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Targeting mutated EGFR is a clinically validated approach for tackling non-small cell lung cancer (NSCLC). Approximately 20% of patients with advanced NSCLC harbor an EGFR mutation. Osimertinib is a 3rd-generation oral EGFR-TKI targeting the EGFR sensitizing mutations Del19 and L858R, as well as an acquired mutation, T790M. Despite osimertinib's efficacy in NSCLC, resistance develops and the mechanisms of resistance to osimertinib are complex. Development of another mutation, C797S is the most common mechanism of acquired resistance following osimertinib treatment. This mutation occurs with about 12% frequency after a 1L therapy of osimertinib, and with approximately 17% frequency after a 2L therapy. Here, we report TRX-221 as a novel 4th-generation EGFR-TKI that can overcome C797S-mediated acquired resistance in NSCLC models in vitro and in vivo. TRX-221 exhibited potent inhibitory activity against multiple EGFR mutant kinases, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, L858R/C797S, Del19/T790M, L858R/T790M, Del19, and L858R. Likewise, TRX-221 potently inhibited the proliferation of Ba/F3 cells stably overexpressing these eight EGFR mutants. TRX-221 however showed sparing activity against EGFR wild-type kinase and cell lines. TRX-221 also demonstrated marked anti-proliferative activity against osimertinib-resistant patient-derived cancer cell lines (PDCs). With favorable DMPK profiles, once-daily oral dosing of TRX-221 induced strong anti-tumor effects in a dose-dependent manner in a variety of osimertinib-resistant CDX and PDX models. As a reversible, selective, and broad-spectrum 4th-generation EGFR-TKI, TRX-221 is currently undergoing IND-enabling studies and shows strong potential as a therapeutic solution to treat advanced NSCLC patients harboring EGFR mutations. Citation Format: Sumin Lim, Seulgi Choi, Ju-Kyung Lee, Eunhyun Choi, Sungwon Lee, Kwangwoo Chun, Myoungki Baek, Jiyeon Park, Jihyun Kim, Areum Kang, Younghoon Kim, Namkyoung Kim, Byoungchul Cho, Taebo Sim, Koo Lee. TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4006.

Dwarfism in crops is a useful breeding trait. In this study, we aimed to identify a candidate gene controlling semi-dwarfism in watermelon (Citrullus lanatus) using a combination of genetic mapping and quantitative trait loci (QTL)-seq. We evaluated phenotypes using an F2 and F2:3 population derived from a cross between a “Bush Sugar Baby” (BSB, semi-dwarf type) and a PCL-J1 (normal type) cultivar. Results indicated that a single recessive gene confers semi-dwarfism in BSB. We constructed a genetic map using 180 F2 plants and 336 single-nucleotide polymorphisms (SNPs), detected using genotyping-by-sequencing, and mapped the semi-dwarfism locus, sdw-1, between the SNP markers linked by 9.6 cM (0.99 Mb) on Chr. 9. QTL analysis pointed to the same genomic location for sdw-1 using single-marker analysis. Further, based on the QTL-seq, we identified a significant genomic region for sdw-1 that matched with the sdw-1-flanking region in the genetic linkage map. This 1-Mb region was narrowed down by mapping three SNP markers developed from the QTL-seq data. The sdw-1 locus was mapped to the 0.44-Mb genomic region, which harbored 13 genes. One of the 13 genes, ClCG09G018320 (ATP-binding cassette (ABC) transporter B family member 19), showed the SNPs in its coding sequence, and cleaved amplified APS markers developed from those SNPs co-segregated with sdw-1 in fine mapping using 620 F2 plants. Our results implied that a frameshift mutation in the ABC transporter gene and the resulting alteration in auxin transportation are the most likely to be responsible for semi-dwarfism in BSB.

Cell identity is determined by the transcriptional regulation of a cell-type-specific gene group. The Paf1 complex (Paf1C), an RNA polymerase II-associating factor, is an important transcriptional regulator that not only participates in transcription elongation and termination but also affects transcription-coupled histone modifications and chromatin organisation. Recent studies have shown that Paf1C is involved in the expression of genes required for self-renewal and pluripotency in stem cells and tumorigenesis. In this review, we focused on the role of Paf1C as a critical transcriptional regulator in cell fate decisions. Paf1C affects the pluripotency of stem cells by regulating the expression of core transcription factors such as Oct4 and Nanog. In addition, Paf1C directly binds to the promoters or distant elements of target genes, thereby maintaining the pluripotency in embryonic stem cells derived from an early stage of the mammalian embryo. Paf1C is upregulated in cancer stem cells, as compared with that in cancer cells, suggesting that Paf1C may be a target for cancer therapy. Interestingly, Paf1C is involved in multiple developmental stages in Drosophila, zebrafish, mice and even humans, thereby displaying a trend for the correlation between Paf1C and cell fate. Thus, we propose that Paf1C is a critical contributor to cell differentiation, cell specification and its characteristics and could be employed as a therapeutic target in developmental diseases.

