Incidence and Predictors of Acute Coronary Syndrome in Patients on Maintenance Hemodialysis: A Prospective Cohort Study.

Background: Cardiovascular diseases are the leading cause of death among patients on hemodialysis, with approximately 40% of the cardiovascular deaths linked to acute coronary syndrome. We aimed to investigate the incidence and risk factors of acute coronary syndrome in patients undergoing hemodialysis. Methods: Patients undergoing hemodialysis were prospectively enrolled from January 2018. Data regarding hospitalization due to acute coronary syndrome were collected at 3-month intervals through December 31, 2021. Cox regression model was used to estimate the association between baseline factors and incident acute coronary syndrome during follow-up. Results: Patients' mean age was 66 years, 48% were men, and 16% had a history of coronary artery disease at enrolment. Over a median follow-up of 1,187 days, 85 patients were hospitalized due to acute coronary syndrome. Left main or triple vessel disease was identified in 67 patients. Risk factors associated with incident acute coronary syndrome included aging, male sex, smoking, low diastolic blood pressure, and baseline comorbidities, in addition to dialysis factors including low urea clearance, central venous catheter use, and history of dialysis access dysfunction. After multivariate analysis, age, diabetes, hyperlipidemia, smoking, and frequent interventions for vascular access remained significant risk factors. Conclusions: A high acute coronary syndrome incidence was observed in our cohort, with traditional risk factors playing a consistent role with that in the general population. A history of frequent dialysis access dysfunction was also associated with incident acute coronary syndrome.

A Randomised Trial Comparing Drug Coated Balloons and Conventional Balloons for the Treatment of Stent Graft Stenosis in Dialysis Vascular Access.

OBJECTIVE: Previous studies on arteriovenous fistulas have demonstrated the potential benefit of drug coated balloons (DCBs) in maintaining the patency of dialysis access. However, stenoses involving stent grafts were excluded from these studies. Therefore, the aim was to evaluate the effectiveness of DCBs in treating stent graft stenosis. METHODS: This was a prospective, single blinded, randomised controlled study. From March 2017 to April 2021, 40 patients with dysfunctional vascular access owing to stent graft stenosis were randomised to treatment with a DCB or conventional balloon. Clinical follow up was scheduled at one, three, and six months, and angiographic follow up was performed six months after the intervention. The primary outcome was angiographic late luminal loss at six months, and secondary outcomes included target lesion and access circuit primary patency at six months. RESULTS: Thirty-six participants completed follow up angiography. The DCB group had a superior mean late luminal loss at six months compared with the control group (1.82 mm ± 1.83 mm vs. 3.63 mm ± 1.08 mm, respectively, p = .001). All 40 patients completed clinical follow up. The DCB group had a superior six month target lesion primary patency compared with the control group [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.07 - 0.71; p = .005). Additionally, the DCB group had a numerically higher six month access circuit primary patency rate than the control group, although the difference was not statistically significant (HR 0.54, 95% CI 0.26 - 1.11, p = .095). CONCLUSION: Conventional balloon angioplasty is not durable in stent graft stenosis treatment. Treatment with DCBs provides less angiographic late luminal loss and potentially superior primary patency of the target lesion than treatment with conventional balloons. [ClinicalTrials ID: NCT03360279.].

α7 nicotinic acetylcholine receptor agonist improved brain injury and impaired glucose metabolism in a rat model of ischemic stroke.

