Assessment of oral hypofunction and its association with age among Korean community-dwelling older adults.

BACKGROUND: Due to the increasing proportion of older adults in Korea and growing interest in aging, the concepts of oral aging and oral hypofunction have recently been introduced. Thus, it is necessary to investigate the age-specific oral function levels of Korean older adults and develop expert intervention methods for healthy aging. METHODS: Dysphagia, independence of daily living, and oral hypofunction were assessed in 206 older adults living in Wonju, Gangwon State, South Korea. Subjective dysphagia was assessed through self-report questionnaires using the Dysphagia Handicap Index (DHI), the Korean version of Eating Assessment Tool-10, and the Korean version of the Modified Barthel Index. In addition, the oral hypofunction assessment items included decreased chewing ability, occlusal pressure, tongue pressure, oral dryness, and oral cleanliness. RESULTS: DHI increased significantly with age, with those in their 80 s reporting the most difficulty swallowing. Oral function in terms of chewing ability (maximum occlusal pressure and number of remaining teeth), maximum occlusal pressure, and maximum tongue pressure also declined with increasing age. While there was no significant difference in oral dryness by age, those in their 80 s had dry mouth according to the criteria of the oral moisture checking device. CONCLUSIONS: In an assessment of oral function in community-dwelling, independent Korean older adults, the number of items that were assessed as oral hypofunction increased with age. The findings can be used to standardize the oral hypofunction assessment item and develop age-based individualized intervention plans for the early management of oral health and individual oral myofunctional rehabilitation in Korean community-dwelling older adults.

Validation of the Korean Academy of Geriatric Dentistry screening questionnaire and oral frailty diagnostic criteria in community-dwelling older adults.

OBJECTIVES: This study aimed to establish the validity-specifically, the sensitivity and specificity-of the screening questionnaire and diagnostic criteria for oral frailty proposed by the Korean Academy of Geriatric Dentistry (KAGD) among community-dwelling older adults. METHODS: This study enrolled 100 participants. Among various definitions of oral frailty, this study used the criteria proposed by Tanaka as the reference test. The screening questionnaire consisted of 11 items for screening physical frailty, chewing ability, swallowing difficulties, oral dryness, and tongue and lip motor function. Each question had a different scoring weight, and if the total score was 1 or higher, an oral frailty diagnostic examination proposed by the KAGD would be recommended. The diagnostic test was the oral frailty diagnostic criteria proposed by the KAGD including 6 measures: chewing ability, occlusal force, tongue pressure, oral dryness, swallowing difficulty, and oral hygiene. If a participant exhibited 2 or more positive measures, this participant was classified as "oral frail." The screening questionnaire was analyzed using a cut-off value of 1 or higher, while the diagnostic criteria utilized a cut-off of 2 or more positive measures. Sensitivity and specificity were calculated. RESULTS: The screening questionnaire showed significant power for screening oral frailty (area under the receiver operating characteristic curve, 0.783; sensitivity, 87.8%; specificity, 52.5%). The diagnostic accuracy of the newly proposed diagnostic criteria was acceptable (sensitivity, 95.1%; specificity, 42.4%). CONCLUSIONS: The newly proposed screening questionnaire and diagnostic criteria in Korea appear to be a useful tool to identify oral frailty in community-dwelling older adults.

Discovery of benzimidazole-indazole derivatives as potent FLT3-tyrosine kinase domain mutant kinase inhibitors for acute myeloid leukemia.