Many heterologous proteins can be secreted by bacterial ATP-binding cassette (ABC) transporters, provided that they are fused with the C-terminal signal sequence, but some proteins are not secretable even though they carry the right signal sequence. The invention of a method to secrete these non-secretable proteins would be valuable both for understanding the secretory physiology of ABC transporters and for industrial applications. Herein, we postulate that cationic “supercharged” regions within the target substrate protein block the secretion by ABC transporters. We also suggest that the secretion of such substrate proteins can be rescued by neutralizing those cationic supercharged regions via structure-preserving point mutageneses. Surface-protruding, non-structural cationic amino acids within the cationic supercharged regions were replaced by anionic or neutral hydrophilic amino acids, reducing the cationic charge density. The examples of rescued secretions we provide include the spike protein of SARS-CoV-2, glutathione-S-transferase, streptavidin, lipase, tyrosinase, cutinase, growth factors, etc. In summary, our study provides a method to predict the secretability and a tool to rescue the secretion by correcting the secretion-blocking regions, making a significant step in understanding the physiological properties of ABC transporter-dependent protein secretion and laying the foundation for the development of a secretion-based protein-producing platform.

Within the Southern Ocean, the greatest warming is occurring on the Antarctic Peninsula (AP) where clear cryospheric and biological consequences are being observed. Antarctic coastal systems harbour a high diversity of marine and terrestrial ecosystems heavily influenced by Antarctic seaweeds (benthonic macroalgae) and bird colonies (mainly penguins). Primary sea spray aerosols (SSA) formed by the outburst of bubbles via the sea-surface microlayer depend on the organic composition of the sea water surface. In order to gain insight into the influence of ocean biology and bio-geochemistry on atmospheric aerosol, we performed in situ laboratory aerosol bubble chamber experiments to study the effect of different leachates of biogenic material - obtained from common Antarctic seaweeds as well as penguin guano - on primary SSA. The addition of different leachate materials on a seawater sample showed a dichotomous effect depending on the leachate material added - either suppressing (up to 52%) or enhancing (22–88%) aerosol particle production. We found high ice nucleating particle number concentrations resulting from addition of guano leachate material. Given the evolution of upper marine polar coastal ecosystems in the AP, further studies on ocean-atmosphere coupling are needed in order to represent the currently poorly understood climate feedback processes., The study was further supported by the Spanish Ministry of Economy through project PI-ICE (no. CTM 2017–89117-R) and the Ramon y Cajal fellowship (no. RYC-2012-11922). This work acknowledges the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S). The National Centre for Atmospheric Science (NCAS) Birmingham group is funded by the UK Natural Environment Research Council. We gratefully acknowledge the funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Projektnummer 268020496–TRR 172) within the Transregional Collaborative Research Center “ArctiC Amplification: Climate Relevant Atmospheric and SurfaCe Processes, and Feedback Mechanisms (AC)3” in subproject B04.

The generation of a mesoporous structure in platinum nanoparticles can effectively enhance physical and chemical properties. In this study, mesoporous platinum nanoparticles (MPNs) were synthesized by a soft template-mediated one-pot chemical method. To develop a mesoporous structure, Pluronic F-127 was employed. The Pluronic F-127 surfactant forms self-assembled micelles, and the micelles act as the pore-directing agents in the synthesis of nanoparticles. Scanning electron microscopy results revealed that the MPN had a uniform size of 70 nm on average and a distinct mesoporous structure. The development of a concave mesoporous structure on the surface of the MPNs can increase the surface area and facilitate the efficient transport of reactants. The synthesized MPNs exhibited peroxidase-like activity. Furthermore, the MPNs showed excellent catalytic efficiency compared to HRP, due to the high surface area derived from the presence of the mesoporous structure. The peroxidase-like MPNs were applied to the enzyme-linked immunosorbent assay (ELISA) of C-reactive protein (CRP). The MPN-based ELISA exhibited sensitive CRP detection in the range from 0.24 to 7.8 ng/mL with a detection limit of 0.13 ng/mL. Moreover, the recoveries of the CRP concentrations in spiked human serum were 98.6% and 102%. These results demonstrate that as a peroxidase mimic, the MPNs can replace the natural enzymes in conventional ELISA for sensitive CRP detection.

Whether subjects with NAFLD are at increased risk of sarcopenia is not well established.This is a cohort study of 52,815 men and women of 20 years of age or older who underwent at least two health check-up exams with bioelectrical impedance analysis and abdominal ultrasound imaging. Bioelectrical impedance analysis was used to calculate appendicular skeletal muscle mass (ASM). NAFLD was assessed by ultrasonography, and its severity was assessed by the NAFLD fibrosis score (NFS). We estimated the 5-year change in ASM comparing participants with and without NAFLD at baseline using mixed linear models. The 5-year change in ASM in participants without and with NAFLD was -225.2 g (95% CI -232.3, -218.0) and -281.3 g (95% CI -292.0, -270.6), respectively (p 0.001). In multivariable adjusted analysis, the difference in 5-year change in ASM comparing participants with and without NAFLD was -39.9 g (95% CI -53.1, -26.8). When participants with NAFLD were further divided by NAFLD severity, ASM loss was much faster in participants with NAFLD with intermediate to high NFS than in those with low NFS.Participants with NAFLD were at increased risk of sarcopenia, indicated by faster loss of skeletal muscle mass. Patients with NAFLD may need screening and early intervention to mitigate skeletal muscle mass loss.

