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Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification ( n  = 17; 16%) and EGFR C797S mutations ( n  = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted. In the phase III FLAURA study (NCT02296125), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib provided superior progression-free survival versus comparator EGFR-TKIs in patients with NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to first-line osimertinib in patients from the FLAURA trial.

Pneumonia leads to changes in body composition and weakness due to the malnourished condition. In addition, patient family caregivers always have a lack of nutritional information, and they do not know how to manage patients’ nutritional intake during hospitalization and after discharge. Most intervention studies aim to provide nutritional support for older patients. However, whether long-term nutritional intervention by dietitians and caregivers from patients’ families exert clinical effects—particularly in malnourished pneumonia—on nutritional status and readmission rate at each interventional phase, from hospitalization to postdischarge, remains unclear. To investigate the effects of an individualized nutritional intervention program (iNIP) on nutritional status and readmission rate in older adults with pneumonia during hospitalization and three and six months after discharge. Eighty-two malnourished older adults with a primary diagnosis of pneumonia participated. Patients were randomly allocated to either a nutrition intervention (NI) group or a standard care (SC) group. Participants in the NI group received an iNIP according to energy and protein intake requirements in addition to dietary advice based on face-to-face interviews with their family caregivers during hospitalization. After discharge, phone calls were adopted for prescribing iNIPs. Anthropometry (i.e., body mass index, limb circumference, and subcutaneous fat thickness), blood parameters (i.e., albumin and total lymphocyte count), hospital stay, Mini-Nutritional Assessment-Short Form (MNA-SF) score, target daily calorie intake, total calorie intake adherence rate, and three-major-nutrient intakes were assessed during hospitalization and three and six months after discharge. Both groups received regular follow-up through phone calls. Furthermore, the rate of readmission resulting from pneumonia was recorded after discharge. During hospital stay, the NI group showed significant increases in daily calorie intake, total calorie intake adherence rate, and protein intake compared with the SC group (p < 0.05); however, no significant difference was found in anthropometry, blood biochemical values, MNA-SF scores, and hospital stay. At three and six months after discharge, the NI group showed significantly higher daily calorie intake and MNA-SF scores (8.2 vs. 6.5 scores at three months; 9.3 vs. 7.6 scores at six months) than did the SC group (p < 0.05). After adjusting for sex, the readmission rate for pneumonia significantly decreased by 77% in the NI group compared with that in the SC group (p = 0.03, OR: 0.228, 95% CI: 0.06–0.87). A six-month iNIP under dietitian and patient family nutritional support for malnourished older adults with pneumonia can significantly improve their nutritional status and reduce the readmission rate.

Epigenetics is defined as the heritable phenotypic changes which do not involve alterations in the DNA sequence, including histone modifications, non-coding RNAs, and DNA methylation. Recently, much attention has been paid to the role of hypoxia-mediated epigenetic regulation in cancer, pulmonary hypertension, adaptation to high altitude, and cardiorenal disease. In contrast to sustained hypoxia, chronic intermittent hypoxia with re-oxygenation (IHR) plays a major role in the pathogenesis of various adverse consequences of obstructive sleep apnea (OSA), resembling ischemia re-perfusion injury. Nevertheless, the role of epigenetics in the pathogenesis of OSA is currently underexplored. This review proposes that epigenetic processes are involved in the development of various adverse consequences of OSA by influencing adaptive potential and phenotypic variability under conditions of chronic IHR. Improved understanding of the interaction between genetic and environmental factors through epigenetic regulations holds great value to give deeper insight into the mechanisms underlying IHR-related low-grade inflammation, oxidative stress, and sympathetic hyperactivity, and clarify their implications for biomedical research.

