An evaluation of the effectiveness of 'ULTRACOL 200' in enhancing nasolabial fold wrinkles through cutaneous repair.

BACKGROUND: Injectable filler, a nonsurgical beauty method, has gained popularity in rejuvenating sagging skin. In this study, polydioxanone (PDO) was utilized as the main component of the ULTRACOL200 filler that helps stimulate collagenesis and provide skin radiant effects. The study aimed to evaluate and compare the effectiveness of ULTRACOL200 with other commercialized products in visually improving dermatological problems. METHODS: Herein, 31 participants aged between 20 and 59 years were enrolled in the study. 1 mL of the testing product, as well as the quantity for the compared groups was injected into each participants face side individually. Subsequently, skin texture and sunken volume of skin were measured using ANTERA 3D CS imaging technology at three periods: before the application, 4 weeks after the initial application, and 4 weeks after the 2nd application of ULTRACOL200. RESULTS: The final results of skin texture and wrinkle volume evaluation consistently demonstrated significant enhancement. Consequently, subjective questionnaires were provided to the participants to evaluate the efficacy of the testing product, illustrating satisfactory responses after the twice applications. CONCLUSION: The investigation has contributed substantially to the comprehension of a PDO-based filler (ULTRACOL200) for skin enhancement and provided profound insight for future clinical trials.

Identification of Ureidocoumarin-Based Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors via Drug Repurposing Approach, Biological Evaluation, and In Silico Studies.

Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of carbonic anhydrase inhibitors. Among these, ureidocoumarins 3a, 3i, and 3q showed the best DDR1 inhibitory activities. The m-trifluoromethoxy phenyl member 3q potently inhibited DDR1 with an IC50 of 191 nM, while it showed less inhibitory activity against DDR2 (IC50 = 5080 nM). 3q also exhibited favorable selectivity in a screening platform with 23 common off-target kinases, including BCR-ABL. In the cellular context, 3q showed moderate antiproliferative effects, while 3i, with the third rank in DDR1 inhibition, exerted the best anticancer activity with sub-micromolar GI50 values over certain DDR1-dependent cell lines. Molecular docking and MD simulations disclosed the putative binding mode of this coumarin chemotype and provided insights for further optimization of this scaffold. The present findings collectively supported the potential improvement of ureidocoumarins 3i and 3q for cancer treatment.

Dihydrostilbenes and flavonoids from whole plants of Jacobaea vulgaris.

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties.

Blood sphingolipid as a novel biomarker in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Sphingolipids are signaling molecules and structural components of the axolemma and myelin sheath. Plasma sphingolipid levels may reflect disease status of neuromyelitis optica spectrum disorder (NMOSD). We aimed to examine plasma sphingolipids as disease severity biomarkers for NMOSD and compare their characteristics with those of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). METHODS: We measured plasma sphingolipids, sNfL, and sGFAP levels in NMOSD cases with anti-aquaporin-4-antibody. An unbiased approach, partial least square discriminant analysis (PLS-DA), was utilized to determine whether sphingolipid profiles differ according to the disease state of NMOSD (presence, moderate-to-severe disability [Expanded Disease Severity Scale, (EDSS) > 3.0], and relapses). RESULTS: We investigated 81 patients and 10 controls. PLS-DA models utilizing sphingolipids successfully differentiated patients with EDSS > 3.0, but failed to identify the presence of disease and relapses. Ceramide-C14-a significant contributor to differentiating EDSS > 3.0-positively correlated with EDSS, while its levels were independent of age and the presence of relapses. This characteristic was unique from those of sNfL and sGFAP, which were affected by age and relapses as well as EDSS. CONCLUSION: Plasma sphingolipids may be useful NMOSD biomarkers for disability with distinct characteristics compared to sNfL and sGFAP.

Caffeic acid phenethyl ester: Unveiling its potential as a potent apoptosis inducer for combating hypopharyngeal squamous cell carcinoma.

