Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

Association between personality, lifestyle behaviors, and cardiovascular diseases in type 2 diabetes mellitus: a population-based cohort study of UK Biobank data.

INTRODUCTION: Various strategies aim to better assess risks and refine prevention for patients with type 2 diabetes mellitus (T2DM), who vary in cardiovascular disease (CVD) risk. However, the prognostic value of personality and its association with lifestyle factors remain elusive. RESEARCH DESIGN AND METHODS: We identified 8794 patients with T2DM from the UK Biobank database between 2006 and 2010 and followed them up until the end of 2021. We assessed personality traits using the Big Five proxies derived from UK Biobank data: sociability, warmth, diligence, curiosity, and nervousness. Healthy lifestyle behaviors were determined from information about obesity, smoking status, and physical activity. The primary outcome was a composite of incident CVD, including myocardial infarction (MI), ischemic stroke (IS), atrial fibrillation (AF), and heart failure (HF). RESULTS: During a median follow-up of 13.6 years, a total of 2110 patients experienced CVDs. Among personality traits, diligence was significantly associated with a reduced risk of primary and secondary outcomes. The adjusted HRs with 95% CIs were: composite CVD, 0.93 (0.89-0.97); MI 0.90 (0.82-1.00); IS 0.83 (0.74-0.94); AF 0.92 (0.85-0.98); HF 0.84 (0.76-0.91). Healthy lifestyle behaviors significantly reduced the risk of composite CVDs in groups with high and low diligence. The findings of a structural equation model showed that diligence directly affected the risk of the primary outcome or indirectly by modifying lifestyle behaviors. CONCLUSION: This study revealed which personality traits can influence CVD risk during T2DM and how patients might benefit from adopting healthy lifestyle behaviors in relation to personality.

Target-Enhanced Whole-Genome Sequencing (TE-WGS) Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel.

Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS. Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches. Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions (VAF) was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability (MSI), and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision-making. Conclusion: TE-WGS is a comprehensive approach in personalized oncology, matching TSO500's key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Automated Association for Osteosynthesis Foundation and Orthopedic Trauma Association classification of pelvic fractures on pelvic radiographs using deep learning.

High-energy impacts, like vehicle crashes or falls, can lead to pelvic ring injuries. Rapid diagnosis and treatment are crucial due to the risks of severe bleeding and organ damage. Pelvic radiography promptly assesses fracture extent and location, but struggles to diagnose bleeding. The AO/OTA classification system grades pelvic instability, but its complexity limits its use in emergency settings. This study develops and evaluates a deep learning algorithm to classify pelvic fractures on radiographs per the AO/OTA system. Pelvic radiographs of 773 patients with pelvic fractures and 167 patients without pelvic fractures were retrospectively analyzed at a single center. Pelvic fractures were classified into types A, B, and C using medical records categorized by an orthopedic surgeon according to the AO/OTA classification system. Accuracy, Dice Similarity Coefficient (DSC), and F1 score were measured to evaluate the diagnostic performance of the deep learning algorithms. The segmentation model showed high performance with 0.98 accuracy and 0.96-0.97 DSC. The AO/OTA classification model demonstrated effective performance with a 0.47-0.80 F1 score and 0.69-0.88 accuracy. Additionally, the classification model had a macro average of 0.77-0.94. Performance evaluation of the models showed relatively favorable results, which can aid in early classification of pelvic fractures.

The association between initial post-resuscitation diastolic blood pressure and survival after pediatric cardiac arrest: a retrospective study.

BACKGROUND: Limited research has analyzed the association between diastolic blood pressure (DBP) and survival after pediatric cardiopulmonary resuscitation (CPR). This study aimed to explore the association between post-resuscitation diastolic blood pressure and survival in pediatric patients who underwent CPR. METHOD: This retrospective single-center study included pediatric patients admitted to the pediatric intensive care unit of Asan Medical Center between January 2016 to November 2022. Patients undergoing extracorporeal CPR and those with unavailable data were excluded. The primary endpoint was survival to ICU discharge. RESULTS: A total of 106 patients were included, with 67 (63.2%) achieving survival to ICU discharge. Multivariate logistic regression analysis identified DBP within 1 h after ROSC as the sole significant variable (p = 0.002, aOR, 1.043; 95% CI, 1.016-1.070). Additionally, DBP within 1 h demonstrated an area under the ROC curve of 0.7 (0.592-0.809) for survival to ICU discharge, along with mean blood pressure within the same timeframe. CONCLUSION: Our study highlights the importance of DBP within 1-hour post-ROSC as a significant prognostic factor for survival to ICU discharge. However, further validation through further prospective large-scale studies is warranted to confirm the appropriate post-resuscitation DBP of pediatric patients.