The purpose of this study is to present a review of instruments developed to measure perceptions of special educators regarding their competencies and to provide a synthesis of research studies using these measurement instruments. A total of 29 studies were included in this review, and 20 instruments were used across the studies. The results were as follows. First, the majority of the instruments in this review were designed for assessing in‐service special educators. Second, there was a shortage of instruments designed for measuring necessary competencies in family supports and collaboration with families. Third, reliability and validity were reported for only 11 of the instruments. Finally, most studies utilised the tools in surveys; only two studies used the tools to investigate the effectiveness of the teacher support programmes implemented in their experiments. These results are discussed, and implications for future studies are proposed. [ABSTRACT FROM AUTHOR]

Protein crystallization is an indispensable process in structural determination by crystallography and consists of nucleation and crystal growth. Nucleation, wherein protein monomers in solution cluster in an ordered fashion to form a stable nucleus, is a critical yet difficult step in crystallization. Herein, we utilized sphere-, star-, and rod-shaped gold nanoparticles (GNPs) functionalized with nitrilotriacetic acid (NTA) or citrate as nucleation cores and showed that the GNPs could facilitate nucleation by interacting with His6-tagged proteins. Evaluation of the crystallization of two proteins indicated that GNPs significantly increased the number of crystallization conditions compared to that of the control. Furthermore, NTA-modified GNPs had better effect on crystallization than did citrate-capped GNPs, which could be attributed to orientation-controlled protein clustering around the GNPs by specific conjugation of NTA-modified GNP–Ni2+–His6-tagged proteins. Our findings indicate that functionalized GNPs can greatly increase the success rate of protein crystallization and accelerate the structural determination process by X-ray crystallography.

Hemopexin is a vital glycoprotein for processing excessive iron in blood and functions as an iron scavenger in mammals. Teleosts however, unlike mammals, have two known hemopexin paralogs called warm temperature acclimation-related 65 kDa protein (Wap65-1 and Wap65-2, collectively termed Wap65s). Although Wap65s in rainbow trout have been considered notable biomarkers with significantly higher and/or lower expression under conditions of stress or disease, the individual roles, similarities and differences between the two paralogs are not well known. The aim of this study was to gain an understanding of the characteristics and functions of trout Wap65s from the perspective of iron-metabolism, physiological roles, and relevant immunological responses. The expression of Wap65-1 and -2 in this study was determined in the face of challenges by Aeromonas salmonicida, infectious hematopoietic necrosis virus (IHNV), and iron-dextran. Immuno-histochemistry (IHC) was employed to localize the major cell types for Wap65-2 expression, and trout leukocytes were isolated and incubated with LPS and OxLDL for comprehending the immunological characteristics of Wap65-2. We demonstrate that Wap65-1 is expressed only in the liver but Wap65-2 is systemically expressed in most organs and tissues. Interestingly, Wap65-1 expression was not significantly changed under A. salmonicida and iron-dextran administration, but was significantly decreased under IHNV. In contrast, Wap65-2 was up-regulated in all challenged groups, however with different expression patterns in the blood and liver. These results suggested that the two paralogs may participate in different biological roles. IHC showed that Wap65-2 antibody had high affinity for leukocyte-like cells, and macrophages but not lymphocytes significantly increased expression under LPS and OxLDL stimulation. These results support the conclusion that trout Wap65-2, not Wap65-1 may have conventional hemopexin functions such as reported in mammals including effects on iron metabolism, inflammation, and acute-phase protein.

Genetic variants in the gene Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families, all with molecularly confirmed diagnoses of KBG syndrome. Twenty-one individuals have de novo variants, three have inherited variants, and one is inherited from a parent exhibiting low-level mosaicism. Of the variants, 20 are truncating (frameshift or nonsense), and the remaining five individuals have missense variants (with one of these in three family members). One of the missense variants has been found in at least two other affected individuals. We created a novel protocol for collection and reporting of data, including prospectively interviewing these individuals and their families throughout eight countries via videoconferencing by a single clinician. Participants’ medical records, including imaging, were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were submitted to GestaltMatcher and Face2Gene (FDNA Inc, USA) for facial analysis, and we found similar facial phenotypes among the participants. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Seventy-two percent of participants had gastrointestinal complaints and 80% had hearing loss. Three participants were started on growth hormone with positive results. Behavioral issues and global developmental delays were found in most participants. Neurologic abnormalities including seizures and/or EEG abnormalities were also very common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Twenty-four percent were diagnosed with attention deficit hyperactivity disorder (ADHD) and 28% were diagnosed with autism spectrum disorder (ASD). Additionally, we have identified minimally reported symptoms, including recurrent sinus infections (16%) and previously unreported migraines (20%). Based on the videoconferencing and these data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