Hypopharyngeal squamous cell carcinoma (HSCC) is a relatively rare form of head and neck cancer that is notorious for its poor prognosis and low overall survival rate. This highlights the need for new therapeutic options for this malignancy. The objective of the present study was to examine the ability of caffeic acid phenethyl ester (CAPE), which is an active compound found in propolis, to combat HSCC tumor growth. CAPE exerted its tumor­suppressive activity in HSCC cell lines through the induction of apoptosis. Mechanistically, the CAPE­mediated apoptotic process was attributed to the perturbation of the mitochondrial membrane potential and the activation of caspase­9. CAPE also modulated survivin and X­linked inhibitor of apoptosis, which are potent members of the inhibitors of apoptosis protein family, either through transcriptional or post­translational regulation, leading to HSCC cell line death. Therefore, the findings of the present study suggested that CAPE is an effective treatment alternative for HSCC via the stimulation of mitochondria­dependent apoptosis.

Neuropilin-2 acts a critical determinant for epithelial-to-mesenchymal transition and aggressive behaviors of human head and neck cancer.

PURPOSE: Neuropilin-2 (NRP2) is a multifunctional single-pass transmembrane receptor that binds to two disparate ligands, namely, vascular endothelial growth factors (VEGFs) and semaphorins (SEMAs). It is reportedly involved in neuronal and vascular development. In this study, we uncovered the exact functional role of NRP2 and its molecular mechanism during aggressive behaviors and lymph node (LN) metastasis in human head and neck cancer (HNC) and identified algal methanol extract as a potential novel NRP2 inhibitor. METHODS: In silico analyses and immunohistochemistry were used to investigate the relationship between NRP2 expression and the prognosis of HNC patients. The functional role of NRP2 on the proliferation, migration, invasion, and cancer stem cell (CSC) properties of HNC cells was examined by MTS, soft agar, clonogenic, transwell migration and invasion assays, and sphere formation assays. Signaling explorer antibody array, western blot, and qPCR were performed toward the investigation of a molecular mechanism that is related to NRP2. RESULTS: NRP2 was highly expressed in HNC and positively correlated with LN metastasis and advanced tumor stage and size in patients. Using loss- or gain-of-function approaches, we found that NRP2 promoted the proliferative, migratory, and invasive capacities of human HNC cells. Furthermore, NRP2 regulated Sox2 expression to exhibit aggressiveness and CSC properties of human HNC cells. We demonstrated that p90 ribosomal S6 kinase 1 (RSK1) elevates the aggressiveness and CSC properties of human HNC cells, possibly by mediating NRP2 and Sox2. Zeb1 was necessary for executing the NRP2/RSK1/Sox2 signaling pathway during the induction of epithelial-to-mesenchymal transition (EMT) and aggressive behaviors of human HNC cells. Moreover, the methanol extract of Codium fragile (MECF) repressed NRP2 expression, inhibiting the RSK1/Sox2/Zeb1 axis, which contributed to the reduction of aggressive behaviors of human HNC cells. CONCLUSIONS: These findings suggest that NRP2 is a critical determinant in provoking EMT and aggressive behaviors in human HNC through the RSK1/Sox2/Zeb1 axis, and MECF may have the potential to be a novel NRP2 inhibitor for treating metastasis in HNC patients.

Apoptotic activity of genipin in human oral squamous cell carcinoma in vitro by regulating STAT3 signaling.

Genipin, a natural compound derived from the fruit of Gardenia jasminoides Ellis, was reported to have activity against various cancer types. In this study, we determined the underlying mechanism for genipin-induced cell death in human oral squamous cell carcinoma (OSCC). The growth-inhibitory effects of genipin in human OSCC cells was examined by the Cell Counting Kit-8 and soft agar assays. The effects of genipin on apoptosis were assessed by nuclear morphological changes by 4',6-diamidino-2-phenylindole staining, measurement of the sub-G1 population, and Annexin V-fluorescein isothiocyanate/propidium iodide double staining. The underlying mechanism of genipin activity was analyzed by western blot analysis, subcellular fractionation of the nucleus and cytoplasm, immunocytochemistry, and quantitative real-time polymerase chain reaction. Genipin inhibited the growth of OSCC cells and induced apoptosis, which was mediated by a caspase-dependent pathway. Genipin reduced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and its nuclear localization. Furthermore, inhibition of p-STAT3Tyr705 levels following genipin treatment was required for the reduction of survivin and myeloid cell leukemia-1 (Mcl-1) expression, leading to apoptotic cell death. The genipin-mediated reduction in survivin and Mcl-1 expression was caused by transcriptional and/or posttranslational regulatory mechanisms. The results provide insight into the regulatory mechanism by which genipin induces apoptotic cell death through the abrogation of nuclear STAT3 phosphorylation and suggest that genipin may represent a potential therapeutic option for the treatment of human OSCC.