Association between intra-articular hyaluronic acid injections in delaying total knee arthroplasty and safety evaluation in primary knee osteoarthritis: analysis based on Health Insurance Review and Assessment Service (HIRA) claim database in Republic of Korea.

BACKGROUND: The prevalence of knee osteoarthritis (KOA), a progressive degenerative disease, is gradually increasing, and it is a progressive degenerative disease. In patients with mild-to-moderate KOA, intra-articular hyaluronic acid (IA-HA) has been shown to be an effective non-operative treatment option that can provide significant pain relief and symptom improvement by increasing intra-articular viscoelasticity. This study aimed to evaluate the efficacy of IA-HA injections in delaying total knee arthroplasty (TKA) and the safety of IA-HA according to IA-HA type and combination with intra-articular corticosteroid (IA-CS) using a large health insurance claim database. METHODS: For this retrospective cohort study, the study population included patients aged ≥ 50 years with a first diagnosis of KOA between 2009 and 2014, who underwent TKA by 2020, using the Health Insurance Review and Assessment Service claim database in Republic of Korea. IA-HA injections were categorized as single or multiple injection regimen agents. Cox proportional hazard models estimated hazard ratios (HR) for TKA risk, adjusted for covariates. Logistic regression assessed the occurrence of adverse events after IA-HA administration. RESULTS: In all, 36,983 patients were included. Patients who received IA-HA injections had a significantly longer time to TKA compared to those who did not (mean delay of approximately 1 year). The IA-HA group had a significantly lower risk of TKA (HR: 0.61, 95% CI: 0.60-0.62) than non-IA-HA group after adjusting for covariates, which included age, sex, medical history, number of hospital beds, and CS injection. Single injection IA-HA regimen agents showed the longest time to TKA and lowest risk (HR: 0.56, 95% CI: 0.53-0.59). TKA risk decreased with the number of IA-HA cycles. Adverse events occurred in 6.7% of IA-HA cases without CS, with very low incidence of infection. Multiple injection regimen agents (multiple injection regimen 7.0% vs. single injection regimen 3.6%) and concurrent IA-CS use (concurrent IA-CS use 13.9% vs. IA-HA only 6.7%) were associated with higher infection risk. CONCLUSION: IA-HA injections were associated with a significant delay in TKA among patients with KOA. Single-injection regimen agents had the lowest TKA risk. Infection risk increased with multiple injections and concurrent IA-CS use. These findings could suggest the use of IA-HA as an effective non-operative intervention option for managing KOA and delaying TKA. Careful selection of IA-HA type and consideration of concurrent IA-CS use could play a role in delaying the time to TKA and reducing complications.

A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance. METHODS: A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from 6 centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n=944), internal validation (n=1,102), and external validation (n=2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death. RESULTS: During a median follow-up of 55.2 (interquartile range=30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. A model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and 7 variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all P<0.001; area under the receiver operating characteristic curve: 0.86 vs. 0.62-0.72, all P<0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all P<0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test P>0.05) and these results were reproduced in the internal and external validation cohorts. CONCLUSION: This novel machine learning model consisting of 7 variables provides reliable risk prediction of LRO after HBsAg seroclearance that can be used for personalized surveillance.

Differential genotoxicity of Polygoni Multiflori in rat and human: insights from Ames test and S9 metabolic activation system.

