Chromothripsis-mediated small cell lung carcinoma.

Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here we performed detailed clinicopathologic, genomic and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis - massive, localized chromosome shattering - recurrently involving chromosomes 11 or 12, and resulting in extrachromosomal (ecDNA) amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.

Reliability of Surface Electromyography From the Lower-limb Muscles During Maximal and Submaximal Voluntary Isometric Contractions in In-bed Healthy Individuals and Patients With Subacute Stroke.

This study aims to develop maximal voluntary isometric contraction (MVIC) and submaximal voluntary isometric contraction (subMVIC) methods and to assess the reliability of the developed methods for in-bed healthy individuals and patients with subacute stroke. The electromyography (EMG) activities from the lower-limb muscles including the tensor fascia lata (TFL), rectus femoris (RF), tibialis anterior (TA), and gastrocnemius (GC) on both sides were recorded during MVIC and subMVIC using surface EMG sensors in 20 healthy individuals and 20 subacute stroke patients. In inter-trial reliability, both MVIC and subMVIC methods demonstrated excellent reliability for all the measured muscles at baseline and follow-up evaluations in both healthy individuals and stroke patients. In inter-day reliability, MVIC showed good reliability for the TFL and moderate reliability for the RF, TA, and GC, while subMVIC showed good reliability for the TFL, RF, and GC and poor reliability for the TA in healthy individuals. In conclusion, the MVIC and subMVIC methods of EMG activities were feasible in in-bed healthy individuals and patients with subacute stroke. The results can serve as a basis for the clinical evaluation of muscular activities using quantitative EMG signals on the lower-limb muscles in stroke patients with impaired mobility.

Serial Cell-Free DNA Sequencing in ROS1 Fusion-Positive Lung Cancers During Treatment With Entrectinib.

PURPOSE: Patients with metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) are effectively treated with entrectinib, a multikinase inhibitor. Whether serial targeted gene panel sequencing of cell-free DNA (cfDNA) can identify response and progression along with mechanisms of acquired resistance to entrectinib is underexplored. METHODS: In patients with ROS1 fusion-positive NSCLC, coclinical trial plasma samples were collected before treatment, after two cycles, and after progression on entrectinib (global phase II clinical trial, ClinicalTrials.gov identifier: NCT02568267). Samples underwent cfDNA analysis using MSK-ACCESS. Variant allele frequencies of detectable alterations were correlated with objective response per RECIST v1.1 criteria. RESULTS: Twelve patients were included, with best response as partial response (n = 9, 75%), stable disease (n = 2, 17%), and progressive disease (PD; n = 1, 8%). A ROS1 fusion was variably detected in cfDNA; however, patients without a ROS1 fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling ROS1 fusion or concurrent non-ROS1 alterations (TP53, CDH1, NF1, or ARID1A mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a ROS1 fusion or non-ROS1 alterations. On-target resistance was rare; only one patient acquired ROS1 G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in NF1. CONCLUSION: Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression.

Feasibility and safety of in-bed cycling/stepping in critically ill patients: A study protocol for a pilot randomized controlled clinical trial.

BACKGROUND: Intensive care unit (ICU)-acquired weakness (ICU-AW) is one of the most common complications of post-ICU syndrome. It is the leading cause of gait disturbance, decreased activities of daily living, and poor health-related quality of life. The early rehabilitation of critically ill patients can reduce the ICU-AW. We designed a protocol to investigate the feasibility and safety of conventional rehabilitation with additional in-bed cycling/stepping in critically ill patients. METHODS: The study is designed as a single-center, single-blind, pilot, randomized, parallel-group study. After the screening, participants are randomly allocated to two groups, stratified by mechanical ventilation status. The intervention group will be provided with exercises of in-bed cycling/stepping according to the level of consciousness, motor power, and function in addition to conventional rehabilitation. In contrast, the control group will be provided with only conventional rehabilitation. The length of intervention is from ICU admission to discharge, and interventions will be conducted for 20 minutes, a maximum of three sessions per day. RESULTS: The outcomes are the number and percentage of completed in-bed cycling/stepping sessions, the duration and percentage of in-bed cycling/stepping sessions, and the number of cessations of in-bed cycling/stepping sessions, the interval from ICU admission to the first session of in-bed cycling/stepping, the number and percentage of completed conventional rehabilitation sessions, the duration and percentage of conventional rehabilitation sessions, the number of cessations of conventional rehabilitation sessions, the number of adverse events, level of consciousness, functional mobility, muscle strength, activities of daily living, and quality of life. DISCUSSION: This study is a pilot clinical trial to investigate the feasibility and safety of conventional rehabilitation with additional in-bed cycling/stepping in critically ill patients. If the expected results are achieved in this study, the methods of ICU rehabilitation will be enriched. TRIAL REGISTRATION: clinicialtrials.gov, Clinical Trials Registration #NCT05868070.

