Roseburia intestinalis-derived extracellular vesicles ameliorate colitis by modulating intestinal barrier, microbiome, and inflammatory responses.

Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent gastrointestinal inflammation, lacking a precise aetiology and definitive cure. The gut microbiome is vital in preventing and treating IBD due to its various physiological functions. In the interplay between the gut microbiome and human health, extracellular vesicles secreted by gut bacteria (BEVs) are key mediators. Herein, we explore the role of Roseburia intestinalis (R)-derived EVs (R-EVs) as potent anti-inflammatory mediators in treating dextran sulfate sodium-induced colitis. R was selected as an optimal BEV producer for IBD treatment through ANCOM analysis. R-EVs with a 76 nm diameter were isolated from R using a tangential flow filtration system. Orally administered R-EVs effectively accumulated in inflamed colonic tissues and increased the abundance of Bifidobacterium on microbial changes, inhibiting colonic inflammation and prompting intestinal recovery. Due to the presence of Ile-Pro-Ile in the vesicular structure, R-EVs reduced the DPP4 activity in inflamed colonic tissue and increased the active GLP-1, thereby downregulating the NFκB and STAT3 via the PI3K pathway. Our results shed light on the impact of BEVs on intestinal recovery and gut microbiome alteration in treating IBD.

All-Cause Death and Major Adverse Events in Atrial Fibrillation with Frailty: Observations from the Korea National Health Insurance Service Data.

Background: Atrial fibrillation (AF) is an indicator of frailty in old patients. This study aimed to investigate the effect of frailty on the use of oral anticoagulants (OAC) and clinical outcomes in a nationwide cohort of patients with new-onset AF. Methods: This study included 451,368 participants without AF from the Korea National Health Insurance Service-Health Screening cohort between 2002 and 2009. The Hospital Frailty Risk Score was retrospectively calculated for each patient using all available International Classification of Disease 10th revision diagnostic codes. According to the aggregate score, patients were divided into two groups: the participants without frailty ( < 5 points) and the participants with frailty ( ≥ 5 points). The primary outcome was death from any cause, and the secondary outcomes were cardiovascular death, ischemic stroke, major bleeding, and heart failure admission. Results: With up to 7.2 ± 1.5 years of follow-up, 11,953 participants (median age, 67 [interquartile range, 59.5-74.5] years; 7200 [60.2%] males) developed new-onset AF. Among the patients with AF, 3224 (26.9%) had frailty. Frailty was significantly associated with old age, female sex, polypharmacy, and other comorbidities. In patients with AF, frailty was negatively associated with OAC prescription after new-onset AF (p < 0.001). Compared to patients without frailty, patients with frailty had a significantly higher incidence and risk of all-cause death (hazard ratio [HR] 2.88, 95% confidence interval [CI] 2.65-3.14), cardiovascular death (HR 2.42, 95% CI 2.10-2.80), ischemic stroke (HR 2.25, 95% CI 2.02-2.51), major bleeding (HR 2.44, 95% CI 2.17-2.73), and heart failure admission (HR 1.29, 95% CI 1.09-1.52). In subgroup analysis, when compared to the non-OAC group, the risks associated with frailty were significantly lower in the OAC group for all-cause death, cardiovascular death, ischemic stroke, and heart failure admission. Conclusions: Frailty was negatively associated with the use of OAC and was a predictor of poor prognosis owing to the association of frailty with death, thromboembolic events, bleeding, and heart failure admission. However, OAC use was associated with lower risks related to frailty for all-cause death and major adverse cardiovascular events in patients with AF.

Long-term clinical outcomes of image-guided percutaneous coronary intervention in acute myocardial infarction from the Korea Acute Myocardial Infarction Registry.

