Comparison of digital and analog [68Ga]Ga-PSMA-11 PET/CT for detecting post-prostatectomy biochemical recurrence in prostate cancer patients: a prospective study.

Digital positron emission tomography/computed tomography (PET/CT) has shown enhanced sensitivity and spatial resolution compared with analog PET/CT. The present study compared the diagnostic performance of digital and analog PET/CT with [68Ga]Ga-PSMA-11 in prostate cancer patients who experienced biochemical recurrence (BCR) after prostatectomy. Forty prostate cancer patients who experienced BCR, defined as serum prostate-specific antigen (PSA) concentrations exceeding 0.2 ng/mL after prostatectomy, were prospectively recruited. These patients were stratified into three groups based on their serum PSA levels. [68Ga]Ga-PSMA-11 was injected into each patient, and images were acquired using both analog and digital PET/CT scanners. Analog and digital PET/CT showed comparable lesion detection rate (71.8% vs. 74.4%), sensitivity (85.0% vs. 90.0%), and positive predictive value (PPV, 100.0% vs. 100.0%). However, digital PET/CT detected more lesions (139 vs. 111) and had higher maximum standardized uptake values (SUVmax, 14.3 vs. 10.3) and higher kappa index (0.657 vs. 0.502) than analog PET/CT, regardless of serum PSA levels. On both analog and digital PET/CT, lesion detection rates and interrater agreement increased with increasing serum PSA levels. Compared with analog PET/CT, digital PET/CT detected more lesions with a higher SUVmax and better interrater agreement in prostate cancer patients who experienced BCR after prostatectomy.

Alveolar Microdynamics during Tidal Ventilation in Live Animals Imaged by SPring-8 Synchrotron.

It is self-evident that our chests expand and contract during breathing but, surprisingly, exactly how individual alveoli change shape over the respiratory cycle is still a matter of debate. Some argue that all the alveoli expand and contract rhythmically. Others claim that the lung volume change is due to groups of alveoli collapsing and reopening during ventilation. Although this question might seem to be an insignificant detail for healthy individuals, it might be a matter of life and death for patients with compromised lungs. Past analyses were based on static post-mortem preparations primarily due to technological limitations, and therefore, by definition, incapable of providing dynamic information. In contrast, this study provides the first comprehensive dynamic data on how the shape of the alveoli changes, and, further, provides valuable insights into the optimal lung volume for efficient gas exchange. It is concluded that alveolar micro-dynamics is nonlinear; and at medium lung volume, alveoli expand more than the ducts.

Effect of Self-Training Using Virtual Reality Head-Mounted Display Simulator on the Acquisition of Holmium Laser Enucleation of the Prostate Surgical Skills.

PURPOSE: We aimed to evaluate the effect of self-training using a virtual reality head-mounted display simulator on the acquisition of surgical skills for holmium laser enucleation surgery. METHODS: Thirteen medical students without surgical skills for holmium laser enucleation of the prostate were trained using multimedia to learn the technique via simulator manipulation. Thereafter, participants performed the technique on a virtual benign prostatic hyperplasia model A (test A). After a 1-week wash-out period, they underwent self-training using a simulator and performed the technique on model B (test B). Subsequently, participants were asked to respond to Training Satisfaction Questions. Video footage of hand movements and endoscope view were recorded during tests A and B for later review by 2 expert surgeons. A 20-step Assessment Checklist, 6-domain Global Rating Scale, and a Pass Rating were used to compare performance on tests A and B. RESULTS: Thirteen participants completed both tests A and B. The 20-step Assessment Checklist and 6-domain Global Rating Scale evaluation results showed significantly improved scores in test B than in test A (P<0.05). No evaluator rated participants as passed after test A, but 11 participants (84.6%) passed after test B. Ten participants (76.9%) indicated that the simulator was helpful in acquiring surgical skills for holmium laser enucleation of the prostate. CONCLUSION: The virtual reality head-mounted display holmium laser enucleation of the prostate simulator was effective for surgical skill training. This simulator may help to shorten the learning curve of this technique in real clinical practice in the future.

Neuroprotective effects of fermented blueberry and black rice against particulate matter 2.5 µm-induced inflammation in vitro and in vivo.

