Sympathetic dysfunction as an early indicator of autonomic involvement in Parkinson's disease.

PURPOSE: The specific characteristics of autonomic involvement in patients with early Parkinson's disease (PD) are unclear. This study aimed to evaluate the characteristics of autonomic dysfunction in drug-naïve patients with early-stage PD without orthostatic hypotension (OH) by analyzing Valsalva maneuver (VM) parameters. METHODS: We retrospectively analyzed drug-naïve patients without orthostatic hypotension (n = 61) and controls (n = 20). The patients were subcategorized into early PD (n = 35) and mid-PD (n = 26) groups on the basis of the Hoehn and Yahr staging. VM parameters, including changes in systolic blood pressure at late phase 2 (∆SBPVM2), ∆HRVM3, Valsalva ratio (VR), pressure recovery time, adrenergic baroreflex sensitivity, and vagal baroreflex sensitivity, were assessed. RESULTS: In the early PD group, ∆SBPVM2, a marker of sympathetic function, was significantly lower compared with that in controls (risk ratio = 0.95, P = 0.027). Receiver operating characteristic (ROC) curve analysis showed an optimal cut-off value of -10 mmHg for ∆SBPVM2 [P = 0.002, area under the curve (AUC): 0.737]. VR exhibited an inverse relationship with Unified Parkinson's Disease Rating Scale Part 3 scores in the multivariable regression analysis (VR: P = 0.038, ß = -28.61), whereas age showed a positive relationship (age: P = 0.027, ß = 0.35). CONCLUSION: The ∆BPVM2 parameter of the VM may help detect autonomic nervous system involvement in early-PD without OH. Our results suggest that sympathetic dysfunction is an early manifestation of autonomic dysfunction in patients with PD.

Ginseng Berry Juice (GBJ) Regulates the Inflammation in Acute Ulcerative Mouse Models and the Major Bioactive Substances Are Ginsenosides Rb3, Rc, Rd, and Re.

Panax ginseng fruit is known to have various biological effects owing to its large amount of saponins such as ginsenosides. In the present study, ginseng berry juice was confirmed to be effective against acute inflammation. Ginseng berry juice was used for analysis of active constituents, antioxidant efficacy, and in vivo inflammation. A high-performance liquid chromatography method was used for analysis of ginsenosides. In an HCl/ethanol-induced acute gastric injury model, microscopic, immunofluorescent, and immunohistochemical techniques were used for analysis of inhibition of gastric injury and mechanism study. In a mouse model of acute gastritis induced with HCl/ethanol, ginseng berry juice (GBJ, 250 mg/kg) showed similar gastric injury inhibitory effects as cabbage water extract (CB, 500 mg/kg, P.O). GBJ dose-dependently modulated the pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and Interleukin-13 (IL-13). GBJ inhibited the activation of Nuclear Factor kappa bB (NF-κB) and suppressed the expressions of cyclooxigenase-2 (COX-2) and prostaglandin 2 (PGE2). The anti-inflammatory effect of GBJ is attributed to ginsenosides which have anti-inflammatory effects. Productivity as an effective food source for acute gastritis was analyzed and showed that GBJ was superior to CB. In addition, as a functional food for suppressing acute ulcerative symptoms, it was thought that the efficacy of gastric protection products would be higher if GBJ were produced in the form of juice rather than through various extraction methods.

A phase II open-label randomized clinical trial of preoperative durvalumab or durvalumab plus tremelimumab in resectable head and neck squamous cell carcinoma.

PURPOSE: Clinical implications of neoadjuvant immunotherapy in patients with locally advanced but resectable head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. PATIENTS AND METHODS: Patients with resectable HNSCC were randomized to receive a single dose of preoperative durvalumab (D) with or without tremelimumab (T) before resection, followed by postoperative (chemo)radiation based on multidisciplinary discretion and 1-year D treatment. Artificial intelligence (AI)-powered spatial distribution analysis of tumor-infiltrating lymphocytes and high-dimensional profiling of circulating immune cells tracked dynamic intratumoral and systemic immune responses. RESULTS: Of the 48 patients enrolled (D: 24 patients, D+T: 24 patients), 45 underwent surgical resection per protocol (D: 21 patients; D+T: 24 patients). D+/-T had a favorable safety profile and did not delay surgery. Distant recurrence-free survival (DRFS) was significantly better in patients treated with D+T than in those treated with D monotherapy. AI-powered whole-slide image analysis demonstrated that D+T significantly reshaped the tumor microenvironment toward immune-inflamed phenotypes, in contrast to D monotherapy or cytotoxic chemotherapy. High-dimensional profiling of circulating immune cells revealed a significant expansion of T cell subsets characterized by proliferation and activation in response to D+T therapy, which was rare following D monotherapy. Importantly, expansion of specific clusters in CD8+ T cells and non-regulatory CD4+ T cells with activation and exhaustion programs was associated with prolonged DRFS in patients treated with D+T. CONCLUSIONS: Preoperative D+/-T is feasible and may benefit patients with resectable HNSCC. Distinct changes in the tumor microenvironment and circulating immune cells were induced by each treatment regimen, warranting further investigation.