Vagus nerve stimulation through the action of acetylcholine can modulate inflammatory responses and metabolism. α7 Nicotinic Acetylcholine Receptor (α7nAChR) is a key component in the biological functions of acetylcholine. To further explore the health benefits of vagus nerve stimulation, this study aimed to investigate whether α7nAChR agonists offer beneficial effects against poststroke inflammatory and metabolic changes and to identify the underlying mechanisms in a rat model of stroke established by permanent cerebral ischemia. We found evidence showing that pretreatment with α7nAChR agonist, GTS-21, improved poststroke brain infarction size, impaired motor coordination, brain apoptotic caspase 3 activation, dysregulated glucose metabolism, and glutathione reduction. In ischemic cortical tissues and gastrocnemius muscles with GTS-21 pretreatment, macrophages/microglia M1 polarization-associated Tumor Necrosis Factor-α (TNF-α) mRNA, Cluster of Differentiation 68 (CD68) protein, and Inducible Nitric Oxide Synthase (iNOS) protein expression were reduced, while expression of anti-inflammatory cytokine IL-4 mRNA, and levels of M2 polarization-associated CD163 mRNA and protein were increased. In the gastrocnemius muscles, stroke rats showed a reduction in both glutathione content and Akt Serine 473 phosphorylation, as well as an elevation in Insulin Receptor Substrate-1 Serine 307 phosphorylation and Dynamin-Related Protein 1 Serine 616 phosphorylation. GTS-21 reversed poststroke changes in the gastrocnemius muscles. Overall, our findings, provide further evidence supporting the neuroprotective benefits of α7nAChR agonists, and indicate that they may potentially exert anti-inflammatory and metabolic effects peripherally in the skeletal muscle in an acute ischemic stroke animal model.

A Retrospective Comparison of Clinical Efficacy between Multimodal Analgesia and Patient-Controlled Epidural Analgesia in Patients Undergoing Total Knee Arthroplasty.

Background and Objectives: Adequate pain management during early rehabilitation is mandatory for improving the outcomes of patients undergoing total knee arthroplasty (TKA). Conventional pain management, mainly comprising opioids and epidural analgesia, may result in certain adverse effects such as dizziness, nausea, and motor blockade. We proposed a multimodal analgesic (MA) strategy involving the use of peripheral nerve block (NB), periarticular injection (PAI), and intravenous patient-controlled analgesia (IVPCA). This study compared the clinical efficacy and adverse effects of the proposed MA strategy and patient-controlled epidural analgesia (PCEA). Materials and Methods: We enrolled 118 patients who underwent TKA under spinal anesthesia. The patients followed either the MA protocol or received PCEA after surgery. The analgesic effect was examined using a numerical rating scale (NRS). The adverse effects experienced by the patients were recorded. Results: A lower proportion of patients in the MA group experienced motor blockade (6.45% vs. 22.98%) compared to those in the PCEA group on the first postoperative day. Furthermore, a lower proportion of patients in the MA group experienced numbness (18.52% vs. 43.33%) than those in the PCEA group on the first postoperative day. Conclusions: The MA strategy can be recommended for reducing the occurrence of motor blockade and numbness in patients following TKA. Therefore, the MA strategy ensures early rehabilitation while maintaining adequate pain relief.

Association of Frailty With Thrombosis of Hemodialysis Vascular Access: A Prospective Taiwanese Cohort Study.

RATIONALE & OBJECTIVE: Frailty, a multidimensional construct, has been associated with poor outcomes in patients receiving maintenance dialysis. This study assessed the association of frailty with dialysis vascular access patency. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: 761 prevalent patients receiving hemodialysis at 9 centers in Taiwan as of January 2018. EXPOSURE: Performance-based frailty was defined as 3 of the following: unintentional weight loss, weakness, exhaustion, low physical activity, and slow gait speed. Patients were categorized as prefrail if they had 1 or 2 of these characteristics. OUTCOME: Rate of and time to dialysis access thrombosis. Data regarding vascular access events were collected for 30 months after enrollment through December 31, 2020. ANALYTICAL APPROACH: Logistic regression analysis was used to estimate the association of clinical characteristics with frailty. Cox proportional hazards regression analysis was used to estimate the association of frailty with vascular access thrombosis adjusted for known clinical risk factors. RESULTS: The patients' mean age was 66 years, 46% were female, 18% had synthetic graft accesses, and 82% arteriovenous fistulas. Overall, 31% were frail, 35% were prefrail, and 34% were not frail. The frailty phenotype was associated with age, female sex, low body mass index, diabetes mellitus, and prior stroke. During a median follow-up of 731 days, 161 patients (21%) had access thrombosis events (not frail, 14%; prefrail, 20%; frail, 30%; P < 0.001). Frail patients had a higher risk of vascular access thrombosis than nonfrail patients (HR, 2.31 [95% CI, 1.55-3.39], P < 0.001). After multivariable adjustment for age and comorbidities, frailty remained significantly associated with access thrombosis for both fistulas and grafts. LIMITATIONS: Limited generalizability and potential residual confounding. CONCLUSIONS: Frailty is associated with an increased risk of vascular access thrombosis. These findings highlight the risks of access failure experienced by frail patients receiving hemodialysis.