Imaging modalities for percutaneous coronary intervention (PCI), such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), have increased in the current PCI era. However, their clinical benefits in acute myocardial infarction (AMI) have not been fully elucidated. This study investigated the long-term outcomes of image-guided PCI in patients with AMI using data from the Korean Acute Myocardial Infarction Registry. A total of 9,271 patients with AMI, who underwent PCI with second-generation drug-eluting stents between November 2011 and December 2015, were retrospectively examined, and target lesion failure (TLF) at 3 years (defined as the composite of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization) was evaluated. From the registry, 2,134 patients (23.0%) underwent image-guided PCI (IVUS-guided: n = 1,919 [20.6%]; OCT-guided: n = 215 patients [2.3%]). Based on propensity score matching, image-guided PCI was associated with a significant reduction in TLF (hazard ratio: 0.76; 95% confidence interval: 0.59-0.98, p = 0.035). In addition, the TLF incidence in the OCT-guided PCI group was comparable to that in the IVUS-guided PCI group (5.3% vs 4.7%, p = 0.903). Image-guided PCI, including IVUS and OCT, is associated with favorable clinical outcomes in patients with AMI at 3 years post-intervention. Additionally, OCT-guided PCI is not inferior to IVUS-guided PCI in patients with AMI.

Long-term impact of angiotensin receptor-neprilysin inhibitor based on short-term treatment response in heart failure.

AIMS: The long-term effect of angiotensin receptor-neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1 year of heart failure (HF) treatment. METHODS AND RESULTS: The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1 year of undergoing index echocardiography. After 1 year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow-up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all-cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4 ± 14.1 years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow-up (median follow-up, 44 [interquartile range, 34-51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P = 0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs. CONCLUSIONS: Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1 year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF.

Thoracoscopic Implantation of Epicardial Left Ventricular Lead for Cardiac Resynchronization Therapy.

(1) Background: Limited data exist on the safety and efficacy of epicardial left ventricular (LV) lead placement using video-assisted thoracoscopic surgery (VATS) for cardiac resynchronization therapy (CRT). (2) Methods: Acute and post-discharge outcomes of CRT were compared between patients with epicardial LV leads (Epicardial-LV group, n = 13) and those with endocardial LV leads (Endocardial-LV group, n = 243). (3) Results: Epicardial LV leads were implanted via VATS alone (n = 8) or along with mini-thoracotomy (n = 5), for failed endocardial implantation (n = 11) or recurrent lead dislodgement (n = 2). All epicardial procedures under general anesthesia with one-lung ventilation were successfully completed in 1.0 ± 0.4 h without phrenic nerve stimulation. LV pacing thresholds in the epicardial-LV (1.5 ± 1.0 V) and endocardial-LV (1.3 ± 0.8 V) were comparable (p = 0.651). All patients were discharged alive post-VATS 8.8 ± 3.9 days. During the follow-up (34.3 ± 28.6 months), all patients with epicardial LV leads stayed alive except for one cardiac death post-CRT 14 months and one heart transplantation post-CRT 30 months. All epicardial LV leads maintained stable performance without dislodgement/significant changes in pacing threshold/impedance. LV lead dislodgement occurred only in endocardial-LV (7/243, 2.9%). Efficacy in both groups was comparable in terms of QRS narrowing, increase in LV ejection fraction, and survival free of cardiac death, or heart-failure-related hospitalization. (4) Conclusions: Epicardial LV lead placement using VATS can be a safe and effective alternative to endocardial implantation, with comparable acute and post-discharge outcomes achieved by both approaches.

Evaluation of Two Methods (Inside-Out/Outside-In) Inferior Articular Process Resection for Uniportal Full Endoscopic Posterolateral Transforaminal Lumbar Interbody Fusion: Technical Note.

