Pre-emptive Aortic Side Branch Embolization during Endovascular Aneurysm Repair Using the Excluder Stent-Graft System: A Prospective Multicenter study.

PURPOSE: To evaluate the effectiveness and safety of pre-emptive transcatheter arterial embolization (P-TAE) for aortic side branches (ASBs) to prevent Type 2 endoleaks (EL2) before endovascular aneurysm repair (EVAR) using the Excluder stent-graft system (Excluder). MATERIALS AND METHODS: In this prospective, multicenter study, 80 patients (mean age, 79.1 years [SD ± 6.7]; 85.0% were men; mean aneurysmal sac diameter, 48.4 mm [SD ± 7.4]) meeting the eligibility criteria were prospectively enrolled from 9 hospitals. Before EVAR, P-TAE was performed to embolize the patent ASBs originating from the abdominal aortic aneurysm. Contrast-enhanced computed tomography (CT) was performed at 1 month and 6 months after EVAR. The primary endpoint was EL2 incidence at 6 months, and the secondary endpoints were aneurysmal sac diameter changes at 6 and 12 months, P-TAE outcomes, adverse events related to P-TAE, reintervention, and aneurysm-related mortality. RESULTS: All patients successfully underwent P-TAE without serious. Coil embolization was successful in 81.6% of ASBs. EL2 incidence at 6 months was identified in 18 of 70 (25.7%) patients. Aneurysmal sac diameter shrinkage (≥5 mm) was observed in 30.0% of patients at 6 months and in 40.9% at 12 months. Only 1 patient required reintervention for EL2 within 1 year of EVAR; aneurysm-related deaths were not observed. CONCLUSIONS: P-TAE for ASBs before EVAR using Excluder is a safe and effective strategy. It aids in achieving early aneurysmal sac shrinkage and reduces EL2 reintervention at 1 year after EVAR.

Real-time Ripple technique: A case report on Ripple map for real-time identification of conduction gaps without first-pass pulmonary vein isolation.

This paper presents a novel approach to gap mapping in pulmonary vein isolation (PVI) for atrial fibrillation (AF) treatment, utilizing the real-time Ripple (RR) technique. Radiofrequency (RF) catheter ablation, particularly encircling PVI, is a common intervention for AF. Identifying left atrium-pulmonary vein conduction gaps is crucial for achieving PVI with minimal additional ablation if first-pass PVI is unsuccessful. However, identifying conduction gaps can be relatively challenging, often necessitating manual electrocardiogram reannotation due to the limitations of local activation time (LAT) maps. In the case of a 63-year-old patient with drug-resistant symptomatic persistent AF, the RR technique was utilized to identify conduction gaps during RF ablation. The technique involved pausing fast anatomical mapping (FAM), activating Ripple map (RM) feature on the CARTO 3 system and acquiring points with an ultrahigh-resolution mapping catheter. This approach revealed that the actual site of earliest activation differs from the LAT map indication, enabling successful PVI. The RM feature's capability to reflect actual excitation propagation without reliance on map annotations was crucial for precise conduction gap identification, overcoming inter-operator variability and inaccuracies of conventional methods. The RR technique not only facilitated real-time analysis during gap mapping but also significantly reduced the procedure time, minimizing potential complications. This case report highlights the efficacy of the RR technique in real-time gap mapping, demonstrating its value in cases where first-pass PVI is unsuccessful. The integration of this technique into PVI procedures can enhance both the accuracy and efficiency of catheter ablation for AF.

Wire ThRoUgh Snare Twice (Wire TRUST) technique: A novel method to grasp a lead with inaccessible ends as a supportive femoral approach for transvenous lead extraction.

