of significant proximal and distal stenosis and posterior inferior cerebellar artery (PICA) involvement were associated with IVADA rupture, while the origin from the dominant vertebral artery was inversely associated with the rupture. Multivariate regression analysis demonstrated that the coexistence of significant proximal and distal stenosis (OR 22.00, 95% CI 5.60 to 86.70, p<0.001) and PICA involvement (OR 4.55, 95% CI 1.36 to 15.20, p=0.014) were independently associated with IVADA rupture. CONCLUSION: The coexistence of significant proximal and distal stenosis and PICA involvement were independently associated with IVADA rupture. These morphological characteristics may facilitate the assessment of rupture risk in patients with IVADAs.

Economic evaluation of intravenous alteplase for stroke with the time of onset between 4.5 and 9 hours.

BACKGROUND: A clinical trial proved the clinical effectiveness of perfusion imaging-guided intravenous thrombolysis with alteplase for patients with acute ischemic stroke (AIS) with the time of onset between 4.5 and 9 hours. This study aimed to assess the lifetime cost-effectiveness of alteplase versus placebo from the perspective of Chinese and United States (US) healthcare payers. METHODS: A decision-analytic model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) associated with alteplase or placebo. Model inputs were extracted from published sources. Incremental costs, incremental QALYs, and incremental cost-effectiveness ratio (ICER) were calculated to evaluate the base-case scenario. One-way and probabilistic sensitivity analysis were performed to evaluate uncertainty in the results. RESULTS: In China, alteplase yielded an additional lifetime QALY of 0.126 with an additional cost of Chinese Yuan (¥) ¥9552 compared with placebo, and the ICER was ¥83 950 (US$12 157)/QALY. In the US, alteplase had a higher QALY (difference: 0.193) with a lower cost (difference: US$-2024) compared with placebo. In probabilistic sensitivity analyses, alteplase had a 42.54% to 78.3% probability of being cost-effective compared with placebo in China when the willingness-to-pay (WTP) threshold ranged from ¥72 447/QALY to ¥217 341/QALY. In the US, alteplase had a 93.47% to 93.57% probability of being cost-effective under the WTP threshold of US$100 000/QALY to US$150 000/QALY. These findings remained robust under one-way sensitivity analysis. CONCLUSION: For patients with AIS with a time of onset between 4.5 and 9 hours, perfusion imaging-guided intravenous alteplase was likely to be cost-effective in China and was cost-effective in the US when compared with placebo.

Parent artery occlusion after pipeline embolization device implantation of intracranial saccular and fusiform aneurysms.

BACKGROUND: Studies reporting parent artery occlusion (PAO) after pipeline embolization device (PED) implantation are limited. The aim of this study was to investigate the incidence rate and risk factors of PAO after PED implantation. METHODS: In this retrospective study, we enrolled consecutive patients with intracranial saccular and fusiform aneurysms treated with PED implantation at our institution. Multivariate logistic regression analysis was subsequently performed to determine the risk factors for PAO. RESULTS: A total of 588 saccular and fusiform aneurysms were finally enrolled in the study. PAO was found in 14 (2.38%) aneurysms. The aneurysm complete occlusion rate was 79.6%. Compared with the non-PAO group, aneurysms in the PAO group were larger in size (20.08 vs 9.61 mm; p<0.001), had a greater neck diameter (9.92 vs 6.15 mm; p=0.001), and had higher frequencies of adjunctive coils (64.3% vs 35.7%; p=0.028). In the multivariate logistic analysis, aneurysm size (OR 1.12, 95% CI 1.02 to 1.24; p=0.016) and the presence of poor wall apposition after balloon angioplasty (OR 7.74, 95% CI 1.28 to 46.82; p=0.026) were associated with PAO occurrence after adjusting for confounding factors. CONCLUSIONS: In this study, the incidence rate of PAO following PED implantation was 2.38% in intracranial saccular and fusiform aneurysms. Aneurysm size and residual presence of poor wall apposition after balloon angioplasty were risk factors for PAO. Further research is required to better understand the mechanisms of PAO.

Phase I/II trial of local interstitial chemotherapy with arsenic trioxide in patients with newly diagnosed glioma.

