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Abstract Background The prognosis of invasive mucinous adenocarcinoma (IMA) remains controversial and should be clarified by comparison with the International Association for the Study of Lung Cancer (IASLC) histologic grading system for invasive nonmucinous adenocarcinoma (INMA). Methods This study included patients with IMA who underwent curative resection. Their clinicopathological outcomes were compared with those of patients with INMA. Propensity score matching was performed to compare the prognosis of IMA with IASLC grade 2 or 3. Kaplan–Meier survival curves and log‐rank tests were used to analyze recurrence‐free survival (RFS) and overall survival (OS). Results The prognoses of IMA and IASLC grade 2 were similar in terms of RFS and OS. Although patients with IMA had better RFS than patients with IASLC grade 3, the OS was not significantly different. After propensity score matching, IMA demonstrated similar RFS to IASLC grade 2 but superior to IASLC grade 3; there was no difference in the OS compared with grades 2/3. Multivariate analysis revealed that tumor size (hazard ratio [HR] = 1.20, p = 0.028), lymphovascular invasion (HR = 127.5, p = 0.003), and maximum standardized uptake value (HR = 1.24, p = 0.005) were poor prognostic predictors for RFS. Patients with IMA demonstrated RFS similar to and significantly better than that of patients with IASLC grades 2 and 3, respectively. For OS, IMA prognosis was between that of IASLC grades 2 and 3. Conclusions Since the prognosis of IMA among lung adenocarcinomas appears to be relatively worse, further clinical studies investigating IMA‐specific treatment and follow‐up plans are necessary to draw more inferences.

Abstract Background The purpose of this study was to investigate the results of postoperative bronchopleural fistula repair and to identify adverse factors for its success. Methods We retrospectively reviewed the surgical results of 39 patients who underwent surgical repair for postoperative bronchopleural fistula between January 2010 and June 2020. Success of bronchopleural fistula repair was defined as the visual closure of the bronchopleural fistula with the absence of an air leak, a recurrence of bronchopleural fistula and infection in the thoracic cavity. Results Twenty‐five (64.1%) bronchopleural fistulas occurred after pulmonary resection and 14 (35.9%) after lung transplantation. Bronchopleural fistula was diagnosed 19 days (median) and repaired 28 days (median) after the initial operation by primary closure in 27 (69.2%) patients, and by additional resection in 12 (30.8%) patients. The overall success rate was 59% (23/39) and the overall mortality was 56.4% (22/39). Multivariable analysis revealed that the patients who were supported by mechanical ventilation at the time of repair had significantly lower success rates than those without (15.4%, 2/13 vs. 80.8%, 21/26, respectively, p

Abstract Background We aimed to investigate the characteristics and pretreatment risk factors for postoperative pulmonary complications (PPCs) after neoadjuvant concurrent chemoradiotherapy (CRTx) in patients with non‐small cell lung cancer (NSCLC). Methods We retrospectively reviewed data of 122 patients who underwent curative resection after neoadjuvant CRTx for NSCLC between 2007 and December 2019. Clinical data, including pulmonary function and body mass index (BMI) at the time of concurrent CRTx initiation, were analyzed. We performed logistic regression analyses to identify the risk factors for PPCs and built a nomogram with significant factors. Results Of the 122 patients included (mean age, 60.1 ± 9.7 years; 69.7% male), 27 experienced PPCs (severity grade ≥ 2). The most common PPCs were pneumonia (n = 17). Patients with PPCs had a significantly longer hospital stay (median 6.0 vs. 17 days, p

Abstract Background The benefits of mediastinal lymph node dissection (MLND) in colorectal cancer‐related pulmonary metastasectomy (PM) have been poorly reported. This study aimed to determine whether MLND affects survival in patients undergoing PM and to identify the prognostic factors for survival. Methods We retrospectively reviewed 275 patients who had undergone colorectal cancer‐related PM from January 2010 to December 2016. MLND was defined as the resection of at least six mediastinal lymph node stations according to the International Association for the Study of Lung Cancer criteria (N1, ≥3 stations; N2, ≥3 stations). The propensity score matching method was used to reduce bias. Results Thirty‐three (12%) patients underwent MLND, and 13 (4.7%) patients had mediastinal lymph node involvement. This study showed no difference in 5‐year overall survival (no MLND, 52.7% vs. MLND, 53.5%; p = 0.81). On multivariable analysis, negative prognostic factors for overall survival were preoperative carcinoembryonic antigen (CEA) level (p