INTRODUCTION: Transvenous lead extraction (TLE) is a crucial procedure for managing cardiac implantable electronic devices. The use of a combined superior and femoral approach has been found to enhance the success rate of TLE. This report introduces a novel technique, named "Wire ThRoUgh Snare Twice" (Wire TRUST), for effectively grasping a lead without a free end during TLE. METHOD: The Wire TRUST technique was applied in a case involving a 49-year-old male patient requiring TLE due to electrical artifact on the right ventricular (RV) lead, replacement of the RV lead, and pacemaker generator exchange. The Wire TRUST technique involved the insertion of a 4-Fr pigtail catheter and a 6-Fr snare catheter through the 14-Fr sheath inserted from the right common femoral vein. The 4-Fr pigtail catheter was hooked to the RV lead under multidirectional fluoroscopic guidance in the right atrium. The 0.014-in. guidewire was advanced through the pigtail catheter, crossing the RV lead until reaching the inferior vena cava. Subsequently, the distal end of the 0.014-in. guidewire was captured using a snare and pulled, facilitating externalization of the guidewire. After externalization, both ends of the 0.014-in. guidewire were passed through the snare outside the body and reinserted into the 14-Fr sheath. By simultaneously advancing and closing the snare while applying tension to the 0.014-in. guidewire, a secure grip on the lead without free ends was achieved. RESULTS: The Wire TRUST technique enabled successful lead extraction and replacement without any complications. The technique facilitated the co-axial alignment of the powered sheath with the RV lead, ensuring safe and efficient extraction. CONCLUSION: The Wire TRUST technique presents a novel and effective approach for grasping leads with inaccessible ends during TLE.

Lenvatinib Mitigates Transarterial Embolization-Induced Polarization of Tumor-Associated Macrophages in a Rat Hepatocellular Carcinoma Model.

PURPOSE: To investigate the effect of transarterial embolization (TAE) on macrophage polarization and the modulatory effect of lenvatinib when used in combination with TAE in a rat hepatocellular carcinoma model. MATERIALS AND METHODS: A N1S1-bearing orthotopic rat model was subjected to TAE and administered 5 mg/kg of lenvatinib. CD8+, CD68+, and CD206+ cells were examined in 4 groups: sham (n = 5), lenvatinib (n = 5), TAE (n = 5), and combination of TAE and lenvatinib (n = 5). Transcriptome analysis was performed to assess gene expression related to macrophage polarization in the sham, TAE, and combination groups. An in vitro coculture experiment with bone marrow-derived macrophages was performed to identify lenvatinib target in macrophage polarization. RESULTS: There were no significant differences in the number of CD8+ and CD68+ cells among the 4 groups. Tumor-associated macrophage positivity for CD206 was significantly higher in the TAE group (58.1 ± 20.9) than in the sham (11.2 ± 14.3; P < .001) and combination (27.1 ± 19.7; P = .003) groups. In the transcriptome analysis, compared with the genes in the sham group, 5 macrophage polarization-related genes, including St6gal1, were upregulated by more than 1.5 fold in the TAE group and downregulated by more than 1.5 fold in the combination group. The coculture experiment showed that lenvatinib did not affect macrophages but affected N1S1 cells, leading to macrophage polarization. CONCLUSIONS: TAE-induced M2 macrophage polarization. Lenvatinib administration with TAE could reprogram macrophage polarization, improving tumor immune microenvironment.

Design, synthesis, structure-activity relationship studies, and evaluation of novel GLS1 inhibitors.

Glutaminase converts glutamine into glutamic acid and has two isoforms: glutaminase 1 (GLS1) and glutaminase 2 (GLS2). GLS1 is overexpressed in several tumors, and research to develop glutaminase inhibitors as antitumor drugs is currently underway. The present study examined candidate GLS1 inhibitors using in silico screening and attempted to synthesize novel GLS1 inhibitors and assess their GLS1 inhibitory activities in a mouse kidney extract and against recombinant mouse and human GLS1. Novel compounds were synthesized using compound C as the lead compound, and their GLS1 inhibitory activities were evaluated using the mouse kidney extract. Among the derivatives tested, the trans-4-hydroxycyclohexylamide derivative 2j exhibited the strongest inhibitory activity. We also assessed the GLS1 inhibitory activities of the derivatives 2j, 5i, and 8a against recombinant mouse and human GLS1. The derivatives 5i and 8a significantly decreased the production of glutamic acid at 10 mM. In conclusion, we herein identified two compounds that exhibited GLS1 inhibitory activities with equal potencies as known GLS1 inhibitors. These results will contribute to the development of effective novel GLS1 inhibitors with more potent inhibitory activity.

Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity.

GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC50 of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.

Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis.

Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.

Nicolaioidesin C: An Antiausterity Agent Shows Promising Antitumor Activity in a Pancreatic Cancer Xenograft Mouse Model.