Background: Glioma is the most common primary brain tumor in adults with poor prognosis. The glioma patients benefit from STUPP strategy, including maximum and safe resection and adjuvant radiotherapy and chemotherapy. Arsenic trioxide could inhibit various tumors. However, it is a challenge to evaluate the efficiency and safety of srsenic trioxide in glioma patients. Objective: The arsenic trioxide has the potent therapeutic effect on glioma. However, the safety and efficacy of local interstitial chemotherapy with arsenic trioxide in newly diagnosed glioma patients is unclear. Methods: All patients received partial or complete tumor resection and intraoperative implantation of Ommaya reservoirs followed by standard radiotherapy. Arsenic trioxide with the starting dose 0.3 mg was administered via an Ommaya reservoir catheter inserted into the tumor cavity for 5 consecutive days every 3 months for a total of eight cycles unless tumor progression or excessive toxicity was observed. Results: No hematological or grade 4 non-hematological toxicity was observed in any patient during arsenic trioxide treatment. The maximum tolerated dose of 1.5 mg of arsenic trioxide was safe and well tolerated. The median overall survival for WHO grade 3 glioma was 33.6 months, and for glioblastoma was 13.9 months. The median progression-free survival for WHO grade 2 glioma was 40.3 months, for grade 3 glioma was 21.5 months, and for glioblastoma was 9.5 months. Conclusion: These results suggest that arsenic trioxide is safe and well tolerated with local delivery into the tumor cavity of the brain, and the dose recommended for a phase II trial is 1.5 mg.

Cost effectiveness of screening for intracranial aneurysms among patients with bicuspid aortic valve: a Markov modelling study.

OBJECTIVE: Bicuspid aortic valve (BAV) is common and 7.7%-9.8% of patients with BAV have intracranial aneuryms (IAs) which might lead to a devastating subarachnoid haemorrhage (SAH). We aimed to evaluate different screening and follow-up strategies using magnetic resonance angiography for IAs among patients with BAV. METHODS: A decision-analytic model was built to evaluate the costs and effectiveness of different management strategies from the Chinese healthcare payer's perspective. The evaluated strategies included natural history without screening for possible IAs, regular screening and no follow-up for detected IAs, and regular screening with regular follow-up (Screen strategy/Follow-up strategy). Base case calculation, as well as probabilistic, one-way, and two-way sensitivity analyses, were performed. RESULTS: According to the base case calculation, natural history had the least cost and effectiveness while Every 5 years (y)/Annual gained the highest cost and effectiveness. Every 10y/Biennial was cost effective when compared with Every 10y/Every 5y under the willingness-to-pay threshold of ¥211 743 (US$30 162). Probabilistic sensitivity analysis showed that Every 10y/Biennial was superior in 88.3% of the cases when compared with Every 10y/Every 5y. One-way and two-way sensitivity analyses proved that Every 10y/Biennial was the dominant strategy under most circumstances. CONCLUSIONS: Screening for possible IAs among patients with BAV and follow-up for detected IAs would increase the effectiveness. Every 10y/Biennial was the optimal strategy from the Chinese healthcare payer's perspective.

Economic Evaluation of Sacituzumab Govitecan for the Treatment of Metastatic Triple-Negative Breast Cancer in China and the US.

BACKGROUND: The effectiveness of Sacituzumab Govitecan (SG) for metastatic triple-negative breast cancer (mTNBC) has been demonstrated. We aimed to evaluate its cost-effectiveness on mTNBC from the Chinese and United States (US) perspective. METHODS: A partitioned survival model was developed to compare the cost and effectiveness of SG versus single-agent chemotherapy based on clinical data from the ASCENT phase 3 randomized trial. Cost and utility data were obtained from the literature. The incremental cost-effectiveness ratio (ICER) was measured, and one-way and probabilistic sensitivity analyses (PSA) were performed to observe model stability. A Markov model was constructed to validate the results. RESULTS: In China, SG yielded an additional 0.35 quality-adjusted life-year (QALY) at an additional cost of Chinese Renminbi ¥2257842. The ICER was ¥6375856 ($924037)/QALY. In the US, SG yielded the same additional QALY at an extra cost of $175393 and the ICER was $494479/QALY. Similar results were obtained from the Markov model. One-way sensitivity analyses showed that SG price had the greatest impact on the ICER. PSA showed the probability of SG to be cost-effective when compared with chemotherapy was zero at the current willing-to-pay threshold of ¥217341/QALY and $150000/QALY in China and the US, respectively. The probability of cost-effectiveness of SG would approximate 50% if its price was reduced to ¥10.44/mg in China and $3.65/mg in the US. CONCLUSION: SG is unlikely to be a cost-effective treatment of mTNBC at the current price both in China and the US.