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract.

Background: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog's poor cellular permeability and gastrointestinal (GI) stability. Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic (db/db) mouse model were evaluated. Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10-6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day. Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.

Separate axillary incision for surgery of axillary lymph node can decrease drain amount and days to drain removal of the breast in direct-to-implant breast reconstruction.

PURPOSE: Sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) can be performed either with a separate axillary incision or through the mastectomy incision. The authors hypothesized that after SLNB or ALND through a single incision, connection of the axilla with mastectomy pocket could increase drainage. This study investigated whether a separate incision decreases drainage amount and duration in implant-based breast reconstruction. METHODS: Medical records of breast cancer patients who underwent nipple-sparing or skin-sparing mastectomy with immediate breast reconstruction with prosthesis from March 2018 to February 2021 in a single tertiary center were reviewed. Demographic data, intraoperative details, and postoperative complications were reviewed. Breast drains were removed if the drain amount was less than 30cc for two consecutive days. Total breast drain amount, duration until removal, and prolonged drainage were compared with multivariate analysis. RESULTS: A total of 206 patients were included in the study, with separate incisions placed in 145 breasts and a single breast incision placed in 70 breasts. Mean duration and amount until drain removal were 12.8 ± 4.9 days and 817 ± 520 cc in the single incision group, respectively, and 9.9 ± 3.1 days and 434 ± 228 cc in the separate incision group, respectively Separate incision placement (p < 0.001), lower mastectomy weight (p < 0.001), and prepectoral plane of insertion (p < 0.001) were significantly associated with less drain amount and duration. None-separate incision placement (p = 0.01) and preoperative radiation therapy (p = 0.023) were significant factors for prolonged drainage. CONCLUSION: Placing a separate incision for axillary surgery during mastectomy and immediate implant-based reconstruction can decrease both drain amount and duration and reduce the risk of prolonged drainage.

Dynamic suprahyoid muscle ultrasound in assessing oropharyngeal dysphagia in neurological disorders.

BACKGROUND: Appropriate evaluation and management of dysphagia are essential in neurological disorders. However, there is currently a lack of a simple yet reliable method for dysphagia evaluation. AIM: This study aimed to investigate the usefulness of new dynamic M-mode ultrasonography (US) parameters of suprahyoid muscle (SHM) to evaluate dysphagia. DESIGN: Prospective observational, cross-sectional study. SETTING: Inpatient setting at neurology department of tertiary medical center. POPULATION: A total of 89 patients with dysphagia and 175 healthy volunteers were enrolled in the study. Patients were subdivided into mild and severe dysphagia groups depending on the need for dietary changes and disease classification, which included amyotrophic lateral sclerosis, peripheral neuromuscular diseases, and stroke. METHODS: Dynamic M-mode US was performed during swallowing to obtain the SHM thickness (the baseline thickness of the SHM), SHM displacement (peak-to-peak amplitude of SHM movement), SHM difference (SHM displacement - SHM thickness), SHM ratio (SHM displacement/SHM thickness), peak-to-peak time, and total duration. A videofluoroscopic swallowing study (VFSS) was performed. RESULTS: Significant differences were found in SHM displacement and SHM difference according to dysphagia severity (P<0.001). The SHM ratio, total duration (P<0.001), and peak-to-peak time (P=0.001) differed significantly according to the patients' underlying diseases. The pharyngeal delay time and penetration-aspiration scale from the VFSS demonstrated significant negative correlations with SHM displacement and difference (P<0.001). By combining SHM difference and total duration, patients with dysphagia could be distinguished from healthy controls, with the highest negative predictive value of 95.6%. CONCLUSIONS: Dynamic M-mode US of the SHM provided added value in evaluating the severity of dysphagia and differentiating swallowing mechanics of dysphagia related to underlying neurological disorders. CLINICAL REHABILITATION IMPACT: Dynamic M-mode US of the SHM can serve as a supportive tool for rapid screening and repetitive follow-up of patients with dysphagia, which would contribute to dysphagia rehabilitation in patients with various neurological disorders.