Human pancreatic tumors are hypovascular in nature, and their tumor microenvironment is often characterized by hypoxia and severe nutrient deprivation due to uncontrolled heterogeneous growth, a phenomenon known as "austerity". However, pancreatic tumor cells have the inherent ability to adapt and thrive even in such low nutrient and hypoxic microenvironments. Anticancer drugs such as gemcitabine and paclitaxel, which target rapidly proliferating cells, are often ineffective against nutrient-deprived pancreatic cancer cells. In order to overcome this limitation, the search for novel agents that can eliminate cancer cells' adaptations to nutrition starvation, also known as "antiausterity" agents, represents a promising strategy to make the cancer cells susceptible to treatment. The natural product (+)-nicolaioidesin C (Nic-C) was found to have potent antiausterity activity against the PANC-1 human pancreatic cancer cell line in a nutrient-deprived condition. However, its efficacy in vivo remained untested. To address this, we synthesized Nic-C in its racemic form and evaluated its antitumor potential in a human pancreatic cancer xenograft model. Nic-C inhibited pancreatic cancer cell migration and colony formation and significantly inhibited tumor growth in MIA PaCa-2 xenografts in a dose-dependent manner. Furthermore, Nic-C inhibited the Akt/mTOR and autophagy signaling pathways in both in vitro and in vivo studies. Metabolomic profiling of in vivo tumor samples suggests that Nic-C downregulates amino acid metabolism while upregulating sphingolipid metabolism.

Open Conversion with Explantation of Stent Grafts After Endovascular Aneurysm Repair for Abdominal Aortic Aneurysm.

BACKGROUND: Although endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) is widely used worldwide, the fact that it is associated with increased rates of reintervention has been considered a problem. This study aimed to analyze the outcomes of primary open AAA repair and open conversion with explantation of stent grafts after EVAR. METHODS: In this retrospective study, we enrolled 1,120 patients (open repair, n = 664; EVAR, n = 456) who underwent AAA repair at Kobe University from 1999 to 2019. Of the 664 patients who underwent open repair, 121 (patients who underwent primary open repair (POR) as a concomitant procedure and patients with ruptured AAA) were excluded from the study. The outcomes of POR were compared with those of open conversion with explantation of stent grafts. RESULTS: Of the 543 patients who underwent open repair, 513 underwent POR and 30 underwent open conversion with explantation of stent grafts. The operation time for POR was significantly less than that for open conversion with explantation. During surgery, patients who underwent open conversion with explantation required significantly more transfusions of red cell concentrate, fresh frozen plasma, and platelet concentrate than those who underwent POR. Overall, 30 patients who underwent open conversion with explantation required a total of 48 reinterventions before surgery. Hospital mortality rates were 0.7% and 0% in the POR and open conversion with explantation groups, respectively (P = 0.62). Although overall survival at 5 years in the POR group was significantly better than that in the open conversion with explantation group (89.3 ± 1.7% vs. 79.5 ± 9.6%; P = 0.01), there were no significant differences between the 2 groups regarding the freedom from aortic event (hospital death, reintervention, and aortic death). According to the multivariate analysis, open conversion with explantation was not an independent risk factor for late death. There were 20 patients who were hesitant to undergo OCE, although we recommended OCE. In a subgroup analysis, the overall mean cost borne by patients who underwent EVAR was approximately 2.3 times higher compared with that borne by patients who underwent POR. CONCLUSIONS: Although demanding, both early and long-term outcomes of OCE have been favorable in our present study. OCE is highly recommended in patients with persistent sac enlargement after EVAR.

Predictors of Pacing Capture Threshold Exacerbation After Leadless Pacemaker Implantation.

The predictors of pacing capture threshold (PCT) exacerbation after leadless pacemaker implantation remain unknown. We analyzed the predictors of poor PCT by identifying risk factors using multivariate logistic regression analysis for 211 patients with leadless pacemaker implantation. Twenty patients met the criteria for elevated PCT levels and were categorized in the poor PCT group. Multivariate analyses revealed that PCT (P < 0.0001) and pacing impedance (P = 0.03) were independent predictors of PCT exacerbation. Elevated PCT levels and low pacing impedance during leadless pacemaker implantation were potential risk factors for the replacement of leadless pacemakers after the procedure.

Efficacy of personal protective equipment to prevent environmental infection of COVID-19 among healthcare workers: a systematic review.