Abstract Background Although perineural invasion is a well known prognostic factor used in several cancers, its prognostic role in esophageal squamous cell carcinoma remains controversial. Here, we investigated the prognostic role of perineural invasion in surgically treated esophageal squamous cell carcinoma. Methods We retrospectively reviewed the medical records of 316 patients who underwent esophagectomy and lymph node dissection for esophageal squamous cell carcinoma between 2007 and 2016. Results Overall, 287 men (mean age: 62.73 ± 7.97 years) were included in the study. The median follow‐up period was 35.97 ± 30.99 months, perineural invasion was confirmed in 25 patients, and three‐year overall and disease‐free survival were significantly lower in the perineural invasion group than in the no‐perineural invasion group (75.9% vs. 40.0%, p

Abstract Nanozymes are nanomaterials with similar catalytic activities to natural enzymes. Compared with natural enzymes, they have numerous advantages, including higher physiochemical stability, versatility, and suitability for mass production. In the past decade, the synthesis of nanozymes and their catalytic mechanisms have advanced beyond the simple replacement of natural enzymes, allowing for fascinating applications in various fields such as biosensing and disease treatment. In particular, the exploration of nanozymes as powerful toolkits in diagnostic viral testing and antiviral therapy has attracted growing attention. It can address the great challenges faced by current natural enzyme‐based viral testing technologies, such as high cost and storage difficulties. Therefore, nanozyme can provide a novel nanozyme‐based antiviral therapeutic regime with broader availability and generalizability that are keys to fighting a pandemic such as COVID‐19. Herein, we provide a timely review of the state‐of‐the‐art nanozymes regarding their catalytic activities, as well as a focused discussion on recent research into the use of nanozymes in viral testing and therapy. The remaining challenges and future perspectives will also be outlined. Ultimately, this review will inform readers of the current knowledge of nanozymes and inspire more innovative studies to push forward the frontier of this field.

Objective: Systemic lupus erythematosus (SLE) is a highly heritable complex disorder with heterogeneous clinical manifestations. In this study, we aimed to identify the genetic risk load using clinical and serological manifestations in SLE patients., Methods: We genotyped a total of 1,655 Korean patients with SLE (n = 1,243 as a discovery set and n = 412 as a replication set) using a customized genome-wide single-nucleotide polymorphism (SNP) array, KoreanChip. A weighted genetic risk score (wGRS) for an individual was calculated from 112 well-validated non-HLA SNPs and HLA haplotypes of SLE-risk loci. We analyzed associations between individual wGRS and clinical SLE subphenotypes and autoantibodies using multivariable linear or logistic regression adjusted by onset age, sex, and disease duration., Results: Childhood-onset SLE (<16 years) conferred the highest genetic risk compared with adult-onset (16-50 years) or late-onset (>50 years) SLE (P = 6.8 × 10 -6 ). High wGRS significantly increased associations with SLE manifestations, regardless of onset age, sex, and disease duration. Individual wGRS significantly correlated positively with more clinical American College of Rheumatology criteria (β = 0.143, P = 1.8 × 10 -6 ). Subphenotype analysis revealed significant associations between the highest and lowest wGRS quartile with risk of renal disorder (hazard ratio [HR] 1.74, P = 2.2 × 10 -8 ) and anti-Sm antibody production (HR 1.85, P = 2.8 × 10 -5 ). Higher wGRS markedly modulated the pathogenesis of proliferative and membranous lupus nephritis class III or IV (HR 1.98, P = 1.6 × 10 -5 ) and class V (HR 2.79, P = 1.0 × 10 -3 ), but especially lupus nephritis class V in anti-Sm-positive SLE (area under the curve 0.68, P = 1.8 × 10 -4 )., Conclusion: Patients with SLE and high wGRS tended to have earlier age of SLE onset, higher anti-Sm antibody positivity, and more diverse clinical phenotypes. Genetic profiling may predict high risk for lupus nephritis and a diverse clinical course in SLE patients., (© 2023 American College of Rheumatology.)

