Inhibition of RAGE signaling through the intracellular delivery of inhibitor peptides by PEI cationization

The receptor for advanced glycation end products (RAGE) is a multi-ligand cell surface receptor and a member of the immunoglobulin superfamily. RAGE is involved in a wide range of inflammatory, degenerative and hyper-proliferative disorders which span over different organs by engaging diverse ligands, including advanced glycation end products, S100 family proteins, high-mobility group protein B1 (HMGB1) and amyloid beta. We previously demonstrated that the cytoplasmic domain of RAGE is phosphorylated upon the binding of ligands, enabling the recruitment of two distinct pairs of adaptor proteins, Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) and myeloid differentiation protein 88 (MyD88). This engagement allows the activation of downstream effector molecules, and thereby mediates a wide variety of cellular processes, such as inflammatory responses, apoptotic cell death, migration and cell growth. Therefore, inhibition of the binding of TIRAP to RAGE may abrogate intracellular signaling from ligand-activated RAGE. In the present study, we developed inhibitor peptides for RAGE signaling (RAGE-I) by mimicking the phosphorylatable cytosolic domain of RAGE. RAGE-I was efficiently delivered into the cells by polyethylenimine (PEI) cationization. We demonstrated that RAGE-I specifically bound to TIRAP and abrogated the activation of Cdc42 induced by ligand-activated RAGE. Furthermore, we were able to reduce neuronal cell death induced by an excess amount of S100B and to inhibit the migration and invasion of glioma cells in vitro. Our results indicate that RAGE-I provides a powerful tool for therapeutics to block RAGE-mediated multiple signaling

Glomangiomyoma of the Trachea

A glomus tumor is an uncommon soft tissue tumor that is most commonly found in the subungual area and a glomus originating in the trachea is extremely rare. Histologically and ultrastructurally, these tumors have been divided into three subtypes: classic glomus tumors, glomangiomas, and glomangiomyomas. Glomangiomyomas account for less than 10% of all glomus tumors and are the least common type. We report a case of a 54-year-old man with glomangiomyoma of the trachea who presented with stridor. We treated the tumor by segmental resection and primary repair via a transcervical approach

I Experienced More than 10 DeFi Scams: On DeFi Users' Perception of Security Breaches and Countermeasures

Decentralized Finance (DeFi) offers a whole new investment experience and has quickly emerged as an enticing alternative to Centralized Finance (CeFi). Rapidly growing market size and active users, however, have also made DeFi a lucrative target for scams and hacks, with 1.95 billion USD lost in 2023. Unfortunately, no prior research thoroughly investigates DeFi users' security risk awareness levels and the adequacy of their risk mitigation strategies. Based on a semi-structured interview study (N = 14) and a follow-up survey (N = 493), this paper investigates DeFi users' security perceptions and commonly adopted practices, and how those affected by previous scams or hacks (DeFi victims) respond and try to recover their losses. Our analysis shows that users often prefer DeFi over CeFi due to their decentralized nature and strong profitability. Despite being aware that DeFi, compared to CeFi, is prone to more severe attacks, users are willing to take those risks to explore new investment opportunities. Worryingly, most victims do not learn from previous experiences; unlike victims studied through traditional systems, DeFi victims tend to find new services, without revising their security practices, to recover their losses quickly. The abundance of various DeFi services and opportunities allows victims to continuously explore new financial opportunities, and this reality seems to cloud their security priorities. Indeed, our results indicate that DeFi users' strong financial motivations outweigh their security concerns - much like those who are addicted to gambling. Our observations about victims' post-incident behaviors suggest that stronger control in the form of industry regulations would be necessary to protect DeFi users from future breaches.Comment: In Proceedings of the 33rd USENIX Security Symposium, Philadelphia, PA, USA, Aug. 202

Postoperative clinical outcomes and radiological healing according to deep and superficial layer detachment in first facet involving subscapularis tendon tear

Background Subscapularis tendon insertion at the first facet has separate layers (deep and superficial). The purpose of this study is to evaluate postoperative clinical outcomes and radiological healing according to each layer of detachment in the first facet involving subscapularis tendon tear. Methods Eighty-three patients who underwent arthroscopic repair due to First facet involving the scapularis tendon tear accompanying small to medium sized posterosuperior cuff tear were classified into three groups (group A: deep layer partial detachment, group B: deep layer complete detachment, but no superficial layer detachment, and group C: deep layer and superficial layer complete detachment). Subscapularis tendon healing was evaluated using computed tomography arthrogram and clinical result was evaluated using American Shoulder and Elbow Surgeons (ASES) shoulder score, Constant score and University of California Los Angeles (UCLA) shoulder score. Results Retear rate of the subscapularis tendon was 2.2%, 18.2%, and 33.3% in group A, group B, and group C, respectively. These rates showed statistically significant difference among the three groups, which were classified by deep and superficial layer detachment in the first facet (p=0.003). Group A showed significant difference in subscapularis tendon healing compared with group B and group C (p=0.018 and p<0.001, respectively), but there was no statistical difference between group B and group C (p=0.292). Regarding clinical outcomes, there was no significant difference among three groups in ASES and UCLA score at final follow-up (p=0.070 and p=0.106, respectively). Conclusions Complete detachment of deep layer may be related with retear occurrence regardless with detachment of superficial layer, but clinical outcome may not be related with each layer detachment in the first facet involving subscapularis tendon tear