Pentraxin 3 Predicts Arteriovenous Fistula Functional Patency Loss and Mortality in Chronic Hemodialysis Patients.

INTRODUCTION: Viable vascular access is the lifeline for hemodialysis patients. In the nondialysis population, emerging evidence suggests that circulating pentraxin 3 (PTX3), neutrophil gelatinase-associated lipocalin (NGAL), and chitinase-3-like protein 1 (CHI3L1) are associated with cardiovascular inflammation and endothelial injury. However, predictive values of these three biomarkers on arteriovenous fistula (AVF) outcomes are unknown. METHODS: This prospective observational cohort study enrolled 135 hemodialysis patients using AVF and then followed them for 3 years. Plasma levels of PTX3, NGAL, and CHI3L1 were measured. Patients were followed up prospectively for two clinical outcomes, including AVF functional patency loss and death. Cox proportional hazards regression models were used to analyze hazard ratios for the commencement of AVF functional patency loss and mortality. RESULTS: Among 135 patients, the mean age was 66.0 ± 15.7 years old and 48.1% were male. The plasma level of PTX3, NGAL, and CHI3L1 was 2.8 ± 2.3 ng/mL, 349.2 ± 111.4 ng/mL, and 185.5 ± 66.8 ng/mL, respectively. During a 3-year follow-up period, the plasma level of PTX3 was an independent predictor for AVF functional patency loss (per 1 ng/mL increase, HR 1.112 [95% CI: 1.001-1.235], p = 0.048). Besides, patients with higher plasma levels of PTX3 were more likely to suffer from cardiovascular mortality (per 1 ng/mL increase, HR 1.320 [95% CI: 1.023-1.703], p = 0.033), infectious mortality (per 1 ng/mL increase, HR 1.394 [95% CI: 1.099-1.769], p = 0.006), and all-cause mortality (per 1 ng/mL increase, HR 1.233 [95% CI: 1.031-1.476], p = 0.022). CONCLUSIONS: The plasma level of PTX3, not NGAL or CHI3L1, was associated with higher risks of AVF functional patency loss in chronic hemodialysis patients, showing its value in reflecting AVF endothelial dysfunction. Furthermore, PTX3 also predicts mortality in chronic hemodialysis patients.

Anti Human CX3CR1 VHH Molecule Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mouse Model.

BACKGROUND: Fractalkine receptor 1 (CX3CR1) mediates macrophage infiltration and accumulation, causing venous neointimal hyperplasia (VNH)/venous stenosis (VS) in arteriovenous fistula (AVF). The effect of blocking CX3CR1 using an anti-human variable VHH molecule (hCX3CR1 VHH, BI 655088) on VNH/VS was determined using a humanized mouse in which the human CX3CR1 (hCX3CR1) gene was knocked in (KI). METHODS: Whole-transcriptomic RNA sequencing with bioinformatics analysis was used on human stenotic AVF samples, C57BL/6J, hCX3CR1 KI mice with AVF and CKD, and in in vitro experiments to identify the pathways involved in preventing VNH/VS formation after hCX3CR1 VHH administration. RESULTS: Accumulation of CX3CR1 and CD68 was significantly increased in stenotic human AVFs. In C57BL/6J mice with AVF, there was increased Cx3cr1, Cx3cl1, Cd68, and Tnf-α gene expression, and increased immunostaining of CX3CR1 and CD68. In hCX3CR1-KI mice treated with hCX3CR1 VHH molecule (KI-A), compared with vehicle controls (KI-V), there was increased lumen vessel area and patency, and decreased neointima in the AVF outflow veins. RNA-seq analysis identified TNF-α and NF-κB as potential targets of CX3CR1 inhibition. In KI-A-treated vessels compared with KI-V, there was decreased gene expression of Tnf- α, Mcp-1, and Il-1 ß; with reduction of Cx3cl1, NF-κB, and Cd68; decreased M1, Ly6C, smooth muscle cells, fibroblast-activated protein, fibronectin, and proliferation; and increased TUNEL and M2 staining. In cell culture, monocytes stimulated with PMA and treated with hCX3CR1 VHH had decreased TNF- α, CD68, proliferation, and migration. CONCLUSIONS: CX3CR1 blockade reduces VNH/VS formation by decreasing proinflammatory cues.