BACKGROUND: Healthcare workers (HCWs) employed personal protective equipment (PPE) during the COVID-19 pandemic, crucial to protecting themselves from infection. To highlight the efficacy of PPE in preventing environmental infection among HCWs, a systematic review was conducted in line with PRISMA guidance. METHODS: A search of the PubMed and Web of Science databases was conducted from January 2019 to April 2021 using pre-defined search terms. Articles were screened by three researchers. The approved papers were read in full and included in this review if relevance was mutually agreed upon. Data were extracted by study design and types of PPEs. RESULTS: 47 of 108 identified studies met the inclusion criteria, with seven reviews and meta-analyses, seven cohort, nine case-control, fifteen cross-sectional studies, four before and after, four case series, and one modeling studies. Wearing PPE offered COVID-19 protection in HCWs but required adequate training. Wearing surgical masks provided improved protection over cloth masks, while the benefit of powered air-purifying respirators is less clear, as are individual gowns, gloves, and/or face shields. CONCLUSIONS: Wearing PPE, especially facial masks, is necessary among HCWs, while training in proper use of PPE is also important to prevent COVID-19 infection.

Histological study of the thin membranous dense connective tissues around the curving portion of the bilateral recurrent laryngeal nerves.

OBJECTIVE/AIM: We aimed to demonstrate the anatomical relationship between the recurrent laryngeal nerves (RLNs), thin membranous dense connective tissue (TMDCT [e.g., the visceral or vascular sheaths around the esophagus]), and the lymph nodes around the esophagus at the curving portion of the RLNs for rational and efficient lymph node dissection. METHODS: Transverse sections of the mediastinum at 5 mm or 1 mm intervals were obtained from four cadavers. Hematoxylin and eosin staining and Elastica van Gieson staining were performed. RESULTS: The visceral sheaths could not be clearly observed the curving portions of the bilateral RLNs, which were observed on the cranial and medial side of the great vessels (aortic arch and right subclavian artery [SCA]). The vascular sheaths could be clearly observed. The bilateral RLNs diverged from the bilateral vagus nerves, which ran along with the vascular sheaths, went up around the caudal side of the great vessels and the vascular sheath, and ran cranially on the medial side of the visceral sheath. Visceral sheaths were not observed around the region containing the left tracheobronchial lymph nodes (No. 106tbL) or the right recurrent nerve lymph nodes (No. 106recR). The regions containing the left recurrent nerve lymph nodes (No. 106recL) and the right cervical paraesophageal lymph nodes (No. 101R) were observed on the medial side of the visceral sheath, with the RLN. CONCLUSION: The recurrent nerve, which branched off from the vagus nerve descending along the vascular sheath, ascended the medial side of the visceral sheath after inversion. However, no clear visceral sheath could be identified in the inverted area. Therefore, during radical esophagectomy, the visceral sheath along No. 101R or 106recL may be recognized and available.

Small-molecule non-peptide antagonists of the PACAP receptor attenuate acute restraint stress-induced anxiety-like behaviors in mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, implicated in emotional stress responses and anxiety-related disorders. Here, we examined whether our recently developed small-molecule non-peptide PACAP receptor antagonists could ameliorate anxiety-like behaviors induced by acute restraint stress in mice. The antagonists PA-9 and its derivative PA-915 improved anxiety-like behaviors in mice subjected to restraint stress. An anxiolytic effect was observed with single acute dose, suggesting their fast-acting properties. PA-915 demonstrated a statistically significant anxiolytic effect whereas fluoxetine did not. These results indicate the potential of PAC1 antagonists as a novel treatment for anxiety.

Design and synthesis of novel pipernonaline derivatives as anti-austerity agents against human pancreatic cancer PANC-1 cells.

Pipernonaline (1), one of the components of the spice pepper, preferentially reduced the survival of human pancreatic cancer PANC-1 cells under nutrient-deprived conditions witha PC50 value of 7.2 µM, suggesting that1couldpotentially lead to the development ofnew anticanceragents basedon theanti-austerity strategy. We have synthesized a total of 31 pipernonaline derivatives, revealing clear structure-activity relationships. Compound 9, which showed the strongest preferential cytotoxicity among synthesized derivatives, inhibited Akt activation and cancer cell migration, making it an extremely promising candidate compound for new pancreatic cancer agents based on the anti-austerity strategy.