Cost-Effectiveness of Short-Course Radiation Plus Temozolomide for the Treatment of Newly Diagnosed Glioblastoma Among Elderly Patients in China and the United States.

Background: Glioblastoma multiforme (GBM) is a fatal type of brain tumor with a high incidence among elderly people. Temozolomide (TMZ) has proven to be an effective chemotherapeutic agent with significant survival benefits. This study aimed to evaluate the economic outcomes of radiotherapy (RT) and TMZ for the treatment of newly diagnosed GBM in elderly people in the United States (US) and China. Methods: A partitioned survival model was constructed for RT plus TMZ and RT alone among patients with methylated and unmethylated tumor status. Base case calculations and one-way and probabilistic sensitivity analyses were performed. Life-years, quality-adjusted life-years (QALYs), costs (in 2021 US dollars [$] and Chinese Yuan Renminbi [¥]), and incremental cost-effectiveness ratios (ICERs) were calculated. Results: RT plus TMZ was found to be associated with significantly higher costs and QALYs in all groups. Only US patients with methylated status receiving RT plus TMZ had an ICER ($89358.51) less than the willingness-to-pay (WTP) threshold of $100000 per QALY gained when compared with receiving RT alone. When the WTP threshold ranged from $100000 to $150000 from the US perspective, the probability of RT plus TMZ being cost-effective increased from 80.5 to 99.8%. The cost of TMZ must be lower than ¥120 per 20 mg for RT plus TMZ to be cost-effective among patients with methylated tumor status in China. Conclusion: RT plus TMZ was not cost-effective in China, and a reduction in the TMZ price was justified. However, it is highly likely to be cost-effective for patients with methylated tumor status in the US.

Expression of TCF7L2 in Glioma and Its Relationship With Clinicopathological Characteristics and Patient Overall Survival.

Background: The TCF7L2 gene is known as transcription factor 7-like 2 which has been identified as a novel transcription factor epithelial-mesenchymal transition (EMT) in tumor cells at 10q25.3. TCF7L2 may affect cancer progression and plays a central role in cancer proliferation, migration, and invasion. However, its clinical and prognostic value have not been researched in glioma. The purpose of our study was to research TCF7L2 expression and evaluate the clinical value of prognosis. Method: We collected glioma specimens including low-grade glioma (n = 46) and glioblastoma (n = 51) from September 2015 to September 2017. Expression of TCF7L2 in 97 specimens was detected by quantitative real-time PCR (qRT-PCR). The chi-square test was applied to analyze the relationship between TCF7L2 expression and clinicopathological characteristics. The overall survival (OS) was estimated by log-rank tests among strata, and the survival curves were drawn by Kaplan-Meier. Univariate and multivariate analysis were utilized to analyze the relationship between prognosis and clinicopathological characteristics including TCF7L2 expression. Results: Compared with the low-grade glioma group, the expression of TCF7L2 was significantly increased in the glioblastoma group (p = 0.001). TCF7L2 overexpression was associated with higher WHO grade (p = 0.001), isocitrate dehydrogenase (IDH) wild-type (p = 0.001), and lack of O(6)-methylguanine-DNA methyltransferase (MGMT) methylation (p = 0.001). Moreover, Kaplan-Meier analysis proved that overexpressed TCF7L2 was associated with poor OS (p = 0.010). The multivariate analysis suggested that TCF7L2 expression was an independent prognostic factor (p = 0.020). Conclusions: Our research proved that TCF7L2 was overexpressed in glioblastoma, and related with tumor long-term prognosis, which, therefore, could be an independent prognostic factor for glioma patients.