The increasing prevalence of particulate matter (PM) has raised significant concerns about its adverse effects on human health. This study investigates the potential of fermented blueberry and black rice (FBBR) in mitigating the effects of PM2.5 in SH-SY5Y cells and mice. Various assays, including MTT, NO, western blot, ELISA, and behavioral studies were conducted. Results showed that PM2.5 induced considerable cytotoxicity and elevated NO production at a concentration of 100 µg/mL of PM2.5 in SH-SY5Y cells. FBBR administration attenuated PM2.5-exposed cytotoxicity and suppressed NO production in SH-SY5Y cells. In an intranasally-exposed mice model, 10 mg/kg body weight (BW) of PM2.5 resulted in cognitive impairments. However, FBBR treatment ameliorated these impairments in both the Y-maze and MWM tests in PM2.5-exposed mice. Additionally, FBBR administration increased the expression of BDNF and reduced inflammatory markers in the brains of PM2.5-exposed SH-SY5Y cells. These findings highlight the detrimental effects of PM2.5 on the nervous system and suggest the potential of FBBR as a nutraceutical agent for mitigating these effects. Importantly, the results emphasize the urgency of addressing the harmful impact of PM2.5 on the nervous system and underscore the promising role of FBBR as a protective intervention against the adverse effects associated with PM2.5 exposure.

Ultrafast and Reversible Superwettability Switching of 3D Graphene Foams via Solvent-Exclusive Plasma Treatments.

For highly active electron transfer and ion diffusion, controlling the surface wettability of electrically and thermally conductive 3D graphene foams (3D GFs) is required. Here, we present ultrasimple and rapid superwettability switching of 3D GFs in a reversible and reproducible manner, mediated by solvent-exclusive microwave arcs. As the 3D GFs are prepared with vapors of nonpolar acetone or polar water exclusively, short microwave radiation (≤10 s) leads to plasma hotspot-mediated production of methyl and hydroxyl radicals, respectively. Upon immediate radical chemisorption, the 3D surfaces become either superhydrophobic (water contact angle = ∼170°) or superhydrophilic (∼0°), and interestingly, the wettability transition can be repeated many times due to the facile exchange between previously chemisorbed and newly introduced radicals via the formation of methanol-like intermediates. When 3D GFs of different surficial polarities are incorporated into electric double-layer capacitors with nonpolar ionic liquids or polar aqueous electrolytes, the polarity matching between graphene surfaces and electrolytes results in ≥548.0 times higher capacitance compared to its mismatching at ≥0.5 A g-1, demonstrating the significance of wettability-controlled 3D GFs.

Clinical outcomes of holmium laser enucleation of the prostate: A large prospective registry-based patient cohort study under regular follow-up protocol.

PURPOSE: To evaluate the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) in a large prospective cohort of patients with benign prostatic hyperplasia (BPH) through systematic follow-up at a single institution. MATERIALS AND METHODS: Clinical outcomes were analyzed between August 2008 and June 2022. Patients were followed-up at 2 weeks, 3 months and 6 months postoperatively. RESULTS: A total of 3,000 patients (mean age, 69.6±7.7 years) underwent HoLEP. Baseline total International Prostate Symptom Score (IPSS) was 19.3±7.7 and maximum flow rate (Qmax) was 9.4±4.8 mL/s. Mean total prostate volume was 67.7±3.4 mL. Total operation time was 60.7±31.5 minutes, and catheterization time was 1.0 days (range, 1.0-1.0 days). At 6 months postoperatively, the total IPSS decreased to 6.6±5.8 and Qmax increased to 22.2±11.3 mL/s. Complications at 6 months postoperatively included stress urinary incontinence (SUI) in 36 patients (1.9%), urgency urinary incontinence (UUI) in 25 (1.3%), bladder neck contracture (BNC) requiring transurethral incision (TUI) in 16 (0.5%), and urethral stricture in 29 (1.0%). Eleven patients (0.4%) with prostatic fossa stones required stone removal. Sixty-one patients (2.0%) required secondary surgery (transurethral coagulation, 16 [0.5%]; TUI for BNC, 16 [0.5%]; stone removal for prostatic fossa stones, 11 [0.4%]; and endoscopic internal urethrotomy for urethral stricture, 18 [0.6%]). CONCLUSIONS: Mid-term follow-up results after HoLEP in BPH patients showed excellent efficacy and low complication rates. Unlike previous reports, the incidence of SUI and UUI after HoLEP was low, but the occurrence of de novo stone formation in prostatic fossa was notable.