The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in obstructive sleep apnea (OSA). Global histone modifications, and their modifying enzyme expressions were assessed in peripheral blood mononuclear cells from 56 patients with OSA and 16 matched subjects with primary snoring (PS). HIF-1α gene promoter-specific H3K36Ac enrichment was assessed in another cohort (28 OSA, 8 PS). Both global histone H3K23Ac and H3K36Ac expressions were decreased in OSA patients versus PS subjects. H3K23Ac expressions were further decreased in OSA patients with prevalent hypertension. HDAC1 expressions were higher in OSA patients, especially in those with excessive daytime sleepiness, and reduced after more than 6 months of continuous positive airway pressure treatment. H3K79me3 expression was increased in those with high C-reactive protein levels. Decreased KDM6B protein expressions were noted in those with a high hypoxic load, and associated with a higher risk for incident cardiovascular events or hypertension. HIF-1α gene promoter-specific H3K36Ac enrichment was decreased in OSA patients versus PS subjects. In vitro intermittent hypoxia with re-oxygenation stimuli resulted in HDAC1 over-expression and HIF-1α gene promoter-specific H3K36Ac under-expression, while HDAC1 inhibitor, SAHA, reversed oxidative stress through inhibiting NOX1. In conclusions, H3K23/H3K36 hypoacetylation is associated with the development of hypertension and disease severity in sleep-disordered breathing patients, probably through up-regulation of HDAC1, while H3K79 hypermethylation is associated with higher risk of cardiovascular diseases, probably through down-regulation of KDM6B.

Background The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors. Methods The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8 + T lymphocytes and FOXP3 + regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining. Results Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS. Conclusions In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.

The purpose of this study is to explore the anti-inflammatory role of microRNAs (miR)-21 and miR-23 targeting the TLR/TNF-α pathway in response to chronic intermittent hypoxia with re-oxygenation (IHR) injury in patients with obstructive sleep apnea (OSA). Gene expression levels of the miR-21/23a, and their predicted target genes were assessed in peripheral blood mononuclear cells from 40 treatment-naive severe OSA patients, and 20 matched subjects with primary snoring (PS). Human monocytic THP-1 cell lines were induced to undergo apoptosis under IHR exposures, and transfected with miR-21-5p mimic. Both miR-21-5p and miR-23-3p gene expressions were decreased in OSA patients as compared with that in PS subjects, while TNF-α gene expression was increased. Both miR-21-5p and miR-23-3p gene expressions were negatively correlated with apnea hypopnea index and oxygen desaturation index, while TNF-α gene expression positively correlated with apnea hypopnea index. In vitro IHR treatment resulted in decreased miR-21-5p and miR-23-3p expressions. Apoptosis, cytotoxicity, and gene expressions of their predicted target genes—including TNF-α, ELF2, NFAT5, HIF-2α, IL6, IL6R, EDNRB, and TLR4—were all increased in response to IHR, while all were reversed with miR-21-5p mimic transfection under IHR condition. The findings provide biological insight into mechanisms by which IHR-suppressed miRs protect cell apoptosis via inhibit inflammation, and indicate that over-expression of the miR-21-5p may be a new therapy for OSA.

Background This study aims to explore the role of autophagy-associated genes (ATG) and their epigenetic markers in the progression of mycobacterium tuberculosis ( M. tb ) infection, and to test the effects of de-methylation agents on macrophage functions against TB. Methods ATG expressions and their gene promoter DNA methylation levels of blood immune cells were measured in 60 patients with active pulmonary TB disease, 31 subjects with latent TB infection (LTBI), and 15 non-infected healthy subjects (NIHS). An in vitro monocytic THP-1 cell culture model under M. tb -specific antigen stimuli was applied. Results LC3B protein expression of blood M1/M2a monocyte, ATG5 protein expression of M2a, and mean DNA methylation levels of the LC3B gene promoter region of peripheral blood mononuclear cells were all increased in active TB patients versus either LTBI or NIHS group. The LC3B methylation levels were negatively correlated with its protein expressions. The discrimination of active TB disease from LTBI or NIHS was optimally captured by prediction scores, which combined LC3B (+) percentage of blood M1/M2a monocyte, LC3B gene promoter DNA methylation level, male gender, and body mass index. LC3B and ATG5 expressions of both blood M2a and neutrophil were decreased after 6-month anti-TB therapy, but hypermethylated LC3B gene promoter persisted. In vitro 5-Aza-2’-deoxycytidine treatment improved bactericidal, apoptosis and phagocytosis functions through augmenting autophagy flux via mechanisms other than demethylation of the LC3B gene promoter in THP-1 cells. Conclusions Increased LC3B expression and LC3B gene promoter hypermethylation may serve as biomarkers for progression of M. tb infection, while use of de-methylation agent may be a potential approach to host-directed immunotherapy in active TB disease.