The FMS-like tyrosine kinase 3 (FLT3) gene encodes a class III receptor tyrosine kinase that is expressed in hematopoietic stem cells. The mutations of FLT3 gene found in 30% of acute myeloid leukemia (AML), leads to an abnormal constitutive activation of FLT3 kinase of the receptor and results in immature myeloblast cell proliferation. Although small molecule drugs targeting the FLT3 kinase have been approved, new FLT3 inhibitors are needed owing to the side effects and drug resistances arising from kinase domain mutations, such as D835Y and F691L. In this study, we have developed benzimidazole-indazole based novel inhibitors targeting mutant FLT3 kinases through the optimization of diverse chemical moieties substituted around the core skeleton. The most optimized compound 22f exhibited potent inhibitory activities against FLT3 and FLT3/D835Y, with IC50 values of 0.941 and 0.199 nM, respectively. Furthermore, 22f exhibited strong antiproliferative activity against an AML cell line, MV4-11 cells with a GI50 of 0.26 nM. More importantly, 22f showed single-digit nanomolar GI50 values in the mutant FLT kinase expressed Ba/F3 cell lines including FLT-D835Y (GI50 = 0.29 nM) and FLT3-F691L (GI50 = 2.87 nM). Molecular docking studies indicated that the compound exhibits a well-fitted binding mode as a type 1 inhibitor in the homology model of active conformation of FLT3 kinase.

Development and evaluation of simulation-based scenario education program for professional oral hygiene care in intubated patient.

PURPOSE: This study was conducted to develop a professional oral hygiene care (POHC) simulation education program for intubated patients and to evaluate the suitability of education by evaluating the performance confidence (PC), critical thinking disposition (CT), and learning satisfaction (LS) of dental hygiene students. METHODS: This study developed a POHC simulation education program (theory, skill training, scenario education, and debriefing) for intubated patients through expert validation and consisted of a single-group pre- and postexperiment design. The subjects were 3rd and 4th year students at the Department of Dental Hygiene in Wonju City, and a total of 30 people were enrolled. The collected data were analyzed using the PASW Statistics version 23.0. The content validity test was measured by the CVI (Content validity index) value, and the PC, CT, and LS of the subjects before and after participating in the program were analyzed using a paired t-test. The significance level (α) was based on .05. RESULTS: After the program, the PC improved from 4.29 ± 0.43 to 4.54 ± 0.44, and there was a significant difference (p = .004). CT improved from 3.73 ± 0.36 to 3.84 ± 0.36, but there was no significant difference (p = .062), and prudence improved from 4.21 ± 0.33 to 4.43 ± 0.27, and there was significant difference. (p = .001). LS increased from 4.66 ± 0.36 to 4.90 ± 0.16 after education, and there was a significant difference (p = .002). CONCLUSION(S): Simulation education program improved dental hygiene students' POHC performance confidence. Various scenarios will need to be developed in the future, and it is necessary to evaluate simulation education within the dental hygiene curriculum and identify areas for improvement.

COVID-19 spike polypeptide vaccine reduces the pathogenesis and viral infection in a mouse model of SARS-CoV-2.

The SARS-CoV-2 coronavirus, which causes a respiratory disease called COVID-19, has been declared a pandemic by the World Health Organization (WHO) and is still ongoing. Vaccination is the most important strategy to end the pandemic. Several vaccines have been approved, as evidenced by the ongoing global pandemic, but the pandemic is far from over and no fully effective vaccine is yet available. One of the most critical steps in vaccine development is the selection of appropriate antigens and their proper introduction into the immune system. Therefore, in this study, we developed and evaluated two proposed vaccines composed of single and multiple SARS-CoV-2 polypeptides derived from the spike protein, namely, vaccine A and vaccine B, respectively. The polypeptides were validated by the sera of COVID-19-vaccinated individuals and/or naturally infected COVID-19 patients to shortlist the starting pool of antigens followed by in vivo vaccination to hACE2 transgenic mice. The spike multiple polypeptide vaccine (vaccine B) was more potent to reduce the pathogenesis of organs, resulting in higher protection against the SARS-CoV-2 infection.

Caspase Cleavage of Receptor Tyrosine Kinases in the Dependence Receptor Family.

Dependence receptors are a group of receptor proteins with shared characteristics of transducing two different signals within cells. They can transduce a positive signal of survival and differentiation in the presence of ligands. On the other hand, dependence receptors can transduce an apoptosis signal in the absence of ligands. The function of these receptors depends on the availability of their ligands. Several receptor tyrosine kinases (RTKs) have been reported as dependence receptors. When cells undergo apoptosis by dependence receptors, the intracellular domain of some RTKs is cleaved by the caspases. Among the RTKs that belong to dependence receptors, we focused on eight RTKs (RET, HER2, MET, ALK, TrkC, EphA4, EphB3, and c-KIT) that are cleaved by caspases. In this review, we describe the features of the receptors, their cleavage sites, and the fate of the cleaved products, as well as recent implications on them being used as potential therapeutics for cancer treatment.

