Multifunctional Pt3Rh-Co3O4 alloy nanoparticles with Pt-enriched surface and induced synergistic effect for improved performance in ORR, OER, and HER.

Engineering high-performance electrocatalysts to improve the kinetics of parallel electrochemical reactions in low-temperature fuel cells, water splitting, and metal-air battery applications is important and inevitable. In this study, by employing a chemical co-reduction method, we developed multifunctional Pt3Rh-Co3O4 alloy with uniformly distributed ultrafine nanoparticles (2-3 nm), supported on carbon. The presence of Co3O4 and the incorporation of Rh led to a strong electronic and ligand effect in the Pt lattice environment, which caused the d-band center of Pt to shift. This shift improved the electrocatalytic performance of Pt3Rh-Co3O4 alloy. When Pt3Rh-Co3O4/C was used to catalyze the oxygen reduction reaction (E1/2: 0.75 V), oxygen evolution reaction (η10: 290 mV), and hydrogen evolution reaction (η10: 55 mV), it showed greater endurance (mass activity loss of only 7%-17%) than Pt-Co3O4/C and Pt/C catalysts up to 5000 potential cycles in perchloric acid. Overall, the as-prepared Pt3Rh-Co3O4/C showed high multifunctional electrocatalytic potency, as demonstrated by typical electrochemical studies, and its physicochemical properties endorse their extended performance for a wide range of energy storage and conversion applications.

The Anti-Inflammatory Activities of Fermented Curcuma That Contains Butyrate Mitigate DSS-Induced Colitis in Mice.

Inflammatory bowel disease is characterized by a radical imbalance of inflammatory signaling pathways in the gastrointestinal tract, and it is categorized into two diseases, such as Crohn's disease and ulcerative colitis. In this study, we investigated anti-inflammatory activities using fermented Curcuma that contains butyrate (FB). Nitric oxide production in RAW 264.7 cells and the expression of inducible nitric oxide synthase in the intestinal mucosa appears to be enhanced in active ulcerative colitis. Here, the cytotoxicity, physiological activity, and anti-inflammatory efficacy of FB in colitis animals were investigated. To verify the anti-inflammatory effect, this study was conducted using the dextran sulfate sodium (DSS)-induced colitis mice model. As a result, non-toxicity was confirmed, and anti-inflammatory effects were revealed by inducing a reduction of LPS-induced NO production. In the DSS-induced colitis, reduced weight was recovered and a decrease in inflammatory factors Ig-E and TNF-α in the mesenteric lymph node (MLN) and spleen was induced, and it was confirmed to help with the morphological remodeling of the intestine. In conclusion, this paper suggests that FB can help to alleviate intestinal inflammation and to improve the intestinal environment, with the help of morphological remodeling.

Abnormal gene expression in regular and aggregated somatic cell nuclear transfer placentas.

BACKGROUND: Placental defects in somatic cell nuclear transfer (SCNT) are a major cause of complications during pregnancy. One of the most critical factors for the success of SCNT is the successful epigenetic reprogramming of donor cells. Recently, it was reported that the placental weight in mice cloned with the aggregated SCNT method was significantly reduced. Here, we examine the profile of abnormal gene expression using microarray technology in both regular SCNT and aggregated SCNT placentas as well as in vivo fertilization placentas. One SCNT embryo was aggregated with two 2 to 4 -cell stage tetraploid embryos from B6D2F1 mice (C57BL/6 × DBA/2). RESULTS: In SCNT placentas, 206 (1.6%) of the 12,816 genes probed were either up-regulated or down-regulated by more than two-fold. However, 52 genes (0.4%) showed differential expression in aggregated SCNT placentas compared to that in controls. In comparison of both types of SCNT placentas with the controls, 33 (92%) out of 36 genes were found to be up-regulated (>2-fold) in SCNT placentas. Among 36 genes, 13 (36%) genes were up-regulated in the aggregated SCNT placentas. Eighty-five genes were down-regulated in SCNT placentas compared with the controls. However, only 9 (about 10.5%) genes were down-regulated in the aggregated SCNT placentas. Of the 34 genes known as imprinted genes, expression was lower in SCNT placentas than that in the controls. Thus, these genes may be the cause of placentomegaly in mice produced post SCNT. CONCLUSIONS: These results suggest that placentomegaly in the SCNT placentas was probably caused by abnormal expression of multiple genes. Taken together, these results suggest that abnormal gene expression in cloned placentas was reduced in a genome-wide manner using the aggregation method with tetraploid embryos.