Selective enrichment of plasma cell-free messenger RNA in cancer-associated extracellular vesicles.

Extracellular vesicles (EVs) have been shown as key mediators of extracellular small RNA transport. However, carriers of cell-free messenger RNA (cf-mRNA) in human biofluids and their association with cancer remain poorly understood. Here, we performed a transcriptomic analysis of size-fractionated plasma from lung cancer, liver cancer, multiple myeloma, and healthy donors. Morphology and size distribution analysis showed the successful separation of large and medium particles from other soluble plasma protein fractions. We developed a strategy to purify and sequence ultra-low amounts of cf-mRNA from particle and protein enriched subpopulations with the implementation of RNA spike-ins to control for technical variability and to normalize for intrinsic drastic differences in cf-mRNA amount carried in each plasma fraction. We found that the majority of cf-mRNA was enriched and protected in EVs with remarkable stability in RNase-rich environments. We observed specific enrichment patterns of cancer-associated cf-mRNA in each particle and protein enriched subpopulation. The EV-enriched differentiating genes were associated with specific biological pathways, such as immune systems, liver function, and toxic substance regulation in lung cancer, liver cancer, and multiple myeloma, respectively. Our results suggest that dissecting the complexity of EV subpopulations illuminates their biological significance and offers a promising liquid biopsy approach.

Discovery of 3-((3-amino-1H-indazol-4-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant.

BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.

Treatment Efficacy of Various Maneuvers for Lateral Canal Benign Paroxysmal Positional Vertigo With Apogeotropic Nystagmus: A Randomized Controlled Trial.

OBJECTIVES: The aim of this study was to determine the most effective treatment approach by comparing the impacts of various otolith reduction techniques in patients with apogeotropic lateral semicircular canal benign paroxysmal positional vertigo (LC-BPPV). METHODS: We performed a multicenter randomized prospective study from January to December 2015, involving 72 consecutive patients with apogeotropic LC-BPPV. The patients were divided into three treatment groups: therapeutic head-shaking (group A), the Gufoni-Appiani maneuver (group B), and the cupulolith repositioning maneuver (CuRM; group C). Each group underwent evaluation and treatment up to the fourth week. Treatment success was defined as the disappearance of positional vertigo and nystagmus. RESULTS: This study included 72 patients (49 male and 23 female), with a mean (±standard deviation) age of 55.4±13.5 years. The mean duration of vertigo experienced prior to treatment was 3.9±4.4 days. The mean latency and duration of nystagmus were 2.7±3.0 seconds and 47.9±15.8 seconds, respectively. The overall treatment frequency was 2.0±0.9. The number of treatments differed significantly among the three groups (P<0.05). After 4 weeks, the success rates for groups A, B, and C were 90.5%, 92.3%, and 100%, respectively. No significant difference was observed in the success rate across treatment. METHODS: and periods (P>0.05). However, CuRM was the only method with a 100% treatment success rate. CONCLUSION: While no clear difference was observed among the three treatments for LC-BPPV, CuRM was found to be superior to the other approaches in the long term.

Design and Synthesis of New 4-(3,4,5-Trimethoxyphenyl)Thiazole-Pyrimidine Derivatives as Potential Antiproliferative Agents.

A new series of 3,4,5-trimethoxyphenyl thiazole pyrimidines has been synthesized and biologically evaluated for its in vitro anticancer activity. Compounds 4a, 4b, and 4h with substituted piperazine showed the best antiproliferative activity. In the NCI-60 cell line screening, compound 4b showed promising cytostatic activity against multiple cell lines. Notably, it elicited a GI value of 86.28% against the NSCL cancer cell line HOP-92 at a 10 µM dose. Compounds 4a and 4h at 10 µM showed promising GI values of 40.87% and 46.14% against HCT-116 colorectal carcinoma and SK-BR-3 breast cancer cell lines, respectively. ADME-Tox prediction of compounds 4a, 4b, and 4h revealed their acceptable drug-likeness properties. In addition, compounds 4a, 4b, and 4h showed a high probability of targeting kinase receptors via Molinspiration and Swiss TargetPrediction.