Preventive Intrathecal Injection of Bupivacaine Alleviated Microglia Activation and Neuropathic Pain in a Rat Model of Chronic Constriction Injury.

Spinal microglia are crucial to neuronal hyper-excitability and pain hypersensitivity. The local anesthetic bupivacaine is commonly used for both peripheral and spinal anesthesia. The pain-relief effects resulting from the peripheral and systemic administration of bupivacaine have been previously reported. In this study, the preventive effects of intrathecal bupivacaine administration against neuropathic pain were revealed in a rat model of sciatic nerve chronic constriction injury (CCI). Using a CCI rat model, pain hypersensitivity, characterized by mechanical allodynia and thermal hyperalgesia, correlated well with microglia M1 polarization, activation and pro-inflammatory cytokine expression in both spinal cord dorsal horns and sciatic nerves. Bupivacaine attenuated pain behaviors and inflammatory alternations. We further identified that the Interferon Regulatory Factor 5 (IRF5)/P2X Purinoceptor 4 (P2X4R) and High Mobility Group Box 1 (HMGB1)/Toll-Like Receptor 4 (TLR4)/NF-κB inflammatory axes may each play pivotal roles in the acquisition of microglia M1 polarization and pro-inflammatory cytokine expression under CCI insult. The relief of pain paralleled with the suppression of microglia M1 polarization, elevation of microglia M2 polarization, and inhibition of IRF5/P2X4R and HMGB1/TLR4/NF-κB in both the spinal cord dorsal horns and sciatic nerve. Our findings provide molecular and biochemical evidence for the anti-neuropathic effect of preventive bupivacaine.

Endoplasmic Reticulum Stress Contributed to Dipyridamole-Induced Impaired Autophagic Flux and Glioma Apoptosis.

Elevation of intracellular cAMP levels has been implicated in glioma cell proliferation inhibition, differentiation, and apoptosis. Inhibition of phosphodiesterase is a way to elevate intracellular cAMP levels. The present study aimed to investigate the anti-glioma potential of dipyridamole, an inhibitor of phosphodiesterase. Upon treatment with dipyridamole, human U87 glioma cells decreased cell viability, clonogenic colonization, migration, and invasion, along with Noxa upregulation, Endoplasmic Reticulum (ER) stress, impaired autophagic flux, Yes-associated Protein 1 (YAP1) phosphorylation, and YAP1 reduction. Pharmacological and genetic studies revealed the ability of dipyridamole to initiate Noxa-guided apoptosis through ER stress. Additionally, the current study further identified the biochemical role of YAP1 in communicating with ER stress and autophagy under situations of dipyridamole treatment. YAP1 promoted autophagy and protected glioma cells from dipyridamole-induced apoptotic cell death. Dipyridamole impaired autophagic flux and rendered glioma cells more vulnerable to apoptotic cell death through ER stress-inhibitable YAP1/autophagy axis. The overall cellular changes caused by dipyridamole appeared to ensure a successful completion of apoptosis. Dipyridamole also duplicated the biochemical changes and apoptosis in glioma T98G cells. Since dipyridamole has additional biochemical and pharmacological properties, further research centered on the anti-glioma mechanisms of dipyridamole is still needed.

Metformin Mitigated Obesity-Driven Cancer Aggressiveness in Tumor-Bearing Mice.