Occupational hazards among dental hygienists: Risk level assessment of scaling work.

OBJECTIVES: This study aimed to classify occupational hazards of ultrasonic scaling by factor and to identify the distribution of occupational risk levels of the study participants according to occupational hazards. In addition, the relationship between the general characteristics of dental hygienists and the occupational risk level of scaling was investigated. METHODS: This study was conducted on 237 dental hygienists. Exposure frequency and the degree of work loss were investigated on a five-point scale for each of the 15 occupational hazards of scaling. RESULTS: Among occupational hazards, the proportion of high-risk individuals for biological hazards (32.9%) was the highest. Dental clinics (33.6%) were found to have a higher proportion of high-risk individuals than dental hospitals (16.5%) (p < 0.05). The proportion of high-risk individuals was higher in the absence of an infection control coordinator (33.9%) (p < 0.05) and infection control education in the preceding 2 years (28.6%) (p < 0.05). CONCLUSION: To create a safe dental work environment, appropriate measures according to the risk level and measurement of occupational risk should be discussed.

Differences in Korean adult inpatients' oral care behaviour in daily life and hospitals.

OBJECTIVES: The objectives of the study were to identify the differences in oral care methods between current and past hospitalizations and to investigate the need for inpatient oral care education for South Korean adults who have been hospitalized for more than 24 h. METHODS: This study employed a cross-sectional design. Between 23 December 2019 and 4 May 2020, a questionnaire was administered to 200 adult inpatients awaiting treatment and their guardians at university hospitals or clinics. Of these, the data of 195 patients were analysed. Frequency analysis, descriptive statistics and chi-square tests were used for data analysis. RESULTS: In daily life, the participants reported brushing their teeth thrice a day (52.3%) for 2 min (60%). A single product was the most used (51.3%). During hospitalization, 40% of the participants brushed their teeth thrice or more a day, 84.1% brushed for <1 min, and 83.6% did not use additional oral care products. CONCLUSIONS: Differences were observed between South Korean adults' oral care behaviours in daily life and those performed in hospitals. Oral hygiene habits, the frequency and duration of tooth brushing, and the use of oral care products decreased during hospitalization. Our findings can be applied to the development of oral care interventions for inpatients, while considering changes in the hospitalization environment and physical activity levels during hospitalization.

Learning outcomes of a mobile application for dental infection control education.

PURPOSE/OBJECTIVES: This study aimed to apply and verify the effectiveness of a mobile-based dental infection control education application to enable students majoring in dental hygiene to learning dental infection control education without time and space constraints. METHODS: This study used a nonequivalent control group pretest-posttest design to examine differences in learning outcomes between an experimental group that learned through the mobile application and a control group that learned with handouts. The Infection Prevention and Control Mobile Application (IPC App) and handouts were developed by referring to the Center for Disease Control's (CDC) guidelines for Infection Prevention and Control in Dental Settings. Both the experimental and control groups were guided to perform self-regulated learning, where they independently led and managed their learning for two weeks. The study was conducted at the D university college with 42 students from the second grade in the Department of Dental Hygiene from August to October 2021. Differences in knowledge, self-efficacy, and summative evaluation were analyzed using an independent sample t-test and repeated measures analysis of variance (p < 0.05). RESULTS: The findings confirmed that the experimental group who learned through the IPC mobile application had improved their knowledge and indicated a higher summative evaluation than the control group that learned via learning documents (p < 0.05). CONCLUSIONS: Owing to the high accessibility and repeatability of the learning content, the mobile application recommended in this study may serve as an effective self-directed learning tool for students to gain knowledge on the standard precautions for dental infection control.