Overcoming the imatinib-resistant BCR-ABL mutants with new ureidobenzothiazole chemotypes endowed with potent and broad-spectrum anticancer activity.

The design of kinase inhibitors targeting the oncogenic kinase BCR-ABL constitutes a promising paradigm for treating chronic myeloid leukaemia (CML). Nevertheless, the efficacy of imatinib, the first FDA-approved targeted therapy for CML, is curbed by the emergence of resistance. Herein, we report the identification of the 2-methoxyphenyl ureidobenzothiazole AK-HW-90 (2b) as a potent pan-BCR-ABL inhibitor against imatinib-resistant mutants, particularly T315I. A concise array of six compounds 2a-f was designed based on our previously reported benzothiazole lead AKE-5l to improve its BCR-ABLT315I inhibitory activity. Replacing the 6-oxypicolinamide moiety of AKE-5l with o-methoxyphenyl and changing the propyl spacer with phenyl afforded 2a and AK-HW-90 (2b) with IC50 values of 2.0 and 0.65 nM against BCR-ABLT315I, respectively. AK-HW-90 showed superior anticancer potency to imatinib against multiple cancer cells (NCI), including leukaemia K-562. The obtained outcomes offer AK-HW-90 as a promising candidate for the treatment of CML and other types of cancer.

Discovery of New Quinolone-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity.

The emergence of cancer resistance to targeted therapy represents a significant challenge in cancer treatment. Therefore, identifying new anticancer candidates, particularly those addressing oncogenic mutants, is an urgent medical demand. A campaign of structural modifications has been conducted to further optimize our previously reported 2-anilinoquinoline-diarylamides conjugate VII as a B-RAFV600E/C-RAF inhibitor. Considering the incorporation of a methylene bridge between the terminal phenyl and cyclic diamine, focused quinoline-based arylamides have been tailored, synthesized, and biologically evaluated. Among them, the 5/6-hydroxyquinolines 17b and 18a stood out as the most potent members, with IC50 values of 0.128 µM, 0.114 µM against B-RAFV600E, and 0.0653 µM, 0.0676 µM against C-RAF. Most importantly, 17b elicited remarkable inhibitory potency against the clinically resistant B-RAFV600K mutant with an IC50 value of 0.0616 µM. The putative binding mode of 17b and 18a were studied by molecular docking and molecular dynamics (MD). Moreover, the antiproliferative activity of all target compounds has been examined over a panel of NCI-60 human cancer cell lines. In agreement with cell-free assays, the designed compounds exerted superior anticancer impact over the lead quinoline VII against all cell lines at a 10 µM dose. Notably, both 17b and 18b showed highly potent antiproliferative activity against melanoma cell lines with growth percent under -90% (SK-MEL-29, SK-MEL-5, and UACC-62) at a single dose, while 17b maintained potency with GI50 values of 1.60-1.89 µM against melanoma cell lines. Taken together, 17b, a promising B-RAFV600E/V600K and C-RAF kinase inhibitor, may serve as a valuable candidate in the arsenal of anticancer chemotherapeutics.

Discovery of new 6-ureido/amidocoumarins as highly potent and selective inhibitors for the tumour-relevant carbonic anhydrases IX and XII.

