Real-Time Dynamic Intelligent Image Recognition and Tracking System for Rockfall Disasters.

Taiwan, frequently affected by extreme weather causing phenomena such as earthquakes and typhoons, faces a high incidence of rockfall disasters due to its largely mountainous terrain. These disasters have led to numerous casualties, government compensation cases, and significant transportation safety impacts. According to the National Science and Technology Center for Disaster Reduction records from 2010 to 2022, 421 out of 866 soil and rock disasters occurred in eastern Taiwan, causing traffic disruptions due to rockfalls. Since traditional sensors of disaster detectors only record changes after a rockfall, there is no system in place to detect rockfalls as they occur. To combat this, a rockfall detection and tracking system using deep learning and image processing technology was developed. This system includes a real-time image tracking and recognition system that integrates YOLO and image processing technology. It was trained on a self-collected dataset of 2490 high-resolution RGB images. The system's performance was evaluated on 30 videos featuring various rockfall scenarios. It achieved a mean Average Precision (mAP50) of 0.845 and mAP50-95 of 0.41, with a processing time of 125 ms. Tested on advanced hardware, the system proves effective in quickly tracking and identifying hazardous rockfalls, offering a significant advancement in disaster management and prevention.

Efficacy and safety of zuranolone in major depressive disorder: a meta-analysis of factor effect and dose-response analyses.

Background: Zuranolone is recognised as a promising antidepressant agent. Our study aimed to investigate the efficacy and safety of zuranolone in treating major depressive disorder (MDD). Methods: A systematic review was conducted by searching major databases from inception to August 20, 2023 (INPLASY: 202360087). A meta-analysis was performed by using a random-effects model to calculate effect sizes, expressed as standardised mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). The primary outcome was improvement in depressive symptoms, while secondary outcomes included response and remission rates of depression, improvement in anxiety symptoms, incidence of dropouts, and any side effects. We conducted subgroup analyses for general MDD and postpartum-onset MDD and a dose-response meta-analysis to estimate the relationship between zuranolone dose and outcomes. Findings: The study included seven randomised control trials involving 1789 patients. Zuranolone reduced depressive symptoms (SMD = -0.37, 95% CIs = -0.51 to -0.23), increased response rate (OR = 2.06, 95% CIs = 1.48-2.85) and remission rate (OR = 2.04, 95% CIs = 1.38-3.02), and reduced anxiety symptoms (SMD = -0.26, 95% CIs = -0.39 to -0.14). Furthermore, zuranolone-treated patients experienced more side effects than those in the control group (OR = 1.40, 95% CIs = 1.10-1.78), although dropout rate did not significantly differ between the two groups (OR = 1.13, 95% CIs = 0.85-1.49). According to the dose-response meta-analysis, zuranolone could effectively improve depression and anxiety at increasing doses up to a maximum daily dose of 30 mg; however, side effects increased with doses exceeding 30 mg. Based on subgroup analyses, zuranolone showed greater efficacy in treatment of postpartum-onset MDD than general MDD, but the difference did not reach statistical significance. Interpretation: Our findings suggested that zuranolone is effective in alleviating depression and anxiety. Nevertheless, there is a potential risk of adverse effects. Given its therapeutic efficacy and risk of side effects, a daily dose of 30 mg appears to be the optimal choice. Funding: Chang Gung Medical Foundation.

HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.