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ ZNF323 (− 296), and hypomethylated SEPT8 (− 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (− 173) gene and hypomethylated CYSLTR1 (+ 348)/ CCDC88C (+ 125,722)/ ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (− 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (− 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2′-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

Governmental non-pharmaceutical interventions (NPIs) and concerns regarding COVID-19 infection greatly affected population mobility during the COVID-19 pandemic. This study analyzed the effect of the COVID-19 pandemic on the business operations of Taiwan High Speed Rail (THSR) and 7-Eleven stores in Taiwan. We collected data from COVID-19 Mobility Reports published by Google, the Our World in Data website, and the monthly financial reports of THSR and 7-Eleven stores. The findings revealed that the mean population mobility at transit stations decreased by over 50% during the pandemic. Changes in population mobility were significantly associated with the reproduction rate (7-day rolling average) and with the daily number of new confirmed cases per million people (7-day rolling average). The operating income of THSR was significantly associated with the decrease in population mobility at transit stations. The monthly and annual operating income of THSR in 2020, 2021, and 2022 (during the pandemic) were significantly lower than those in 2019 (before the pandemic). THSR’s monthly operating income was lowest compared with the 2019 value during the Alpha variant period (89.89% lower). No significant correlation was noted between the operating income of 7-Eleven stores and population mobility. Moreover, no significant differences were discovered between the monthly and annual operating incomes of 7-Eleven stores in 2019 and those in 2020, 2021, and 2022. Implementation of the policy of coexistence with the virus by the Taiwanese government began in May 2022, and from May 2022 to October 2022, the monthly income of 7-Eleven stores was higher than that in 2019 whereas the monthly income of THSR began lower than and then slowly increased to the level in 2019. In conclusion, the operating performance of THSR was closely related to population mobility and government NPIs, whereas the operating performance of 7-Eleven stores was less strongly affected by NPIs. These stores increased their operating income by providing e-commerce and delivery services; they thus remained popular in the community.

We hypothesized that DNA methylation patterns may contribute to the development of active pulmonary tuberculosis (TB). Illumina’s DNA methylation 450 K assay was used to identify differentially methylated loci (DML) in a discovery cohort of 12 active pulmonary TB patients and 6 healthy subjects (HS). DNA methylation levels were validated in an independent cohort of 64 TB patients and 24 HS. Microarray analysis identified 1028 DMLs in TB patients versus HS, and 3747 DMLs in TB patients after versus before anti-TB treatment, while autophagy was the most enriched signaling pathway. In the validation cohort, PARP9 and miR505 genes were hypomethylated in the TB patients versus HS, while RASGRP4 and GNG12 genes were hypermethylated, with the former two further hypomethylated in those with delayed sputum conversion, systemic symptoms, or far advanced lesions. MRPS18B and RPTOR genes were hypomethylated in TB patients with pleural involvement. RASGRP4 gene hypermethylation and RPTOR gene down-regulation were associated with high mycobacterial burden. TB patients with WIPI2/GNG12 hypermethylation or MRPS18B/FOXO3 hypomethylation had lower one-year survival. In vitro ESAT6 and CFP10 stimuli of THP-1 cells resulted in DNA de-methylation changes of the PARP9, RASGRP4, WIPI2, and FOXO3 genes. In conclusions, aberrant DNA methylation over the PARP9/miR505/RASGRP4/GNG12 genes may contribute to the development of active pulmonary TB disease and its clinical phenotypes, while aberrant DNA methylation over the WIPI2/GNG12/MARPS18B/FOXO3 genes may constitute a determinant of long-term outcomes.