Steric and electronic modulation of iron catalysts as a route to remarkably high molecular weight linear polyethylenes.

Five structurally related bis(arylimino)pyridine-iron(ii) chloride complexes, [2-[CMeN{2,6-{(4-FC6H4)2CH}2-4-NO2}]-6-(CMeNAr)C5H3N]FeCl2 (Ar = 2,6-Me2C6H3Fe1, 2,6-Et2C6H3Fe2, 2,6-i-Pr2C6H3Fe3, 2,4,6-Me3C6H2Fe4, and 2,6-Et2-4-MeC6H2Fe5), incorporating one N-2,6-bis{di(4-fluorophenyl)methyl}-4-nitrophenyl group and one distinct N-aryl group, have been prepared in good yield through the interaction of the corresponding free ligands (L1-L5) with FeCl2·4H2O. All ferrous complexes were paramagnetic which was manifested by broad and highly shifted peaks in their 1H NMR spectra. The marked steric imbalance imposed by the two inequivalent N-aryl groups was a key feature highlighted in the molecular structures of representative complexes Fe1 and Fe2. Upon activation with either MAO or MMAO, Fe1-Fe5 all exhibited high activities for ethylene polymerization with good thermal stability [activities as high as 1.58 × 107 g (PE) mol-1 (Fe) h-1 at 60 °C], affording especially high molecular weight linear polyethylenes (3.92 × 105 g mol-1 at 70 °C; Tm > 130 °C). To the best of our knowledge, the molecular weights of the polyethylenes produced by the current class of iron catalysts exceed the highest values reported for related bis(imino)pyridine-iron catalysts to date; changes in the ortho-R1 substitution pattern offered some additional fine control of the molecular weight. Moreover, the nature of the aluminoxane co-catalyst employed had a noticeable effect on the polymer end group composition. When using MAO, unsaturated polymers containing both vinyl and n-propyl end groups were evident, whereas with MMAO, fully saturated polymers were generated containing both isobutyl and n-propyl end groups.

Downregulation of NGAL is Required for the Inhibition of Proliferation and the Promotion of Apoptosis of Human Gastric Cancer MGC-803 Cells.

BACKGROUND/AIMS: Gastric cancer is considered as a common malignancy with a poor prognosis as well as unsatisfactory treatment. Neutrophil gelatinase-associated lipocalin (NGAL) has been reported to affect multiple aspects of human tumor, including gastric cancer. This study aims to explore the effects of NGAL gene silencing on the proliferation as well as apoptosis of human gastric cancer MGC-803 cells. METHODS: This study included 87 patients with gastric cancer. MGC-803 cells were collected and mainly treated with siRNA against NGAL and recombinant NGAL plasmid. The expression of NGAL mRNA and the expressions of NGAL protein and apoptosis-related proteins were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. Cell cycle and apoptosis were tested by flow cytometry, and cell proliferation was detected by water soluble tetrazolium-1 (WST-1) assay. The effect of NGAL gene silencing on tumorigenicity of MGC-803 cells in vivo was detected through establishment of xenograft in nude mice. RESULTS: NGAL was highly expressed in gastric cancer tissues. The protein and mRNA expressions of NGAL gene in MGC-803 cells treated with NGAL-siRNA were obviously reduced, and the amount of cells in G0/G1 phase was increased. Moreover, MGC-803 cells treated with NGAL-siRNA exhibited inhibited proliferation, enhanced apoptosis, decreased expressions of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) as well as B-cell lymphoma-2 (Bcl-2) and increased expressions of cysteine-aspartic acid specific protease-9 (caspase-9) and Bcl2-associated X (Bax), as well as repressed tumorigenicity in vivo. CONCLUSION: NGAL gene silencing inhibits proliferation and promotes apoptosis of MGC-803 cells, which can provide a novel theory for treatment of gastric cancer.

Structural characterization of a polysaccharide from Sargassum henslowianum, and its immunomodulatory effect on gastric cancer rat.

