Gaining Insights into Key Structural Hotspots within the Allosteric Binding Pockets of Protein Kinases.

Protein kinases are essential regulators of cell function and represent one of the largest and most diverse protein families. They are particularly influential in signal transduction and coordinating complex processes like the cell cycle. Out of the 518 human protein kinases identified, 478 are part of a single superfamily sharing catalytic domains that are related in sequence. The dysregulation of protein kinases due to certain mutations has been associated with various diseases, including cancer. Although most of the protein kinase inhibitors identified as type I or type II primarily target the ATP-binding pockets of kinases, the structural and sequential resemblances among these pockets pose a significant challenge for selective inhibition. Therefore, targeting allosteric pockets that are beside highly conserved ATP pockets has emerged as a promising strategy to prevail current limitations, such as poor selectivity and drug resistance. In this article, we compared the binding pockets of various protein kinases for which allosteric (type III) inhibitors have already been developed. Additionally, understanding the structure and shape of existing ligands could aid in identifying key interaction sites within the allosteric pockets of kinases. This comprehensive review aims to facilitate the design of more effective and selective allosteric inhibitors.

Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

School Nurses' Experiences and Needs in COVID-19 Pandemic Response: A Qualitative Study.

The coronavirus disease 2019 pandemic drastically shifted the public health burden onto the school health system. We, therefore, explored the school nurses' experiences and needs for confronting the pandemic in school settings across Korea. This qualitative investigation enrolled 30 participants after their written consent. A written interview conducted through email and focus group interviews using an online meeting application verified participants' opinions and experiences. Collected data were subjected to text-mining and content analysis. The school nurse was found to be responsible for many tasks, including education on preventive measures with unclear quarantine guidelines. Content analysis identified three key themes: "aggravated difficulties owing to lack of support resulted in burnout," "reflection on supportive resources; direct provisions were helpful," and "needs and suggestions to safeguard students' health in the event of another pandemic." Recommendations should all be considered to keep schools and students safe from future pandemics.

Current status and needs in the primary healthcare system in Yangon, Myanmar: a mixed-method evaluation.

BACKGROUND: Many low- and middle-income countries and international organisations have invested resources to strengthen primary health care (PHC). This study aimed to identify the challenges and unmet needs in the current PHC by assessing the experiences and perceptions of healthcare workers in three townships (Htan Ta Pin, Hmawbi, and Taikkyi) in Yangon, Myanmar. METHODS: The study was conducted among healthcare professionals and community leaders in three townships. Adopting a mixed-method approach, a cross-sectional health needs assessment survey was conducted for quantitative data (n = 66), and focus group discussions (FGDs) were conducted online for qualitative data. FINDINGS: Enhancing the management and leadership capacity had the lowest average score on the current achievement (2.81 out of 5 ratings) while strengthening infectious disease control service and accessibility was perceived as the highest mean on the priority of intervention (4.28) and the impact of the intervention (4.7). The FGDs revealed that while specific infrastructures and equipment were reported insufficient and necessary, the need for financial support has been the recurrent theme throughout the discussions. INTERPRETATION: Utilising the World Health Organisation's six building block frameworks, our findings suggest that a long-term targeted financial investment in the PHC system is critical in Myanmar through increasing healthcare expenditure per capita.

Development and psychometric testing of the Heart-Healthy Information Questionnaire.

AIMS: This study aimed to develop a reliable and valid scale, i.e. the Heart-Healthy Information Questionnaire (HHIQ). METHODS AND RESULTS: The HHIQ was developed in three phases: (i) creating the item pool, (ii) conducting a preliminary evaluating the items, and (iii) refining the scale and evaluating psychometric properties. An initial item pool of 77 items with a 3-point True/False format with a 'Don't know' option was extracted from the literature review and 54 items reached content validity. The psychometric properties of HHIQ were tested with 1315 individuals without cardiovascular disease. By using the exclusion criteria of the difficulty index (>0.95), discrimination index (<10.0), and item-total correlation (tetrachoric coefficient <0.2), 50 items were finally selected. The construct validity was determined by using the known-groups validation: Individuals (n = 107) who were educated with heart-healthy education sessions showed significantly higher scores of the HHIQ than those (n = 107) who were not educated (P = 0.015). The Kuder-Richardson formula 20 coefficient indicated good internal consistency (0.85), and the test-retest reliability coefficient with a 15-day interval also indicated good stability (0.78). A total score of the HHIQ was significantly correlated with a total score of the Evaluation Tool for Metabolic Syndrome Modification Lifestyles (ρ = 0.23, P < 0.001). CONCLUSION: The HHIQ showed good psychometric properties of validity and reliability and may be useful to evaluate the knowledge levels of heart-healthy information in the areas of cardiovascular disease prevention.

Effects and Mechanism of Particulate Matter on Tendon Healing Based on Integrated Analysis of DNA Methylation and RNA Sequencing Data in a Rat Model.

Exposure to particulate matter (PM) has been linked with the severity of various diseases. To date, there is no study on the relationship between PM exposure and tendon healing. Open Achilles tenotomy of 20 rats was performed. The animals were divided into two groups according to exposure to PM: a PM group and a non-PM group. After 6 weeks of PM exposure, the harvest and investigations of lungs, blood samples, and Achilles tendons were performed. Compared to the non-PM group, the white blood cell count and tumor necrosis factor-alpha expression in the PM group were significantly higher. The Achilles tendons in PM group showed significantly increased inflammatory outcomes. A TEM analysis showed reduced collagen fibrils in the PM group. A biomechanical analysis demonstrated that the load to failure value was lower in the PM group. An upregulation of the gene encoding cyclic AMP response element-binding protein (CREB) was detected in the PM group by an integrated analysis of DNA methylation and RNA sequencing data, as confirmed via a Western blot analysis showing significantly elevated levels of phosphorylated CREB. In summary, PM exposure caused a deleterious effect on tendon healing. The molecular data indicate that the action mechanism of PM may be associated with upregulated CREB signaling.

Intention to quit electronic cigarette smoking among university students who are e-cigarette users.

OBJECTIVE: To identify factors that are significantly associated with the intention to quit electronic cigarette smoking (ECS) at multiple, ecological levels among university students. PARTICIPANTS: 365 students who were e-cigarette users from Seoul metropolitan areas, South Korea. METHODS: A cross-sectional study through an online survey. RESULTS: Of participants, 62.7% had the intention to quit ECS-17.2% within one month, 14.0% within six months, and 31.5% when the time is right. Factors significantly associated with the intention to quit ECS were identified: "device type," "a shorter duration of ECS," and "having started ECS for quitting traditional cigarette smoking" at the intrapersonal-level; "negative attitudes of either peers or family members toward ECS" at the interpersonal-level; and "exposure to community smoking cessation educations" at the community-level. CONCLUSIONS: Approximately one-thirds of university e-cigarette users had no intention to quit ECS. The factors identified should be integrated into university level, behavioral smoking cessation strategies.

Expert Consensus on COVID-19 Vaccination in Korean Adolescents: A Modified Delphi Survey.

The effectiveness of coronavirus disease 2019 (COVID-19) vaccines had been shown in many studies in adult population, however, the real-world evidence in the childhood population was scarce. We aimed to organize the collective expert's opinions on adolescent vaccination against COVID-19 in Korea, therefore to guide the vaccination policy in the setting of available evidence. The Delphi panels responded that adolescents were greatly impacted by the quarantine measures, and COVID-19 is an important health problem for adolescents. Panels responded that in general, the benefits of the COVID-19 vaccine overweigh the potential risks in Korean adolescents. Continuing monitoring of available data is needed to provide the best vaccination practices in adolescents guided by the updated evidence.

Seroreactivity to Coxiella burnetii in an Agricultural Population and Prevalence of Coxiella burnetii Infection in Ticks of a Non-Endemic Region for Q Fever in South Korea.

Coxiella burnetii infects humans and wild and domesticated animals. Although reported cases on Jeju Island, off the coast of South Korea, are rare, the region is considered to have a high potential for Q fever. We investigated the seroprevalence of antibodies to C. burnetii in 230 farmers living in ten rural areas on Jeju Island between January 2015 and December 2019. Blood samples were collected and examined for C. burnetii Phase I/II IgM and IgG antibodies. Trained researchers collected ticks from rural areas. Clone XCP-1 16S ribosomal RNA gene sequencing was performed to identify Coxiella species from the collected ticks. The overall seroprevalence of antibodies to C. burnetii in farmers was 35.7%. The seroprevalence was significantly higher in fruit farmers. Of the collected ticks, 5.4% (19/351) of the Haemaphysalis longicornis ticks harbored C. burnetti. A high seroprevalence of antibodies to C. burnetii was observed in this region of Jeju Island, confirming that C. burnetti is endemic. Physicians should thus consider Q fever in the differential diagnosis of patients that present with acute fever after participating in outdoor activities.

Correlation between neutrophil to lymphocyte ratio and overactive bladder in South Korean women: a community-based, cross-sectional study.

OBJECTIVE: Many women with overactive bladder (OAB) do not seek medical care despite urinary symptoms. As the diagnosis and treatment of OAB are often late, there is a need to identify undiagnosed OAB patients and start effective treatment. Furthermore, an objective and appropriate screening biomarker for OAB is needed. This study aimed to investigate the relationship between serum neutrophil-to-lymphocyte ratio (NLR) and OAB in South Korean women. DESIGN: Cross-sectional, retrospective study. SETTING: Jeju National University Hospital. PARTICIPANTS: This study included a total of 4394 women (mean age=48.6 years) who underwent self-referred health screenings. INTERVENTIONS: Blood tests were conducted and the NLR was calculated by dividing the number of neutrophils by the number of lymphocytes. OUTCOME MEASURES: The severity of OAB was evaluated using the OAB Symptom Score (OABSS). RESULTS: Approximately 9.8% of participants (n=432) were diagnosed with OAB. The association pattern between the NLR and urinary tract symptoms was variable; however, NLR was associated with OAB, by the OABSS and OAB severity (p<0.001). The NLR had a significant relationship with OAB after age, body mass index, homoeostatic model assessment for insulin resistance, 25-hydroxyvitamin D, stress status, and medication for hypertension (OR 1.19, 95% CI 1.06 to 1.32) were adjusted. CONCLUSIONS: Elevated NLR is associated with OAB; hence, NLR may be a cost-effective and readily available biomarker of OAB in women.

Enriching CCL3 in the Tumor Microenvironment Facilitates T cell Responses and Improves the Efficacy of Anti-PD-1 Therapy.

Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc). Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.

Perspectives on immune checkpoint ligands: expression, regulation, and clinical implications.

In the tumor microenvironment, immune checkpoint ligands (ICLs) must be expressed in order to trigger the inhibitory signal via immune checkpoint receptors (ICRs). Although ICL expression frequently occurs in a manner intrinsic to tumor cells, extrinsic factors derived from the tumor microenvironment can fine-tune ICL expression by tumor cells or prompt non-tumor cells, including immune cells. Considering the extensive interaction between T cells and other immune cells within the tumor microenvironment, ICL expression on immune cells can be as significant as that of ICLs on tumor cells in promoting antitumor immune responses. Here, we introduce various regulators known to induce or suppress ICL expression in either tumor cells or immune cells, and concise mechanisms relevant to their induction. Finally, we focus on the clinical significance of understanding the mechanisms of ICLs for an optimized immunotherapy for individual cancer patients. [BMB Reports 2021; 54(8): 403-412].

Job Stress and Cardiometabolic Lifestyle Modification Behaviors Among Workers in High-risk and Low-risk Workplaces.

OBJECTIVE: There is scarce evidence revealing an association between job stress and cardiometabolic lifestyle modification behaviors among workers. METHODS: A cross-sectional, correlation study was conducted among workers in high-risk and low-risk workplaces by work characteristics. RESULTS: Workers in high-risk workplaces had significantly higher job stress levels than low-risk workplaces. Higher job stress was significantly associated with lower cardiometabolic lifestyle modification behaviors (ß = -0.14, P = .001). This significant association was evident only for high-risk workplaces in total job stress (ß = -0.16, P = .001), including job demand (ß = -0.16, P = .005) and job insecurity (ß = -0.11, P = .026). CONCLUSIONS: Strategies for alleviating job stress should be prioritized to high-risk workplaces, and these efforts may concomitantly contribute to cardiometabolic risk reduction.

Association of decreased grip strength with lower urinary tract symptoms in women: a cross-sectional study from Korea.

BACKGROUND: Lower urinary tract symptoms (LUTS) including frequency, nocturia, urgency, and incontinence, are common in women and cause significant discomfort in daily life. However, diagnosis and treatment of LUTS are often delayed because many patients with such symptoms do not complain to the physician of discomfort and do not seek medical attention. LUTS are known to be associated with muscle weakness. We investigated the association between grip strength and LUTS in women of different ages. METHODS: This study included 4225 women (mean age 48.6 years) who underwent self-referred health screening between April 2015 and December 2019. LUTS were evaluated using a self-reported questionnaire, and the overactive bladder symptom score was used to screen for an overactive bladder. Low muscle strength was defined as a hand grip strength of < 18 kg (decreased grip strength). RESULTS: We observed decreased grip strength in 13.7% (n = 580) of the participants. Nocturia, urgency, incontinence, and overactive bladder were more common in women with decreased grip strength than in women with normal grip strength. After adjusting for age, comorbidities (hypertension, diabetes, hyperlipidemia), smoking status, alcohol consumption, regular exercise, and stress, nocturia (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.01-1.52), urinary incontinence (OR 1.32, 95% CI 1.01-1.72), and an overactive bladder (OR 1.75, 95% CI 1.35-2.27) were significantly associated with decreased grip strength. CONCLUSIONS: The findings suggest that LUTS, especially nocturia, incontinence, and an overactive bladder are associated with decreased grip strength in women. Therefore, physicians should be aware that patients may not seek help, even if they are uncomfortable, and it is important to obtain a detailed medical history and perform additional tests, even in the absence of complaints, in patients with low grip strength, who are at high risk of LUTS.

Effectiveness of a Mobile Health Management Program With a Challenge Strategy for Improving the Cardiovascular Health of Workers.

BACKGROUND: Workers' cardiovascular health can be influenced by individual willingness to practice healthy behaviors. A mobile health management program with a challenge strategy was administered to promote workers' healthy behaviors among small to medium-sized enterprises. METHODS: A 12-week program consisted of health communication with a challenge strategy was administered to the workers. RESULTS: The intervention group showed significantly improved scores for cardiovascular disease-related health behavior (Z = -2.44, P = 0.013), the job stress contributing factor of inadequate social support (F = 4.10, P = 0.049), and the cardiovascular disease-related health status of waist circumference (t = 3.22, P = 0.004), body fat (Z = -2.23, P = 0.024), and triglycerides (Z = -3.04, P = 0.001). CONCLUSION: This study's significance is its potential for increasing the convenience and joy of participating in intervention programs and acquiring health information through mobile platforms, which are easily accessible to the workers.

Patterns of change in cardiovascular risks of Korean male workers: a 10-year cohort analysis using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) 2.0 database.

OBJECTIVE: Health behaviour is one of the major determinants of cardiovascular diseases in working population. This study was tried to investigate the trend of cardiovascular health level, the relationship between continuous health behaviours, and changes in the risk of cardiovascular diseases of male workers by using a nationwide database. DESIGN: This study is a retrospective cohort study. SETTING AND PARTICIPANTS: The study analysed data of 57 837 male workers whose personal health examination data were continuously traced using Korea's National Health Insurance Service-National Sample Cohort 2.0 database. PRIMARY OUTCOME MEASURES: A 10-year trend for all cardiovascular risks and change for the risks according to the consistent performance of healthy behaviours. RESULTS: The results showed that the risk of being overweight (adjusted OR (aOR) 1.63, 95% CI 1.59 to 1.68) and obese (aOR 1.51, 95% CI 1.47 to 1.56) increased. The index of cardiovascular risk also increased for high fasting glucose (aOR 1.77, 95% CI 1.62 to 1.95) and high total cholesterol (aOR 1.68, 95% CI 1.60 to 1.76), respectively. The risks of high fasting glucose (aOR 2.09, 95% CI 1.40 to 3.13), high triglycerides (aOR 1.27, 95% CI 1.14 to 1.42) and high low-density lipoprotein cholesterol (aOR 1.38, 95% CI 1.14 to 1.66) were increased among high-risk smokers. Similarly, the risk of high total cholesterol (aOR 2.20, 95% CI 1.35 to 3.58) and high triglycerides (aOR 1.42, 95% CI 1.09 to 1.85) were increased among high-risk drinkers. In addition, the increase in the risk of being overweight (aOR 2.20, 95% CI 1.83 to 2.65) and obese (aOR 1.90, 95% CI 1.59 to 2.27) were analysed among who had not consistently exercised. CONCLUSIONS: Since the pattern of change in the level of cardiovascular risk related to the continuous health behaviours of male workers was identified, the findings of the present study can be used as basic data to develop health promotion policies for the population.

The Evolving Policy Debate on Border Closure in Korea.

OBJECTIVES: In this paper, we aimed to investigate the evolving debate over border closure in Korea during the coronavirus disease 2019 (COVID-19) pandemic, to address the main themes associated with border closure, and to discuss the factors that need to be considered when making such decisions. METHODS: We collated and reviewed previously conducted review studies on border closures during infectious disease outbreaks to derive relevant themes and factors. RESULTS: According to our systematic review on border closures and travel restrictions, the effects of such containment efforts are limited. We suggest considering the following factors when determining whether to impose border closure measures: (1) disease characteristics, (2) timeliness of implementation, (3) transmission delay and the basic reproduction number, (4) globalization and pandemics, and (5) social and economic costs. CONCLUSIONS: Our assessment indicates that the effects of border closures are at best temporary and limited. Alternative measures must be contemplated and implemented to suppress the spread of COVID-19 in particular and infectious diseases more broadly.

Implications of electronic cigarette use for depressive mood: A nationwide cross-sectional study.

Despite the controversy surrounding electronic cigarette (e-cigarette) safety, global consumption has been rapidly increasing. We investigated the relationship between e-cigarette use and mental health conditions in adults of various ages.We conducted a secondary data analysis of adults aged 19 to 80 who participated in the first year of the 7th Korea National Health and Nutrition Examination Survey (2016). The total number of participants was 5469, including 3398 non-smokers, 1700 smokers who had never used e-cigarettes, and 371 smokers who had previously used e-cigarettes, selected based on self-report questionnaires. Mental health factors including stress status, depressive mood, suicide plan, and suicide attempt were assessed by self-reported questionnaire. The Patient Health Questionnaire (PHQ-9) was used to assess depressive mood, with a cut-off value of 10. The relationship between e-cigarette use and stress status with depressive mood were analyzed with adjustment for potential confounders.Both male and female smokers who previously used e-cigarettes showed higher levels of stress than non-smokers or smokers who had never used e-cigarettes. The average PHQ-9 score was higher among previous e-cigarette-using smokers relative to non-smokers and smokers who had never used e-cigarettes, regardless of gender. The number of participants with depressive mood was significantly higher in the group of smokers who previously used e-cigarettes. In multivariable-adjusted logistic regression analyses, there was a significantly higher odds ratio for higher stress in male smokers who had previously used e-cigarettes and for depressive mood in female smokers who had previously used e-cigarettes, compared with non-smokers.This study analyzed the association between adult e-cigarette use and mental health conditions, including stress and depressive mood, and showed that e-cigarette use was significantly related to both conditions in men and women.

Tumor-Infiltrating Regulatory T-cell Accumulation in the Tumor Microenvironment Is Mediated by IL33/ST2 Signaling.

Regulatory T cells (Treg) are enriched in the tumor microenvironment (TME) and suppress antitumor immunity; however, the molecular mechanism underlying the accumulation of Tregs in the TME is poorly understood. In various tumor models, tumor-infiltrating Tregs were highly enriched in the TME and had significantly higher expression of immune checkpoint molecules. To characterize tumor-infiltrating Tregs, we performed bulk RNA sequencing (RNA-seq) and found that proliferation-related genes, immune suppression-related genes, and cytokine/chemokine receptor genes were upregulated in tumor-infiltrating Tregs compared with tumor-infiltrating CD4+Foxp3- conventional T cells or splenic Tregs from the same tumor-bearing mice. Single-cell RNA-seq and T-cell receptor sequencing also revealed active proliferation of tumor infiltrating Tregs by clonal expansion. One of these genes, ST2, an IL33 receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL33-directed ST2 signaling induced the preferential proliferation of tumor-infiltrating Tregs and enhanced tumor progression, whereas genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrated the IL33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of Tregs in the TME and suggests that the IL33/ST2 axis may be a potential therapeutic target for cancer immunotherapy.