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10-10 and p = 8.5 × 10-9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10-4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10-8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70-0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

Design and validation of a wearable dynamometry system for knee extension-flexion torque measurement.

Muscle strength assessments are vital in rehabilitation, orthopedics, and sports medicine. However, current methods used in clinical settings, such as manual muscle testing and hand-held dynamometers, often lack reliability, and isokinetic dynamometers (IKD), while reliable, are not easily portable. The aim of this study was to design and validate a wearable dynamometry system with high accessibility, accuracy, and reliability, and to validate the device. Therefore, we designed a wearable dynamometry system (WDS) equipped with knee joint torque sensors. To validate this WDS, we measured knee extension and flexion strength in 39 healthy adults using both the IKD and WDS. Comparing maximal isometric torque measurements, WDS and IKD showed strong correlation and good reliability for extension (Pearson's r: 0.900; intraclass correlation coefficient [ICC]: 0.893; standard error of measurement [SEM]: 9.85%; minimal detectable change [MDC]: 27.31%) and flexion (Pearson's r: 0.870; ICC: 0.857; SEM: 11.93%; MDC: 33.07%). WDS demonstrated excellent inter-rater (Pearson's r: 0.990; ICC: 0.993; SEM: 4.05%) and test-retest (Pearson's r: 0.970; ICC: 0.984; SEM: 6.15%) reliability during extension/flexion. User feedback from 35 participants, including healthcare professionals, underscores WDS's positive user experience and clinical potential. The proposed WDS is a suitable alternative to IKD, providing high accuracy, reliability, and potentially greater accessibility.

Reduction in limb-movement complexity at term-equivalent age is associated with motor developmental delay in very-preterm or very-low-birth-weight infants.

Reduced complexity during the writhing period can be crucial in the spontaneous movements of high-risk infants for neurologic impairment. This study aimed to verify the association between quantified complexity of upper and lower-limb movements at term-equivalent age and motor development in very-preterm or very-low-birth-weight infants. Video images of spontaneous movements at term-equivalent age were collected from very-preterm or very-low-birth-weight infants. A pretrained pose-estimation model and sample entropy (SE) quantified the complexity of the upper- and lower-limb movements. Motor development was evaluated at 9 months of corrected age using Bayley Scales of Infant and Toddler Development, Third Edition. The SE measures were compared between infants with and without motor developmental delay (MDD). Among 90 infants, 11 exhibited MDD. SE measures at most of the upper and lower limbs were significantly reduced in infants with MDD compared to those without MDD (p < 0.05). Composite scores in the motor domain showed significant positive correlations with SE measures at most upper and lower limbs (p < 0.05). The results show that limb-movement complexity at term-equivalent age is reduced in infants with MDD at 9 months of corrected age. SE of limb movements can be a potentially useful kinematic parameter to detect high-risk infants for MDD.

Reconstruction of all hepatic arteries in right lobe grafts with 2 hepatic arteries and zero percent hepatic artery thrombosis.