Evaluation of antimicrobial activity of chlorhexidine-containing oral gels against aspiration pneumonia-inducing bacteria: An In Vitro study.

Aim: Hospitalised patients have a high risk of developing aspiration pneumonia because of poor oral care and oral microbial flora changes. Chlorhexidine (CHX) solution has been used to reduce inflammation and prevent infections in oral cavity, but it is difficult to use in inpatients. Gel-type antimicrobial agents rather than the liquid form may be effective for the oral management of hospitalised patients. Therefore, we evaluated the in vitro antimicrobial effects of CHX-containing oral gels on aspiration pneumonia-inducing bacteria compared to the CHX solution. Materials and Methods: The experimental products of two oral gel types containing 1% and 0.1% CHX, respectively, were selected. Hexamedine, a 0.12% CHX solution, was used as a positive control. The antimicrobial activity of CHX agents against six pneumonia-causing bacteria and Streptococcus mutans, one of the most common oral bacteria, was comparatively analysed using the agar disk diffusion method. Results: In the disk diffusion assay, the 1% CHX gels showed the highest inhibitory effect on all bacteria. All CHX agents including gels and solution had the highest antibacterial activity against Staphylococcus aureus compared with other bacteria. Conclusions: We confirmed the significant antimicrobial effects of the 1% CHX oral gels on aspiration pneumonia-inducing bacteria. These results suggest that CHX gels may be an effective oral care method for preventing infection in inpatients who have difficulty using the solution.

The Effect of Professional Oral Care on the Oral Health Status of Critical Trauma Patients Using Ventilators.

BACKGROUND: Oral care reduces the incidence of ventilator-associated pneumonia. In addition, it is important that critically ill patients to maintain their oral health in order to restore their quality of life and to receive adequate nutrition after recovery. OBJECTIVE: The purpose of this study was to evaluate the effect of professional oral hygiene care (POHC) on the oral health status of patients using a ventilator. METHODS: Fifty-seven ventilated trauma patients were admitted to a tertiary medical institution. For 5 days, the dental hygienist performed POHC every 24 h along with routine oral hygiene care (ROHC) every 8 h for the experimental group (Exp.) (n = 29), whereas only ROHC was provided the control group (Cont.) (n = 28). Oral health status was evaluated using a modified bedside oral exam (MBOE). RESULTS: There was no significant difference between the two groups in the total MBOE score up to 48 h after admission. However, the difference between the two groups was significant for MBOE (F = 16.10, p = 0.000), gingiva (F = 6.02, p = 0.018), buccal mucosa (F = 4.21, p = 0.046), and dental plaque score after 72 h (F = 13.15, p = 0.000). CONCLUSION: This study confirms the importance of POHC in improving the oral health.

Discovery of indirubin-3'-aminooxy-acetamide derivatives as potent and selective FLT3/D835Y mutant kinase inhibitors for acute myeloid leukemia.

Mutations in Fms-like tyrosine kinase 3 (FLT3) have been implicated in the pathogenesis of acute myeloid leukemia (AML) by affecting the proliferation and differentiation of hematopoietic stem and progenitor cells. Although several FLT3 inhibitors have been developed, the occurrence of secondary TKD mutations of FLT3 such FLT3/D835Y and FLT3/F691L lead to drug resistance and has become a key area of unmet medical needs. To overcome the obstacle of secondary TKD mutations, a new series of indirubin-3'-aminooxy-acetamide derivatives was discovered as potent and selective FLT3 and FLT3/D835Y inhibitors that were predicted to bind at the DFG-in active conformation of FLT3 in molecular docking studies. Through structure-activity relationship studies, the most optimized compound 13a was developed as a potent inhibitor at FLT3 and FLT3/D835Y with IC50 values of 0.26 nM and 0.18 nM, respectively, which also displayed remarkably strong in vitro anticancer activities, with single-digit nanomolar GI50 values for several AML (MV4-11 and MOLM14) and Ba/F3 cell lines expressed with secondary TKD mutated FLT3 kinases as well as FLT3-ITD. The selectivity profiles of compound 13a in the oncology kinase panel and various human cancer cell lines were prominent, demonstrating that its inhibitory activities were mainly focused on a few members of the receptor tyrosine kinase family and AML versus solid tumor cell lines. Furthermore, significant in vivo anticancer efficacy of compound 13a was confirmed in a xenograft animal model implanted with FLT3-ITD/D835Y-expressing MOLM-14 cells related to secondary TKD mutation.