An integrated analysis of dysregulated SCD1 in human cancers and functional verification of miR-181a-5p/SCD1 axis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC), one of the most lethal cancers, has become a global health issue. Stearoyl-coA desaturase 1 (SCD1) has been demonstrated to play a crucial role in human cancers. However, pan-cancer analysis has revealed little evidence to date. In the current study, we systematically inspected the expression patterns and potential clinical outcomes of SCD1 in multiple human cancers. SCD1 was dysregulated in several types of cancers, and its aberrant expression acted as a diagnostic biomarker, indicating that SCD1 may play a role in tumorigenesis. We used ESCC as an example to demonstrate that SCD1 was dramatically upregulated in tumor tissues of ESCC and was associated with clinicopathological characteristics in ESCC patients. Furthermore, Kaplan-Meier analysis showed that high SCD1 expression was correlated with poor progression-free survival (PFS) and disease-free survival (DFS) in ESCC patients. The protein-protein interaction (PPI) network and module analysis by PINA database and Gephi were performed to identify the hub targets. Meanwhile, the functional annotation analysis of these hubs was constructed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Functionally, the gain-of-function of SCD1 in ESCC cells promoted cell proliferation, migration, and invasion; in contrast, loss-of-function of SCD1 in ESCC cells had opposite effects. Bioinformatic, QPCR, Western blotting and luciferase assays indicated that SCD1 was a direct target of miR-181a-5p in ESCC cells. In addition, gain-of-function of miR-181a-5p in ESCC cells reduced the cell growth, migratory, and invasive abilities. Conversely, inhibition of miR-181a-5p expression by its inhibitor in ESCC cells had opposite biological effects. Importantly, reinforced SCD1 in miR-181a-5p mimic ESCC transfectants reversed miR-181a-5p mimic-prevented malignant phenotypes of ESCC cells. Taken together, these results indicate that SCD1 expression influences tumor progression in a variety of cancers, and the miR-181a-5p/SCD1 axis may be a potential therapeutic target for ESCC treatment.

Enhancing Efficacy of Albumin-Bound Paclitaxel for Human Lung and Colorectal Cancers through Autophagy Receptor Sequestosome 1 (SQSTM1)/p62-Mediated Nanodrug Delivery and Cancer therapy.

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.

Design, synthesis and evaluation of 2-pyrimidinylindole derivatives as anti-obesity agents by regulating lipid metabolism.

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment.

In Situ Encapsulation of Camptothecin by Self-Assembly of Poly(acrylic acid)-b-Poly(N-Isopropylacrylamide) and Chitosan for Controlled Drug Delivery.

Camptothecin (CPT) has been shown to exhibit anticancer activity against several cancers. Nevertheless, CPT is very hydrophobic with poor stability, and thus its medical application is limited. Therefore, various drug carriers have been exploited for effectively delivering CPT to the targeted cancer site. In this study, a dual pH/thermo-responsive block copolymer of poly(acrylic acid-b-N-isopropylacrylamide) (PAA-b-PNP) was synthesized and applied to encapsulate CPT. At temperatures above its cloud point, the block copolymer self-assembled to form nanoparticles (NPs) and in situ encapsulate CPT, owing to their hydrophobic interaction as evidenced by fluorescence spectrometry. Chitosan (CS) was further applied on the surface through the formation of a polyelectrolyte complex with PAA for improving biocompatibility. The average particle size and zeta potential of the developed PAA-b-PNP/CPT/CS NPs in a buffer solution were 168 nm and -30.6 mV, respectively. These NPs were still stable at least for 1 month. The PAA-b-PNP/CS NPs exhibited good biocompatibility toward NIH 3T3 cells. Moreover, they could protect the CPT at pH 2.0 with a very slow-release rate. At pH 6.0, these NPs could be internalized by Caco-2 cells, followed by intracellular release of the CPT. They became highly swollen at pH 7.4, and the released CPT was able to diffuse into the cells at higher intensity. Among several cancer cell lines, the highest cytotoxicity was observed for H460 cells. As a result, these environmentally-responsive NPs have the potential to be applied in oral administration.

Model-informed dose optimisation of polymyxin-rifampicin combination therapy against multidrug-resistant Acinetobacter baumannii.

OBJECTIVES: Antimicrobial resistance is a major global threat. Because of the stagnant antibiotic pipeline, synergistic antibiotic combination therapy has been proposed to treat rapidly emerging multidrug-resistant (MDR) pathogens. We investigated antimicrobial synergy of polymyxin/rifampicin combination against MDR Acinetobacter baumannii. METHODS: In vitro static time-kill studies were performed over 48 h at an initial inoculum of ∼107 CFU/mL against three polymyxin-susceptible but MDR A. baumannii isolates. Membrane integrity was examined at 1 and 4 h post-treatment to elucidate the mechanism of synergy. Finally, a semi-mechanistic PK/PD model was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by mono- and combination therapies. RESULTS: Polymyxin B and rifampicin alone produced initial killing against MDR A. baumannii but were associated with extensive regrowth. Notably, the combination showed synergistic killing across all three A. baumannii isolates with bacterial loads below the limit of quantification for up to 48 h. Membrane integrity assays confirmed the role of polymyxin-driven outer membrane remodelling in the observed synergy. Subsequently, the mechanism of synergy was incorporated into a PK/PD model to describe the enhanced uptake of rifampicin due to polymyxin-induced membrane permeabilisation. Simulations with clinically utilised dosing regimens confirmed the therapeutic potential of this combination, particularly in the prevention of bacterial regrowth. Finally, results from a neutropenic mouse thigh infection model confirmed the in vivo synergistic killing of the combination against A. baumannii AB5075. CONCLUSION: Our results showed that polymyxin B combined with rifampicin is a promising option to treat bloodstream and tissue infection caused by MDR A. baumannii and warrants clinical evaluations.