Objective: There is limited literature comparing the uniportal full endoscopic posterolateral transforaminal lumbar interbody fusion outside-in approach (ETLIF (O)) with the inside-out approach (ETLIF (I)). Methods: Radiological evaluation was performed on disc height restoration and coronal wedging angle, and operation time (inferior articular process resection time/total operation time) and clinical evaluation were made. Result: 48 cases of inside-out and 38 cases of outside-in cases were included. Compared to inside-out, the outside-in approach had significantly less operative time required to resect inferior articular process: 36.55 ± 10.37, and total operative time: 87.45 ± 20.14 min compared to 49.83 ± 23.97 and 102.56 ± 36.53 min, respectively, for the inside-out approach, p < 0.05. Compared to the preoperative state, both cohorts achieved significant improvement of VAS and ODI at post-operative 1 week, 3 months and at final follow up. Both cohorts achieved statistically significant increased disc height with 5.00 ± 2.87 mm, 5.49 ± 2.33 mm and statistically significant improvement in coronal wedge angle with 1.76 ± 1.63°, 3.24 ± 2.92° in the inside-out and outside-in approaches respectively. Conclusions: Complete removal of inferior articular process is the key part of endoscopic fusion with two methods that can be applied: an inside-out approach or an outside-in approach. Comparing both techniques, the outside-in approach has a shorter operative time required for inferior articular process resection and total length of operation with similar good clinical and radiological outcomes.

A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.

Necrotizing myopathy presenting as congestive heart failure and life-threatening ventricular arrhythmias: a case report.

BACKGROUND: Necrotizing autoimmune myopathy is a rare subtype of idiopathic inflammatory myopathy; however, it can be associated with fatal cardiac manifestations. CASE SUMMARY: A 58-year-old female patient was referred for congestive heart failure with dysrhythmia. Electrocardiograms showed ventricular arrhythmias of various QRS complex morphologies and coupling intervals with beat-to-beat differences. Despite optimal medical therapy for heart failure, the patient was admitted for the progression of dyspnoea and generalized motor weakness. The burden of non-sustained ventricular tachycardia gradually increased, and ventricular fibrillation eventually occurred. In view of a differential diagnosis of an inflammatory myocardial diseases such as sarcoidosis, a cardiac biopsy was performed. However, pathologic examinations revealed only necrotic muscle fibres without granuloma. Further examinations revealed proximal dominant motor weakness, an elevated serum creatinine-phosphokinase level, myogenic potentials on needle electromyography, and biceps muscle biopsy findings that were compatible with necrotizing autoimmune myopathy. High-dose steroid therapy improved the patient's motor weakness, including her respiratory impairment, and successfully suppressed ventricular arrhythmias. DISCUSSION: This case suggests that intensive immunosuppressive therapy with high-dose steroid could be useful in the necrotizing autoimmune myopathy manifested as congestive heart failure and life-threatening ventricular arrhythmias.

Cardiac intramural arteriovenous malformations presented as ventricular tachycardia and fibrillation storm.

We report a case of cardiac intramural arteriovenous malformations (AVMs) misdiagnosed as hypertrophic cardiomyopathy and presented as life-threatening ventricular arrhythmia storm that was successfully controlled by cardiac sympathetic denervation. A 46-year-old male patient with an implantable cardioverter-defibrillator was admitted for recurrent ventricular tachycardia requiring repeated shock refractory to antiarrhythmic drugs. Although the patient was previously diagnosed with hypertrophic cardiomyopathy, multimodality imaging studies showed large left ventricular intramural AVMs, potentially representing arrhythmogenic substrates. Life-threatening ventricular arrhythmia storm, which could not be controlled by radiofrequency catheter ablation and therapeutic hypothermia. However, cardiac sympathetic denervation surgery successfully controlled the ventricular arrhythmia storm.

Prognostic effect of increased left ventricular wall thickness in severe aortic stenosis.

BACKGROUND: It is unclear whether increased left ventricular (LV) thickness is associated with worse clinical outcomes in severe aortic stenosis (AS). The aim of this study was to determine the effect of increased LV wall thickness (LVWT) on major clinical outcomes in patients with severe AS. METHODS AND RESULTS: This study included 290 severe AS patients (mean age 69.4 ± 11.0 years; 136 females) between January 2008 and December 2018. For outcome assessment, the endpoint was defined as death from all causes, cardiovascular death, and the aortic valve replacement (AVR) surgery rate. During follow-up (48.7 ± 39.0 months), 157 patients had AVR, 43 patients died, and 28 patients died from cardiovascular causes. Patients with increased LVWT underwent AVR surgery much more than those without LVWT (60.0% vs. 39.0%, p < 0.001). Furthermore, in patients with increased LVWT, the all-cause and cardiovascular death rates were significantly lower in the AVR group than in the non-AVR group (8.8% vs. 27.3%, p < 0.001, 4.8%, vs. 21.0%, p < 0.001). Multivariate analysis revealed that increased LVWT, age, dyspnea, and AVR surgery were significantly correlated with cardiovascular death. CONCLUSIONS: In patients with severe AS, increased LVWT was associated with a higher AVR surgery rate and an increased rate of cardiovascular death independent of other well-known prognostic variates. Thus, these findings suggest that increased LVWT might be used as a potential prognostic factor in severe AS patients.