Imaging Procedure and Clinical Studies of [18F]FP-CIT PET.

N-3-[18F]fluoropropyl-2ß-carbomethoxy-3ß-4-iodophenyl nortropane ([18F]FP-CIT) is a radiopharmaceutical for dopamine transporter (DAT) imaging using positron emission tomography (PET) to detect dopaminergic neuronal degeneration in patients with parkinsonian syndrome. [18F]FP-CIT was granted approval by the Ministry of Food and Drug Safety in 2008 as the inaugural radiopharmaceutical for PET imaging, and it has found extensive utilization across numerous institutions in Korea. This review article presents an imaging procedure for [18F]FP-CIT PET to aid nuclear medicine physicians in clinical practice and systematically reviews the clinical studies associated with [18F]FP-CIT PET.

Application of TSPO-Specific Positron Emission Tomography Radiotracer as an Early Indicator of Acute Liver Failure Induced by Propacetamol, a Prodrug of Paracetamol.

Acetaminophen overdose is a leading cause of acute liver failure (ALF), and effective treatment depends on early prediction of disease progression. ALF diagnosis currently requires blood collection 24-72 h after APAP ingestion, necessitating repeated tests and hospitalization. Here, we assessed earlier ALF diagnosis using positron emission tomography (PET) imaging of translocator proteins (TSPOs), which are involved in molecular transport, oxidative stress, apoptosis, and energy metabolism, with the radiotracer [18F]GE180. We intraperitoneally administered propacetamol hydrochloride to male C57BL/6 mice to induce ALF. We performed in vivo PET/CT imaging 3 h later using the TSPO-specific radiotracer [18F]GE180 and quantitatively analyzed the PET images by determining the averaged standardized uptake value (SUVav) in the liver parenchyma. We assessed liver TSPO expression levels via real-time polymerase chain reaction, Western blotting, and immunohistochemistry. [18F]GE180 PET imaging 3 h after propacetamol administration (1500 mg/kg) significantly increased liver SUVav compared to controls (p = 0.001). Analyses showed a 10-fold and 4-fold increase in TSPO gene and protein expression, respectively, in the liver, 3 h after propacetamol induction compared to controls. [18F]GE180 PET visualized and quantified propacetamol-induced ALF through TSPO overexpression. These findings highlight TSPO PET's potential as a non-invasive imaging biomarker for early-stage ALF.

Loss of Ninjurin1 alleviates acetaminophen-induced liver injury via enhancing AMPKα-NRF2 pathway.

Acetaminophen (APAP), a widely used pain and fever reliever, is a major contributor to drug-induced liver injury, as its toxic metabolites such as NAPQI induce oxidative stress and hepatic necrosis. While N-acetylcysteine serves as the primary treatment for APAP-induced liver injury (AILI), its efficacy is confined to a narrow window of 8-24 h post-APAP overdose. Beyond this window, liver transplantation emerges as the final recourse, prompting ongoing research to pinpoint novel therapeutic targets aimed at enhancing AILI treatment outcomes. Nerve injury-induced protein 1 (Ninjurin1; Ninj1), initially recognized as an adhesion molecule, has been implicated in liver damage stemming from factors like TNFα and ischemia-reperfusion. Nonetheless, its role in oxidative stress-related liver diseases, including AILI, remains unexplored. In this study, we observed up-regulation of Ninj1 expression in the livers of both human DILI patients and the AILI mouse model. Through the utilization of Ninj1 null mice, hepatocyte-specific Ninj1 KO mice, and myeloid-specific Ninj1 KO mice, we unveiled that the loss of Ninj1 in hepatocytes, rather than myeloid cells, exerts alleviative effects on AILI irrespective of sex dependency. Further in vitro experiments demonstrated that Ninj1 deficiency shields hepatocytes from APAP-induced oxidative stress, mitochondrial dysfunctions, and cell death by bolstering NRF2 stability via activation of AMPKα. In summary, our findings imply that Ninj1 likely plays a role in AILI, and its deficiency confers protection against APAP-induced hepatotoxicity through the AMPKα-NRF2 pathway.