Fluorescent Quinolinium Derivative as Novel Mitochondria Probe and Function Modulator by Targeting Mitochondrial RNA.

Mitochondria have a crucial role in regulating energy metabolism and their dysfunction has been linked to tumorigenesis. Cancer diagnosis and intervention have a great interest in the development of new agents that target biomolecules within mitochondria. However, monitoring and modulating mitochondria RNA (mtRNA), an essential component in mitochondria, in cells is challenging due to limited functional research and the absence of targeting agents. In this study, we designed and synthesized a fluorescent quinolinium derivative, QUCO-1, which actively lit up with mtRNA in both normal and cancer cells in vitro. Additionally, we evaluated the function of QUCO-1 as an mtRNA ligand and found that it effectively induced severe mitochondrial dysfunction and OXPHOS inhibition in RKO colorectal cancer cells. Treatment with QUCO-1 resulted in apoptosis, cell cycle blockage at the G2/M phase, and the effective inhibition of cell proliferation. Our findings suggest that QUCO-1 has great potential as a promising probe and therapeutic agent for mtRNA, with the potential for treating colorectal cancer.

Pharmacokinetics/pharmacodynamics of phage therapy: a major hurdle to clinical translation.

BACKGROUND: The increasing emergence of antimicrobial resistance worldwide has led to renewed interest in phage therapy. Unlike antibiotics, the lack of pharmacokinetics/pharmacodynamics (PK/PD) information represents a major challenge for phage therapy. As therapeutic phages are biological entities with the ability to self-replicate in the presence of susceptible bacteria, their PK/PD is far more complicated than that of antibiotics. OBJECTIVES: This narrative review examines the current literature on phage pharmacology and highlights major pharmacological challenges for phage therapy. SOURCES: Included articles were identified by searching PubMed and Google Scholar till June 2022. The search terms were 'bacteriophage', 'antimicrobial', 'pharmacokinetics' and 'pharmacodynamics'. Additional relevant references were obtained from articles retrieved from the primary search. CONTENT: In this review, phage PK is first discussed, focusing on absorption, distribution, metabolism, and elimination. Key factors affecting phage antimicrobial activities are reviewed, including multiplicity of infection, passive and active phage therapy, and the involvement of the human immune system. Importantly, we emphasize the impact of phage self-replication on the PK/PD and the fundamental phage characteristics that are required for PK/PD modelling and clinical translation. IMPLICATIONS: Recent progress in phage pharmacology has shown that we are in a far better position now to treat infections with phage therapy than a century ago. However, phage therapy is still in its infancy when compared to antibiotics due to the scarce pharmacological knowledge (e.g. PK/PD). Optimization of phage PK/PD is key for translation of phage therapy in patients.

Population PK and Semimechanistic PK/PD Modeling and Simulation of Relugolix Effects on Testosterone Suppression in Men with Prostate Cancer.

Relugolix, the first orally active, nonpeptide gonadotropin-releasing hormone receptor antagonist, is approved in the United States and the European Union for the treatment of adult patients with advanced prostate cancer. The recommended dosing regimen is a 360-mg loading dose followed by a 120-mg daily dose. Relugolix and testosterone concentration data and clinical information from two phase I studies, two phase II studies, and the phase III safety and efficacy study (HERO) were used to develop a population pharmacokinetic (PopPK) model and a semimechanistic population pharmacokinetic/pharmacodynamic (PopPK/PD) model that characterized relugolix exposure and its relationship to testosterone concentrations. Age, body weight, and Black/African American race had at most minimal effects on relugolix exposure or testosterone concentrations with no clinical relevance. Simulations using the PopPK/PD model confirmed the recommended dosing regimen of relugolix, with the median simulated testosterone concentrations predicted to achieve castration levels (< 50 ng/dL) and profound castration levels (< 20 ng/dL) by day 2 and day 9, respectively, and demonstrated that 97.3% and 85.5% of the patients remained at castration levels (< 50 ng/dL) upon temporary interruption of treatment for 7 days and 14 days, respectively. Collectively, simulations based on the PopPK and PopPK/PD models were consistent with actual data from clinical studies, reflecting the high predictiveness of the models and supporting the reliability of model-based simulations. These models can be used to provide guidance regarding dosing recommendations under various circumstances (e.g., temporary interruption of treatment, if needed) for relugolix.

