Effectiveness of optimized food-based recommendation promotion to improve nutritional status and lipid profiles among Minangkabau women with dyslipidemia: A cluster-randomized trial.

BACKGROUND: In women of Minangkabau ethnicity, a high prevalence of dyslipidemia, overweight, and obesity is thought to be closely related to poor dietary practices. Promotion of local specific food-based recommendations (FBRs) was previously found to be effective in improving dietary practice and nutrient intakes related to dyslipidemia. This study aimed to describe the effects of the FBR promotion on the nutritional status and lipid profiles of Minangkabau women with dyslipidemia. METHODS: We used a cluster-randomized design with a total subject of 123 Minangkabau women of reproductive age with dyslipidemia. They were recruited from 16 sub-villages and assigned to either the FBR group (n = 61) or the non-FBR group (n = 62). Data on body weight, height, waist circumference, and lipid profiles were collected at the baseline and the end of the trial. Linear mixed model analysis was used to analyze the effect of the intervention on nutritional status and lipid profiles. RESULTS: The mean effect (95% confidence interval) of the intervention on body weight, body mass index, and waist circumference for the FBR group versus the non-FBR group were -1.1 (-1.8; -0.39) kg, -0.43(-0.76; -0.11) kg/m2 and -2.1(-3.7;-0.46) mm respectively (p <0.05). The Castelli's index in the FBR group improved, but there was no significant between-group difference in the change of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides at the end of the intervention. CONCLUSION: The promotion of the FBRs positively impact the nutritional status but did not significantly affect the blood lipid profile of Minangkabau women with dyslipidemia. TRIAL REGISTRATION: The trial was retrospectively registered at ClinicalTrials.gov Protocol Registration and Result System (PRS) as NCT04085874, in September 2019.

Fat and vitamin E intake affect multidrug-resistant tuberculosis patients' quality of life: A cross-sectional study.

OBJECTIVE: To determine the association between fat and vitamin E intake with quality of life in patients with pulmonary MDR-TB. METHODS: This was a cross-sectional study conducted at Dr. M. Goenawan Partowidig do Hospital, Cisarua, Indonesia, from April to May 2019. Ninety-two patients were enrolled in this study. Fat intake was assessed using 24 hours food recall, vitamin E intake was assessed using a semi-quantitative food frequency questionnaire (FFQ), and quality of life was obtained by a short form 36 questionnaire (SF 36). Data were analyzed using Pearson and Spearman correlation test. RESULTS: Subjects' mean fat intake was 32.9 ± 11.1% of total calories per-day, which meant that most of the subjects consumed enough fat. Mean vitamin E intake was 4.6 ± 2.7 mg/day, which did not meet the recommended dietary allowance (RDA). The mean quality of life score was 47.22 ± 14.9. There was a significant association between fat intake and quality of life (r = 0.22; p = 0.032) and vitamin E intake with quality of life (r = 0.22, p = 0.035). CONCLUSIONS: There is a significant association between fat and vitamin E intake with quality of life among pulmonary MDR-TB patients. Further research is needed to evaluate the intervention by modifying food intake and giving vitamin E to MDR-TB patients.

Promotion of optimized food-based recommendations to improve dietary practices and nutrient intakes among Minangkabau women of reproductive age with dyslipidemia.

BACKGROUND AND OBJECTIVES: Using a linear programming approach, an optimized food-based recommendations (FBRs) had been formulated for Minangkabau women of reproductive age with dyslipidemia in Indonesia. This study aimed to assess the effectiveness of the promotion of the FBRs for improving dietary practices and nutrient intakes. METHODS AND STUDY DESIGN: A community-based, clustered-randomized trial was conducted among Minangkabau women of reproductive age (20-44 years) with dyslipidemia. The subjects were assigned either into the FBR group (n=48), or the non-FBR group (n=54). Baseline and end-line dietary data were assessed through interviews using a one-week semiquantitative food frequency questionnaire (SQ-FFQ) and two replicate 24-hour dietary recalls. The changes in dietary practice and nutrient intakes were analysed using ANCOVA test. RESULTS: Significant changes were observed (p<0.005) in the consumption of the promoted food items and subgroups (sea fish, soy protein, dark green leafy vegetables, and potatoes). Significant changes were also observed in nutrient intake, especially energy intake from carbohydrates and unsaturated fatty acids (total PUFA, MUFA, n-3 and n-6 fatty acids), as well as the dietary P/S ratio and fiber intake. CONCLUSIONS: With current dietary practices, intakes of some typical problem nutrients such as n-6, zinc, iron, and fiber still could not achieve 100% of the RNIs, while the intake of SFA still exceeded the recommended intake. Further approaches are needed to expand the population food basket and promote behavioral change to address established cultural food habits, including reducing the use of cooking oil in food preparation and increasing vegetable consumption.