Understanding Epidemiological Trends in Geriatric Burn Injuries: A National Multicenter Analysis from NEISS 2004-2022.

Burn injuries pose a significant source of patient morbidity/mortality and reconstructive challenges for burn surgeons, especially in vulnerable populations such as geriatric patients. Our study aims to provide new insights into burn epidemiology by analyzing the largest national, multicenter sample of geriatric patients to date. Utilizing the National Electronic Injury and Surveillance System (NEISS) database (2004-2022), individuals with a "Burn" diagnosis were extracted and divided into two comparison age groups of 18-64 and 65+. Variables including sex, race, affected body part, incident location, burn etiology, and clinical outcomes were assessed between the two groups utilizing two proportion z-tests. 60,581 adult patients who sustained burns were identified from the NEISS database with 6,630 of those patients categorized as geriatric (65+). Geriatric patients had a significantly greater frequency of scald burns (36.9% vs. 35.4%; p<0.01), and third degree/full-thickness burns (10.4% vs 5.5%, p<0.01) relative to non-geriatric adult patients with most of these burns occurring at home (75.9% vs 67.4%; p<0.01). The top five burn sites for geriatric patients were the hand, face, foot, lower arm, and lower leg and the top five burn injury sources were hot water, cookware, oven/ranges, home fires, and gasoline. Geriatric patients had over two times greater risk of hospital admission (OR: 2.32, 95% CI: 2.17-2.49, p<0.01) and over five times greater risk of ED mortality (OR: 6.22, 95% CI: 4.00-9.66, p<0.01) after incurring burn injuries. These results highlight the need for stronger awareness of preventative measures for geriatric burn injuries.

Deep learning based ECG segmentation for delineation of diverse arrhythmias.

Accurate delineation of key waveforms in an ECG is a critical step in extracting relevant features to support the diagnosis and treatment of heart conditions. Although deep learning based methods using segmentation models to locate P, QRS, and T waves have shown promising results, their ability to handle arrhythmias has not been studied in any detail. In this paper we investigate the effect of arrhythmias on delineation quality and develop strategies to improve performance in such cases. We introduce a U-Net-like segmentation model for ECG delineation with a particular focus on diverse arrhythmias. This is followed by a post-processing algorithm which removes noise and automatically determines the boundaries of P, QRS, and T waves. Our model has been trained on a diverse dataset and evaluated against the LUDB and QTDB datasets to show strong performance, with F1-scores exceeding 99% for QRS and T waves, and over 97% for P waves in the LUDB dataset. Furthermore, we assess various models across a wide array of arrhythmias and observe that models with a strong performance on standard benchmarks may still perform poorly on arrhythmias that are underrepresented in these benchmarks, such as tachycardias. We propose solutions to address this discrepancy.

International Consensus Statements on Intraoperative Testing for Cochlear Implantation Surgery.

OBJECTIVES: A wide variety of intraoperative tests are available in cochlear implantation. However, no consensus exists on which tests constitute the minimum necessary battery. We assembled an international panel of clinical experts to develop, refine, and vote upon a set of core consensus statements. DESIGN: A literature review was used to identify intraoperative tests currently used in the field and draft a set of provisional statements. For statement evaluation and refinement, we used a modified Delphi consensus panel structure. Multiple interactive rounds of voting, evaluation, and feedback were conducted to achieve convergence. RESULTS: Twenty-nine provisional statements were included in the original draft. In the first voting round, consensus was reached on 15 statements. Of the 14 statements that did not reach consensus, 12 were revised based on feedback provided by the expert practitioners, and 2 were eliminated. In the second voting round, 10 of the 12 revised statements reached a consensus. The two statements which did not achieve consensus were further revised and subjected to a third voting round. However, both statements failed to achieve consensus in the third round. In addition, during the final revision, one more statement was decided to be deleted due to overlap with another modified statement. CONCLUSIONS: A final core set of 24 consensus statements was generated, covering wide areas of intraoperative testing during CI surgery. These statements may provide utility as evidence-based guidelines to improve quality and achieve uniformity of surgical practice.

Senescent Astrocytes Derived from Human Pluripotent Stem Cells Reveal Age-Related Changes and Implications for Neurodegeneration.