Production and characterization of monoclonal antibodies against recombinant tethered follicle-stimulating hormone from Japanese eel Anguilla japonica.

We prepared monoclonal antibodies (mAbs) against a recombinant tethered follicle-stimulating hormone (rec-FSH) from Japanese eel Anguilla japonica that was produced in Escherichia coli. Positive hybridomas (clones eFA-C5, eFA-C10, eFA-C11, eFA-C12, eFA-C13, and eFB-C14) were selected by using the eel FSH antigen in ELISA, and anti-eel FSH mAbs were purified from culture supernatants by performing affinity chromatography. Three of the 6mAbs were characterized and their isotypes were identified as IgG2b (eFA-C5 and eFA-C11) and IgG1 (eFB-C14). In western blotting assays, the mAbs recognized the antigen as a 24.3-kDa band, and further detected bands of 34 and 32kDa in the supernatants of CHO cells transfected with cDNA encoding tethered eel FSHß/α and LHß/α, respectively. PNase F-mediated deglycosylation of the recombinant proteins resulted in a drastic reduction in their molecular weight, to 7-9kDa. The mAbs eFA-C5 and eFA-C11 recognized the eel FSHα-subunit that is commonly encoded among glycoprotein hormones, whereas eFB-C14 recognized the eel FSHß-subunit, and immunohistochemical analysis revealed that the staining by these mAbs was specifically localized in the eel pituitary. We also established an ELISA system for detecting rec-tethered FSHß/α and LHß/α produced from CHO cell lines. Measurement of biological activities in vitro revealed that only weak activity of rec-FSHß/α was detected. The activity of rec-LHß/α was found to be increased in a dose-dependent manner for eel oocyte maturation.

GRK5-Knockout Mice Generated by TALEN-Mediated Gene Targeting.

Transcription activator-like effector nucleases (TALENs) are a new type of engineered nuclease that is very effective for directed gene disruption in any genome sequence. We investigated the generation of mice with genetic knockout (KO) of the G protein-coupled receptor kinase (GRK) 5 gene by microinjection of TALEN mRNA. TALEN vectors were designed to target exons 1, 3, and 5 of the mouse GRK5 gene. Flow cytometry showed that the activity of the TALEN mRNAs targeted to exons 1, 3, and 5 was 8.7%, 9.7%, and 12.7%, respectively. The TALEN mRNA for exon 5 was injected into the cytoplasm of 180 one-cell embryos. Of the 53 newborns, three (5.6%) were mutant founders (F0) with mutations. Two clones from F028 showed a 45-bp deletion and F039 showed the same biallelic non-frame-shifting 3-bp deletions. Three clones from F041 were shown to possess a combination of frame-shifting 2-bp deletions. All of the mutations were transmitted through the germline but not to all progenies (37.5%, 37.5%, and 57.1% for the F028, F039, and F041 lines, respectively). The homozygote GRK5-KO mice for 28 and 41 lines created on F3 progenies and the homozygous genotype was confirmed by PCR, T7E1 assay and sequencing.

Secretion of human protein C in mouse milk.

To determine the production of recombinant human protein C (rec-hPC) in milk, we created two homozygous mice lines for the goat ß-casein/hPC transgene. Females and males of both lines (#10 and #11) displayed normal growth, fertility, and lactated normally. The copy number of the transgene was about fivefold higher in #10 line as compared to #11 line. mRNA expression of the transgene was only detected in the mammary glands of both lines. Furthermore, mRNA expression was fourfold higher on day 7 than on day 1 during lactation. Northern blot analysis of mRNA expression in the #10 line of transgenic (Tg) mice indicated a strong expression of the transgene in the mammary glands after seven days of lactation. Comparison of rec-hPC protein level with that of mRNA in the mammary glands showed a very similar pattern. A 52-kDa band corresponding to the hPC protein was strongly detected in mammary glands of the #10 line during lactation. We also detected two bands of heavy chain and one weak band of light chain in the milk of the #10 and #11 lines. One single band at 52 kDa was detected from CHO cells transfected with hPC cDNA. hPC was mainly localized in the alveolar epithelial cell of the mammary glands. The protein is strongly expressed in the cytoplasm of the cultured mammary gland tissue. hPC protein produced in milk ranged from 2 to 28 ng/mL. These experiments indicated that rec-hPC can be produced at high levels in mice mammary glands.