The usefulness of the oxygen reserve index (ORi) in reducing hyperoxemia remains unclear. We designed this study to investigate whether fraction of inspired oxygen (FiO2) adjustment under a combination of ORi and peripheral oxygen saturation (SpO2) guidance can reduce intraoperative hyperoxemia compared to SpO2 alone.In this prospective, double-blind, randomized controlled study, we allocated patients scheduled for laparoscopic gastrectomy to the SpO2 group (FiO2 adjusted to target SpO2 ≥ 98%) or the ORi-SpO2 group (FiO2 adjusted to target 00 ORi.3 and SpO2 ≥ 98%). The ORi, SpO2, FiO2, arterial partial pressure of oxygen (PaO2), and incidence of severe hyperoxemia (PaO2 ≥ 200 mm Hg) were recorded before and 1, 2, and 3 hours after surgical incision. Data from 32 and 30 subjects in the SpO2 and ORi-SpO2 groups, respectively, were analyzed.PaO2 was higher in the SpO2 group (250.31 ± 57.39 mm Hg) than in the ORi-SpO2 group (170.07 ± 49.39 mm Hg) 1 hour after incision (P.001). PaO2 was consistently higher in the SpO2 group than in the ORi-SpO2 group, over time (P = .045). The incidence of severe hyperoxemia was higher in the SpO2 group (84.4%) than in the ORi-SpO2 group (16.7%, P.001) 1 hour after incision. Higher FiO2 was administered to the SpO2 group [52.5 (50-60)] than the ORi-SpO2 group [40 (35-50), P.001] 1 hour after incision. SpO2 was not different between the 2 groups.The combination of ORi and SpO2 guided FiO2 adjustment reduced hyperoxemia compared to SpO2 alone during laparoscopic gastrectomy.

Despite growing evidence of the relevance of alternative splicing (AS) to cancer development and progression, the biological implications of AS for tumor behaviors, including papillary thyroid cancer (PTC), remain elusive. With the aim of further understanding the molecular and histological subtypes of PTC, we in this study explored whether AS events might act as new molecular determinants. For this purpose, AS profiles were analyzed in RNA-sequencing data from The Cancer Genome Atlas (TCGA) and from a Korean patient dataset. A total of 23 distinct exon-skipping (ES) events that correlated significantly with PTC oncogenic activity and differentiation scores were identified. The two top-ranked ES events, NUMA1_17515 in exon 18 of NUMA1 and TUBB3_38175 in exon 6 of TUBB3, showed high correlations with oncogenic activities and discriminated histological and molecular subtypes of PTC. Furthermore, two novel intron-retention (IR) events for TUBB3 were uncovered. All ES and IR events for the TUBB3 gene were predicted to induce nonsense-mediated mRNA decay. The relative abundances of intron reads in the PTC dataset from TCGA showed IR levels to differ significantly among PTC subtypes, possibly reflecting their different tumor behaviors. This study provides a landscape of AS changes among PTC subtypes and identified two significant AS events, NUMA1_17515 and TUBB3_38175, as potential AS biomarkers for PTC subclassification and characterization. The AS events identified in this study may be involved in the development of phenotypic differences underlying the functional characteristics and histological differentiation of PTCs.

Ichthyophthirius multifiliisis a major pathogen that causes a high mortality rate in trout farms. However, systemic responses to the pathogen and its interactions with multiple organs during the course of infection have not been well described. In this study, dual-organ transcriptomic responses in the liver and head kidney and hemato-serological indexes were profiled underI. multifiliisinfection and recovery to investigate systemic immuno-physiological characteristics. Several strategies for massive transcriptomic interpretation, such as differentially expressed genes (DEGs), Poisson linear discriminant (PLDA), and weighted gene co-expression network analysis (WGCNA) models were used to investigate the featured genes/pathways while minimizing the disadvantages of individual methods. During the course of infection, 6,097 and 2,931 DEGs were identified in the head kidney and liver, respectively. Markers of protein processing in the endoplasmic reticulum, oxidative phosphorylation, and the proteasome were highly expressed. Likewise, simultaneous ferroptosis and cellular reconstruction was observed, which is strongly linked to multiple organ dysfunction. In contrast, pathways relevant to cellular replication were up-regulated in only the head kidney, while endocytosis- and phagosome-related pathways were notably expressed in the liver. Moreover, interestingly, most immune-relevant pathways (e.g., leukocyte trans-endothelial migration, Fc gamma R-mediated phagocytosis) were highly activated in the liver, but the same pathways in the head kidney were down-regulated. These conflicting results from different organs suggest that interpretation of co-expression among organs is crucial for profiling of systemic responses during infection. The dual-organ transcriptomics approaches presented in this study will greatly contribute to our understanding of multi-organ interactions underI. multifiliisinfection from a broader perspective.