Metformin may offer benefits to certain cancer populations experiencing metabolic abnormalities. To extend the anticancer studies of metformin, a tumor model was established through the implantation of murine Lewis Lung Carcinoma (LLC) cells to Normal Diet (ND)-fed and High-Fat Diet (HFD)-fed C57BL/6 mice. The HFD-fed mice displayed metabolic and pro-inflammatory alterations together with accompanying aggressive tumor growth. Metformin mitigated tumor growth in HFD-fed mice, paralleled by reductions in circulating glucose, insulin, soluble P-selectin, TGF-ß1 and High Mobility Group Box-1 (HMGB1), as well as tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets and neutrophils molecules. The suppressive effects of metformin on cell proliferation, migration and oncogenic signaling molecules were confirmed in cell study. Moreover, tumor-bearing HFD-fed mice had higher contents of circulating and tumor immunopositivity of Neutrophil Extracellular Traps (NETs)-associated molecules, with a suppressive effect from metformin. Data taken from neutrophil studies confirmed the inhibitory effect that metformin has on NET formation induced by HMGB1. Furthermore, HMGB1 was identified as a promoting molecule to boost the transition process towards NETs. The current study shows that metabolic, pro-inflammatory and NET alterations appear to play roles in the obesity-driven aggressiveness of cancer, while also representing candidate targets for anticancer potential of metformin.

The Impact of Frailty on the Outcomes of Hemodialysis Vascular Access.

BACKGROUND: Frailty has been associated with mortality and adverse cardiovascular outcomes in patients with hemodialysis (HD), however the relevance of frailty on the outcomes of HD vascular access remains unclear. METHODS: We enrolled a cohort of patients with prevalent HD between August 2018 and November 2018. The presence of 5 frailty phenotypes was determined at enrollment, using the modified Fried's criteria. Data regarding vascular access events or mortality were linked to prospectively collected data up to 24 months after enrollment. RESULTS: Of the 382 patients screened, 313 were recruited in the final analysis. The participants' mean age was 66 years, and 42.5% were female. Among all participants, 40.3% were determined to be frail and 29.4% pre-frail. The frail phenotype was associated with age, female gender, lower body mass index, unemployment, lower education level, and higher dialysis clearance. During the follow-up period (median, 24 months), 112 patients had vascular access events (non-frail, 27.4%; pre-frail, 35.9%; frail, 46.1%; p = 0.003) and 45 patients experienced thrombosis of the vascular access (non-frail, 4.2%; pre-frail, 9.8%; frail, 18.3%; p = 0.002). Cox regression analysis showed that frail patients had a 2.2-fold higher risk of experiencing vascular access events than non-frail patients [hazard ratio (HR): 2.205, 95% confidence interval (CI): 1.377-3.532, p = 0.001], but the association was not significant (HR: 1.634, 95% CI: 0.938-2.848, p = 0.082) after multivariate adjustment. CONCLUSIONS: The frail phenotype is common in Taiwanese patients who undergo maintenance HD and is associated with adverse outcomes of dialysis vascular access.

Efficacy and Safety of High-Dose Intracoronary Adenosine Injection in Fractional Flow Reserve Assessment.

Background: The recommended dosage of intracoronary adenosine in fractional flow reserve (FFR) assessment is controversial. High-dose adenosine may overcome the biological variability of adenosine response in hyperemia. Objectives: We aimed to test the efficacy and safety of a high-dose escalation protocol at our institute. Methods: Using the adenosine dose escalation protocol, the percentages of FFR ≤ 0.75 and 0.80 after high-dose escalation were compared with those at conventional doses. The chi-squared test was used to evaluate the accuracy of FFR values with the tested doses by comparing them with the results of a non-invasive pretest. Results: A total of 87 patients (130 vessels) were included, and protocol adherence was 93.1%. High-dose intracoronary adenosine was injected in 78.5% of the vessels. The dose escalation strategy was well-tolerated without serious complications. The positive rate increased significantly after conducting the protocol compared to that with a conventional dose (28.2% vs. 23.6% with an FFR threshold of 0.75, and 48.7% vs. 42.5% with a threshold of 0.80, both p < 0.05). In the validation cohort, only FFR ≤ 0.75 was associated with the binary result of the non-invasive pretest (p < 0.01 vs. p = 0.37). The high-dose adenosine escalation strategy did not increase the accuracy of FFR (77.8% vs. 75.6% in conventional dose and high-dose adenosine, respectively). Conclusions: The use of a high-dose escalation strategy increased the positive rate in FFR assessments.