Atto-Scale Noise Near-Infrared Organic Photodetectors Enabled by Controlling Interfacial Energetic Offset through Enhanced Anchoring Ability.

The near-infrared (NIR) sensor technology is crucial for various applications such as autonomous driving and biometric tracking. Silicon photodetectors (SiPDs) are widely used in NIR applications; however, their scalability is limited by their crystalline properties. Organic photodetectors (OPDs) have attracted attention for NIR applications owing to their scalability, low-temperature processing, and notably low dark current density (JD), which is similar to that of SiPDs. However, the still high JD (at NIR band) and few measurements of noise equivalent powers (NEPs) pose challenges for accurate performance comparisons. This study addresses these issues by quantitatively characterizing the performance matrix and JD generation mechanism using electron-blocking layers (EBLs) in OPDs. The energy offset at an EBL/photosensitive layer interface determines the thermal activation energy and directly affects JD. A newly synthesized EBL (3PAFBr) substantially enhances the interfacial energy barrier by forming a homogeneous contact owing to the improved anchoring ability of 3PAFBr. As a result, the OPD with 3PAFBr yields a noise current of 852 aA (JD = 12.3 fA cm⁻2 at V → -0.1 V) and several femtowatt-scale NEPs. As far as it is known, this is an ultralow of JD in NIR OPDs. This emphasizes the necessity for quantitative performance characterization.

Sodium butyrate ameliorates neurotoxicity and exerts anti-inflammatory effects in high fat diet-fed mice.

The prevalence of high-fat diet consumption-related disorders is increasing, and it is often associated with oxidative stress, inflammation, and dysregulation in the brain may lead to neurodegenerative diseases (NDDs). Our study aims to evaluate the neuroprotective effects of sodium butyrate (NaB) on HFD-fed mice. In this study, four-week-old male C57Bl/6NTac mice were divided into three groups; the control group, the HFD group, and the HFD + NaB group where mice received 11 mg/kg body weight of NaB with HFD. Western blotting, reverse transcription-PCR, and ELISA were used for biochemical analysis of brain specimens. We found that NaB restored bodyweight and attenuated P-53, Bcl-2-associated X protein (BAX), and caspase cascades in the brains of HFD-fed mice. In addition. NaB reduced the expressions of proinflammatory cytokines and positively modulated antioxidant biomarkers. NaB treatment upregulated the expression of the growth factor-related factors PPARγ, CREB, and BDNF in the brain tissues of HFD-fed mice. Furthermore, we found that NaB significantly ameliorated glucocorticoid receptor and NLRP3 inflammasome expression. Based on our findings, NaB suppressed apoptotic and inflammatory cytokines and enhanced the expression of endogenous antioxidants in brain tissues of HFD-fed mice. Our data strongly suggests that NaB could be utilized as an effective therapeutic agent for NDDs.

Quantification of physical stress experienced by obstetrics and gynecology sonographers: A comparative study of two ultrasound devices.

This study aims to quantify the stresses of sonographers using two different ultrasound devices, one of conventional and one of ergonomic design. A total of 20 obstetricians and gynecologists participated in this study, and two types of tasks (scanning and positioning) were evaluated while using the two different devices. To quantify workload, four dependent variables (muscle activity, estimated grip force, subjective comfort rating, and task time) were measured. The muscular activity required while using the conventional device was 14.4% MVC (Maximum voluntary contraction) for the scanning task, which was significantly higher than that of the ergonomic device. The subjective comfort rating for the conventional design was lower than that of the ergonomic design. For the positioning task, the ergonomic device (33.2% MVC) resulted in significantly higher muscle activity in the extensor digitorum (ED) and flexor digitorum superficialis (FDS) than the conventional design (22.2% MVC), whereas the deltoid muscle showed significantly lower activity than in users of conventional design (4.5% MVC). Ergonomically-designed ultrasound devices improve ease of moving and the probe's supporters, reduce physical load and increase ease of use for sonographers. Our results may be used as guidelines for usability testing of ultrasound devices.

SKI-G-801, an AXL kinase inhibitor, blocks metastasis through inducing anti-tumor immune responses and potentiates anti-PD-1 therapy in mouse cancer models.