[Purpose] Weight loss can reduce obesity-induced arterial stiffening that is attributed to decreased inflammation. Angiopoietin-like protein 2 (ANGPTL2) is a pro-inflammatory adipokine that is upregulated in obesity and is important in the progression of atherosclerosis and cardiovascular disease. The purpose of this study is to investigate the effects of dietary modification on circulating ANGPTL2 levels and arterial stiffness in overweight and obese men. [Methods] Twenty-two overweight and obese men (with mean age of 56 ± 2 years and body mass index of 28.6 ± 2.6 kg/m2) completed a 12-week dietary modification program. We measured the arterial compliance and β-stiffness index (as the indices of arterial stiffness) and serum ANGPTL2 levels before and after the program. [Results] After the 12-week dietary modification, body mass and daily energy intake were significantly reduced. Arterial compliance was significantly increased and β-stiffness index was significantly decreased after the 12-week dietary modification program. Serum ANGPTL2 levels were significantly decreased. Also, the changes in arterial compliance were negatively correlated with the changes in serum ANGPTL2 levels, whereas the changes in β-stiffness index were positively correlated with the changes in serum ANGPTL2 levels. [Conclusion] These results suggest that the decrease in circulating ANGPTL2 levels can be attributed to the dietary modification-induced reduction of arterial stiffness in overweight and obese men.

We evaluated the effects of three different inspired oxygen concentrations (40%, 80%, and 100%) at anaesthesia emergence on postoperative lung volumes as measured by global impedance of electrical impedance tomography (EIT). This is a randomised, controlled, and assessor-blinded study in single-centre from May 2017 to August 2017. Seventy-one patients undergoing elective laparoscopic colorectal surgery with healthy lung condition were randomly allocated into the three groups based on the concentration of inspired oxygen applied during anaesthesia emergence: 40%-, 80%- or 100%-oxygen. End-expiratory lung impedance (EELI) with normal tidal ventilation and total lung impedance (TLI) with full respiratory effort were measured preoperatively and before discharge in the post-anaesthesia care unit by EIT, and perioperative changes (the ratio of difference between preoperative and postoperative value to preoperative value) were compared among the three groups. Postoperative lung impedances were significantly reduced compared with preoperative values in all patients (P < 0.001); however, perioperative lung impedance reduction (%) did not differ among the three oxygen groups. The mean reduction ratio in each 40%-, 80%-, and 100%-oxygen group were 37% ± 13%, 41% ± 14%, and 46% ± 14% for EELI (P = 0.125) and 40% ± 20%, 44% ± 17% and 49% ± 20% for TLI (P = 0.276), respectively. Inspired oxygen concentrations applied during anaesthesia emergence did not show a significant difference in postoperative lung volume as measured by EIT in patients undergoing laparoscopic colorectal surgery with healthy lungs.Trial registration cris.nih.go.kr (KCT0002642).

Purpose: This article is a comprehensive review for concept clarification of critical thinking, clinical reasoning, and clinical judgment, which still lack a consensus and are of mixed use. Methods: Norris's method of concept clarification was used to review concepts that have no clear definition or conceptualization yet. Results: This review summarized literature from various disciplines, classified each concept based on similarities and differences, and provided hypothetic conceptual schema. Conclusion: Clinical reasoning and clinical judgment are clinical situation specific concepts, while critical thinking is a concept applied in general situations. Critical thinking is a broader concept and serves as a foundation for clinical reasoning and clinical judgment. Clinical reasoning precedes clinical judgment. Clinical judgement implies the end point or conclusion of clinical reasoning. Each of critical thinking, clinical reasoning, and clinical judgment is a cognitive and affective process not a psychomotor process. The concept of clinical competency involves action taken after the cognitive processes of clinical reasoning and clinical judgment.

Background Since the femoral artery frequently overlaps the femoral vein, femoral central venous catheterization carries the risk of arterial puncture in pediatric patients. Aims We evaluated the angle range of leg abduction with external hip rotation to minimize the overlap between the femoral artery and vein in pediatric patients undergoing general anesthesia. Methods Eighty-two pediatric patients who underwent elective surgery with general anesthesia were enrolled in this study. Using ultrasonography, patients were divided into groups N (patients with non-overlap) and O (patients with continuing overlap) based on the presence of non-overlap range between the femoral artery and vein. The range minimizing the overlap was defined as the range without overlap in group N and as the range presenting the overlap that was less-than-half of the radius of the femoral vein in group O. By increasing the angle of leg abduction with external hip rotation, the starting and ending angles minimizing the overlap were found using ultrasonographic images. Results The angle range of leg abduction with external hip rotation minimizing the overlap between the femoral artery and vein was defined as the range from the maximum 99% confidence interval of starting angles to the minimum 99% confidence interval of ending angles, which was between 45° and 65° in group N and between 48° and 58° in group O, respectively. Conclusion Positioning patients in a range of 48° and 58° leg abduction with external hip rotation can minimize the overlap between the femoral artery and vein. However, the clinical usefulness of this positioning for femoral venous catheterization remains to be seen.