A series of 6-ureido/amidocoumarins (5a-p and 7a-c) has been designed and synthesised to develop potent and isoform- selective carbonic anhydrase hCA XI and XII inhibitors. All coumarin derivatives were investigated for their CA inhibitory effect against hCA I, II, IX, and XII. Interestingly, target coumarins potently inhibited both tumour-related isoforms hCA IX (KIs: 14.7-82.4 nM) and hCA XII (KIs: 5.9-95.1 nM), whereas the cytosolic off-target hCA I and II isoforms have not inhibited by all tested coumarins up to 100 µM. These findings granted the target coumarins an excellent selectivity profile towards both hCA IX and hCA XII isoforms, supporting their development as promising anticancer candidates. Moreover, all target molecules were evaluated for their anticancer activities against HCT-116 and MCF-7 cancer cells. The 3,5-bis-trifluoromethylphenyl ureidocoumarin 5i, exerted the best anticancer activity. Overall, ureidocoumarins, particularly compound 5i, could serve as a promising prototype for the development of potent anticancer CAIs.

Application of convolutional neural network for analyzing hepatic fibrosis in mice.

Recently, with the development of computer vision using artificial intelligence (AI), clinical research on diagnosis and prediction using medical image data has increased. In this study, we applied AI methods to analyze hepatic fibrosis in mice to determine whether an AI algorithm can be used to analyze lesions. Whole slide image (WSI) Sirius Red staining was used to examine hepatic fibrosis. The Xception network, an AI algorithm, was used to train normal and fibrotic lesion identification. We compared the results from two analyses, that is, pathologists' grades and researchers' annotations, to observe whether the automated algorithm can support toxicological pathologists efficiently as a new apparatus. The accuracies of the trained model computed from the training and validation datasets were greater than 99%, and that obtained by testing the model was 100%. In the comparison between analyses, all analyses showed significant differences in the results for each group. Furthermore, both normalized fibrosis grades inferred from the trained model annotated the fibrosis area, and the grades assigned by the pathologists showed significant correlations. Notably, the deep learning algorithm derived the highest correlation with the pathologists' average grade. Owing to the correlation outcomes, we conclude that the trained model might produce results comparable to those of the pathologists' grading of the Sirius Red-stained WSI fibrosis. This study illustrates that the deep learning algorithm can potentially be used for analyzing fibrotic lesions in combination with Sirius Red-stained WSIs as a second opinion tool in non-clinical research.

Identification of New N-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors.

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer's disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 µM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 µM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 µM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 µM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19-3.87 µM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (-11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood-brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.

The Relationship between Dietary Na/K Ratio and Bone Mineral Density in Korean Middle-Aged Women.

BACKGROUND: Dietary Na+ or Na+/K+ ratio has been reported to be associated with bone mineral density (BMD). However, this remains unclear, and only a few studies have been reported on the Korean population. Therefore, this study aimed to determine the association between dietary Na+, K+, and Na+/K+ ratios and BMD in middle-aged Korean women. METHODS: This study used data from the Korea National Health and Nutrition Examination Survey 2008-2011. A total of 3,690 women aged >50 years were included. Study participants were classified into quartiles (lowest quartile Q1-highest quartile Q4) according to dietary Na+, K+, and Na+/K+ ratio, and we examined the association of these parameters with BMD. Total femur and lumbar spine BMD were measured using dual-energy X-ray absorptiometry. Multiple linear regression analyses were performed using IBM SPSS ver. 19.0. RESULTS: The mean age was 62 years, and a significant negative trend in the ß-coefficient regarding dietary Na+ was only observed in the total femur BMD. However, the total femur and lumbar spine BMD decreased from Q1 to Q4 regarding the dietary Na+/K+ ratio (P-value for trend: 0.044 for total femur BMD and 0.002 for lumbar spine BMD). CONCLUSION: A significant negative trend in the ß-coefficient for both total femur and lumbar spine BMD was observed regarding the Na+/K+ ratio. Therefore, based on the results of this study, a higher dietary Na+/K+ ratio may be associated with a lower BMD.

Targeting tumor-intrinsic PD-L1 suppresses the progression and aggressiveness of head and neck cancer by inhibiting GSK3ß-dependent Snail degradation.