The Ames test is used worldwide to initially screen the mutagenic potential of new chemicals. In the standard Ames test, S. typhimurium strains (TA100, TA98, TA1535, and TA1537) and Escherichia coli (WP2uvrA) are treated with substances with/without cytochrome P450s (CYPs)-induced rat S9 fractions for identifying mutagens and pro-mutagens. However, many substances show completely different toxicity patterns depending on whether the liver S9 fraction belongs to rats or humans. The natural product Polygoni Multiflori Radix (PMR) can also show bacterial reverse mutation, followed by the rat or human liver S9 fraction. While PMR elicits reverse mutations in the TA1537 strain in rat liver S9 but not in human liver S9, this mechanism has not been verified yet. To explain this, the differences in metabolic enzymes compositions commonly observed between rats and humans have been implicated. This study aimed to explore the key factors that cause differences in the genotoxicity of PMR between rat and human liver S9 metabolic enzymes. The results of next-generation sequencing (NGS) analysis showed that both rat and human metabolic enzymes caused similar mutations in TA1537. However, when the metabolic enzymes in each S9 fraction were analyzed using ion mobility tandem mass spectrometry (IM-MS), rat- and human-specific enzymes were identified among the cytochrome (CYP) family, especially aryl hydrocarbon receptor (AHR)-related CYPs. These findings suggest that CYP1A1 isoforms contribute to the mechanism of PMR in the Ames test. Therefore, an in vitro Ames test might be more reliable in predicting genotoxicity for both rodents and humans. This will also help overcome the limitations of laboratory animal-based toxicity evaluations, which provide unreliable results due to interspecies differences between humans and rodents.

Enhanced lithium host performance of multi-walled carbon nanotubes through acidic functionalization for lithium-sulfur batteries.

Carbon nanotubes (CNTs) have been explored as a potential cathode material for lithium-sulfur (Li-S) batteries owing to their unique structure. However, traditional CNTs exhibit poor dispersion properties when preparing electrodes. The non-uniform distribution of the conductive agents hinders the formation of enough sites for sulfur loading, which results in the aggregation of sulfur/Li2S and severe polarization. In this study, we propose the acidic functionalization of CNTs in the cathode structure as a practical solution for mitigating the poor dispersion and polysulfide shuttling in lithium-sulfur batteries. Multiwalled CNTs were functionalized by oxidation through acidic treatment using sulfuric, nitric, and mixed acids. The cathode prepared with a mixture of sulfuric and nitric acids showed a coulombic efficiency of 99 % after 100 cycles, with a discharge capacity of 743 mAh g-1. These findings demonstrate the effectiveness of the acidic functionalization of CNTs as a promising approach for enhancing the electrochemical performance and commercial viability of lithium-sulfur batteries.

Dexamethasone nanocrystals-embedded hydroxypropyl methylcellulose hydrogel increases cochlear delivery and attenuates hearing loss following intratympanic injection.

Herein, dexamethasone (DEX) nanocrystalline suspension (NS)-embedded hydrogel (NS-G) was constructed using a hydroxypropyl methylcellulose (HPMC) polymer to enhance cochlear delivery and attenuate hearing loss following intratympanic (IT) injection. Hydrophobic steroidal nanocrystals were prepared using a bead milling technique and incorporated into a polysaccharide hydrogel. The NS-G system with HPMC (average molecular weight, 86,000 g/mol; 15 mg/mL) was characterized as follows: rod-shaped drug crystalline; particle size <300 nm; and constant complex viscosity ≤1.17 Pa·s. Pulverization of the drug particles into submicron diameters enhanced drug dissolution, while the HPMC matrix increased the residence time in the middle ear cavity, exhibiting a controlled release profile. The IT NS-G system elicited markedly enhanced and prolonged drug delivery (> 9 h) to the cochlear tissue compared with that of DEX sodium phosphate (DEX-SP), a water-soluble prodrug. In mice with kanamycin- and furosemide-induced ototoxicity, NS-G markedly enhanced hearing preservation across all frequencies (8-32 kHz), as revealed by an auditory brainstem response test, compared with both saline and DEX-SP. Moreover, treatment with NS-G showed enhanced anti-inflammatory effects, as evidenced by decreased levels of inflammation-related cytokines. Therefore, the IT administration of DEX NS-loaded HPMC hydrogels is a promising strategy for treating hearing loss.

Overview of a novel osmotin abolishes abnormal metabolic-associated adiponectin mechanism in Alzheimer's disease: Peripheral and CNS insights.