Objectives: This study presents processes and outcomes of school-wide positive behavior support (SW-PBS) funded by Seoul Metropolitan Office of Education (SMOE) in South Korea. Methods: The SW-PBS effort has been implemented in six special schools serving students with developmental disabilities. With technical assistance from the SMOE consulting team, these schools organized PBS leadership teams, conducted functional assessment, planned multi-tiered support, implemented universal and individual support, and measured outcomes and fidelity. Results: The SW-PBS efforts resulted in positive behavioral outcomes for students and increased perceptions of efficacy and class management skills for teachers. Conclusions: Future research should continue to examine the effectiveness of SW-PBS and identify the best ways to implement SW-PBS both in special schools and general schools in Korea.

Ultrasound is not widely used to evaluate optimal supraglottic airway positioning even though it could potentially be used to identify and correct problem areas.We evaluated a new ultrasound scoring method to identify the position of the supraglottic airway and detect the location of air leaks during ventilation in pediatric patients.Using a prospective observational study design, we enrolled 90 pediatric patients of ASA physical status I-III scheduled for elective surgery under general anesthesia. After anesthesia induction, patients were assigned to a noncorrection group or a correction group after their first ultrasound evaluation. Noncorrection group comprised patients with tolerable I-Gel positioning based on ultrasound evaluation and no problems with clinical parameters, while the correction group comprised patients with I-Gel mispositioning based on ultrasound.After the first ultrasound evaluation, 61 patients did not need I-Gel correction (noncorrection group), while 29 patients needed I-Gel correction (correction group) and underwent a second ultrasound evaluation. Airway sealing pressure and total ultrasound score showed a negative correlation (r = -.845, p .001). The area under the receiver operating curve for total ultrasound score was 0.97 (95% confidence interval, 0.94-0.99; p .001). In the correction group, ultrasound score and ventilation parameters improved after correction based on ultrasound evaluation.Ultrasound scores were negatively correlated with airway sealing pressure in pediatric patients. Ultrasound evaluation is useful for detecting misplacement of the I-Gel and can be a useful tool for correction.

Virtual manipulatives are interactive and dynamic visual objects on a screen, which allow students to manipulate them to construct mathematical knowledge. The purpose of this study was to synthesize the literature on interventions that used virtual manipulatives to improve the mathematics performance of K–12 students with learning disabilities. A total of 19 single-case design studies (16 peer-reviewed articles and three dissertations) were selected using specific selection criteria. Overall, students with learning disabilities demonstrated mathematical improvement after receiving interventions involving virtual manipulatives. Although many students with learning disabilities maintained and generalized the intervention effects, further research is required to verify the current findings.

Here, we report the complete genome sequence of Flavobacterium psychrophilum FPRT1, isolated from the spleen and kidney of diseased rainbow trout (Oncorhynchus mykiss). Whole-genome sequencing was performed using the PacBio RS II platform, which yielded a circular chromosome of 2,795,347 bp harboring 2,895 protein-coding genes.

Tomato is one of the major vegetable crops consumed worldwide. Tomato yellow leaf curl virus (TYLCV) and fungal Oidium sp. are devastating pathogens causing yellow leaf curl disease and powdery mildew. Such viral and fungal pathogens reduce tomato crop yields and cause substantial economic losses every year. Several commercial tomato varieties include Ty-5 (SlPelo) and Mildew resistance locus o 1 (SlMlo1) locus that carries the susceptibility (S-gene) factors for TYLCV and powdery mildew, respectively. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) is a valuable genome editing tool to develop disease-resistant crop varieties. In this regard, targeting susceptibility factors encoded by the host plant genome instead of the viral genome is a promising approach to achieve pathogen resistance without the need for stable inheritance of CRISPR components. In this study, the CRISPR/Cas9 system was employed to target the SlPelo and SlMlo1 for trait introgression in elite tomato cultivar BN-86 to confer host-mediated immunity against pathogens. SlPelo-knockout lines were successfully generated, carrying the biallelic indel mutations. The pathogen resistance assays in SlPelo mutant lines confirmed the suppressed accumulation of TYLCV and restricted the spread to non-inoculated plant parts. Generated knockout lines for the SlMlo1 showed complete resistance to powdery mildew fungus. Overall, our results demonstrate the efficiency of the CRISPR/Cas9 system to introduce targeted mutagenesis for the rapid development of pathogen-resistant varieties in tomato.