An oral absorbent, AST-120, restores vascular growth and blood flow in ischemic muscles in diabetic mice via modulation of macrophage transition.

Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with the corresponding expression of pro-inflammatory cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into the M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory cytokines.

DHA attenuated Japanese Encephalitis virus infection-induced neuroinflammation and neuronal cell death in cultured rat Neuron/glia.

Japanese Encephalitis Virus (JEV) is a neurotropic virus and its Central Nervous System (CNS) infection causes fatal encephalitis with high mortality and morbidity. Microglial activation and consequences of bystander damage appear to be the dominant mechanisms for Japanese Encephalitis and complications. Docosahexaenoic acid (DHA), an essential fatty acid and a major component of brain cell membranes, possesses additional biological activities, including anti-apoptosis, anti-inflammation, and neuroprotection. Through this study, we have provided experimental evidence showing the anti-inflammatory, neuroprotective, and anti-viral effects of DHA against JEV infection in rat Neuron/glia cultures. By Neuron/glia and Neuron cultures, DHA protected against neuronal cell death upon JEV infection and reduced JEV amplification. In Neuron/glia and Microglia cultures, the effects of DHA were accompanied by the downregulation of pro-inflammatory M1 microglia, upregulation of anti-inflammatory M2 microglia, and reduction of neurotoxic cytokine expression, which could be attributed to its interference in the Toll-Like Receptor (TLR), Mitogen-Activated Protein Kinase (MAPK), and Interferon/Janus Kinase/Signal Transducers and Activators of Transcription (Stat), along with the NF-κB, AP-1, and c-AMP Response Element Binding Protein (CREB) controlled transcriptional programs. Parallel anti-inflammatory effects against JEV infection were duplicated by G Protein-Coupled Receptor (GPR120) and GPR40 agonists and a reversal of DHA-mediated anti-inflammation was seen in the presence of GPR120 antagonist, while the GPR40 was less effectiveness. Since increasing evidence indicates its neuroprotection against neurodegenerative diseases, DHA is a proposed anti-inflammatory and neuroprotective candidate for the treatment of neuroinflammation-accompanied viral pathogenesis such as Japanese Encephalitis.

Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma.

Adequate stress on the Endoplasmic Reticulum (ER) with the Unfolded Protein Response (UPR) could maintain glioma malignancy. Uncontrolled ER stress, on the other hand, predisposes an apoptosis-dominant UPR program. We studied here the proapoptotic actions of the Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib, with the focus on ER stress. The study models were human H4 and U87 glioma cell lines. We found that the glioma cell-killing effects of gefitinib involved caspase 3 apoptotic cascades. Three branches of ER stress, namely Activating Transcription Factor-6 (ATF6), Protein Kinase R (PKR)-Like ER Kinase (PERK), and Inositol-Requiring Enzyme 1 (IRE1), were activated by gefitinib, along with the elevation of intracellular free Ca2+, Reactive Oxygen Species (ROS), and NADPH Oxidase2/4 (NOX2/4). Specifically, elevated IRE1 phosphorylation, Tumor Necrosis Factor (TNF) Receptor-Associated Factor-2 (TRAF2) expression, Apoptosis Signal-Regulating Kinase-1 (Ask1) phosphorylation, c-Jun N-Terminal Kinase (JNK) phosphorylation, and Noxa expression appeared in gefitinib-treated glioma cells. Genetic, pharmacological, and biochemical studies further indicated an active ROS/ER stress/Ask1/JNK/Noxa axis causing the glioma apoptosis induced by gefitinib. The findings suggest that ER-stress-based therapeutic targeting could be a promising option in EGFR inhibitor glioma therapy, and may ultimately achieve a better patient response.