Hepatic artery thrombosis (HAT) is a common cause of graft loss in living-donor liver transplantation, occurring in ~2.5%-8% of patients. Some right lobe grafts have 2 hepatic arteries (HAs), and the optimal reconstruction technique remains controversial. This study aimed to identify risk factors for HAT and to evaluate the efficacy of reconstructing 2 HAs in right lobe grafts. This retrospective, single-center study analyzed 1601 living-donor liver transplantation recipients with a right liver graft and divided them into 1 HA (n = 1524) and 2 HA (n = 77) groups. The reconstruction of all HAs was performed using a microscope with an interrupted suture. The primary outcome was any HAT event. Of the 1601 patients, 37.8% had a history of transcatheter arterial chemoembolization, and 130 underwent pretransplant hepatectomy. Extra-anatomical arterial reconstruction was performed in 38 cases (2.4%). HAT occurred in 1.2% of patients (20/1601) who underwent surgical revascularization. In the multivariate analysis, undergoing pretransplant hepatectomy ( p = 0.008), having a female donor ( p = 0.02), having a smaller graft-to-recipient weight ratio ( p = 0.002), and undergoing extra-anatomical reconstruction ( p = 0.001) were identified as risk factors for HAT. However, having 2 HA openings in right liver grafts was not a risk factor for HAT in our series. Kaplan-Meier survival analysis showed no significant difference in graft survival and patient survival rates between the 1 HA and 2 HA groups ( p = 0.09, p = 0.97). In our series, although the smaller HA in the 2 HA group should increase the risk of HAT, HAT did not occur in this group. Therefore, reconstructing both HAs when possible may be a reasonable approach in living-donor liver transplantation using a right liver graft with 2 HA openings.

Inter-rater and Intra-rater Reliability of the Videofluoroscopic Dysphagia Scale with the Standardized Protocol.

This study aimed to develop a standardized protocol for the assessment of videofluoroscopic dysphagia scale (VDS) and to demonstrate the inter-rater and intra-rater reliability of the VDS by applying the new standard protocol. A standardized protocol for the VDS was developed by dysphagia experts, including the original developer. To identify the reliability of the VDS using the protocol, 60 patients who underwent videofluoroscopic swallowing study (VFSS) for various etiologies were recruited retrospectively from three tertiary medical centers. Ten randomly selected cases were duplicated to evaluate the intra-rater reliability. Six physicians evaluated the VFSS data sets. Intraclass correlation coefficients were calculated for inter-rater and intra-rater reliability of the VDS score, and Gwet's kappa values for each VDS item were calculated. The inter-rater and intra-rater reliability of the total VDS score was 0.966 and 0.896, respectively. Notably, the evaluators' experience did not appear to have a significant impact on the reliability (physiatrists: 0.933/0.869, residents: 0.922/0.922). The reliability was consistent across different centers and dysphagia etiologies. The inter-rater and intra-rater reliability of the oral and pharyngeal sub-scores were 0.953/0.861 and 0.958/0.907, respectively. The inter-rater agreement of individual items ranged from 0.456 to 0.929, and nine items demonstrated good to very good level of agreement. Assessment of dysphagia using the VDS with the standard protocol showed excellent inter-rater and intra-rater reliabilities regardless of the evaluator's experience, VFSS equipment, and dysphagia etiologies. The VDS can be a useful assessment scale in the quantitative analysis of dysphagia based on VFSS findings.

Evaluation of the Antiviral Activity of Tabamide A and Its Structural Derivatives against Influenza Virus.

Influenza viruses cause severe endemic respiratory infections in both humans and animals worldwide. The emergence of drug-resistant viral strains requires the development of new influenza therapeutics. Tabamide A (TA0), a phenolic compound isolated from tobacco leaves, is known to have antiviral activity. We investigated whether synthetic TA0 and its derivatives exhibit anti-influenza virus activity. Analysis of structure-activity relationship revealed that two hydroxyl groups and a double bond between C7 and C8 in TA0 are crucial for maintaining its antiviral action. Among its derivatives, TA25 showed seven-fold higher activity than TA0. Administration of TA0 or TA25 effectively increased survival rate and reduced weight loss of virus-infected mice. TA25 appears to act early in the viral infection cycle by inhibiting viral mRNA synthesis on the template-negative strand. Thus, the anti-influenza virus activity of TA0 can be expanded by application of its synthetic derivatives, which may aid in the development of novel antiviral therapeutics.