Gracilaria chorda subcritical-water extracts as ameliorant of insulin resistance induced by high-glucose in zebrafish and dexamethasone in L6 myotubes.

Background and aim: Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. Loss of insulin sensitivity disrupts glucose homeostasis and elevates the risk of developing the metabolic syndrome that includes Type 2 diabetes. This study assesses the effect on subcritical-water extract of Gracilaria chorda (GC) at 210 °C (GCSW210) in IR induction models of high glucose (HG)-induced zebrafish larvae and dexamethasone (DEX)-induced L6 myotubes. Experimental procedure: The dose of HG and DEX for IR induction in zebrafish larvae and L6 myotubes was 130 mM or 0.5 µM. The capacity of glucose uptake was quantified by fluorescence staining or intensity. In addition, the activation of protein and mRNA expressions for insulin signaling (insulin-dependent or independent pathways) was measured. Results and conclusion: Exposure of zebrafish larvae to HG significantly reduced the intracellular glucose uptake with dose-dependnet manner compared to control. However, the group treated with GCSW210 significantly averted HG levels like the insulin-treated group, and significantly up- or down-regulated the mRNA expressions related to insulin production (insα) and insulin signaling pathways. Moreover, the treatment with GCSW210 effectively regulated the protein expression of PI3K/AKT, AMPK, and GLUT4 involved in the action of insulin in IR models of L6 myotubes compared to DEX-treated control. Our data indicate that GCSW210 stimulates activation of PI3K/AKT and AMPK pathways to attenuate the development of IR induced by HG in zebrafish and DEX in L6 myotubes. In conclusion, GCSW210 is a potential agent for alleviating various diseases associated with the insulin resistance.

Licochalcone C Inhibits the Growth of Human Colorectal Cancer HCT116 Cells Resistant to Oxaliplatin.

Licochalcone C (LCC; PubChem CID:9840805), a chalcone compound originating from the root of Glycyrrhiza inflata, has shown anticancer activity against skin cancer, esophageal squamous cell carcinoma, and oral squamous cell carcinoma. However, the therapeutic potential of LCC in treating colorectal cancer (CRC) and its underlying molecular mechanisms remain unclear. Chemotherapy for CRC is challenging because of the development of drug resistance. In this study, we examined the antiproliferative activity of LCC in human colorectal carcinoma HCT116 cells, oxaliplatin (Ox) sensitive and Ox-resistant HCT116 cells (HCT116-OxR). LCC significantly and selectively inhibited the growth of HCT116 and HCT116-OxR cells. An in vitro kinase assay showed that LCC inhibited the kinase activities of EGFR and AKT. Molecular docking simulations using AutoDock Vina indicated that LCC could be in ATP-binding pockets. Decreased phosphorylation of EGFR and AKT was observed in the LCC-treated cells. In addition, LCC induced cell cycle arrest by modulating the expression of cell cycle regulators p21, p27, cyclin B1, and cdc2. LCC treatment induced ROS generation in CRC cells, and the ROS induction was accompanied by the phosphorylation of JNK and p38 kinases. Moreover, LCC dysregulated mitochondrial membrane potential (MMP), and the disruption of MMP resulted in the release of cytochrome c into the cytoplasm and activation of caspases to execute apoptosis. Overall, LCC showed anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, inducing ROS generation and disrupting MMP. Thus, LCC may be potential therapeutic agents for the treatment of Ox-resistant CRC cells.

Comparison between remimazolam and propofol anaesthesia for interventional neuroradiology: a randomised controlled trial.