Utilization rate and long-term persistence of combination pharmacotherapy with ß3-agonists and antimuscarinics for overactive bladder refractory to monotherapy in a real-world setting.

AIM: To assess real-world treatment profiles, including utilization rate, time to and reasons for discontinuation of combination pharmacotherapy with ß3 -agonists and antimuscarinics for refractory overactive bladder (OAB) through a retrospective chart review. METHODS: We retrospectively reviewed the records of OAB patients who received ß3 -agonists or antimuscarinics at our hospital between 2012 and 2020 and analyzed the clinical course of patients who progressed to combination therapy. Data on age, sex, major complaints, OAB symptom score at the initiation of combination therapy, treatment persistence, and reasons for discontinuation were collected. Treatment persistence was assessed with respect to the median time to discontinuation and persistence rate at 12 months. RESULTS: Of the 2163 patients receiving ß3 -agonists or antimuscarinics, only 84 (3.8%) progressed to combination therapy with both drug classes. At therapy initiation, most (98%) of these patients had moderate to severe OAB symptoms. Median treatment duration and 12-month persistence rate for combination therapy were 595 days and 64.0%, respectively. The reasons for discontinuation were insufficient treatment efficacy followed by adverse effects including voiding impairment in nearly 10% of the patients. None of the baseline parameters was independently associated with persistence in the multivariate analysis. CONCLUSION: While underutilized among OAB patients refractory to monotherapy, combination pharmacotherapy showed a greater persistence rate than published mirabegron or antimuscarinic monotherapy when applied to patients with moderate to severe symptoms. Treatment-emergent voiding impairment is a concern associated with this mode of therapy. A small sample size at a single institution is the limitation of this study.

Mucosal Congestion on the First Day Following Endoscopy Predicts Anastomotic Stricture After Esophagectomy.

BACKGROUND: Anastomotic stricture is a relatively common postoperative complication after esophagectomy. Previous studies have indicated that impaired perioperative blood perfusion at the anastomosis is associated with the occurrence of stricture. Therefore, we analyzed the association between endoscopically assessed blood perfusion during the early postoperative period and anastomotic stricture. METHODS: This retrospective study evaluated patients who underwent esophagectomy at Tokyo Medical and Dental University between 2010 and 2015. The patients had undergone nasal endoscopy on the 1st and 8th postoperative days. The findings were used to evaluate blood perfusion at the anastomosis and gastric tube, which was classified based on mucosal color as ischemia (white) or congestion (blue or black). Univariate and multivariable logistic regression analyses were performed to identify risk factors for anastomotic stricture. RESULTS: The study included 197 patients and anastomotic stricture was observed in 60 patients (30.4%). The multivariable analysis revealed that postoperative gastric tube congestion was a risk factor for stricture (odds ratio [OR]: 6.440, 95% confidence interval [CI]: 2.660-15.600; p < 0.001). Lower risks of anastomotic stricture were associated with pathological stage III-IV disease (OR: 0.325, 95% CI: 0.161-0.656; p = 0.002). CONCLUSION: This study revealed that endoscopically detected congestion at the anastomosis on the first postoperative day was a risk factor for anastomotic stricture.

Mesenchymal Stem Cells Promote IL-6 Secretion and Suppress the Gene Expression of Proinflammatory Cytokines in Contractile C2C12 Myotubes.

Sarcopenia is not only a major cause of disability but also a risk factor for obesity and diabetes in elderly persons. Exercise is an effective method for improving the sarcopenic condition by inducing the secretion of interleukin (IL)-6, which has the capacities to both promote muscle hypertrophy and regulate lipid metabolism and glucose homeostasis, by skeletal muscle. We previously showed that mesenchymal stem cells (MSCs) promote IL-6 secretion by lipopolysaccharide-stimulated C2C12 mouse skeletal muscle myotubes via paracrine mechanisms. Therefore, in this study, we investigated the effect of paracrine actions of MSCs on IL-6 and proinflammatory cytokine expression in contractile C2C12 myotubes by applying electrical stimulation. IL-6 secretion by C2C12 myotubes was increased by electrical stimulation, and a more significant increase in IL-6 secretion was observed in electrically stimulated C2C12 myotubes cultured in conditioned medium from MSCs. The activation of nuclear factor-κB in C2C12 myotubes was also promoted by the combination of conditioned medium from MSCs and electrical stimulation. Moreover, the increases in tumor necrosis factor-α and IL-1ß mRNA expression in C2C12 myotubes induced by electrical stimulation were suppressed by culture in conditioned medium from MSCs. The present findings suggest that MSCs transplantation or injection of their extracellular vesicles improve the therapeutic effect of exercise against sarcopenia without exacerbating inflammation.