Tyrosine kinase inhibitor neratinib attenuates liver fibrosis by targeting activated hepatic stellate cells.

Liver fibrosis, a common outcome of chronic liver disease characterized by excessive accumulation of extracellular matrix (ECM), is a leading cause of mortality worldwide. The tyrosine kinase inhibitor neratinib is a human epidermal growth factor receptor 2 (HER2) inhibitor approved by the FDA for HER2-positive breast cancer treatment; however, it has not yet been evaluated for liver fibrosis treatment. We elucidated the anti-fibrotic effects of neratinib in hepatic stellate cells (HSCs) and in vivo models of CCl4-induced liver fibrosis. HSC activation is a key step in liver fibrogenesis and has a crucial role in collagen deposition, as it is primarily responsible for excessive ECM production. The effect of neratinib on HSC was evaluated in transforming growth factor (TGF-ß)-incubated LX-2 cells and culture-activated primary human HSCs. In vivo study results indicated that neratinib inhibited the inflammatory response, HSC differentiation, and collagen accumulation induced by CCl4. Moreover, the anti-fibrotic effects of neratinib were not associated with the HER2 signaling pathways. Neratinib inhibited FGF2 expression in activated HSCs and serum FGF2 level in the model, suggesting that neratinib possessed therapeutic potency against liver fibrosis and the potential for application against other fibrotic diseases.

Stereotactic Cardiac Radiation to Control Ventricular Tachycardia and Fibrillation Storm in a Patient with Apical Hypertrophic Cardiomyopathy at Burnout Stage: Case Report.

Stereotactic cardiac radiation for ablation (radioablation) of life-threatening ventricular arrhythmia was recently introduced into clinical practice. A 76-year-old male patient with apical hypertrophic cardiomyopathy at burnout stage, who received defibrillator implantation for the secondary prevention of sudden arrhythmic death, was admitted for repeated defibrillator therapy. Radiofrequency catheter ablation was unsuccessful due to the induction of ventricular fibrillation (VF) and hemodynamically unstable sustained monomorphic ventricular tachycardia (VT). However, intracardiac activation mapping for the induced VT revealed the earliest ventricular activation at the apical aneurysm. Radioablation was performed to control VT and VF storm refractory to antiarrhythmic drug therapy. A total of 24 Gray was radiated, divided into three fractions around the apical aneurysm. The onset of electrical modulation was instantaneous and the antiarrhythmic effect was maintained for at least 6 months without significant radiation toxicities. This case suggests that radioablation may be considered as a rescue therapy for VT and VF storm refractory to other treatment modalities.

Long-Term Outcomes of Unprotected Left Main Coronary Artery Disease: Comparison of Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention.