Astrocytes play a crucial role in maintaining brain homeostasis by regulating synaptic activity, providing metabolic support to neurons, and modulating immune responses in the central nervous system (CNS). During aging, astrocytes undergo senescence with various changes that affect their function and frequently lead to neurodegeneration. This study presents the first evidence of senescent astrocytes derived from human pluripotent stem cells (hPSCs). These senescent hPSC-derived astrocytes exhibited altered cellular and nuclear morphologies, along with increased expression of senescence-associated markers. Additionally, nuclear localization of NFκB, telomere shortening, and frequent signs of DNA damage were observed in these cells. Furthermore, senescent astrocytes showed defects in various critical functions necessary for maintaining a healthy CNS environment, including a reduced ability to support neuronal survival and clear neurotransmitters, synaptic debris, and toxic protein aggregates. Altered structural dynamics and reduced mitochondrial function were also observed in senescent astrocytes. Notably, treating hPSC-derived senescent astrocytes with chemicals targeting reactive oxygen species or an enzyme that regulates mitochondrial function can reverse senescence phenotypes. Thus, this study offers a valuable cellular model that can be utilized to investigate the mechanisms of brain aging and may present new avenues for discovering innovative therapeutic approaches for neurodegenerative diseases.

Arginine-Rich Cell-Penetrating Peptides Induce Lipid Rearrangements for Their Active Translocation across Laterally Heterogeneous Membranes.

Arginine-rich cell-penetrating peptides (CPPs) have emerged as valuable tools for the intracellular delivery of bioactive molecules, but their membrane perturbation during cell penetration is not fully understood. Here, nona-arginine (R9)-mediated membrane reorganization that facilitates the translocation of peptides across laterally heterogeneous membranes is directly visualized. The electrostatic binding of cationic R9 to anionic phosphatidylserine (PS)-enriched domains on a freestanding lipid bilayer induces lateral lipid rearrangements; in particular, in real-time it is observed that R9 fluidizes PS-rich liquid-ordered (Lo) domains into liquid-disordered (Ld) domains, resulting in the membrane permeabilization. The experiments with giant unilamellar vesicles (GUVs) confirm the preferential translocation of R9 through Ld domains without pore formation, even when Lo domains are more negatively charged. Indeed, whenever R9 comes into contact with negatively charged Lo domains, it dissolves the Lo domains first, promoting translocation across phase-separated membranes. Collectively, the findings imply that arginine-rich CPPs modulate lateral membrane heterogeneity, including membrane fluidization, as one of the fundamental processes for their effective cell penetration across densely packed lipid bilayers.

Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression.

Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.

Clinical Feasibility of a Markerless Gait Analysis System.

Background: The gait analysis method that has been used in clinical practice to date is an optical tracking system (OTS) using a marker, but a markerless gait analysis (MGA) system is being developed because of the expensive cost and complicated examination of the OTS. To apply this MGA clinically, a comparative study of the MGA and OTS methods is necessary. The purpose of this study was to evaluate the compatibility between the OTS and the MGA methods and to evaluate the usefulness of the MGA system in actual clinical settings. Methods: From March 2021 to August 2021, 14 patients underwent gait analysis using the OTS and MGA system, and the spatiotemporal parameters and kinematic results obtained by the 2 methods were compared. To evaluate the practicality of the MGA system in an actual clinical setting, MGA was performed on 14 symptomatic children with idiopathic toe walking, who had been treated with a corrective cast, and the pre-cast and post-cast results were compared. For the OTS, the Motion Analysis Eagle system was used, and for MGA, DH Walk was used. Results: The spatiotemporal parameters showed no significant difference between the OTS and MGA system. The joint angle graphs of the kinematics along the sagittal plane showed similar shapes as a whole, with particularly high correlations in the hip and knee (pelvis: 29.4%, hip joint: 96.7%, knee joint: 94.9%, and ankle joint: 68.5%). A quantified comparison using the CORrelation and Analysis (CORA) score also showed high similarity between the 2 methods. The MGA results of pre-cast application and post-cast removal for children with idiopathic toe walking showed a statistically significant improvement in ankle dorsiflexion after treatment (p < 0.001). Conclusions: MGA showed a good correlation with the conventional OTS in terms of spatiotemporal parameters and kinematics. We demonstrated that ankle sagittal kinematics improved after treatment by corrective cast in children with idiopathic toe walking using the MGA method. Thus, after the improvement of a few limitations, the MGA system may soon be able to be clinically applied.