A randomized controlled trial of drug-coated balloon angioplasty in venous anastomotic stenosis of dialysis arteriovenous grafts.

OBJECTIVE: Paclitaxel-coated balloons are used to reduce neointimal hyperplasia in native arteriovenous (AV) fistulas. However, no study specifically evaluated their effect on venous anastomotic stenosis of dialysis grafts. We aimed to compare the efficacy of angioplasty with drug-coated balloons (DCBs) and angioplasty with conventional balloons (CBs) for venous anastomotic stenosis in dysfunctional AV grafts. METHODS: In this investigator-initiated, single-center, single-blinded, prospective randomized controlled trial, we randomly assigned 44 patients who had venous anastomotic stenosis to undergo angioplasty with DCBs (n = 22) or CBs (n = 22) from July 2015 to August 2018. Access function was observed per the hemodialysis center's protocols; ancillary angiographic follow-up was performed every 2 months for 1 year after the interventions. The primary end point was target lesion primary patency at 6 months. Secondary outcomes included anatomic and clinical success after angioplasty, circuit primary patency at 6 months and 1 year, and target lesion primary patency at 1 year. RESULTS: At 6 months, target lesion primary patency in the DCB group was significantly greater than that in the CB group (41% vs 9%; hazard ratio [HR], 0.393; 95% confidence interval [CI], 0.194-0.795; P = .006), as was the primary patency of the entire access circuit (36% vs 9%; HR, 0.436; 95% CI, 0.218-0.870; P = .013). At 1 year, the target lesion primary patency in the DCB group remained greater than that in the CB group (23% vs 9%; HR, 0.477; 95% CI, 0.243-0.933; P = .019) but not the primary patency of the access circuit (14% vs 9%; HR, 0.552; 95% CI, 0.288-1.059; P = .056). No difference in anatomic or clinical success was observed; no major complications were noted. CONCLUSIONS: Angioplasty with DCBs showed a modest improvement in primary patency of venous anastomotic stenosis and all dialysis AV grafts at 6 months. The short-term benefit was not durable to 1 year, and reinterventions were eventually needed.

Semiparametric mixture cure model analysis with competing risks data: Application to vascular access thrombosis data.

The article is motivated by a nephrology study in Taiwan, which enrolled hemodialysis patients who suffered from vascular access thrombosis. After treatment, some patients were cured of thrombosis, while some may experience recurrence of either type (acute or nonacute) of vascular access thrombosis. Our major interest is to estimate the cumulative incidence probability of time to the first recurrence of acute thrombosis after therapy. Since the occurrence of one type of vascular access thrombosis precludes occurrence of the other type, patients are subject to competing risks. To account for the presence of competing risks and cured patients, we develop a mixture model approach to the regression analysis of competing-risks data with a cure fraction. We make inference about the effects of factors on both the cure rate and cumulative incidence function (CIF) for a failure of interest, which are separately specified in the logistic regression model and semiparametric regression model with time-varying and time-invariant effects. Based on two-stage method, we develop novel estimation equations using the inverse probability censoring weight techniques. The asymptotic properties of the estimators are rigorously studied and the plug-in variance estimators can be obtained for constructing interval estimators. We also propose a lack-of-fit test for assessing the adequacy of the proposed model and several tests for time-varying effects. The simulation studies and vascular access thrombosis data analysis are conducted to illustrate the proposed method.

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis.