BACKGROUND: General anaesthesia can immobile patients during interventional neuroradiology to improve image quality. Remimazolam, an ultrashort-acting benzodiazepine, is advantageous for haemodynamic stability. This study compared remimazolam and propofol anaesthesia during neuroradiology procedures regarding intraoperative hypotensive events and rapid recovery. METHODS: This single-masked randomised-controlled study included 76 participants who underwent elective endovascular embolisation in a single centre. Patients were randomised between a continuous remimazolam infusion (n = 38) or a target-controlled propofol infusion group (n = 38). In the remimazolam group, flumazenil (0.2 mg) was administered at the end of the procedure. Phenylephrine was titrated to maintain the mean arterial pressure within ± 20% of the baseline value. The primary outcome was the total phenylephrine dose during the procedure. RESULTS: The total phenylephrine dose was 0.0 [0.0-30.0] µg in the remimazolam group and 30.0 [0.0-205.0] µg in the propofol group (p = 0.001). Hypotensive events were observed in 11 (28.9%) patients in the remimazolam group and 23 (60.5%) patients in the propofol group (p = 0.001). Recovery times to spontaneous breathing, eye-opening, extubation, and orientation were shorter in the remimazolam group than in the propofol group (all p < 0.001). CONCLUSIONS: Remimazolam anaesthesia showed superior haemodynamic stability compared with propofol anaesthesia during neuroradiology procedures. Systematic use of flumazenil enabled rapid recovery from remimazolam anaesthesia. REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry; Registration number: UMIN000047384; URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000054046.

Comparison of the Effects of Botulinum Toxin Doses on Nerve Regeneration in Rats with Experimentally Induced Sciatic Nerve Injury.

This study was designed to compare the effects of various doses of botulinum neurotoxin A (BoNT/A) on nerve regeneration. Sixty-five six-week-old rats with sciatic nerve injury were randomly allocated to three experimental groups, a control group, and a sham group. The experimental groups received a single session of intraneural BoNT/A (3.5, 7.0, or 14 U/kg) injection immediately after nerve-crushing injury. The control group received normal intraneural saline injections after sciatic nerve injury. At three, six, and nine weeks after nerve damage, immunofluorescence staining, an ELISA, and toluidine blue staining was used to evaluate the regenerated nerves. Serial sciatic functional index analyses and electrophysiological tests were performed every week for nine weeks. A higher expression of GFAP, S100ß, GAP43, NF200, BDNF, and NGF was seen in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The average area and myelin thickness were significantly greater in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The sciatic functional index and compound muscle action potential amplitudes exhibited similar trends. These findings indicate that the 3.5 U/kg and 7.0 U/kg BoNT/A groups exhibited better nerve regeneration than the 14 U/kg BoNT/A and control group. As the 3.5 U/kg and the 7.0 U/kg BoNT/A groups exhibited no statistical difference, we recommend using 3.5 U/kg BoNT/A for its cost-effectiveness.

Physical Properties of Poly(ether-thiourea)-Based Elastomer Formed by Zigzag Hydrogen Bonding and Slidable Cross-Linking.

In this study, the effects of zigzag hydrogen bonding and slidable cross-linking on the design of stretchable elastomers were explored. Poly(ether-thiourea) (TU), capable of generating strong zigzag hydrogen bonds without crystallization, was introduced as the main chain in the non-cross-linked region of the developed elastomer. Consequently, the toughness of the TU-based elastomer was 14 times higher than that of elastomers formed using linear poly(ethylene glycol), despite the relatively low molecular weight of TU (∼3k). When a slidable polyrotaxane cross-linker was introduced into the TU-based elastomer, its flexibility became twice as high as that of the rigid polymer cross-linker. Moreover, the mechanical properties of the elastomer were prevented from deterioration against repeated deformation under the limited strain condition of 150%.

Brain Tumor Classification by Methylation Profile.

The goal of the methylation classifier in brain tumor classification is to accurately classify tumors based on their methylation profiles. Accurate brain tumor diagnosis is the first step for healthcare professionals to predict tumor prognosis and establish personalized treatment plans for patients. The methylation classifier can be used to perform classification on tumor samples with diagnostic difficulties due to ambiguous histology or mismatch between histopathology and molecular signatures, i.e., not otherwise specified (NOS) cases or not elsewhere classified (NEC) cases, aiding in pathological decision-making. Here, the authors elucidate upon the application of a methylation classifier as a tool to mitigate the inherent complexities associated with the pathological evaluation of brain tumors, even when pathologists are experts in histopathological diagnosis and have access to enough molecular genetic information. Also, it should be emphasized that methylome cannot classify all types of brain tumors, and it often produces erroneous matches even with high matching scores, so, excessive trust is prohibited. The primary issue is the considerable difficulty in obtaining reference data regarding the methylation profile of each type of brain tumor. This challenge is further amplified when dealing with recently identified novel types or subtypes of brain tumors, as such data are not readily accessible through open databases or authors of publications. An additional obstacle arises from the fact that methylation classifiers are primarily research-based, leading to the unavailability of charging patients. It is important to note that the application of methylation classifiers may require specialized laboratory techniques and expertise in DNA methylation analysis.