PURPOSE: PD-L1 is an immune checkpoint protein that allows cells to evade T-cell-mediated immune responses. Herein, we uncover a tumor-intrinsic mechanism of PD-L1 that is responsible for the progression and aggressiveness of HNC and reveal that the extracts of a brown alga can target the tumor-intrinsic signaling pathway of PD-L1. METHODS: The biological functions of PD-L1 in the proliferation and aggressiveness of HNC cells in vitro were examined by metabolic activity, clonogenic, tumorigenicity, wound healing, migration, and invasion assays. The clinical importance of PD-L1 in the prognosis of patients with HNC was analyzed by immunohistochemistry. The relationship between PD-L1 and EMT was confirmed via western blotting, qPCR, and immunocytochemistry. RESULTS: Through our in silico approach, we found that PD-L1 was upregulated in HNC and was correlated with an unfavorable clinical outcome in patients with HNC. PD-L1 was crucial for promoting tumor growth, both in vitro and in vivo. High expression of PD-L1 was closely correlated with LN metastasis in OSCC. PD-L1 facilitated the cytoskeletal reorganization and aggressiveness of HNC cells. Moreover, PD-L1 enhanced the EMT of HNC cells by regulating the Snail/vimentin axis. Consistently, MEIO suppressed the PD-L1/Snail/vimentin axis, thereby inhibiting the aggressiveness of HNC cells. Inhibition of PD-L1 induced by PD-L1 silencing or MEIO treatment caused Snail degradation through a GSK3ß-dependent mechanism. The tumor-intrinsic function of PD-L1 could be attributed to the regulation of the GSK3ß/Snail/vimentin axis. CONCLUSION: The discovery of MEIO targeting the tumor-intrinsic function of PD-L1 may prove particularly valuable for the development of novel and effective anticancer drug candidates for HNCs overexpressing PD-L1.

Automated deep neural network analysis of lateral cephalogram data can aid in detecting obstructive sleep apnea.

STUDY OBJECTIVES: Information on obstructive sleep apnea (OSA) is often latently detected in diagnostic tests conducted for other purposes, providing opportunities for maximizing value. This study aimed to develop a convolutional neural network (CNN) to identify the risk of OSA using lateral cephalograms. METHODS: The lateral cephalograms of 5,648 individuals (mean age, 49.0 ± 15.8 years; men, 62.3%) with or without OSA were collected and divided into training, validation, and internal test datasets in a 5:2:3 ratio. A separate external test dataset (n = 378) was used. A densely connected CNN was trained to diagnose OSA using a cephalogram. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC). Gradient-weighted class activation mapping (Grad-CAM) was used to evaluate the region of focus, and the relationships between the model outputs, anthropometric characteristics, and OSA severity were evaluated. RESULTS: The AUROC of the model for the presence of OSA was 0.82 (95% confidence interval, 0.80-0.84) and 0.73 (95% confidence interval, 0.65-0.81) in the internal and external test datasets, respectively. Grad-CAM demonstrated that the model focused on the area of the tongue base and oropharynx in the cephalogram. Sigmoid output values were positively correlated with OSA severity, body mass index, and neck and waist circumference. CONCLUSIONS: Deep learning may help develop a model that classifies OSA using a cephalogram, which may be clinically useful in the appropriate context. The definition of ground truth was the main limitation of this study. CITATION: Jeong H-G, Kim T, Hong JE, et al. Automated deep neural network analysis of lateral cephalogram data can aid in detecting obstructive sleep apnea. J Clin Sleep Med. 2023;19(2):327-337.

Isocoumarins and Benzoquinones with Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activities from Dried Roots of Lysimachia vulgaris.

A phytochemical investigation of the n-hexane-soluble chemical constituents of Lysimachia vulgaris roots allowed for selection using a proprotein convertase subtilisin-kexin type 9 (PCSK9) mRNA expression monitoring assay in HepG2 cells. This led to the isolation of two previously undescribed isocoumarins of natural origin, 8'Z,11'Z-octadecadienyl-6,8-dihydroxyisocoumarin (1) and 3-pentadecyl-6,8-dihydroxyisocoumarin (2), along with 20 previously reported compounds (3-22). All of the structures were established using NMR spectroscopic data and MS analysis. Of the isolates, 1 and 3 were found to inhibit PCSK9, inducible degrader of the low-density lipoprotein receptor (IDOL), and SREBP2 mRNA expression. Further computational dockings of both 1 and 3 to C-ring of IDOL E3 ubiquitin ligase predicted the mechanism behind the inhibitory effect of these compounds on the enzyme.