Dasatinib Suppresses TGFß-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis.

PURPOSE: Transforming growth factor ß (TGFß)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFß1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo. METHODS: TGFß1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM). RESULTS: A549 and BEAS-2B cells exposed to TGFß1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFß1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model. CONCLUSIONS: These findings suggest that DAS inhibited TGFß-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFß/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

Regional heterogeneity in response of airway epithelial cells to cigarette smoke.

BACKGROUND: Cigarette smoke (CS) exposure causes an abnormal inflammatory response, which can result in chronic obstructive pulmonary disease (COPD). Previous studies show that this disorder predominantly occurs in peripheral or small-airway areas, whereas the same condition has not been identified in the larger airways during the course of COPD. However, the different biochemical and genetic alterations occurring in response to CS exposure among airway epithelial cells from different sites in the lungs have not been fully investigated. METHODS: Human small airway epithelial cells (SAECs) and normal human bronchial epithelial cells (NHBEs) were exposed to CS extract (CSE), and microarray analysis was used to determine gene- and protein-expression profiles and identify alterations following CSE exposure in both cell types. An in vivo smoking experiment was also performed to confirm differential responses to CS between sites in the lung. RESULTS: Microarray analysis of SAECs and NHBEs following 24 h of CSE exposure showed that inflammatory related pathways and terms, including the tumor necrosis factor-signaling pathway, were overrepresented, especially in SAECs. Clustering analysis highlighted prostaglandin-endoperoxide synthase-2 [also known as cyclooxygenase (COX)-2] as a gene specifically upregulated in SAECs, with COX-2 mRNA and protein expression significantly elevated by CSE exposure in SAECs (3.1- and 3.1-fold, respectively), but not in NHBEs. Furthermore, time-course analysis of COX-2 expression revealed earlier increases in SAECs compared with NHBEs following CS exposure. Short-term exposure of mouse lungs to CS was found to predominantly induce COX-2 expression in the small airway. CONCLUSIONS: The small airway is more susceptible to CSE than the large airway and could be the initial site of development of CS-related respiratory diseases, such as COPD.

Hydrogen-rich pure water prevents cigarette smoke-induced pulmonary emphysema in SMP30 knockout mice.

Chronic obstructive pulmonary disease (COPD) is predominantly a cigarette smoke (CS)-triggered disease with features of chronic systemic inflammation. Oxidants derived from CS can induce DNA damage and stress-induced premature cellular senescence in the respiratory system, which play significant roles in COPD. Therefore, antioxidants should provide benefits for the treatment of COPD; however, their therapeutic potential remains limited owing to the complexity of this disease. Recently, molecular hydrogen (H2) has been reported as a preventive and therapeutic antioxidant. Molecular H2 can selectively reduce hydroxyl radical accumulation with no known side effects, showing potential applications in managing oxidative stress, inflammation, apoptosis, and lipid metabolism. However, there have been no reports on the efficacy of molecular H2 in COPD patients. In the present study, we used a mouse model of COPD to investigate whether CS-induced histological damage in the lungs could be attenuated by administration of molecular H2. We administered H2-rich pure water to senescence marker protein 30 knockout (SMP30-KO) mice exposed to CS for 8 weeks. Administration of H2-rich water attenuated the CS-induced lung damage in the SMP30-KO mice and reduced the mean linear intercept and destructive index of the lungs. Moreover, H2-rich water significantly restored the static lung compliance in the CS-exposed mice compared with that in the CS-exposed H2-untreated mice. Moreover, treatment with H2-rich water decreased the levels of oxidative DNA damage markers such as phosphorylated histone H2AX and 8-hydroxy-2'-deoxyguanosine, and senescence markers such as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase inhibitor 1, and ß-galactosidase in the CS-exposed mice. These results demonstrated that H2-rich pure water attenuated CS-induced emphysema in SMP30-KO mice by reducing CS-induced oxidative DNA damage and premature cell senescence in the lungs. Our study suggests that administration of molecular H2 may be a novel preventive and therapeutic strategy for COPD.

Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice.

OBJECTIVE: We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. APPROACH AND RESULTS: The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1α was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11(-/-) mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11(-/-) mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1α was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1α knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. CONCLUSIONS: LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice. The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension.

Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells.

Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.

Implications of Insulin-like Growth Factor 1 Receptor Activation in Lung Cancer.

Insulin-like growth factor 1 receptor (IGF1R) has been intensively investigated in many preclinical studies using cell lines and animal models, and the results have provided important knowledge to help improve the understanding of cancer biology. IGF1R is highly expressed in patients with lung cancer, and high levels of circulating insulin-like growth factor 1 (IGF1), the main ligand for IGF1R, increases the risk of developing lung malignancy in the future. Several phase I clinical trials have supported the potential use of an IGF1R-targeted strategy for cancer, including lung cancer. However, the negative results from phase III studies need further attention, especially in selecting patients with specific molecular signatures, who will gain benefits from IGF1R inhibitors with minimal side effects. This review will discuss the basic concept of IGF1R in lung cancer biology, such as epithelial-mesenchymal transition (EMT) induction and cancer stem cell (CSC) maintenance, and also the clinical implications of IGF1R for lung cancer patients, such as prognostic value and cancer therapy resistance.

TWEAK enhances TGF-ß-induced epithelial-mesenchymal transition in human bronchial epithelial cells.

BACKGROUND: Chronic airway inflammatory disorders, such as asthma, are characterized by airway inflammation and remodeling. Chronic inflammation and damage to the airway epithelium cause airway remodeling, which is associated with improper epithelial repair, and is characterized by elevated expression of transforming growth factor-ß (TGF-ß). Epithelial-mesenchymal transition (EMT) is an important mechanism during embryonic development and tissue remodeling whereby epithelial cells gain the capacity to increase motility by down-regulation of epithelial markers and up-regulation of mesenchymal markers. TGF-ß is a central inducer of EMT, and TGF-ß-induced EMT is enhanced by pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß. We investigated whether the pro-inflammatory cytokine TWEAK (TNF-like weak inducer of apoptosis) enhanced TGF-ß1-induced EMT in the human bronchial epithelial cell line BEAS-2B. METHODS: Quantitative RT-PCR and western blotting were used to define alterations in epithelial and mesenchymal marker expression in BEAS-2B cells. The cells were assessed for 48 h after stimulation with TGF-ß1 alone or in combination with TWEAK. RESULTS: TGF-ß1 induced spindle-like morphology and loss of cell contact, and reduced the expression of epithelial marker E-cadherin and increased the expression of mesenchymal markers N-cadherin and vimentin. Our data, for the first time, show that TWEAK reduced the expression of E-cadherin, and that co-treatment with TGF-ß1 and TWEAK enhanced the TGF-ß1-induced features of EMT. Moreover, hyaluronan synthase 2 expression was up-regulated by a combination with TGF-ß1 and TWEAK, but not TNF-α. We also demonstrated that the Smad, p38 MAPK, and NF-κB signaling pathways, and the transcriptional repressor ZEB2 might mediate N-cadherin up-regulation by TGF-ß1 in combination with TWEAK. CONCLUSIONS: These findings suggest that the pro-inflammatory cytokine TWEAK and TGF-ß1 have synergistic effects in EMT and may contribute to chronic airway changes and remodeling.

Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer.

Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT-related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor ß1 (TGFß1). Inhibition of hypoxia-inducible factor 1α (HIF1α) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT.

Dynamic Changes in Body Composition and Protein Intake in Epithelial Ovarian Cancer Patients Undergoing Chemotherapy: A Preliminary Study.

BACKGROUND: Ovarian cancer patients often face poor nutritional status, with body composition (BC) serving as a significant prognostic indicator. Skeletal muscle mass (SMM) and fat-free mass (FFM) are crucial predictors of both survival and hospitalization duration. Increasing protein intake has been linked to improvements in SMM and FFM. OBJECTIVE: This study aimed to document the alterations in BC parameters among ovarian cancer patients undergoing chemotherapy and correlate these changes with their nutrient intake. METHODS: Twelve female patients with stage III ovarian cancer who received first-line chemotherapy were categorized based on their body mass indices (BMI). BC parameters were assessed using an 8-point bioelectrical impedance analysis with a frequency of 50 Hz-60 Hz and measurement impedance range of 10 Ω-1000 Ω. Nutrient intake (energy, protein, fat, and carbohydrate) was assessed before (T0), during the 3rd (T3), and 6th cycle of chemotherapy (T6) through 24-hour food recall. RESULTS: Significant increases in body weight (BW)were observed in the underweight group (from 40.9 to 46.8 kg, p=0.001), concomitant with enhancements in all BC parameters. While changes were noted in SMM, they were not statistically significant (p=0.105).Among the underweight group, a protein intake above 1.2 g/kg BW led to an uptrend trend in SMM. Conversely, FFM in overweight/obese patients decreased significantly (from 37.6 to 36.4 kg, p=0.005) due to a a reduction in body water. Throughout chemotherapy, fat mass (FM), visceral fat (VAT), and phase angle (PhA) increased in all patient groups, reflecting heightened fat and carbohydrate intake. CONCLUSION: Among stage III ovarian cancer patients, BC undergoes dynamic changes dynamically during the course of chemotherapy, with more pronounced enhancements observed in FFM among underweight patients. Notably, improvements in PhA, SMM or FFM were particularly evident among underweight patients with a protein intake above 1.2 g/kg BW.

The Fungal and Bacterial Interface in the Respiratory Mycobiome with a Focus on Aspergillus spp.

The heterogeneity of the lung microbiome and its alteration are prevalently seen among chronic lung diseases patients. However, studies to date have primarily focused on the bacterial microbiome in the lung rather than fungal composition, which might play an essential role in the mechanisms of several chronic lung diseases. It is now well established that Aspergillus spp. colonies may induce various unfavorable inflammatory responses. Furthermore, bacterial microbiomes such as Pseudomonas aeruginosa provide several mechanisms that inhibit or stimulate Aspergillus spp. life cycles. In this review, we highlighted fungal and bacterial microbiome interactions in the respiratory tract, with a focus on Aspergillus spp.

Severe acute respiratory syndrome coronavirus-2 antibody response after Moderna vaccine booster on healthcare providers.

INTRODUCTION: As an endeavor to control SARS-CoV-2 infection, the Moderna vaccine booster was given to healthcare workers to prevent reinfection and reduce the risk of complications from COVID-19. A heterologous booster vaccine is also thought to provide better protection against the current SARS-CoV-2 variants of concern. However, research that evaluates the effectiveness of the Moderna vaccine booster and the resulting SARS-CoV-2 antibody concentration is needed. OBJECTIVE: To evaluate the concentration of SARS-CoV-2 antibodies after the Moderna vaccine booster and the severity of SARS-CoV-2 infection before and after the Moderna vaccine booster. RESULTS: A total of 93 healthcare providers who received Moderna vaccine booster were included in the study. Examination of antibody concentration 3 months after the booster showed an average concentration of 10081.65 U/mL. There was an increase in antibody concentration before the booster and 3 months after, from a median of 1.7 U/mL to 9540 U/mL. Every subject showed a statistically significant increment of antibody concentration 3 months after the booster (p < 0.01). Thirty-seven (39.8%) subjects received two doses of the Sinovac vaccine and were confirmed to have COVID-19 with the Delta variant. After the booster, 26 (28%) subjects were infected with the Omicron Variant. Among the subjects who received two doses of the Sinovac vaccine and were confirmed with COVID-19, 36 (30.1%) had mild symptoms, and 1 (1.1%) was asymptomatic. CONCLUSIONS: Heterologous Moderna vaccine booster effectively increases antibody response against SARS-CoV-2 variants and shows mild symptoms of COVID-19 infection.

Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene, such as exon 19 deletion mutations, are important factors in determining therapeutic responses to gefitinib in non-small-cell lung cancer (NSCLC). However, some patients have activating mutations in EGFR and show poor responses to gefitinib. In this study, we examined three NSCLC cell lines, HCC827, PC9, and HCC2935, that expressed an EGFR exon 19 deletion mutation. All cells expressed mutant EGFR, but the PC9 and HCC2935 cells also expressed wild-type EGFR. The HCC827 cells were highly sensitive to gefitinib under both normoxia and hypoxia. However, the PC9 and HCC2935 cells were more resistant to gefitinib under hypoxic conditions compared to normoxia. Phosphorylation of EGFR and ERK was suppressed with gefitinib treatment to a lesser extent under hypoxia. The expression of transforming growth factor-α (TGFα) was dramatically upregulated under hypoxia, and the knockdown of TGFα or hypoxia-inducible factor-1α (HIF1α) reversed the resistance to gefitinib in hypoxic PC9 and HCC2935 cells. Finally, introduction of the wild-type EGFR gene into the HCC827 cells caused resistance to gefitinib under hypoxia. This phenomenon was also reversed by the knockdown of TGFα or HIF1α. Our results indicate that hypoxia causes gefitinib resistance in EGFR-mutant NSCLC through the activation of wild-type EGFR mediated by the upregulation of TGFα. The presence of wild-type and mutant EGFR along with tumor hypoxia are important factors that should be considered when treating NSCLC patients with gefitinib.

Hochuekkito (TJ-41), a Kampo Formula, Ameliorates Cachexia Induced by Colon 26 Adenocarcinoma in Mice.

Cachexia, a major cause of cancer-related death, is characterized by depletion of muscle and fat tissues, anorexia, asthenia, and hypoglycemia. Recent studies indicate that secretions of proinflammatory cytokines such as interleukin-6 (IL-6) play a crucial role in cachexia development, and that these cytokines are secreted from not only cancer cells but also host cells such as macrophages. In this study, we investigated the therapeutic effects of hochuekkito, a Kampo formula, on cachexia induced by colon 26 adenocarcinoma in mice. Hochuekkito treatment did not inhibit tumor growth, but significantly attenuated the reduction in carcass weight, food and water intake, weight of the gastrocnemius muscle and fat tissue around the testes, and decrease of serum triglyceride level compared with controls. Furthermore, hochuekkito treatment significantly reduced serum IL-6 level and IL-6 expression level in macrophages in tissues surrounding the tumor. In vitro studies showed that hochuekkito suppressed the production of IL-6 by THP-1 or RAW264.7 macrophage cells, although it did not affect IL-6 production by colon 26 carcinoma cells. These results suggest that hochuekkito inhibits the production of proinflammatory cytokines, particularly IL-6, by host cells such as macrophages. Therefore, hochuekkito may be a promising anticachectic agent for the treatment of patients with cancer.

Challenges on tuberculosis care in health care facilities during COVID-19 pandemic: Indonesian perspective.

Indonesia is among the top three countries globally with the highest tuberculosis burden. During the past decades, Indonesian health authorities have struggled to improve tuberculosis care quality in health care facilities by optimizing the regulation and strengthening the private sector contributions. The coronavirus disease 2019 (COVID-19) pandemic has hardly affected the Indonesian health care system, including the National Tuberculosis Control Program. While the end of the COVID-19 pandemic in Indonesia is uncertain, the measure to control tuberculosis must not be weakened. Early identification and measurement of the problem size are essential to decide the most appropriate approach to maintain the sustainability of National Tuberculosis Control Program, particularly in health care facilities during the COVID-19 pandemic. This article points out the possible threats to the sustainability of TB care in Indonesia during the COVID-19 pandemic, including some approaches to overcome those problems.