OBJECTIVES: AXL-mediated activation of aberrant tyrosine kinase drives various oncogenic processes and facilitates an immunosuppressive microenvironment. We evaluated the anti-tumor and anti-metastatic activities of SKI-G-801, a small-molecule inhibitor of AXL, alone and in combination with anti-PD-1 therapy. METHODS: In vitro pAXL inhibition by SKI-G-801 was performed in both human and mouse cancer cell lines. Immunocompetent mouse models of tumor were established to measure anti-metastatic potential of SKI-G-801. Furthermore, SKI-G-801, anti-PD-1 or their combination was administered as an adjuvant or neoadjuvant in the 4T1 tumor model to assess their potential for clinical application. RESULTS: SKI-G-801 robustly inhibited pAXL expression in various cell lines. SKI-G-801 alone or in combination with anti-PD-1 potently inhibited metastasis in B16F10 melanoma, CT26 colon and 4T1 breast models. SKI-G-801 inhibited the growth of B16F10 and 4T1 tumor-bearing mice but not immune-deficient mice. An antibody depletion assay revealed that CD8+ T cells significantly contributed to SKI-G-801-mediated survival. Anti-PD-1 and combination group were observed the increased CD8+Ki67+ and effector T cells and M1 macrophage and decreased M2 macrophage, and granulocytic myeloid-derived suppressor cell (G-MDSC) compared to the control group. The neoadjuvant combination of SKI-G-801 and anti-PD-1 therapy achieved superior survival benefits by inducing more profound T-cell responses in the 4T1 syngeneic mouse model. CONCLUSION: SKI-G-801 significantly suppressed tumor metastasis and growth by enhancing anti-tumor immune responses. Our results suggest that SKI-G-801 has the potential to overcome anti-PD-1 therapy resistance and allow more patients to benefit from anti-PD-1 therapy.

Guidelines for Working Heights of the Lower-Limb Exoskeleton (CEX) Based on Ergonomic Evaluations.

The aim of this study was to evaluate the muscle activities and subjective discomfort according to the heights of tasks and the lower-limb exoskeleton CEX (Chairless EXoskeleton), which is a chair-type passive exoskeleton. Twenty healthy subjects (thirteen males and seven females) participated in this experiment. The independent variables were wearing of the exoskeleton (w/ CEX, w/o CEX), working height (6 levels: 40, 60, 80, 100, 120, and 140 cm), and muscle type (8 levels: upper trapezius (UT), erector spinae (ES), middle deltoid (MD), triceps brachii (TB), biceps brachii (BB), biceps femoris (BF), rectus femoris (RF), and tibialis anterior (TA)). The dependent variables were EMG activity (% MVC) and subjective discomfort rating. When wearing the CEX, the UT, ES, RF, and TA showed lower muscle activities at low working heights (40-80 cm) than not wearing the CEX, whereas those muscles showed higher muscle activities at high working heights (100-140 cm). Use of the CEX had a positive effect on subjective discomfort rating at lower working heights. Generally, lower discomfort was reported at working heights below 100 cm when using the CEX. At working heights of 100-140 cm, the muscle activity when wearing the CEX tended to be greater than when not wearing it. Thus, considering the results of this study, the use of the lower-limb exoskeleton (CEX) at a working height of 40-100 cm might reduce the muscle activity and discomfort of whole body and decrease the risk of related disorders.

A Comparison Study of Posture and Fatigue of Neck According to Monitor Types (Moving and Fixed Monitor) by Using Flexion Relaxation Phenomenon (FRP) and Craniovertebral Angle (CVA).

This study quantified the neck posture and fatigue using the flexion relaxation phenomenon (FRP) and craniovertebral angle (CVA); further, it compared the difference between the level of fatigue and neck posture induced by two types of monitors (regular fixed monitor and moving monitor). Twenty-three male participants were classified into two groups-the low-flexion relaxation ratio (FRR) group and the normal-FRR group, depending on the FRR value. All participants performed a document task for 50 min using both types of monitors. It was found that the FRR values significantly decreased after the documentation task. The CVA analysis showed that the moving monitor's frequency of forward head posture (FHP) was lower than that for the fixed monitor. Overall, the moving monitor worked better than the fixed monitor; this can be interpreted as proof that such monitors can reduce neck fatigue.

Application of AULA Risk Assessment Tool by Comparison with Other Ergonomic Risk Assessment Tools.