OBJECTIVE: We compared the long-term outcomes of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) disease in a real-world population. BACKGROUND: CABG is the standard of care for ULMCA disease. Contemporary randomized trials have reported conflicting results with the two revascularization strategies for the treatment of ULMCA disease at intermediate-term follow-up. METHODS: We evaluated 422 consecutive patients with ULMCA disease who underwent CABG (n = 273) or PCI (n = 149) from 1998-2008. The primary outcome measure was major adverse cardiac and cerebrovascular event (MACCE) rate, defined as the composite of all-cause death, myocardial infarction (MI), stroke, or target-vessel revascularization (TVR) at 10 years. Propensity-score matched (PSM) analysis was used to assess long-term MACCE. RESULTS: The cumulative 10-year incidence of risk for MACCE was not significantly different between the PCI and CABG groups (24.8% vs 20.5%, respectively; log rank P=.22; log rank PSM P=.45). The risk for all-cause death was not significantly different between the two groups (log rank P=.09; PSM log rank P=.51). The risk for stroke was significantly lower with PCI (log rank P=.02), but was not significant after matching (PSM log rank P=.27). The risk for TVR was significantly higher with PCI vs CABG prior to and after matching (log rank P<.001; log rank PSM P=.01). There were no significant differences in MACCE between the two groups when stratified by SYNTAX scores ≤22% (log rank P=.61) and >23% (log rank P=.06). CONCLUSION: In patients with ULMCA disease, PCI was comparable with CABG for long-term MACCE and death rates. The TVR rate was higher in the PCI group.

Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma.

Scleroderma is an autoimmune rheumatic disorder accompanied by severe fibrosis in skin and other internal organs. During scleroderma progression, resident fibroblasts undergo activation and convert to α-smooth muscle actin (α-SMA) expressing myofibroblasts (MFBs) with increased capacity to synthesize collagens and fibrogenic components. Accordingly, MFBs are a major therapeutic target for fibrosis in scleroderma and treatment with blocking MFBs could produce anti-fibrotic effects. TLY012 is an engineered human TNF-related apoptosis-inducing ligand (TRAIL) which induces selective apoptosis in transformed cells expressing its cognate death receptors (DRs). Here we report that TLY012 selectively blocks activation of dermal fibroblasts and induces DR-mediated apoptosis in α-SMA+ MFBs through upregulated DR5 during its activation. In vivo, TLY012 reverses established skin fibrosis to near-normal skin architecture in mouse models of scleroderma. Thus, the TRAIL pathway plays a critical role in tissue remodeling and targeting upregulated DR5 in α-SMA+ MFBs is a viable therapy for fibrosis in scleroderma.

PEGylated TRAIL ameliorates experimental inflammatory arthritis by regulation of Th17 cells and regulatory T cells.

TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand that can induce apoptosis in cells expressing its cognate death receptors (DRs). Previously, we demonstrated the therapeutic potential of recombinant human TRAIL in experimental rheumatoid arthritis (RA) models. However, the mechanisms of how DR-mediated apoptosis elicits these actions is not known. Here, we show that systemically administering a potent, long-acting PEGylated TRAIL (TRAILPEG) is profoundly anti-rheumatic against two complementary experimental RA mouse models, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA), via targeting IL-17 secreting Th17 cells and regulatory T cells (Treg). Systemic administration of TRAILPEG after disease onset ameliorated the severity of inflammatory arthritis including arthritis indices, paw thickness, cartilage damage and neutrophil infiltration in both CIA and CAIA models. Additionally, the levels of inflammatory molecules (p-p65, ICAM-1, Cox-2, MMP3, and iNOS), pro-inflammatory cytokines (TNF-α, IL-1ß, IFN-γ, IL-6, IL-17) and accumulation of activated macrophages were significantly reduced after the TRAILPEG treatment. Importantly, TRAILPEG decreased the number of pro-inflammatory Th17 cells in inflamed arthritic joints through TRAIL-induced apoptosis while increasing anti-inflammatory Treg population in vivo. These results suggest that TRAILPEG ameliorates autoimmunity by targeting the Th 17-Tregs axis, making it a promising candidate drug for the treatment of RA.

Inhibition of Angiotensin II-Induced Cardiac Fibrosis by Atorvastatin in Adiponectin Knockout Mice.