Evidence of Log Integrity in Policy-based Security Monitoring

Abstract-Monitoring systems are commonly used by many organizations to collect information about their system and network operations. Typically, SNMP, IDS, or software agents generate log data and store them in a centralized monitoring system for analysis. However, malicious employees, attackers, or even organizations themselves can modify such data to hide malicious activities or to avoid expensive non-compliance fines. This paper proposes a cloud-based framework for verifying the trustworthiness of the logs based on a small amount of evidence data. A simple Cloud Security Monitoring (CSM) API, made available on the cloud services, allows organizations operating on the cloud to collect additional &quot;evidence&quot; about their systems. Such evidence is used to verify system compliance against the policies set by security managers or regulatory authorities. We present a strategy for randomly auditing and verifying resource compliance, and propose an architecture that allows the organizations to prove compliance to an external auditing agency

AMI threats, intrusion detection requirements and deployment recommendations

Abstract—Advanced Metering Infrastructures (AMI) facilitate bidirectional communication between smart meters and utilities, allowing information about consumption, outages, and electricity rates to be shared reliably and efficiently. However, the numerous smart meters being connected through mesh networks open new opportunities for attackers to interfere with communications and compromise utilities ’ assets or steal customers ’ private information. The goal of this paper is to survey the various threats facing AMIs and the common attack techniques used to realize them in order to identify and understand the requirements for a comprehensive intrusion detection solution. The threat analysis leads to an extensive “attack tree ” that captures the attackers’ key objectives (e.g., energy theft) and the individual attack steps (e.g., eavesdropping on the network) that would be involved in achieving them. With reference to the attack tree, we show the type of information that would be required to effectively detect attacks. We also suggest that the widest coverage in monitoring the attacks can be provided by a hybrid sensing infrastructure that uses both a centralized intrusion detection system and embedded meter sensors. I

Impact of early diagnosis on surgical outcomes in patients with Loeys-Dietz syndrome

BackgroundThis study aimed to investigate the influence of early diagnosis (ED) on surgical outcomes in patients definitively diagnosed with Loeys-Dietz syndrome (LDS).MethodsA retrospective review was conducted on 38 patients with LDS who underwent aortic surgery at our institution between January 1995 and June 2022. The primary endpoint was freedom from aortic reoperation.ResultsAmong the patients, the median age at the initial surgery was 33 (range: 39–44) years, and 23 (60.5%) patients were male. Twenty-one (55.3%; aortic dissection or rupture (n = 2) and aneurysm (n = 19)) patients were diagnosed with LDS before the initial surgery (ED group). Meanwhile, the remaining 17 (44.7%; aortic dissection or rupture (n = 13) and aneurysm (n = 4)) patients were after surgery [delayed diagnosis (DD) group]. The ED group had significantly lower rates of emergency surgery and concomitant arch procedure (P &lt; .001, respectively) but a higher rate of valve-sparing root surgery (P = .018) compared to the DD group. No in-hospital mortality was observed in either group. Nevertheless, the ED group had a shorter postoperative hospital stay (median difference: 3 days, P = .032) and a lower rate of aortic reoperation (P = .013).ConclusionEarly detection of LDS may help in preventing acute aortic syndrome, reducing the risk of aortic reoperation, and potentially shortening hospital stay. Careful medical management before surgery could contribute to better clinical outcomes and an improved quality of life for patients with LDS

A phase 2a double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of NuGel, a novel topical GPCR19-mediated inflammasome inhibitor, in patients with mild to moderate atopic dermatitis: a proof-of-concept study with Post-hoc biomarker analysis

BackgroundCurrent guidelines to treat atopic dermatitis (AD) overlook disease heterogeneity, limiting personalized care. This study assessed NuGel, a topical GPCR19 agonist, for efficacy, safety, and predictive baseline biomarkers in AD patients.MethodsIn a multicenter, double-blind, randomized, placebo-controlled Phase 2a trial (August 2020–September 2021, five hospitals, 80 participants), patients received placebo, 0.3% NuGel, or 0.5% NuGel twice daily for four weeks.ResultsNuGel (0.3% [Nu0.3] and 0.5% [Nu0.5]) was well-tolerated, with no adverse drug reactions or serious adverse events. Nu0.3 showed a significant decrease in EASI score from baseline (-12.2%, [-30.3%, 5.9%], p = 0.04). Treatment with Nu0.5 resulted in a numerically decreased EASI score (-11.9%, [-34.9%, 11.1%], p &gt; 0.05), which is comparable with placebo group (-2.9%, [-21.5%, 15.6%], p &gt; 0.05). No significant difference was observed between groups (p&gt;0.05). Plasma proteomic analysis identified biomarkers associated with blood coagulation, complement activation, and cell adhesion as predictors of response to Nu0.5. Patients with baseline profiles characterized by K2C5high, ENTP6low, or CRKlow demonstrated significant clinical improvement when treated with Nu0.5 compared to the placebo group. Among these, the CRKlow subgroup, comprising 54.3% of the biomarker analysis set, showed a ΔEASI of -61.3% [-99.9, -22.8; p = 0.003] and a ΔIGA of -35.2% [-58.2, -12.1; p = 0.004] compared to the placebo group. The biomarker signature demonstrated high predictive accuracy (AUC = 0.92, p = 0.002). Logistic regression analysis revealed that the threshold of predicted probability derived from the baseline plasma level of K2C5 and ENTP6 successfully stratified 100% of participants who responded to Nu0.5 (ΔEASI from baseline ≤ -50%), whereas none (0%) in the placebo group responded (p = 0.035).ConclusionBaseline biomarkers, such as K2C5, ENTP6, and CRK, may serve as predictors of clinical improvement in AD patients treated with Nu0.5, highlighting the potential for personalized treatment strategies. Further research is required to validate these findings in larger patient cohorts.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT04530643