A leptin-loaded poly-ϵ-caprolactone 3D printing scaffold for odontoblastic differentiation in human dental pulp cells.

This study investigated the effects on odontoblast differentiation of a 3D-printed poly-ϵ-caprolactone (PCL) scaffold that incorporated leptin. Material extrusion-type 3D printing with a 43 000-molecular weight PCL material was used to fabricate a PCL scaffold with a 6 mm diameter, 1 mm height, and 270-340 µm pore size. The experimental groups were PCL scaffolds (control group), PCL scaffolds with aminated surfaces (group A), and PCL scaffolds with leptin on the aminated surface (group L). The aminated surface was treated with 1,6-hexanediamine and verified by ninhydrin analysis. Leptin loading was performed using Traut's reagent and 4-(N-Maleimidomethyl)cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxysuccinimide ester sodium salt (Sulfo-SMCC). Groups A and L showed significantly higher surface wettability, pulp cell adhesion, and proliferation than the control group. Group L exhibited increased alkaline phosphatase, calcification deposits, and mRNA and protein expression of dentin sialophosphoprotein and dentin matrix acidic phosphoprotein 1 compared with the control group. In this study, a 3D-printed PCL scaffold containing leptin was enhanced odontoblast differentiation and dental pulp cells adhesion and proliferation.

Development and validation of a portable articulated dynamometry system to assess knee extensor muscle strength.

Muscle strength assessment is important in predicting clinical and functional outcomes in many disorders. Manual muscle testing, although commonly used, offers suboptimal accuracy and reliability. Isokinetic dynamometers (IKDs) have excellent accuracy and reliability; but are bulky and expensive, offering limited accessibility. This study aimed to design a portable dynamometer that is accessible, accurate and reliable, and to validate the device in a general population. The portable articulated dynamometry system (PADS) is a portable device with an embedded high-precision load cell, designed to measure muscle strength with optimal accuracy. Seventy-two participants underwent maximal isometric and isokinetic knee extensor torque measurement with the PADS and IKD, respectively. The PADS results were cross-validated against IKD results using change in mean (CIM). Interrater and intra-rater reliabilities were assessed using intraclass correlation coefficients, standard error of measurement, and minimal detectable change. The PADS maximal knee extensor strength results were not significantly different from those by IKD (CIM: - 2.13 Nm; 95% CI - 4.74, 0.49 Nm). The PADS showed interrater reliability (Pearson's r: 0.958; ICC: 0.979; SEM: 5.51%) and excellent intra-rater reliability (Pearson's r: 0.912; ICC: 0.954; SEM: 8.38%). The proposed PADS may be an effective alternative to IKD, offering good accuracy, reliability, and potentially better accessibility.

Mini-incision Right Hepatectomy for Living Donor Hepatectomy.

BACKGROUND: The application of a minimally invasive technique to graft procurement in living donor liver transplantation has minimized skin incisions and led to early recovery in donor hepatectomy while ensuring donor safety. This study aimed to evaluate the safety and feasibility of mini-incision living donor right hepatectomy compared with conventional open surgery. METHODS: The study population consisted of 448 consecutive living donors who underwent living donor right hepatectomy performed by a single surgeon between January 2015 and December 2019. According to the incision type, the donors were divided into 2 groups: a right subcostal mini-incision group (M group: n = 187) and a conventional J-shaped incision group (C group: n = 261). A propensity score matching analysis was conducted to overcome bias. RESULTS: The estimated graft volume and measured graft weight were significantly lower in the M group ( P = 0.000). The total of 17 (3.8%) postoperative complications were identified. The readmission rate and overall postoperative complication rate of donors was not significantly different between the groups. The biliary complication rates in the recipients were 12.6% and 8.6% in the C group and M group, respectively ( P = 0.219). Hepatic artery thrombosis requiring revision developed in 2 patients (0.8%) in the C group and 7 patients (3.7%) in the M group ( P = 0.038). After propensity score matching, these complications were not significantly different between the groups. CONCLUSIONS: Mini-incision living donor right hepatectomy shows comparable biliary complications to open surgery and is considered a safe and feasible operative technique.