Anatomical Structures to Be Concerned With During Peripherally Inserted Central Catheter Procedures.

BACKGROUND: The central line has been frequently used for drug and nutrition supply and regular blood sampling of patients with chronic diseases. However, this procedure is performed in a highly sensitive area and has several potential complications. Therefore, peripherally inserted central catheters (PICC), which have various advantages, are being extensively used. Although the number of PICC procedures is increasing, the anatomy for safe procedures has not yet been properly established. Therefore, we studied basic anatomical information for safe procedures. METHODS: We used 20 fixed cadavers (40 arms) donated to the Korea University College of Medicine. The mean age was 76.75 years (range, 48-94 years). After dissection of each arm, the distribution pattern of the basilic vein and close structures was recorded, and some important parameters based on bony landmarks were measured. In addition, the number of vein branches (axillary region) and basilic vein diameter were also checked. RESULTS: The mean length from the insertion site to the right atrium was 38.39 ± 2.63 cm (left) and 34.66 ± 3.60 cm (right), and the basilic vein diameter was 4.93 ± 1.18 mm (left) and 4.08 ± 1.49 mm (right). The data showed significant differences between the left and right arms (P < 0.05). The mean distance from the basilic vein to brachial artery was 8.29 ± 2.78 mm in men and 7.81 ± 2.78 mm in women, while the distance to the ulnar nerve was 5.41 ± 1.67 mm in men and 5.52 ± 2.06 mm in women. CONCLUSION: According to these results, the right arm has a shorter distance from the insertion site to the right atrium, and the left arm has a wider vein diameter, which is advantageous for the procedure. In addition, the ulnar nerve and brachial artery were located close to or behind the insertion site. Therefore, special attention is required during the procedure to avoid damaging these important structures.

Licochalcone H Targets EGFR and AKT to Suppress the Growth of Oxaliplatin -Sensitive and -Resistant Colorectal Cancer Cells.

Treatment of colorectal cancer (CRC) has always been challenged by the development of resistance. We investigated the antiproliferative activity of licochalcone H (LCH), a regioisomer of licochalcone C derived from the root of Glycyrrhiza inflata, in oxaliplatin (Ox)-sensitive and -resistant CRC cells. LCH significantly inhibited cell viability and colony growth in both Ox-sensitive and Ox-resistant CRC cells. We found that LCH decreased epidermal growth factor receptor (EGFR) and AKT kinase activities and related activating signaling proteins including pEGFR and pAKT. A computational docking model indicated that LCH may interact with EGFR, AKT1, and AKT2 at the ATP-binding sites. LCH induced ROS generation and increased the expression of the ER stress markers. LCH treatment of CRC cells induced depolarization of MMP. Multi-caspase activity was induced by LCH treatment and confirmed by Z-VAD-FMK treatment. LCH increased the number of sub-G1 cells and arrested the cell cycle at the G1 phase. Taken together LCH inhibits the growth of Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, and inducing ROS generation and ER stress-mediated apoptosis. Therefore, LCH could be a potential therapeutic agent for improving not only Ox-sensitive but also Ox-resistant CRC treatment.

Preclinical assessment of rodent jumping power with a novel electrical stimulation-assisted device.

Sarcopenia is a progressive loss of muscle mass and strength that is associated with increasing the risk of falls, musculoskeletal diseases, and chronic metabolic diseases. However, the animal models adopted to study sarcopenia face limitations since the functional tests conducted on human cannot be directly adapted to animals because the animals do not follow instructions. Moreover, current preclinical research tools for muscle function assessment, such as the rotarod, grip strength, and treadmill, have limitations, including low-intensity simple movements, evaluator subjectivity, and limited power indicators. Hence, in this study, we present a new jumping-power assessment tool in a preclinical rodent model to demonstrate muscle functions. To overcome the light weight and command issues in the rodent model, we developed an electrical stimulation-assisted jump power assessment device. Precisely, the device utilizes a load cell with a 0.1 g resolution and a 50 points/s data acquisition rate to capture the short period of the mouse jump. Additionally, interdigitated electrodes are used to electrically stimulate the mice and make them jump. While our primary focus in this article is the validation of the newly developed jump power assessment device, it is worth noting that this tool has several potential utilities. These include the phenotypic comparison of sarcopenia models, the exploration of muscle function reduction mechanisms, muscle function-related blood biomarkers, and the evaluation of drug intervention effects.