Objective: HLA association fine-mapping studies have shown the effects of missense variants in HLA-DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA-DRB1 remain poorly understood. Therefore, we investigated the allele-specific expression of HLA-DRB1 and its effect on an HLA-DRβ1 structure-associated trait in RA., Methods: We quantified the allele-specific expression of each HLA-DRB1 3-field classic allele in 48 Korean RA patients with anti-citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA-DRB1 genotype data to calculate the relative expression strength of multiple HLA-DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA-DRβ1 in ACPA-positive RA was revisited to understand the phenotypic effect of allele-specific expression of HLA-DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala-74 in 2 independent sets of 1,723 Korean RA patients with ACPA., Results: The relative expression strength was highly allele-specific, causing imbalanced allelic expression in HLA-DRB1 heterozygotes. The association between HLA-DRβ1 Ala-74 and ACPA level in RA was better explained by relative expression dosage of Ala-74 than by the genomic dosage (change in Akaike's information criterion = -6.98). Moreover, the expression variance of Ala-74 in Ala-74 heterozygotes with no genomic variance of Ala-74 was significantly associated with ACPA level (P = 2.26 × 10 -3 )., Conclusion: Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA-DRB1 into a single model for understanding HLA-DRB1 associations., (© 2020, American College of Rheumatology.)

Background: Components of the metabolic syndrome (MetS), such as elevated fasting glucose levels and abdominal obesity, have been suggested as potential risk factors for pancreatic cancer. However, data are still insufficient to assure the influence of MetS on incident pancreatic cancer. The objective of the current study was to investigate the association between MetS, metabolic components, and the risk of pancreatic cancer., Methods: In the Korea National Health Information Database, 223,138 individuals who were without pancreatic cancer in 2009 were enrolled and followed until 2013. They were categorized into 4 groups according to the number of baseline metabolic components (0, 1, 2, 3, and 4-5). A multivariate Cox proportional hazard model was used to calculate the adjusted hazard ratios (HRs) and 95% CIs for incident pancreatic cancer according to the presence of MetS and the number of metabolic components. In addition, the risk of pancreatic cancer was evaluated in individuals who had a single metabolic component., Results: The presence of MetS was significantly associated with incident pancreatic cancer (adjusted HR, 1.47; 95% CI, 1.19-1.81). The group with 4 or 5 baseline metabolic components had a higher risk of pancreatic cancer than the other groups (0 components: reference category; 1 component: adjusted HR, 0.94 [95% CI, 0.61-1.45]; 2 components: adjusted HR, 1.03 [95% CI, 0.68-1.56]; 3 components: adjusted HR, 1.35 [95% CI, 0.89-2.04]; 4-5 components: adjusted HR, 1.64 [95% CI, 1.06-2.51]). Regarding associations between the individual metabolic components and pancreatic cancer, no metabolic component alone had a statistically significant association with pancreatic cancer., Conclusions: MetS is a potential risk factor for pancreatic cancer. The presence of ≥4 metabolic components leads to a higher risk of pancreatic cancer even within categories of the MetS., (© 2020 American Cancer Society.)

The excessive proliferation and migration of synoviocytes are well-characterized phenomena that play key roles in the pathophysiology of rheumatoid arthritis (RA). Melatonin has been shown to have potent anti-proliferative effect in various cancer cells such as breast and prostate cancer cells. In this study, we examined the role of melatonin on synoviocyte proliferation in primary cultured human fibroblast-like synoviocytes (FLSs) by analyzing protein expression of P21(CIP1) (P21) and P27(KIP1) (P27), the cyclin-dependent kinase inhibitors that are important in cell cycle control, and the phosphorylation of mitogen-activated protein kinases (MAPKs). RA-FLS proliferation was determined by a [(3)H]-thymidine incorporation assay. Western blot analysis was applied to examine the underlying mechanisms of melatonin's effect. Melatonin inhibited RA-FLS proliferation in a dose-dependent manner. It reduced proliferation of passage 2 FLSs by 25% at 10 microm and by nearly 40% at 100 microm concentrations. The inhibitory effect of melatonin on RA-FLS proliferation was also observed in passages 4 and 6. Melatonin upregulated the expression levels of P21 and P27 dose-dependently (24 hr), induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) time-dependently (10 microm), but did not affect phosphorylation of P38 in RA-FLSs. In addition, the expression of P21 and P27 triggered by melatonin was inhibited by the pretreatment of the ERK inhibitor, PD98059 (10 microm). The anti-proliferative action of melatonin in RA-FLSs was also blocked by PD98059. Taken together, these results suggest that melatonin exerts the inhibitory effect of the proliferation of RA-FLSs through the activation of P21 and P27 mediated by ERK. Hence we suggest that melatonin could be used as a therapeutic agent for the treatment of RA.