Supplemental material, sj-pdf-1-ldx-10.1177_00222194211006336 for Effects of Interventions Using Virtual Manipulatives for Students With Learning Disabilities: A Synthesis of Single-Case Research by Jiyeon Park, Diane P. Bryant and Mikyung Shin in Journal of Learning Disabilities

This study investigated the abundance and diversity of antibiotic resistance genes (ARGs) and the composition of bacterial communities along a transect covering the western Pacific Ocean (36°N) to the Southern Ocean (74°S) using the Korean icebreaker R/V Araon (total cruise distance: 14,942 km). The relative abundances of ARGs and bacteria were assessed with quantitative PCR and next generation sequencing, respectively. The absolute abundance of ARGs was 3.0 × 10

The L858R activating mutation in Epidermal Growth Factor Receptor (EGFR) accounts for approximately 40% of EGFR-mutant non-small cell lung cancer (NSCLC). These patients receive targeted therapy targeting EGFR mutation. To date all approved EGFR tyrosine kinase inhibitors (TKIs) are ATP competitive inhibitors, inevitably lead to drug resistance and to disease progress. Osimertinib is a third-generation EGFR TKI that selectively inhibits both EGFR TKI-sensitizing (L858R) mutation and T790M mutation that confers acquired resistance to first- and second-generation EGFR-TKIs. The patients develop secondary resistance L858R/C797S and L858R/T790M/C797S to this treatment in some cases. There have been strong unmet needs for specific therapies targeting C797S resistance mutations. Additionally, toxicities caused by inhibition of wild-type (WT) EGFR are frequently reported with the first-generation inhibitors (e.g. Gefitinib and Erlotinib). Our Compound A is a highly mutant-selective fourth-generation allosteric inhibitor that targets L858 activating mutations and without affecting EGFR WT that compares favorably with all ATP competitive inhibitors, indicating that it might avoid potential toxicities from targeting EGFR WT. Compound A has a single-digit nanomolar potency against L858R activating mutation and those harboring T790M and C797S resistance mutations. Oral administration of Compound A to tumor-bearing mice showed significant antitumor activity as a single-agent at well-tolerated doses via inhibiting EGFR pathway in the engineered osimertinib-resistance EGFRL858R/T790M/C797S and EGFRL858R/C797S CDX models. Furthermore, Compound A demonstrated excellent efficacy in EGFRL858R/T790M CDX model as a single-agent. Collectively, Compound A has a robust potency against L858R activating mutations including T790M, C797S, and T790M/C797S that cause acquired resistance to ATP competitive EGFR TKIs in vitro and in vivo. Based on the preclinical data, Compound A is a potent, orally available, and mutant-selective fourth-generation allosteric inhibitor of EGFR with L858R activating mutations for the treatment of NSCLC, suggesting that it might have the potential to demonstrate activity in the first line and resistance settings as a single agent. The pre-clinical data described here supports the clinical development of Compound A in NSCLC patients with L858R activating mutations of EGFR. Citation Format: Yeji Byeon, Seung Hee Jung, Daseul Yoon, Seock Yong Kang, Jiyeon Park, Hyeim Jo, Seong-Il Choi, Somyi Park, Seung-chul Lee, Yang Hun Tae, Tae Min Kim, Sung-Yup Cho, Soyeon Kim, Donghyun Ko, Dong-Kyu Kim, Dong-Wan Kim. Compound A, a fourth-generation allosteric inhibitor, a potent and highly selective EGFR with L858R activating and C797S resistance mutations for the treatment of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5477.

Introduction: Pancreatic cancer is a lethal disease showing dismal prognosis and therapeutic resistance. Previous molecular subtypes from genome or transcriptome did not show clinical relevance regarding precision strategy for optimal therapeutic options followed by precise patient classification. This study aims to uncover consensus molecular subtypes from cancer-specific multi-omics data showing clinically relevant therapeutic opportunities. Methods: We performed comprehensive analyses using the dataset from the cancer dependency map (DepMap) project, including cancer-specific molecular characterization with multi-omics data, genome-wide loss-of-function screening using the CRISPR-Cas9 system, and cancer drug sensitivity. The subtype-specific molecular signatures were validated in independent translational cohorts (TCGA-PAAD; n=150, ICGC-PACA-AU; n=461, ICGC-PACA-CA; n=317). Results: Integrative profiling of multi-omics molecular layers (Mutational signature, Copy number alteration, Transcriptome, MicroRNA, Chromatic profile, Proteome, and Metabolome) from pancreatic cancer cell lines (n=59) from the Cancer Cell Line Encyclopedia (CCLE) revealed a total of three cancer-specific molecular subtypes showing distinct tumor biology through all omics layer as well as clinical relevance with unique molecular dependency. Major molecular features of each subtype were reproducible in the validation cohorts. Subtype-specific molecular biomarkers, including mutational signature and metabolites, were identified. Finally, the target drug with subtype-specific genetic dependency was analyzed to provide precision strategy according to distinct subtypes’ molecular characterization. Conclusions: Integrative profiling from multi-omics molecular layers revealed precision strategies based on cancer-specific molecular subtypes of pancreatic cancer in terms of tumor classification and discriminative therapeutic opportunities. Prospective translational studies companion with clinical trials based on cancer-specific molecular subtypes is mandatory to establish the precision strategy for managing pancreatic cancer. Citation Format: Sung Hwan Lee, Jiyeon Park. Unsupervised clustering of multi-omics molecular layers reveals consensus molecular subtypes showing potential therapeutic opportunities for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2273.