A complicated sulfated fucoidan, SHPPB2, was purified from Sargassum henslowianum by DEAE-cellulose 52 and Sephacryl S-300 column chromatography. Via chemical and spectral method, SHPPB2 was found to contain mannose, glucuronic acid, galactose, xylose, and fucose, in a ratio of 17.4: 13.5: 10.5: 16.8: 41.8, as well as 21.4% of sulfate. The methylation analysis demonstrated terminal, 3-, 4-, 2, 3-, and 3, 4- linked fucose, 2-, 2, 3-, 2, 4-, and 2, 4, 6- linked mannose, terminal, 4-, 6-, 2, 4-, 3, 4-, and 3, 6- linked galactose, terminal and 4- linked xylose, and 4- linked glucuronic acid. In addition, the sulfate groups were substituted on the C-2, C-3 or C-4 of 3- and 4- linked fucose, on the C-4 or C-6 of 2- linked mannose, and on C-2 or C-3 of 4- and 6- linked galactose. With the treatment of SHPPB2 in the N-methyl-N'-nitro-nitrosoguanidine (MNNG) induced gastric cancer rats, it was observed with an increased body weight, and improved immune organ indices. Furthermore, SHPPB2 could significantly promote splenocyte proliferation induced by ConA or LPS in gastric cancer rats, and improve anti-inflammatory cytokines (IL-2, IL-4, and IL-10) secretion, but reduce pro-inflammatory cytokines (IL-6 and TNF-α). Taken together, it suggested that SHPPB2 could improve immune function in gastric cancer rats. Thus, it could be explored as a potential immuno-therapy for gastric cancer treatment.

[Meta-analysis of sacral nerve stimulation for fecal incontinence].

OBJECTIVE: To evaluate the efficacy of sacral nerve stimulation (SNS) therapy for fecal incontinence. METHODS: Clinical researches which evaluated the efficacy of SNS and were published between 1946 and 2016 were systematically searched from electronic databases, including PubMed, Ovid Medline, Web of Science, Wanfang database and Chinese Journal Full-text Database. Grey area literatures were also searched. Influence of SNS therapy on fecal incontinence episodes (FIE) or Wexner incontinence score (WIS) was systematically evaluated. The statistical analysis was performed by RevMan5.2. RESULTS: A total of 6 studies including 270 patients (147 patients in SNS group and 123 patients in control group) with fecal incontinence were enrolled in this systematic review. SNS therapy was associated with a significant reduction in FIE (SMD=-0.69, 95%CI: -0.97 to -0.41, P<0.001) and a significant reduction in WIS (SMD=-5.05, 95%CI: -8.73 to -1.36, P=0.007). Sensitivity analysis showed that the results of this study were stable and the direction and significance of results were not changed (P=0.000 for both). Publication bias was not found by funnel picture in this study. CONCLUSION: SNS significantly improves the outcome of patients with fecal incontinence.

Quercetin Suppresses the Migration and Invasion in Human Colon Cancer Caco-2 Cells Through Regulating Toll-like Receptor 4/Nuclear Factor-kappa B Pathway.