Clinical practice pattern in patients with advanced urothelial cancer who had progressed on pembrolizumab in the pre-enfortumab vedotin era.

OBJECTIVES: Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment for advanced urothelial carcinoma. However, the standard treatment for patients after disease progression with pembrolizumab had not been established until the recent approval of enfortumab vedotin. We analyzed the treatment of these patients in the real world, and the patient background and outcomes. METHODS: We extracted data from 543 patients who experienced progressive disease after pembrolizumab initiation from a Japanese nation-wide cohort of platinum-refractory, metastatic urothelial carcinoma. RESULTS: The median overall survival of the 543 patients was 3.5 months (95% confidence interval 3.0-4.1). Of these, only 20.6% (n = 112) received chemotherapy as a subsequent systemic treatment after progressive disease. The regimen of chemotherapy was very diverse. The median overall survival was 11.9 months (95% confidence interval 9.2-14.7) for patients who received chemotherapy, compared to 2.4 months for those who did not receive chemotherapy (95% confidence interval 2.1-2.9; P < 0.0001). Patients who received subsequent chemotherapy were more likely to have better performance status, neutrophil-to-lymphocyte ratio <3, hemoglobin >11 mg/dL, and history of a single chemotherapeutic regimen at pembrolizumab initiation. CONCLUSIONS: This report highlights the real-world practice of the management after pembrolizumab treatment failure in the pre-enfortumab vedotin era, characterized by infrequent use of subsequent anticancer therapy comprising various regimens, reflecting the lack of a standard treatment. Clinical introduction of enfortumab vedotin is expected to improve treatment outcomes in this setting. The present study will provide important baseline data for evaluating the influence of enfortumab vedotin on clinical practices and outcomes.

A New Method for Albuminuria Measurement Using a Specific Reaction between Albumin and the Luciferin of the Firefly Squid Watasenia scintillans.

This study demonstrates that the luciferin of the firefly squid Watasenia scintillans, which generally reacts with Watasenia luciferase, reacted with human albumin to emit light in proportion to the albumin concentration. The luminescence showed a peak wavelength at 540 nm and was eliminated by heat or protease treatment. We used urine samples collected from patients with diabetes to quantify urinary albumin concentration, which is essential for the early diagnosis of diabetic nephropathy. Consequently, we were able to measure urinary albumin concentrations by precipitating urinary proteins with acetone before the reaction with luciferin. A correlation was found with the result of the immunoturbidimetric method; however, the Watasenia luciferin method tended to produce lower albumin concentrations. This may be because the Watasenia luciferin reacts with only intact albumin. Therefore, the quantification method using Watasenia luciferin is a new principle of urinary albumin measurement that differs from already established methods such as immunoturbidimetry and high-performance liquid chromatography.

Inhibitory activities of anthraquinone and xanthone derivatives against transthyretin amyloidogenesis.

Transthyretin is a tetrameric protein which functions as a transporter of thyroxine and retinol-binding protein. Misfolding and amyloid aggregation of transthyretin are known to cause wild-type and hereditary transthyretin amyloidosis. Stabilization of the transthyretin tetramer by low molecular weight compounds is an efficacious strategy to inhibit the aggregation pathway in the amyloidosis. Here, we investigated the inhibitory activities of anthraquinone and xanthone derivatives against amyloid aggregation, and found that xanthone-2-carboxylic acid with one chlorine or methyl group has strong inhibitory activity comparable with that of diflunisal, which is one of the best known stabilizers of transthyretin. X-ray crystallographic structures of transthyretin in complex with the compounds revealed that the introduction of chlorine, which is buried in a hydrophobic region, is important for the strong inhibitory effect of the stabilizer against amyloidogenesis. An in vitro absorption, distribution, metabolism and elimination (ADME) study and in vivo pharmacokinetic study demonstrated that the compounds have drug-like features, suggesting that they have potential as therapeutic agents to stabilize transthyretin.