Agricultural upper limb assessment (AULA), which was developed for evaluating upper limb body postures, was compared with the existing assessment tools such as rapid upper limb assessment (RULA), rapid entire body assessment (REBA), and ovako working posture analysis system (OWAS) based on the results of experts' assessments of 196 farm tasks in this study. The expert group consisted of ergonomists, industrial medicine experts, and agricultural experts. As a result of the hit rate analysis, the hit rate (average: 48.6%) of AULA was significantly higher than those of the other assessment tools (RULA: 33.3%, REBA: 30.1%, and OWAS: 34.4%). The quadratic weighted kappa analysis also showed that the kappa value (0.718) of AULA was significantly higher than those of the other assessment tools (0.599, 0.578, and 0.538 for RULA, REBA, and OWAS, respectively). Based on the results, AULA showed a better agreement with expert evaluation results than other evaluation tools. In general, other assessment tools tended to underestimate the risk of upper limb posture in this study. AULA would be an appropriate evaluation tool to assess the risk of various upper limb postures.

Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in ALK-positive non-small-cell lung cancer.

BACKGROUND: EML4-ALK is a distinct molecular entity that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) have not proved efficacy in ALK-positive non-small cell lung cancer so far. In this study, we performed a mouse clinical trial using EML4-ALK transgenic mice model to comprehensively investigate immunomodulatory effects of ALK TKI and to investigate the mechanisms of resistance to ICIs. METHODS: EML4-ALK transgenic mice were randomized to three treatment arms (arm A: antiprogrammed death cell protein-1 (PD-1), arm B: ceritinib, arm C: anti-PD-1 and ceritinib), and tumor response was evaluated using MRI. Progression-free survival and overall survival were measured to compare the efficacy. Flow cytometry, multispectral imaging, whole exome sequencing and RNA sequencing were performed from tumors obtained before and after drug resistance. RESULTS: Mouse clinical trial revealed that anti-PD-1 therapy was ineffective, and the efficacy of ceritinib and anti-PD-1 combination was not more effective than ceritinib alone in the first line. Dynamic changes in immune cells and cytokines were observed following each treatment, while changes in T lymphocytes were not prominent. A closer look at the tumor immune microenvironment before and after ceritinib resistance revealed increased regulatory T cells and programmed death-ligand 1 (PD-L1)-expressing cells both in the tumor and the stroma. Despite the increase of PD-L1 expression, these findings were not accompanied by increased effector T cells which mediate antitumor immune responses. CONCLUSIONS: ALK-positive tumors progressing on ceritinib is not immunogenic enough to respond to immune checkpoint inhibitors.

Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC.

EGFR exon 20 insertion driver mutations (Exon20ins) in non-small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR-MET, has shown preclinical activity in TKI-sensitive EGFR-mutated NSCLC models and in an ongoing first-in-human study in patients with advanced NSCLC. However, the activity of amivantamab in Exon20ins-driven tumors has not yet been described. Ba/F3 cells and patient-derived cells/organoids/xenograft models harboring diverse Exon20ins were used to characterize the antitumor mechanism of amivantamab. Amivantamab inhibited proliferation by effectively downmodulating EGFR-MET levels and inducing immune-directed antitumor activity with increased IFNγ secretion in various models. Importantly, in vivo efficacy of amivantamab was superior to cetuximab or poziotinib, an experimental Exon20ins-targeted TKI. Amivantamab produced robust tumor responses in two Exon20ins patients, highlighting the important translational nature of this preclinical work. These findings provide mechanistic insight into the activity of amivantamab and support its continued clinical development in Exon20ins patients, an area of high unmet medical need. SIGNIFICANCE: Currently, there are no approved targeted therapies for EGFR Exon20ins-driven NSCLC. Preclinical data shown here, together with promising clinical activity in an ongoing phase I study, strongly support further clinical investigation of amivantamab in EGFR Exon20ins-driven NSCLC.This article is highlighted in the In This Issue feature, p. 1079.

Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer.

PURPOSE: Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1+ patient-derived preclinical models. EXPERIMENTAL DESIGN: Antitumor activity of repotrectinib was evaluated in ROS1+ patient-derived preclinical models including treatment-naïve and ROS1G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model. RESULTS: Repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent in vitro and in vivo activity against ROS1G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial. CONCLUSIONS: Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.

Exploring novel single nucleotide polymorphisms and haplotypes of the diacylglycerol O-acyltransferase 1 (DGAT1) gene and their effects on protein structure in Iranian buffalo.