Pediatric oncology drug development and dosage optimization.

Oncology drug discovery and development has always been an area facing many challenges. Phase 1 oncology studies are typically small, open-label, sequential studies enrolling a small sample of adult patients (i.e., 3-6 patients/cohort) in dose escalation. Pediatric evaluations typically lag behind the adult development program. The pediatric starting dose is traditionally referenced on the recommended phase 2 dose in adults with the incorporation of body size scaling. The size of the study is also small and dependent upon the prevalence of the disease in the pediatric population. Similar to adult development, the dose is escalated or de-escalated until reaching the maximum tolerated dose (MTD) that also provides desired biological activities or efficacy. The escalation steps and identification of MTD are often rule-based and do not incorporate all the available information, such as pharmacokinetic (PK), pharmacodynamic (PD), tolerability and efficacy data. Therefore, it is doubtful if the MTD approach is optimal to determine the dosage. Hence, it is important to evaluate whether there is an optimal dosage below the MTD, especially considering the emerging complexity of combination therapies and the long-term tolerability and safety of the treatments. Identification of an optimal dosage is also vital not only for adult patients but for pediatric populations as well. Dosage-finding is much more challenging for pediatric populations due to the limited patient population and differences among the pediatric age range in terms of maturation and ontogeny that could impact PK. Many sponsors defer the pediatric strategy as they are often perplexed by the challenges presented by pediatric oncology drug development (model of action relevancy to pediatric population, budget, timeline and regulatory requirements). This leads to a limited number of approved drugs for pediatric oncology patients. This review article provides the current regulatory landscape, incentives and how they impact pediatric drug discovery and development. We also consider different pediatric cancers and potential clinical trial challenges/opportunities when designing pediatric clinical trials. An outline of how quantitative methods such as pharmacometrics/modelling & simulation can support the dosage-finding and justification is also included. Finally, we provide some reflections that we consider helpful to accelerate pediatric drug discovery and development.

Fulminant Type 1 Diabetes Mellitus after SARS-CoV-2 Vaccination: A Case Report.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been used worldwide to control the coronavirus disease pandemic. However, several adverse effects have been reported following vaccination. Therefore, further research on the adverse effects in individuals predisposed to life-threatening conditions is needed. Herein, we present a 39-year-old woman without any systemic disease who developed fulminant type 1 diabetes mellitus (T1DM) (low glycohemoglobin levels, despite hyperglycemia and diabetic ketoacidosis (DKA)) following SARS-CoV-2 vaccination. The patient was initially misdiagnosed as having fresh type 2 diabetes mellitus after the first episode of DKA, which was resolved by short-term insulin therapy and treated with oral anti-diabetic agents after the DKA was resolved. This made her develop a second episode of DKA shortly after treatment. The course and presentation of our case are noteworthy for alerting clinicians to vaccine-related fulminant T1DM.

Ethambutol optic neuropathy with correspondent chiasmitis manifestation in magnetic resonance imaging.

We present a case of an older patient with toxic chiasmatic optic neuropathy accompanied by bitemporal hemianopia associated with ethambutol use. The patient experienced gradual visual defect recovery that was concurrent with an improvement of chiasmal enhancement in the repeat magnetic resonance imaging performed at his 6-month follow-up. However, his visual field pattern sharply changed to left inferior homonymous quadrantanopia because of a new episode of occipital lobe infarction. After 2 years, the patient's visual function reached the best-corrected visual acuity of 20/20 in both eyes, although he had the sequela of homonymous quadrantanopia related to the infarction. Optical coherence tomography revealed that the loss on the macular ganglion cell-inner plexiform layer was related to retrograde transsynaptic degeneration caused by ethambutol-related chiasmopathy.