The dormancy of cellular apoptotic machinery has been highlighted as a crucial factor in therapeutic resistance, recurrence, and poor prognosis in patients with malignancy, such as malignant glioma. Increasing evidence indicates that nonsteroidal anti-inflammatory drugs (NSAIDs) confer chemopreventive effects, and indomethacin has been shown to have a novel chemotherapeutic application targeting glioma cells. To extend these findings, herein, we studied the underlying mechanisms of apoptosis activation caused by indomethacin in human H4 and U87 glioma cells. We found that the glioma cell-killing effects of indomethacin involved both death receptor- and mitochondria-mediated apoptotic cascades. Indomethacin-induced glioma cell apoptosis was accompanied by a series of biochemical changes, including reactive oxygen species generation, endoplasmic reticulum (ER) stress, apoptosis signal-regulating kinase-1 (Ask1) activation, p38 hyperphosphorylation, protein phosphatase 2A (PP2A) activation, Akt dephosphorylation, Mcl-1 and FLICE-inhibiting protein (FLIP) downregulation, Bax mitochondrial distribution, and caspases 3/caspase 8/caspase 9 activation. Data on pharmacological inhibition related to oxidative stress, ER stress, free Ca2+, and p38 revealed that the axis of oxidative stress/ER stress/Ask1/p38/PP2A/Akt comprised an apoptotic cascade leading to Mcl-1/FLIP downregulation and glioma apoptosis. Since indomethacin is an emerging choice in chemotherapy and its antineoplastic effects have been demonstrated in glioma tumor-bearing models, the findings further strengthen the argument for turning on the aforementioned axis in order to activate the apoptotic machinery of glioma cells.

ß-Funaltrexamine Displayed Anti-inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke.

Chronic treatment involving opioids exacerbates both the risk and severity of ischemic stroke. We have provided experimental evidence showing the anti-inflammatory and neuroprotective effects of the µ opioid receptor antagonist ß-funaltrexamine for neurodegenerative diseases in rat neuron/glia cultures and a rat model of cerebral Ischemia/Reperfusion (I/R) injury. Independent of in vitro Lipopolysaccharide (LPS)/interferon (IFN-γ)-stimulated neuron/glia cultures and in vivo cerebral I/R injury in Sprague-Dawley rats, ß-funaltrexamine downregulated neuroinflammation and ameliorated neuronal degeneration. Alterations in microglia polarization favoring the classical activation state occurred in LPS/IFN-γ-stimulated neuron/glia cultures and cerebral I/R-injured cortical brains. ß-funaltrexamine shifted the polarization of microglia towards the anti-inflammatory phenotype, as evidenced by decreased nitric oxide, tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2, along with increased CD163 and arginase 1. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by ß-funaltrexamine was accompanied by the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein, along with signal transducers and activators of transcription transcriptional activities and associated upstream activators. The effects of ß-funaltrexamine are closely linked with its action on neuroinflammation by switching microglia polarization from pro-inflammatory towards anti-inflammatory phenotypes. These findings provide new insights into the anti-inflammatory and neuroprotective mechanisms of ß-funaltrexamine in combating neurodegenerative diseases, such as stroke.

Propofol Improved Glucose Tolerance Associated with Increased FGF-21 and GLP-1 Production in Male Sprague-Dawley Rats.

Anesthetics, particularly volatile anesthetics, have been shown to impair glucose metabolism and cause hyperglycemia, closely linking them with mortality and morbidity as related to surgery. Beyond being an anesthetic used for general anesthesia and sedation, intravenous hypnotic propofol displays an effect on glucose metabolism. To extend the scope of propofol studies, its effects on glucose metabolism were evaluated in male Sprague-Dawley rats of various ages. Unlike chloral hydrate and isoflurane, propofol had little effect on basal glucose levels in rats at 2 months of age, although it did reduce chloral hydrate- and isoflurane-induced hyperglycemia. Propofol reduced postload glucose levels after either intraperitoneal or oral administration of glucose in both 7- and 12-month-old rats, but not those at 2 months of age. These improved effects regarding propofol on glucose metabolism were accompanied by an increase in insulin, fibroblast growth factor-21 (FGF-21), and glucagon-like peptide-1 (GLP-1) secretion. Additionally, an increase in hepatic FGF-21 expression, GLP-1 signaling, and FGF-21 signaling, along with a decrease in endoplasmic reticulum (ER) stress, were noted in propofol-treated rats at 7 months of age. Current findings imply that propofol may turn into insulin-sensitizing molecules during situations of existing insulin resistance, which involve FGF-21, GLP-1, and ER stress.