Alzheimer's disease (AD) is a degenerative brain disease that affects millions of people worldwide. It is caused by abnormalities in cholinergic neurons, oxidative stress, and inflammatory cascades. The illness is accompanied by personality changes, memory issues, and dementia. Metabolic signaling pathways help with fundamental processes like DNA replication and RNA transcription. Being adaptable is essential for both surviving and treating illness. The body's metabolic signaling depends on adipokines, including adiponectin (APN) and other adipokines secreted by adipose tissues. Energy homeostasis is balanced by adipokines, and nutrients. Overconsumption of nutrients messes with irregular signaling of adipokines, such as APN in both peripheral and brain which leads to neurodegeneration, such as AD. Despite the failure of traditional treatments like memantine and cholinesterase inhibitors, natural plant bioactive substances like Osmotin (OSM) have been given a focus as potential therapeutics due to their antioxidant properties, better blood brain barrier (BBB) permeability, excellent cell viability, and especially nanoparticle approaches. The review highlights the published preclinical literature regarding the role of OSM in AD pathology while there is a need for more research to investigate the hidden therapeutic potential of OSM which may open a new gateway and further strengthen its healing role in the pathogenesis of neurodegeneration, especially AD.

Recent discovery of natural substances with cathepsin L-inhibitory activity for cancer metastasis suppression.

Cathepsin L (CTSL), a cysteine cathepsin protease of the papain superfamily, plays a crucial role in cancer progression and metastasis. Dysregulation of CTSL is frequently observed in tumor malignancies, leading to the degradation of extracellular matrix and facilitating epithelial-mesenchymal transition (EMT), a key process in malignant cancer metastasis. This review mainly provides a comprehensive information about recent findings on natural inhibitors targeting CTSL and their anticancer effects, which have emerged as potent anticancer therapeutic agents or metastasis-suppressive adjuvants. Specifically, inhibitors are categorized into small-molecule and macromolecule inhibitors, with a particular emphasis on cathepsin propeptide-type macromolecules. Additionally, the article explores the molecular mechanisms of CTSL involvement in cancer metastasis, highlighting its regulation at transcriptional, translational, post-translational, and epigenetic levels. This work underscores the importance of understanding natural CTSL inhibitors and provides researchers with practical insights to advance the relevant fields and discover novel CTSL-targeting inhibitors from natural sources.

Discrepancy Between Genetically Predicted and Observed BMI Predicts Incident Type 2 Diabetes.

OBJECTIVE: Obesity is a key predictor of type 2 diabetes (T2D). However, metabolic complications are not solely due to increased BMI. We hypothesized that differences between genetically predicted BMI and observed BMI (BMI-diff) could reflect deviation from individual set point and may predict incident T2D. RESEARCH DESIGN AND METHODS: From the UK Biobank cohort, we selected participants of European ancestry without T2D (n = 332,154). The polygenic risk score for BMI was calculated via Bayesian regression and continuous shrinkage priors (PRS-CS). According to the BMI-diff, the 10-year risk of T2D was assessed using multivariable Cox proportional hazards model. Independent data from the Korean Genome and Epidemiology Study (KoGES) cohort from South Korea (n = 7,430) were used for replication. RESULTS: Participants from the UK Biobank were divided into train (n = 268,041) and test set (n = 115,119) to establish genetically predicted BMI. In the test set, the genetically predicted BMI explained 7.1% of the variance of BMI, and there were 3,599 T2D cases (3.1%) during a 10-year follow-up. Participants in the higher quintiles of BMI-diff (more obese than genetically predicted) had significantly higher risk of T2D than those in the lowest quintile after adjusting for observed BMI: the adjusted hazard ratio of the 1st quintile (vs. 5th quintile) was 1.61 (95% CI 1.26-2.05, P < 0.001). Results were consistent among individuals in the KoGES study. Moreover, higher BMI than predicted was associated with impaired insulin sensitivity. CONCLUSIONS: Having a higher BMI than genetically predicted is associated with an increased risk of T2D. These findings underscore the potential to reassess T2D risk based on individual levels of obesity using genetic thresholds for BMI.

First-in-Human Evaluation of a Polymer-Free Everolimus-Eluting Stent Using a Titanium Dioxide Film.