Clinical characteristics and quality of life of persistent symptoms of COVID-19 syndrome in Indonesia.

Introduction: Coronavirus disease-2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) manifests in a broad clinical spectrum. COVID-19 survivors report various symptoms up to several months after being infected. The purpose of this study was to determine the prevalence of persistent COVID-19 syndrome in Indonesia, the factors that influence the incidence, and the quality of life. Methods: This was a cross-sectional study with an online questionnaire conducted in January 2021. Inclusion criteria were: adult Indonesian citizens who had recovered from COVID-19, and were confirmed negative by RT-PCR of nasal swabs or had undergone an isolation period for a minimum of 14 days. Data analysis was performed by the Chi-square test, followed by multivariate analysis with the backward likelihood ratio method. Results: From a total of 385 respondents, 256 (66.5%) experienced persistent COVID-19 syndrome. The most prevalent symptoms were fatigue (29.4%), cough (15.5%), and muscle pain (11.2%). Of the five aspects of quality of life, the most commonly reported aspects were pain/discomfort and anxiety/depression. The risk of persistent COVID-19 syndrome was significantly higher in subjects with older age, comorbidities, higher clinical severity, previous treatment in hospital, presence of pneumonia, and those who had required oxygen therapy. In the multivariate analysis, the most influential factor for the incidence of persistent COVID-19 syndrome was pneumonia (aOR 2.31, 95% CI 1.29-4.11, p<0.002). Conclusions: The prevalence of the persistent COVID-19 syndrome in Indonesia was high, which affects the quality of life of COVID-19 survivors. Pneumonia was the main factor that influenced the incidence of persistent COVID-19 syndrome. Further research with a larger sample size and a longer study time is recommended to control COVID-19 and its impact on the health and quality of life of COVID-19 survivors.

Zinc-finger E-box-binding homeobox 1 (ZEB1) plays a crucial role in the maintenance of lung cancer stem cells resistant to gefitinib.

BACKGROUND: Zinc-finger E-box-binding homeobox 1 (ZEB1) is an important regulator of epithelial-mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR-200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT-mediated acquired resistance to gefitinib in EGFR-mutant non-small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear. METHODS: PC9 and HCC827 NSCLC cell lines were treated with high concentrations of gefitinib, and surviving cells were referred to as "gefitinib-resistant persisters" (GRPs). ZEB1 knockdown or overexpression was performed to determine the biological significance of ZEB1 in the CSC features of GRPs, and animal models were studied for in vivo validation. Expression of ZEB1, BMI1, and ALDH1A1 was analyzed by immunohistochemistry in tumor specimens from NSCLC patients with acquired resistance to gefitinib. RESULTS: GRPs had characteristic features of mesenchymal and CSC phenotypes with high expression of ZEB1 and BMI1, and decreased miR-200c, in vitro and in vivo. ZEB1 silencing attenuated the suppression of miR-200c, resulting in the reduction in BMI1 and reversed the mesenchymal and CSC features of GRPs. Furthermore, ZEB1 overexpression induced EMT and increased the levels of CD133- and BMI1-positive GRPs in vitro and gefitinib resistance in vivo. Finally, ZEB1, BMI1, and ALDH1A1 were highly expressed in tumor specimens from EGFR-mutant NSCLC patients with gefitinib resistance. CONCLUSIONS: ZEB1 plays an important role in gefitinib-resistant lung CSCs with EMT features via regulation of miR-200c and BMI1.

Tranilast Inhibits Pulmonary Fibrosis by Suppressing TGFß/SMAD2 Pathway.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) ß-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFß expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified. METHODS: We investigated the in vitro effect of tranilast on ECM production and TGFß/SMAD2 pathway in TGFß2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin. RESULTS: Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFß2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFß, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice. CONCLUSION: These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFß/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.