The prevalence of diabetes has exponentially increased in recent decades due to environmental factors such as nocturnal lifestyle and aging, both of which influence the amount of melatonin produced in the pineal gland. The present study investigated the effect of melatonin on signaling pathways of glucose transport in C2C12 mouse skeletal muscle cells. Intriguingly, treatment of C2C12 cells with melatonin (1 nm) stimulated glucose uptake twofold increase. Melatonin-stimulated glucose transport was inhibited with co-treatment with the melatonin receptor antagonist luzindole. Furthermore, treatment of stably over-expressed melatonin receptor type 2B containing C2C12 myotubes with melatonin amplified glucose transport c. 13-fold. Melatonin also increased the phosphorylation level of insulin receptor substrate-1 (IRS-1) and the activity of phosphoinositide 3-kinase (PI-3-kinase). However, 3',5'-cyclic adenosine monophosphate-activated protein kinase (AMPK), another important glucose transport stimulatory mediator via an insulin-independent pathway, was not influenced by melatonin treatment. Activity of p38 mitogen-activated protein kinase (MAPK), a downstream mediator of AMPK, was also not changed by melatonin. In addition, melatonin increased the expression level of forkhead box A2, which was recently discovered to regulate fatty acid oxidation and to be inhibited by insulin. In summary, melatonin stimulates glucose transport to skeletal muscle cells via IRS-1/PI-3-kinase pathway, which implies, at the molecular level, its role in glucose homeostasis and possibly in diabetes. Additionally, exposure to light at night and aging, both of which lower endogenous melatonin levels may contribute to the incidence and/or development of diabetes.

The existence of specific melatonin-binding sites in lymphoid cells led to the discovery of signal transduction pathway for melatonin in human lymphocytes and immunomodulatory role of melatonin in immune cells. In recent years, transcriptional regulation of melatonin on various transcription factors has been demonstrated. Therefore, this study was designed to assess by cDNA microarray analysis the regulatory effects of melatonin on transcription factors in human peripheral blood mononuclear cells (PBMCs). Forty-six genes were upregulated and 23 were downregulated more than twofold in melatonin-treated PBMCs. Of the more than twofold upregulated transcription factor genes, homeo box A4 (HOXA4), forkhead box O1A (FOXO1A), transcription elongation factor B (SIII), polypeptide 3 (TCEB3), and peroxisome proliferative activated receptor delta (PPARD) were identified. Of the more than twofold downregulated genes, PHD finger protein 15 (PHF15) and zinc finger protein 33a (ZNF33A) were identified. In summary, identification of these genes by cDNA microarray analysis in response to melatonin administration may provide a foundation for further studies on the function of melatonin in human PBMCs.

Melatonin is reported to be an anti-inflammatory agent. No genetic study concerning the association between melatonin and inflammatory disease has yet been reported. Here we performed a polymorphism study on the melatonin receptor type 1B (MTNR1B) in Korean rheumatoid arthritis (RA) patients and controls. The polymorphism of MTNR1B located in 3'-untranslated region (rs 1562444) was selected for its higher rate of heterozygosity among other single nucleotide polymorphisms (SNPs) in both MTNR1A and MTNR1B genes and investigated in RA patients (n = 173) and healthy controls (n = 195) by polymerase chain reaction-restriction fragment length polymorphism assay using NlaIII restriction enzyme. No statistically significant difference in either genotype distribution or allele frequency was observed between RA patients and controls. The genotype distributions and allele frequencies of rheumatoid factor negative [RF(-)] patients were similar to those of controls. However, statistical analysis of genotype revealed a significant association (chi2 = 6.42, P = 0.04) is present between RF(+) and MTNR1B SNP (rs 1562444). Although no statistically significant difference in allele frequency between RF(+) and controls was observed (chi2 = 2.75, P = 0.10), the results might suggest that MTNR1B SNP (rs 1562444) is associated with the presence of RF in RA. This is the first study, to our knowledge, to report a positive genetic relationship between melatonin and RA.