BACKGROUND: In patients with coronary artery disease treated with permanent polymer-coated drug-eluting stents (DES), the persistent presence of a less biocompatible polymer might delay arterial healing. Thin strut polymer-free DES have the potential to improve clinical outcomes and reduce the duration of dual antiplatelet therapy (DAPT). The purpose of this first-in-human study was to assess the safety and effectiveness of a novel polymer-free DES in patients with de novo coronary lesions. The TIGERevolutioN® stent (CG Bio Co., Ltd., Seoul, Korea) consists of a cobalt chromium platform with a strut thickness of 70 µm and a surface treated with titanium dioxide onto which everolimus-eluting stent (EES) is applied abluminally (6 µg/mm of stent length) without utilization of a polymer. METHODS: A total of 20 patients were enrolled, with de novo coronary lesions (stable or unstable angina) and > 50% diameter stenosis in a vessel 2.25 to 4.00 mm in diameter and ≤ 40 mm in length for angiographic, optical coherence tomography (OCT), and clinical assessment at 8 months. All patients received DAPT after stent implantation. The primary endpoint was angiographic in-stent late lumen loss (LLL) at 8 months. RESULTS: Twenty patients with 20 lesions were treated with TIGERevolutioN®. At 8 months, in-stent LLL was 0.7 ± 0.4 mm. On OCT, percent area stenosis was 29.2 ± 9.4% and stent strut coverage was complete in all lesions. No adverse cardiovascular event occurred at 8 months. CONCLUSION: The new polymer-free EES was safe and effective with low LLL and excellent strut coverage at 8 months of follow-up. TRIAL REGISTRATION: Trial Registration: Clinical Research Information Service Identifier: KCT0005699.

Developmental temperature modulates microplastics impact on amphibian life history without affecting ontogenetic microplastic transfer.

This study examines how temperature influences the response of Japanese tree frogs (Dryophytes japonicus) to microplastic (MP) pollution, assessing whether temperature can regulate the harmful effects of MPs on their life history and the dispersal of MPs across habitats. This analysis aims to understand the ecological and physiological ramifications of MP pollution. Our results demonstrated an ontogenetic transfer of MP particles across amphibian metamorphosis, possibly allowing and facilitating the translocation of MPs across ecosystems. Temperature did not significantly affect the translocation of aquatic MPs to land. However, high temperatures significantly reduced mortality and hindlimb deformities caused by MPs, thereby mitigating their harmful impact on amphibian life histories. Importantly, our study found that MPs cause hindlimb deformities during amphibian metamorphosis, potentially linked to oxidative stress. Additionally, MP exposure and ingestion induced a plastic response in the morphology of the digestive tract and changes in the fecal microbiome, which were evident at high temperatures but not at low temperatures. The effects of MPs persisted even after the frogs transitioned to the terrestrial stage, suggesting that MPs may have complex, long-term impacts on amphibian population sustainability. Our results enhance the understanding of the intricate environmental challenges posed by MPs and underscore the significant role of temperature in ectotherms regarding ontogenetic impacts and pollutant interactions.

Reverse tube direction and epistaxis in left nasotracheal intubation: a randomized controlled trial.

Background: The incidence of epistaxis during nasotracheal intubation via the left nostril is more frequent than that during intubation via the right nostril. This study evaluated the effect of the reverse bevel and tip direction of the nasotracheal tube on the incidence of epistaxis during nasotracheal intubation via the left nostril. Methods: Patients undergoing right-sided maxillofacial surgery requiring left nasotracheal intubation were randomly allocated to the control (tracheal tube in the conventional direction) or reverse (a 180˚ reverse direction, with the tube bevel facing the nasal septum and the leading edge (i.e., the tip) of the bevel pointing away from the nasal septum) groups (n = 37 for both). The primary outcome was the incidence of epistaxis evaluated using videolaryngoscopy. Results: The incidence of epistaxis in the reverse group was significantly lower than that in the control group (9 [24.3%] vs. 20 [54.1%], P = 0.009; relative risk = 0.45; 95% CI: 0.24, 0.85; absolute risk reduction = 29.8%; number needed to treat = 3.36). The severity of epistaxis was significantly lower in the reverse group (P = 0.002). The first attempt nasal passage (P = 0.027) was significantly higher in the reverse group. Postoperative nasal pain was lower (P < 0.001), and patient satisfaction was higher (P < 0.001) in the reverse group. Nasotracheal tube-related complications did not occur in either group. Conclusions: The reverse bevel and tip direction of the nasotracheal tube reduced the incidence and severity of epistaxis and increased patient satisfaction among patients undergoing left nasotracheal intubation.

EpCAM-targeted betulinic acid analogue nanotherapy improves therapeutic efficacy and induces anti-tumorigenic immune response in colorectal cancer tumor microenvironment.

BACKGROUND: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME. METHODS: After the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models. RESULTS: We found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model. CONCLUSIONS: Enhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted.