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.

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.

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.

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].

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.

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.

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.

Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade.

Expression of immune checkpoint ligands (ICLs) is necessary to trigger the inhibitory signal via immune checkpoint receptors (ICRs) in exhausted T cells under tumor immune microenvironment. Nevertheless,to our knowledge, ICL expression profile in cancer patients has not been investigated. Using previously reported RNA-seq data sets, we found that expression of ICLs was patient specific but their coexpression can be patterned in non-small-cell lung cancers (NSCLCs). Since the expression of PD-L1 and poliovirus receptor (PVR) among various ICLs was independently regulated, we could stratify the patients who were treated with anti-PD-1 later into 4 groups according to the expression level of PD-L1 and PVR. Of interest, high PVR and low PVR expressions in PD-L1-expressing patients enriched nonresponders and responders to PD-1 blockade, respectively, helping in further selection of responders. Using a genetically engineered cancer model, we also found that PVR-deficient and PD-L1-sufficient tumor-bearing mice were highly sensitive to anti-PD-1 therapy, whereas PVR-sufficient and PD-L1-deficient tumor-bearing mice were resistant to anti-PD-1 therapy. Taken together, our study provides a concept that combinatorial expression patterns of PVR and PD-L1 are key determinants for PD-1 blockade and furthermore suggest a better therapeutic usage of immune checkpoint blockades (ICBs).

Sex Differences in Cardiovascular Disease Risk by Socioeconomic Status (SES) of Workers Using National Health Information Database.

The socioeconomic status (SES) and health behaviors of workers are associated with the risks of developing obesity, diabetes, hypertension, hyperlipidemia, and other cardiovascular diseases. Herein, we investigated the factors influencing cardiovascular disease (CVD) risk based on the SES of male and female workers. This cross-sectional analysis used the National Health Information Database to assess the associations between gender, SES (income level, residential area), health behaviors, and CVD-related health status of workers, through multinomial logistic regression. Upon analysis of a large volume of data on workers during 2016, the smoking and drinking trends of male and female workers were found to differ, causing different odds ratio (OR) tendencies of the CVD risk. Also, while for male workers, higher ORs of obesity or abdominal obesity were associated with higher incomes or residence in metropolitan cities, for female workers, they were associated with lower incomes or residence in rural areas. Additionally, among the factors influencing CVD risk, lower income and residence in rural areas were associated with higher CVD risk for male and female workers. The study findings imply the importance of developing gender-customized intervention programs to prevent CVD, due to gender-specific associations between CVD-related health status and health behaviors according to SES.

Association Between Electronic Cigarette Use and Levels of High-Sensitivity C-Reactive Protein and Uric Acid.

The present study investigated whether electronic cigarette use, which is becoming increasingly common, was related to systemic inflammation that may lead to cardiovascular disease, similar to conventional cigarette smoking. The study included 1208 men (19-65 years old) who participated in the 7th Korean National Health and Nutrition Examination Survey (2016). The participants were categorized as electronic cigarette users, conventional cigarette users, and nonsmokers. Serum high-sensitivity C-reactive protein was used as an inflammatory index, and uric acid level was used as a metabolic indicator. After adjusting for confounding factors, electronic cigarette use was significantly associated with elevated serum high-sensitivity C-reactive protein levels (ß = 1.326, P = .002), uric acid levels (ß = 0.400, P = .042), and hyperuricemia (uric acid level of >7 mg/mL; odds ratio = 2.67, 95% confidence interval = 1.27-5.58). These findings suggest that electronic cigarette use may be associated with systemic inflammation markers, similar to conventional cigarette use.

Structures of iron-dependent alcohol dehydrogenase 2 from Zymomonas mobilis ZM4 with and without NAD+ cofactor.

The ethanologenic bacterium Zymomonas mobilis ZM4 is of special interest because it has a high ethanol yield. This is made possible by the two alcohol dehydrogenases (ADHs) present in Z. mobilis ZM4 (zmADHs), which shift the equilibrium of the reaction toward the synthesis of ethanol. They are metal-dependent enzymes: zinc for zmADH1 and iron for zmADH2. However, zmADH2 is inactivated by oxygen, thus implicating zmADH2 as the component of the cytosolic respiratory system in Z. mobilis. Here, we show crystal structures of zmADH2 in the form of an apo-enzyme and an NAD+­cofactor complex. The overall folding of the monomeric structure is very similar to those of other functionally related ADHs with structural variations around the probable substrate and NAD+ cofactor binding region. A dimeric structure is formed by the limited interactions between the two subunits with the bound NAD+ at the cleft formed along the domain interface. The catalytic iron ion binds near to the nicotinamide ring of NAD+, which is likely to restrict and locate the ethanol to the active site together with the oxidized Cys residue and several nonpolar bulky residues. The structures of the zmADH2 from the proficient ethanologenic bacterium Z. mobilis, with and without NAD+ cofactor, and modeling ethanol in the active site imply that there is a typical metal-dependent catalytic mechanism.

A case report of a chemical burn due to the misuse of glacial acetic acid.

As young and elastic skin is what everyone dreams of, various measures have been implemented including chemical, laser resurfacing and dermabrasion to improve the condition of ageing skin. However, the high cost of these procedures prevents the poor from having access to treatment. Glacial acetic acid is widely used as a substitute for chemical peeling because it is readily easily available and affordable. However, its use can result in a number of serious complications. A 28-year-old female patient was admitted to our hospital with deep second-degree chemical burns on her face caused by the application of a mixture of glacial acetic acid and flour for chemical peeling. During a 6-month follow-up, hypertrophic scarring developed on the both nasolabial folds despite scar management. Glacial acetic acid is a concentrated form of the organic acid, which gives vinegar its sour taste and pungent smell, and it is also an important reagent during the production of organic compounds. Unfortunately, misleading information regarding the use of glacial acetic acid for chemical peeling is causing serious chemical burns. Furthermore, there is high possibility of a poor prognosis, which includes inflammation, hypertrophic scar formation and pigmentation associated with its misuse. Therefore, we report a case of facial chemical burning, due to the misuse of glacial acetic acid, and hope that this report leads to a better understanding regarding the use of this reagent.

FAF1 suppresses IkappaB kinase (IKK) activation by disrupting the IKK complex assembly.

This study presents a molecular inhibitory mechanism by Fas-associated factor 1 (FAF1) on IkappaB kinase (IKK) activation, where divergent NF-kappaB-activating stimuli converge. FAF1 interacts with IKKbeta in response to proinflammatory stimuli (such as tumor necrosis factor-alpha, interleukin-1beta, and lipopolysaccharide) and suppresses IKK activation. Interaction of the leucine-zipper domain of IKKbeta with FAF1 affected the IKK heterocomplex (IKKalpha/beta) and homocomplex (IKKalpha/alpha, IKKbeta/beta) formations and attenuated IKKgamma recruitment to IKKbeta. Overexpression of FAF1 reduced the level of IKKbeta activity, whereas FAF1 depletion increased the activity. These results indicate that FAF1 inhibits IKK activation and its downstream signaling by interrupting the IKK complex assembly through physical interaction with IKKbeta. Taken together, FAF1 robustly suppresses NF-kappaB activation through the inhibition of IKK activation in combination with previously reported cytoplasmic retention of NF-kappaB p65 (Park, M. Y., Jang, H. D., Lee, S. Y., Lee, K. J., and Kim, E. (2004) J. Biol. Chem. 279, 2544-2549). Such redundant suppression would prevent inadvertent activation of the NF-kappaB pathway.

A genetic link between cold responses and flowering time through FVE in Arabidopsis thaliana.

Cold induces expression of a number of genes that encode proteins that enhance tolerance to freezing temperatures in plants. A cis-acting element responsive to cold and drought, the C-repeat/dehydration-responsive element (C/DRE), was identified in the Arabidopsis thaliana stress-inducible genes RD29A and COR15a and found in other cold-inducible genes in various plants. C/DRE-binding factor/DRE-binding protein (CBF/DREB) is an essential component of the cold-acclimation response, but the signaling pathways and networks are mostly unknown. Here we used targeted genetic approach to isolate A. thaliana mutants with altered cold-responsive gene expression (acg) and identify ACG1 as a negative regulator of the CBF/DREB pathway. acg1 flowered late and had elevated expression of FLOWERING LOCUS C (FLC), a repressor of flowering encoding a MADS-box protein. We showed that acg1 is a null allele of the autonomous pathway gene FVE. FVE encodes a homolog of the mammalian retinoblastoma-associated protein, a component of a histone deacetylase (HDAC) complex involved in transcriptional repression. We also showed that plants sense intermittent cold stress through FVE and delay flowering with increasing expression of FLC. Dual roles of FVE in regulating the flowering time and the cold response may have an evolutionary advantage for plants by increasing their survival rates.