OBJECTIVE: The migration and invasion features, which were associated with inflammatory response, acted as vital roles in the development of colon cancer. Quercetin, a bioflavonoid compound, was widely spread in vegetables and fruits. Although quercetin exerts antioxidant and anticancer activities, the molecular signaling pathways in human colon cancer cells remain unclear. Hence, the present study was conducted to investigate the suppression of quercetin on migratory and invasive activity of colon cancer and the underlying mechanism. MATERIALS AND METHODS: The effect of quercetin on cell viability, migration, and invasion of Caco-2 cells was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound-healing assay, and transwell chambers assay, respectively. The protein expressions of toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB) p65, mitochondrial membrane potential-2 (MMP-2), and MMP-9 were detected by Western blot assay. The inflammatory factors, such as tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (Cox-2), and interleukin-6 (IL-6), in cell supernatant were detected by enzyme-linked immunosorbent assay. RESULTS: The concentration of quercetin <20 µM was chosen for further experiments. Quercetin (5 µM) could remarkably suppress the migratory and invasive capacity of Caco-2 cells. The expressions of metastasis-related proteins of MMP-2, MMP-9 were decreased, whereas the expression of E-cadherin protein was increased by quercetin in a dose-dependent manner. Interestingly, the anti-TLR4 (2 µg) antibody or pyrrolidine dithiocarbamate (PDTC; 1 µM) could affect the inhibition of quercetin on cell migration and invasion, as well as the protein expressions of MMP-2, MMP-9, E-cadherin, TLR4, and NF-κB p65. In addition, quercetin could reduce the inflammation factors production of TNF-α, Cox-2, and IL-6. CONCLUSION: The findings suggested for the 1(st) time that quercetin might exert its anticolon cancer activity via the TLR4- and/or NF-κB-mediated signaling pathway. SUMMARY: Quercetin could remarkably suppress the migratory and invasive capacity of Caco-2 cellsThe expressions of metastasis-related proteins of mitochondrial membrane potential-2 (MMP-2), MMP-9 were decreased, whereas the expression of E-cadherin protein was increased by quercetin in a dose-dependent mannerThe anti-toll-like receptor 4 (TLR4) antibody or pyrrolidine dithiocarbamate affected the inhibition of quercetin on cell migration and invasion, as well as the protein expressions of MMP-2, MMP-9, E-cadherin, TLR4, and nuclear factor-kappa B p65Quercetin could reduce the inflammation factors production of tumor necrosis factors-α, cyclooxygenase-2, and interleukin-6. Abbreviations used: MTT: 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphen yltetrazolium bromide, TLR4: Toll-like receptor 4, NF-κB: Nuclear factor-kappa B, MMP-2: Mitochondrial membrane potential-2, MMP-9: Mitochondrial membrane potential-9, TNF-α: Tumor necrosis factor-α, Cox-2: Cyclooxygenase-2, IL-6: Interleukin-6, ELISA: Enzyme-linked immunosorbent assay, PDTC: Pyrrolidine dithiocarbamate, ROS: Reactive oxygen species, DMSO: Dimethyl sulfoxide, FBS: Fetal bovine serum, DMEM: Dulbecco modified Eagle medium, OD: Optical density, IPP: Image Pro-plus, PBS: Phosphate buffered saline, SD: Standard deviation, ANOVA: One-way analysis of variance, SPSS: Statistical Package for the Social Sciences, ECM: Extracellular matrix, TLRs: Toll-like receptors, LPS: Lipopolysaccharide.

Association of genetic polymorphisms in PTEN and additional interaction with alcohol consumption and smoking on colorectal cancer in Chinese population.

AIMS: To investigate the association of phosphatase and tensin homologue deleted on chromosome ten (PTEN) gene rs3830675, and additional interaction with drinking and smoking on colorectal cancer (CRC), based on a hospital based Chinese case-control study. METHODS: A total of 850 subjects (413 males and 437 females) were studied, including 422 colorectal cancer cases and 428 controls. Rs3830675 was selected for genotyping in the case-control study. Logistic regression model was used to examine the association between rs3830675 and colorectal cancer, and additional interaction with alcohol consumption and smoking. RESULTS: The frequencies for rs3830675 (-) alleles was higher in cases than that in controls, (-) allele of rs3830675 was 24.4% in controls and 29.4% in CRC subjects (p=0.005). Logistic analysis showed that the carriers of (-) allele of rs3830675 revealed increased CRC risk than those with (+/+) genotype, adjusted OR (95% CI) was 1.35(1.12-1.98). We found a significant interaction between alcohol consumption and rs3830675, drinkers with (-/-) or (-/+) of rs3830675 genotype have highest colorectal cancer risk, compared to never drinking subjects with (+/+) genotype, OR (95% CI) was 2.57 (1.66-3.33), after covariates adjustment. In addition, we also found that smokers with (-/-) or (-/+) of rs3830675 genotype have highest colorectal cancer risk, compared to never smokers with (+/+) genotype, OR (95% CI) was 3.01 (1.58-6.05). CONCLUSIONS: The (-) allele of rs3830675 was positively with colorectal cancer risk. There was a significant role of interaction of rs3830675 with alcohol consumption and smoking on colorectal cancer.