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components.

Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial selective autophagy, is critical for cell quality control because it can efficiently break down, remove, and recycle defective or damaged mitochondria. As cancer cells use mitophagy to rapidly sweep away damaged mitochondria in order to mediate their own drug resistance, it influences the efficacy of tumor chemotherapy as well as the degree of drug resistance. Yet despite the importance of mitochondria and mitophagy in chemotherapy resistance, little is known about the precise mechanisms involved. As a consequence, identifying potential therapeutic targets by analyzing the signal pathways that govern mitophagy has become a vital research goal. In this paper, we review recent advances in mitochondrial research, mitophagy control mechanisms, and their implications for our understanding of chemotherapy resistance.

Differences in Determinants Influencing Self-Rated Oral Health in Korean and American Adults.

This study aims to identify the differences in the determinants that influence self-rated oral health (SROH) among Korean and American adults aged 20 years or older and the differences in objective oral health status between Korea and the United States. It included 13,068 Koreans and 5569 Americans who participated in the seventh Korea National Health and Nutrition Examination Survey and the 2017-2018 National Health and Nutrition Examination Survey. All analyses were conducted using the SPSS 25 program. The 39% of Koreans and 27.7% of Americans rated their oral health as "poor". The mean SROH score was lower in Korea (2.66) than in the US (3.15). Conversely, objective oral health was better among Koreans. Further, an analysis of the differences in the predictors of SROH between the two countries confirmed that there were significant differences in age, household income, education level, insurance type (none), type of smoking, self-rated health, and decayed teeth index. Government-led projects or policy-based changes that can improve objective oral health status are needed to boost SROH in Korea, and subsequent studies should examine other objective oral health indices (e.g., periodontal disease) as well as differences in sociocultural backgrounds between countries.

Small Molecule Induced FLT3 Degradation.

Target protein degrader is a new paradigm in the small molecule drug discovery field and relates to the term 'event-driven pharmacology'. Fms-like tyrosine kinase 3 (FLT3) is a significant target for treating acute myeloid leukemia (AML). A few FLT3 kinase inhibitors are currently used in the clinic for AML patients. However, resistance to current FLT3 inhibitors has emerged, and strategies to overcome this resistance are required. Small molecules downregulating FLT3 protein level are reported, exhibiting antileukemic effects against AML cell lines. Small molecules with various mechanisms such as Hsp90 inhibition, proteasome inhibition, RET inhibition, and USP10 inhibition are explained. In addition, reports of FLT3 as a client of Hsp90, current knowledge of the ubiquitin proteasome system for FLT3 degradation, the relationship with FLT3 phosphorylation status and susceptibility of FLT3 degradation are discussed.

Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects.

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited anti-tumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

The influence of professional oral hygiene care on reducing ventilator-associated pneumonia in trauma intensive care unit patients.

Aim This study aimed to examine the effects of professional oral hygiene care for the prevention of ventilator-associated pneumonia (VAP) and the improvement of oral hygiene among patients in the trauma intensive care unit (TICU).Materials and methods TICU patients who underwent intubation were randomly assigned to either the experimental group (n = 29) or control group (n = 28). The developed professional oral hygiene care protocol was administered to patients in the experimental group every 24 hours. Additionally, data regarding general characteristics, medical history, oral hygiene status, Clinical Pulmonary Infection Score and quantitative polymerase chain reaction were assessed.Results The incidence of VAP differed between the control group (10.58) and experimental group (0) post intervention. Post-admission bedside oral exam scores with significant differences in oral hygiene were observed in the experimental group (in contrast to the control group) from 48 hours onwards (10.69 ± 3.43, p = 0.06). Staphylococcus aureus and Klebsiella pneumoniae exhibited significant differences in count as professional oral hygiene care continued.Conclusions This study suggests a model in which different health care professionals can cooperate to reduce the incidence of VAP and improve oral health conditions.