Spontaneous movements as prognostic tool of neurodevelopmental outcomes in preterm infants: a narrative review.

An estimated 15 million infants are born prematurely each year. Although the survival rate of preterm infants has increased with advances in perinatal and neonatal care, many still experience various complications. Since improving the neurodevelopmental outcomes of preterm births is a crucial topic, accurate evaluations should be performed to detect infants at high risk of cerebral palsy. General movements are spontaneous movements involving the whole body as the expression of neural activity and can be an excellent biomarker of neural dysfunction caused by brain impairment in preterm infants. The predictive value of general movements with respect to cerebral palsy increases with continuous observation. Automated approaches to examining general movements based on machine learning can help overcome the limited utilization of assessment tools owing to their qualitative or semiquantitative nature and high dependence on assessor skills and experience. This review covers each of these topics by summarizing normal and abnormal general movements as well as recent advances in automatic approaches based on infantile spontaneous movements.

Deciphering Functional Connectivity Differences Between Motor Imagery and Execution of Target-Oriented Grasping.

This study aimed to delineate overlapping and distinctive functional connectivity in visual motor imagery, kinesthetic motor imagery, and motor execution of target-oriented grasping action of the right hand. Functional magnetic resonance imaging data were obtained from 18 right-handed healthy individuals during each condition. Seed-based connectivity and multi-voxel pattern analyses were employed after selecting seed regions with the left primary motor cortex and supplementary motor area. There was equivalent seed-based connectivity during the three conditions in the bilateral frontoparietal and temporal areas. When the seed region was the left primary motor cortex, increased connectivity was observed in the left cuneus and superior frontal area during visual and kinesthetic motor imageries, respectively, compared with that during motor execution. Multi-voxel pattern analyses revealed that each condition was differentiated by spatially distributed connectivity patterns of the left primary motor cortex within the right cerebellum VI, cerebellum crus II, and left lingual area. When the seed region was the left supplementary motor area, the connectivity patterns within the right putamen, thalamus, cerebellar areas IV-V, and left superior parietal lobule were significantly classified above chance level across the three conditions. The present findings improve our understanding of the spatial representation of functional connectivity and its specific patterns among motor imagery and motor execution. The strength and fine-grained connectivity patterns of the brain areas can discriminate between motor imagery and motor execution.

Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.

Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7+SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy.

Exploratory Investigation of the Effects of Tactile Stimulation Using Air Pressure at the Auricular Vagus Nerve on Heart Rate Variability.

OBJECTIVE: To explore the effects of tactile stimulation using air pressure at the auricular branch of the vagus nerve on autonomic activity in healthy individuals. METHODS: Three types of tactile stimulation were used in this study: continuous low-amplitude, continuous high-amplitude, and pulsed airflow. The tactile stimulations were provided to the cymba concha to investigate autonomic activity in 22 healthy participants. The mean heart rate (HR) and parameters of HR variability, including the standard deviation of R-R intervals (SDNN) and root mean square of successive R-R interval differences (RMSSD) were compared at baseline, stimulation, and recovery periods. RESULTS: Two-way repeated measures ANOVA indicated a significant main effect of time on HR (p=0.001), SDNN (p=0.003), and RMSSD (p<0.001). These parameters showed significant differences between baseline and stimulation periods and baseline and recovery periods in the post-hoc analyses. There were no significant differences in the changes induced by stimulation type and the interaction between time and stimulation type for all parameters. One-way repeated measures ANOVA showed that HR, SDNN, and RMSSD did not differ significantly among the three time periods during sham stimulation. CONCLUSION: Parasympathetic activity can be enhanced by auricular tactile stimulation using air pressure, targeting the cymba concha. Further studies are warranted to investigate the optimal stimulation parameters for potential clinical significance.