INHAT subunit SET/TAF-Iß regulates PRC1-independent H2AK119 mono-ubiquitination via E3 ligase MIB1 in colon cancer.

SET/TAF-Iß, a subunit of the inhibitor of acetyltransferases (INHAT) complex, exhibits transcriptional repression activity by inhibiting histone acetylation. We find that SET/TAF-Iß regulates mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub), which is involved in polycomb-mediated transcriptional repression, in HCT116 cells. In this report, we demonstrate that SET/TAF-Iß acts as an E2 ubiquitin-conjugating enzyme for PRC1-independent H2AK119ub. Furthermore, we identify that MIB1 is the E3 ligase partner for SET/TAF-Iß using LC-MS/MS and in vitro ubiquitination assays. Transcriptome analysis reveals that SET/TAF-Iß and MIB1 regulate the expression of genes related to DNA replication and cell cycle progression in HCT116 cells, and knockdown of either protein reduces proliferation of HCT116 cells by impeding cell cycle progression. Together, our study reveals a novel PRC1-independent epigenetic regulatory mechanism for H2AK119ub by SET/TAF-Iß and MIB1 in colon cancer.

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery.

BACKGROUND: Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). METHODS: In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. RESULTS: In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 µg/kg) lowered the glucose level more than bD-G1A (50 µg/kg) compared with the control (35.5% vs. 26.4%). CONCLUSION: GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment.

Tongue retraction using a McIvor blade improves airway condition during fiberoptic intubation: a randomized controlled trial.

Airway clearance is crucial for successful fiberoptic intubation. We hypothesized that tongue retraction using a McIvor blade could facilitate fiberoptic intubation. This randomized clinical trial aimed to compare intubation time and airway condition between the jaw thrust maneuver and tongue retraction with the McIvor blade during fiberoptic intubation. Ninety-four adult patients scheduled for elective surgery were randomly assigned to one of two groups. During fiberoptic intubation, airway clearance was secured by applying the jaw-thrust maneuver (J group) or by tongue retraction using the McIvor blade (M group). We assessed the total intubation time, number of attempts for tube advancement, and airway clearance at the soft palate and epiglottis levels. The total intubation time was significantly shorter in the M group than in the J group (p = 0.035). The number of attempts to advance the tube was significantly lower in the M group (p = 0.033). Airway clearance at the soft palate level was significantly better in the M group than in the J group (p = 0.027). Retracting the tongue with the McIvor blade demonstrated a better condition for fiberoptic intubation and shortened total intubation time compared with the jaw-thrust maneuver.Clinicalregistiration: CRIS; http://cris.nih.go.kr (KCT0002392) registered 28/07/2017.

Downregulation of DNA methylation enhances differentiation of THP-1 cells and induces M1 polarization of differentiated macrophages.

DNA methylation is an epigenetic modification that regulates gene expression and plays an essential role in hematopoiesis. UHRF1 and DNMT1 are both crucial for regulating genome-wide maintenance of DNA methylation. Specifically, it is well known that hypermethylation is crucial characteristic of acute myeloid leukemia (AML). However, the mechanism underlying how DNA methylation regulates the differentiation of AML cells, including THP-1 is not fully elucidated. In this study, we report that UHRF1 or DNMT1 depletion enhances the phorbol-12-myristate-13-acetate (PMA)-induced differentiation of THP-1 cells. Transcriptome analysis and genome-wide methylation array results showed that depleting UHRF1 or DNMT1 induced changes that made THP-1 cells highly sensitive to PMA. Furthermore, knockdown of UHRF1 or DNMT1 impeded solid tumor formation in xenograft mouse model. These findings suggest that UHRF1 and DNMT1 play a pivotal role in regulating differentiation and proliferation of THP-1 cells and targeting these proteins may improve the efficiency of differentiation therapy in AML patients.