Data-Driven Materials Informatics for Novel Piezoelectric Janus-Type Nanomaterials Discovery.

In the recent era of green and sustainable energy, the demand for effective and efficient energy harvesting has dramatically increased. Piezoelectric energy harvesting, which converts mechanical energy into electrical energy, is considered a viable strategy to achieve this goal. Janus-type nanomaterial, a noncentrosymmetric material with different elemental species in the upper and lower atomic layers, has gained interest due to its exotic properties compared to conventional bulk and symmetric materials. In this work, we systematically design and investigate a new class of Janus nanomaterials with enhanced intrinsic polarization via the successive ionic exchange method. Multiple layers of stability standards, including both thermodynamic and dynamic stabilities, are employed in the high-throughput screening procedure of novel Janus-type nanomaterials. The newly proposed Janus-type nanomaterials exhibit more than 10 times higher piezoelectric response compared to that of reported low-dimensional materials and even comparable to that of bulk materials.

The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Age-Related Decrease in Pellino-1 Expression Contributes to Osteoclast-Mediated Bone Loss.

Aging-related bone loss is driven by various biological factors, such as imbalanced bone metabolism from decreased osteoblast and increased osteoclast activities. Various transcriptional and post-transcriptional factors increase osteoclast activity with aging; however, studies regarding the post-translational regulators of osteoclast activity are still limited. The ubiquitin E3 ligase Pellino-1 is a well-known post-translational regulator of inflammation. However, how Pellino-1 expression regulation affects osteoclast differentiation remains unclear. This study determined that Pellino-1 levels are reduced in bone marrow monocytes (BMMs) from 40-week-old mice compared to 4-week-old mice. Interestingly, conditional Knockout (cKO) of Pellino-1 in 6-week-old mice resulted in decreased bone mass, reduced body size, and lower weight than in Pellino-1 floxed mice; however, these differences are not observed in 20-week-old mice. The increased number of tartrate-resistant acid phosphatase (TRAP)-positive cells and serum levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, in 6-week-old Pellino-1 cKO mice implied a connection between Pellino-1 and the osteoclast population. Enhanced TRAP activity and upregulation of osteoclast genes in BMMs from the cKO mice indicate that Pellino-1 deletion affects osteoclast differentiation, leading to decreased bone mass and heightened osteoclast activity. Thus, targeting Pellino-1 could be a potential gene therapy for managing and preventing osteoporosis.

hsa-miR-CHA2, a novel microRNA, exhibits anticancer effects by suppressing cyclin E1 in human non-small cell lung cancer cells.

Despite considerable therapeutic advancements, the global survival rate for lung cancer patients remains poor, posing challenges in developing an effective treatment strategy. In many cases, microRNAs (miRNAs) exhibit abnormal expression levels in cancers, including lung cancer. Dysregulated miRNAs often play a crucial role in the development and progression of cancer. Therefore, understanding the mechanisms underlying aberrant miRNA expression during carcinogenesis may provide crucial clues to develop novel therapeutics. In this study, we identified and cloned a novel miRNA, hsa-miR-CHA2, which is abnormally downregulated in non-small cell lung cancer (NSCLC)-derived cell lines and tissues of patients with NSCLC. Furthermore, we found that hsa-miR-CHA2 regulates the post-transcriptional levels of Cyclin E1 (CCNE1) by binding to the 3'-UTR of CCNE1 mRNA. CCNE1, a cell cycle regulator involved in the G1/S transition, is often amplified in various cancers. Notably, hsa-miR-CHA2 overexpression led to the alteration of the Rb-E2F pathway, a significant signaling pathway in the cell cycle, by targeting CCNE1 in A549 and SK-LU-1 cells. Subsequently, we confirmed that hsa-miR-CHA2 induced G1-phase arrest and exhibited an anti-proliferative effect by targeting CCNE1. Moreover, in subcutaneous xenograft mouse models, intra-tumoral injection of polyplexed hsa-miR-CHA2 mimic suppressed tumor growth and development. In conclusion, hsa-miR-CHA2 exhibited an anticancer effect by targeting CCNE1 both in vitro and in vivo. These findings suggest the potential role of hsa-miR-CHA2 as an important regulator of cell proliferation in molecular-targeted therapy for NSCLC.