Atypical presentations of drug-induced hypersensitivity syndrome caused by carbamazepine with concurrent use of corticosteroid: Report of a case with a brief literature review

Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, KoreaCarbamazepine (CBZ) is the common antiepileptic drug prescribed for the management of neuropathic pain in patients with neurologic injury. CBZ can rarely be the causative agent to result in drug-induced hypersensitivity syndrome (DIHS), which is a life-threatening drug reaction. Delayed diagnosis of DIHS may occur in complicated clinical settings. We have reported a case of a 12-year-old girl whose initial manifestations of CBZ-induced DIHS were atypical due to concurrent administration of corticosteroids. After open biopsy of brainstem glioma, she was administered corticosteroids and CBZ to mitigate postoperative complications, including mild weakness of ankle dorsiflexion and otalgia. Not only fever but also elevation of liver enzymes and inflammatory markers were presented 1 month after CBZ initiation, without any skin rash or leukocytosis. A maculopapular rash on the whole body and leukocytosis developed afterward; consequently, the diagnostic criteria for DIHS were fulfilled. After discontinuation of CBZ, her fever and increased liver enzymes subsided and the rash slowly improved. This case indicates that typical signs, such as skin rash or leukocytosis, can be initially masked or delayed in CBZ-induced DIHS if it overlaps with corticosteroid administration. The atypical manifestations of DIHS should be considered if CBZ is concurrently administered with corticosteroids.

Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum Persistence Exhibits Excellent Antitumor Potency.

Endothelin receptor A (ETA), a class A G protein-coupled receptor (GPCR), is a promising tumor-associated antigen due to its close association with the progression and metastasis of many types of cancer, such as colorectal, breast, lung, ovarian, and prostate cancer. However, only small-molecule drugs have been developed as ETA antagonists with anticancer effects. In a previous study, we identified an antibody (AG8) with highly selective binding to human ETA through screening of a human naïve immune antibody library. Although both in vitro and in vivo experiments indicated that the identified AG8 had anticancer effects, there is a need for improvement in biochemical and physicochemical properties such as the ETA binding affinity, thermostability, and productivity. In this study, we engineered the framework regions of AG8 and isolated an anti-ETA antibody (MJF1) exhibiting significantly improved thermostability and ETA binding affinity. Subsequently, our previously isolated PFc29, an Fc variant with an enhanced pH-dependent human FcRn binding profile, was introduced to MJF1, and the resulting Fc-engineered anti-ETA antibody (MJF1-PFc29) inhibited the proliferation of tumor cells comparably to MJF1 and showed a 4.2-fold increased serum half-life in human FcRn transgenic mice. Moreover, MJF1-PFc29 elicited higher tumor growth inhibition in colorectal cancer xenograft mice compared to MJF1. Our results demonstrate that the engineered human anti-ETA antibody MJF1-PFc29 has great therapeutic potential and high antitumor potency against various types of cancers including colorectal cancer.

Exploratory Investigation of the Effects of Tactile Stimulation Using Air Pressure at the Auricular Vagus Nerve on Heart Rate Variability

Objective@#To explore the effects of tactile stimulation using air pressure at the auricular branch of the vagus nerve on autonomic activity in healthy individuals. @*Methods@#Three types of tactile stimulation were used in this study: continuous low-amplitude, continuous high-amplitude, and pulsed airflow. The tactile stimulations were provided to the cymba concha to investigate autonomic activity in 22 healthy participants. The mean heart rate (HR) and parameters of HR variability, including the standard deviation of R-R intervals (SDNN) and root mean square of successive R-R interval differences (RMSSD) were compared at baseline, stimulation, and recovery periods. @*Results@#Two-way repeated measures ANOVA indicated a significant main effect of time on HR (p=0.001), SDNN (p=0.003), and RMSSD (p<0.001). These parameters showed significant differences between baseline and stimulation periods and baseline and recovery periods in the post-hoc analyses. There were no significant differences in the changes induced by stimulation type and the interaction between time and stimulation type for all parameters. One-way repeated measures ANOVA showed that HR, SDNN, and RMSSD did not differ significantly among the three time periods during sham stimulation. @*Conclusion@#Parasympathetic activity can be enhanced by auricular tactile stimulation using air pressure, targeting the cymba concha. Further studies are warranted to investigate the optimal stimulation parameters for potential clinical significance.