BACKGROUND: Diacylglycerol O-acyltransferase 1 (DGAT1) plays a key role in the synthesis of triglycerides. Recent studies have shown that a transition mutation resulting in substitutions of guanine by adenine in the DGAT1 gene in cattle has considerable effects on milk yield and composition. Currently, there is no systematic research reporting on the utilization of this gene segment in Iranian buffalo (Bubalus bubalis). OBJECTIVE: In this study, the genetic differentiation of three indigenous Iranian buffalo populations was investigated in the region spanning exon 3 to exon 17 of the DGAT1 gene. METHODS: A total of 200 buffaloes were genotyped, all the samples were sequenced directly in both directions with forward and reverse sequencing primers. RESULTS: Sequence analysis showed novel SNPs compared to the reference GenBank sequence (DQ886485) at nucleotide positions g.6097A>G, g.7036C>T, g.7338G>A, g.7710C>T, g.8087C>T, g.8259G>A, g.8275G>A, g.8367C>T, and g.8426C>T. No polymorphisms were found within exon 8. Therefore, the K232A position was thought to be a conserved and fixed region for high milk fat content (K allele) in Bos indicus and all buffalo breeds. Comparison with Indian buffalo revealed three exonic SNPs, one of which was nonsynonymous. A unique 22 bp insertion was observed in intron 10 of DGAT1. Linkage disequilibrium analysis allowed the identification of nine haplotypes among the sampled animals. To our knowledge, this is the first report of sequencing analysis of the DGAT1 gene in Iranian buffalo. CONCLUSION: Our results suggest that genetic diversity exists and could be useful in examining the association between the DGAT1 gene and milk production traits in buffalo.

Evaluation of subjective perceived rating for grip strength depending on handedness for various target force levels.

BACKGROUND: Measurement of hand exertion is very important to quantify the risk of Work-related Musculoskeletal Disorders (WMSDs) in manufacturing fields. Although a direct measurement is the most accurate way to quantify physical load, it is expensive and time consuming. To solve this limitation, a subjective self-report method has been proposed as a possible alternative. OBJECTIVE: The purpose of this study was to analyze the accuracy of subjective perception for grip force exertions associated with handedness (dominant and non-dominant hands). METHODS: A total of nine healthy adults participated in this study. All participants were asked to exert hand grip forces for randomly selected target force levels without any information about the actual target force levels. Then, participants were also asked to rate the subjective perception of their exertion level using % Maximum Voluntary Contraction (MVC) after each hand grip force exertion. RESULTS: The trend of subjective perception for various target force levels was different according to the handedness. In the case of the dominant hand, participants tend to rate less MVC levels (under-estimation) than the actual target force levels at lower than 50% MVC, whereas they tend to rate more MVC levels (over-estimation) than the actual target force levels at higher than 50% MVC, respectively. In case of non-dominant hand, generally participants showed over-estimate for all levels of MVCs in this study. CONCLUSIONS: According to the results of this study, subjective perception of exertion showed different patterns on the handedness (S-shape for dominant hand vs. over-estimation for non-dominant hand) for various target force levels. Therefore, it would be necessary to apply different criteria for each hand to evaluate subjective perception of hand grip exertion tasks.

Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma.

Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer.

PURPOSE: Given that osimertinib is the only approved third-generation EGFR-TKI against EGFR activating and resistant T790M mutated non-small cell lung cancer (NSCLC), additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models. EXPERIMENTAL DESIGN: Antitumor activity of YH25448 was investigated in vitro using mutant EGFR-expressing Ba/F3 cells and various lung cancer cell lines. In vivo antitumor efficacy, ability to penetrate the blood-brain barrier (BBB), and skin toxicity of YH25448 were examined and compared with those of osimertinib using cell lines and PDX model. RESULTS: Compared with osimertinib, YH25448 showed a higher selectivity and potency in kinase assay and mutant EGFR-expressing Ba/F3 cells. In various cell line models harboring EGFR activating and T790M mutation, YH25448 effectively inhibited EGFR downstream signaling pathways, leading to cellular apoptosis. When compared in vivo at equimolar concentrations, YH25448 produced significantly better tumor regression than osimertinib. Importantly, YH25448 induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. YH25448 rarely suppressed the levels of p-EGFR in hair follicles, leading to less keratosis than osimertinib in animal model. The potent systemic and intracranial activity of YH25448 has been shown in an ongoing phase I/II clinical trial for advanced EGFR T790M mutated NSCLC (NCT03046992). CONCLUSIONS: Our findings suggest that YH25448 is a promising third-generation EGFR inhibitor, which may be more effective and better tolerated than the currently approved osimertinib.