Adiponectin is a polypeptide known to inhibit cardiac fibrosis via the activation of adenosine monophosphate-activated protein kinase (AMPK). Statins can also activate AMPK, resulting in the secretion of adiponectin. We determined whether atorvastatin inhibits angiotensin II-induced cardiac fibrosis (AICF) in the presence or absence of adiponectin. Adiponectin knockout (APN-KO, n = 44) and wild type (WT, n = 44) mice were received subcutaneous angiotensin II (1.5 mg/kg/day), and atorvastatin (10 mg/kg/day) was administered orally for 15 days. The mRNA expression levels of collagen type I and III, as well as AMPK phosphorylation levels in cardiac tissue were then measured. In the APN-KO mice, collagen type I (p < 0.001) and type III (p = 0.001) expression was significantly greater when treated with angiotensin II, while their expression was significantly reduced in the presence of angiotensin II and atorvastatin. Relative AMPK phosphorylation levels in APN-KO mice were also significantly higher in the angiotensin II + atorvastatin group when compared with angiotensin II group alone. We conclude that atorvastatin attenuates AICF independently from adiponectin by activating AMPK. These data suggest potential cardioprotection beyond lipid modulation potentially supporting statin pleiotropic hypothesis.

Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.

UNLABELLED: Liver fibrosis is a common outcome of chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. No US Food and Drug Administration-approved targeted antifibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAILPEG ) that has a much longer half-life in rodents than native-type TRAIL. In this study, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. CONCLUSION: TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. (Hepatology 2016;64:209-223).

Comparison of Prasugrel and Ticagrelor Antiplatelet Effects in Korean Patients Presenting With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: There is insufficient data on the efficacy of prasugrel and ticagrelor in Korean patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: I n the current double-blind, prospective pilot study, 39 patients with STEMI undergoing primary percutaneous coronary intervention were randomized to receive prasugrel 60 mg loading dose (LD) followed by 10 mg daily maintenance dose (n=19), or ticagrelor 180 mg LD followed by 90 mg twice daily maintenance dose (n=20). We assessed platelet reactivity with the VerifyNow and Vasodilator-Stimulated Phosphoprotein (VASP) P2Y12 assays. Compared to baseline platelet reactivity, both prasugrel and ticagrelor groups achieved similar and significantly lower P2Y12 reaction units (PRU) (259 [IQR: 230 to 281] vs. 28 [12 to 55] for prasugrel; 261 [196 to 286] vs. 43 [11 to 61] for ticagrelor), and platelet reactivity indexes (PRI) (51.2% [39.3 to 61.3] vs. 8.1% [6.1 to 14.7] for prasugrel; 47.5% [38.4 to 50.4] vs. 11.2% [7.1 to 15.5] for ticagrelor, all P values <0.001) at 48 h post-LD. Most patients had low platelet reactivity with 95% PRU values <85 and 82% with PRI <16%. CONCLUSIONS: Both prasugrel and ticagrelor were effective for platelet inhibition in Korean STEMI patients with almost no patients exhibiting high platelet reactivity at 48 h after the LD. Our finding of a high number of patients with very low platelet reactivity deserves further studies to assess the safety of the drugs (Prasugrel and Ticagrelor in ST-segment Elevation Myocardial Infarction Study, NCT02075125).

Polyplex-releasing microneedles for enhanced cutaneous delivery of DNA vaccine.

Microneedle (MN)-based DNA vaccines have many advantages over conventional vaccines administered by hypodermic needles. However, an efficient strategy for delivering DNA vaccines to intradermal cells has not yet been established. Here, we report a new approach for delivering polyplex-based DNA vaccines using MN arrays coated with a pH-responsive polyelectrolyte multilayer assembly (PMA). This approach enabled rapid release of polyplex upon application to the skin. In addition to the polyplex-releasing MNs, we attempted to further maximize the vaccination by developing a polymeric carrier that targeted resident antigen presenting cells (APCs) rich in the intradermal area, as well as a DNA vaccine encoding a secretable fusion protein containing amyloid beta monomer (Aß1-42), an antigenic determinant. The resulting vaccination system was able to successfully induce a robust humoral immune response compared to conventional subcutaneous injection with hypodermal needles. In addition, antigen challenge after immunization elicited an immediate and strong recall immune response due to immunogenic memory. These results suggest the potential utility of MN-based polyplex delivery systems for enhanced DNA vaccination.