Gray leaf spot (GLS) disease, caused by the Stemphylium (Sm) fungus, affects a wide range of horticultural crops including tomato. In this study, the South Korean Sm isolate (PNU-SM01) was identified, and the applicability of Sm-resistance gene (Sm)-linked DNA markers in marker-assisted selection was validated. ITS/gpd sequencing and morphological observation identified the isolate as S. lycopersici. A GLS disease assay was conducted on 80 tomato varieties, including commercial F1 hybrids and elite inbred lines. The reference line ‘Motelle’ was highly resistant (R, DSI = 4.0), whereas the ‘Moneymaker’ line was susceptible (S) and showed severe disease symptoms (DSI = 79.3). Among 30 commercial F1 hybrids, five were scored as S by DSI; whereas the rest, including all 17 hybrids claimed as Sm-resistant by the supplier, were R or moderately resistant (MR). Among 48 inbred lines, four were scored as S and 44, including five Lycopersicon accessions reported as R, were R or MR. Three known Sm-linked DNA markers (CT55, D5, and Sm-InDel) were genotyped in all 80 cultivars; the highest match (92.5%) to the GLS disease assay was observed for Sm-InDel. We converted the recessive marker CT55 into a codominant marker (CT55-Co) and developed dCAPS (Sm-SNP) and KASP (Sm-KASP) markers from a previously identified Sm-linked SNP. Sm-SNP and Sm-KASP showed a similar level of phenotype to marker genotype association as Sm-InDel, whereas CT55-Co displayed a high level of mismatch. To screen for the source of Sm resistance, 138 tomato accessions were genotyped with Sm-InDel and Sm-SNP: 15 were homozygous for the resistance allele of both markers. In this study, resistance to the Korean isolate of S. lycopersici in commercial F1 hybrids and breeding sources was characterized to reveal which DNA markers can be effectively applied for marker-assisted selection of Sm-resistance.

Although over-nutrition from overfeeding-induced obesity is known to be highly associated with metabolic and immunological disorders in humans, little is known about overfeeding-induced obesity in fish farming. The purpose of this study was to investigate changes in immuno-physiological parameters, to better understand the potential risk of overfeeding&ndash, induced obesity in fish. Commercial feed was provided to fish in the overfed group until they refuse to eat, but fish in the control group was fed with the feed at 1% bodyweight per day. The hemato-serological, histological, and immunological changes were observed at weeks 2 and 8. Rainbow trout leukocytes were co-incubated with oxidized low-density lipoprotein (OxLDL), and the phagocytes engulfing the OxLDL and the presence of apoptotic cells were evaluated. The body weight, body mass index (BMI), and hepatosomatic index (HSI) index were significantly higher in the overfed group, and high lipid accumulation and fatty changes were also observed in their livers, indicating that the feeding regime used in this study led to overfeeding-induced obesity. Likewise, much higher numbers of and larger vacuoles were observed in overfed fish macrophages, showing unclear boundaries between the cytoplasm and extracellular space. In the overfed group, the expression of IL-10, HSP70, TLR2, and CD36 was significantly higher, and lymphocyte apoptosis was more evident, indicating that overfeeding-induced obese fish might have immunologic disorders. This was the first study to demonstrate that overfeeding-induced obesity could cause an immune-physiological imbalance in rainbow trout, making them more vulnerable to infectious diseases and various stressful conditions. This study will contribute to improvements in fish nutrition, feeding practices, fish nutrition, and disease prevention in the aquaculture industry.

Aspergillus nodules represent a subtype of chronic pulmonary aspergillosis, but details on their characteristics and outcomes are limited. We evaluated 80 patients with pathologically confirmed Aspergillus nodules between January 2009 and December 2016. The median age of the patients was 59 years, and 46 (58%) were women. Seventy-three (91%) patients were surgically diagnosed with Aspergillus nodules and the remaining seven (9%) patients were diagnosed by percutaneous transthoracic needle biopsy. The median long-axis diameter of nodules was 22 mm, and nodules had an internal cavity in 49 (61%) patients. Spiculation and calcification were observed in 20% and 39% of patients, respectively. Ninety percent (18/20) of nodules showed uptake on positron emission tomography. Serum Aspergillus precipitin IgG antibody was positive in 42% (10/24) of tested patients. Seventy-three (91%) patients underwent surgery without (n = 58) or with (n = 15) adjuvant antifungal therapy, and the remaining seven (9%) patients received antifungal therapy alone (n = 5) or no treatment (n = 2). Three patients experienced postoperative pulmonary complications: pneumothorax, hemoptysis, and acute lung injury (n = 1 each). There was no recurrence during the median follow-up period of 36.8 months. In conclusion, surgery could be a treatment strategy worth considering for most Aspergillus nodules. However, given that our study population was heterogeneous, further well-designed studies are need.