Detection of nosocomial pneumonia pathogens using a fluorescence-based device.

BACKGROUND: Early detection of nosocomial pneumonia pathogens is a significant factor in hospital-acquired pneumonia care. This study aimed to determine the autofluorescence properties of five nosocomial pneumonia pathogens using a fluorescence-based device and to establish evidence for clinical guidelines. METHODS: The following bacterial strains were assessed: Acinetobacter baumannii (AB), Escherichia coli (EC), Enterococcus faecalis (EF), Klebsiella pneumoniae (KP), and Staphylococcus aureus (SA). The bacteria were cultured separately on tryptic soy agar at 37 °C under aerobic conditions for 168 h. Fluorescence photographs of each species were captured every 24 h using a fluorescence-based device with fixed camera settings. The images were analyzed by measuring the red and green values (R/G ratio) at a central point in each colony, and the R/G ratios were analyzed using the Kruskal-Wallis non-parametric test. RESULTS: KP and SA showed red fluorescence with their R/G values, which were significantly higher than those of the other strains (p < 0.001). In particular, the R/G ratio of KP increased steadily until 72 h of incubation, peaking at 3.65. In addition, AB and EC showed orange fluorescence with higher red ratios than green ratios. EF and SA showed green fluorescence all through 168 h of incubation, with R/G ratio less than 1.0. CONCLUSIONS: Nosocomial pneumonia pathogens can be identified and classified via bacterial autofluorescence emission. It is possible to develop a rapid and easy-to-use identification technology based on bacterial autofluorescence for clinical applications.

Oral health status of inpatients with varying physical activity limitations in rehabilitation wards: A cross-sectional study.

ABSTRACT: Poor oral hygiene can be potentially life-threatening in inpatients. However, no basic protocol on oral hygiene customized for inpatients exists, and lack of oral care related knowledge, attitude, and skills among caregivers could be detrimental to the general health of patients. This study sought to identify the oral care practices and oral health status of inpatients with varying physical activity limitations in a rehabilitation ward.Sixty-one inpatients in a rehabilitation ward were evaluated for their medical and physical conditions and oral health status. These were assessed using the bedside oral exam, decayed, missing, filled teeth index, plaque index, gingival index, and caries activity test.In total, 40 men and 21 women (mean age, 56.6 years) were included in this study. Among them, 50.8% of the patients could brush their teeth unassisted, whereas 49.2% required assistance from an assistant for oral care. The proportion of patients receiving nasogastric tube feeding was higher in the group that could not provide oral self-care; 36.7% and 33.3% of these patients showed moderate and severe dysfunction, respectively, based on bedside oral exam. Scores for the swallowing, tongue, and total domains of bedside oral exam were poorer for patients who could not provide oral self-care (P < .01). The caries activity test indicated a moderate risk for both groups.Our findings suggest that an oral care protocol that considers the physical activity limitations in inpatients in rehabilitation wards is necessary to minimize negative influences on the systemic health of these patients.

TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs.

Recently, two tropomycin receptor kinase (Trk) inhibitors, larotrectinib and entrectinib, have been approved for Trk fusion-positive cancer patients. Clinical trials for larotrectinib and entrectinib were performed with patients selected based on the presence of Trk fusion, regardless of cancer type. This unique approach, called tissue-agnostic development, expedited the process of Trk inhibitor development. In the present review, the development processes of larotrectinib and entrectinib have been described, along with discussion on other Trk inhibitors currently in clinical trials. The on-target effects of Trk inhibitors in Trk signaling exhibit adverse effects on the central nervous system, such as withdrawal pain, weight gain, and dizziness. A next generation sequencing-based method has been approved for companion diagnostics of larotrectinib, which can detect various types of Trk fusions in tumor samples. With the adoption of the tissue-agnostic approach, the development of Trk inhibitors has been accelerated.