Clinical significance of the advanced lung cancer inflammation index in patients with limited-stage small cell lung cancer treated with chemoradiotherapy.

The aim of the study was to investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with limited-stage small-cell lung cancer (LS-SCLC) undergoing definite chemo-radiotherapy (CRT). We included 87 patients with LS-SCLC from South Korea, treated between 2005 and 2019 with definite CRT. ALI was calculated using body mass index, serum albumin, and neutrophil-lymphocyte ratio. We categorized 38 patients into the high ALI group (ALI ≥ 44.3) and 48 into the low ALI group (ALI < 44.3). Patients in the high ALI group exhibited longer overall survival (OS) than patients in the low ALI group. In multivariate analysis, prophylactic cranial irradiation (hazard ratio [HR] = 0.366, 95% confidence interval [CI] 0.20-0.66, P = 0.0008), and high ALI (HR = 0.475, 95% CI 0.27-0.84, P = 0.0103) were identified as independent prognostic factors for predicting better OS. Notably, a high ALI score was particularly indicative of longer survival in patients treated with the combination of etoposide and cisplatin. In conclusion, this study demonstrated that a high pretreatment ALI was significantly associated with better OS in patients with LS-SCLC undergoing definite CRT. This suggests that ALI could be a useful tool for predicting prognosis and guiding chemotherapy regimen selections in clinical practice for LS-SCLC.

Comprehensive Transcriptomic Profiling of Diverse Brain Tumor Types Uncovers Complex Structures of the Brain Tumor Microenvironment.

Various types of brain tumors occur in both children and adults. These tumors manifest with different characteristics such as malignancy, cellular lineage, location of origin, and genomic profile. Recently, immunotherapy, which manipulates immune cells in the tumor microenvironment (TME) to kill tumor cells, has attracted attention as a treatment strategy for tumors. Here, we analyzed the transcriptomic architecture of the brain tumor microenvironment to provide potential guidelines to overcome the therapeutic vulnerabilities to brain tumors. We decomposed the cellular populations of six brain tumor types (meningioma, pilocytic astrocytoma, ependymoma, medulloblastoma, glioblastoma, and lower-grade glioma) using publicly available microarray data and single-cell RNA sequencing (scRNA-seq) data. Interestingly, transcriptome-based immune cell profiling revealed that infiltrating immune cell types in the brain TME, particularly M2 macrophages, CD8+ T cells, and CD4+ T cells, could be distinguished by tumor type, malignancy, and location. scRNA-seq revealed differences in the proportions of dendritic and mural cells. Unsupervised clustering using immune-related genes divided all samples into two distinct clusters with different characteristics. In addition, immune subpopulations showed disparate reactions after anti-PD-1 therapy for glioblastoma. Our results unveiled the distinct TME across brain tumor types and provided a transcriptomic landscape. Our findings may contribute to realizing future precision medicine, providing a basic rationale for the therapeutics of brain tumors.

Incidence, prevalence, and pattern of medical service utilization of children's rare lung diseases in South Korea.

INTRODUCTION: Children's rare lung diseases are a heterogeneous group of rare lung diseases with significant morbidity and mortality. There is very limited information on the incidence and prevalence of children's rare lung diseases in Asia. We investigated the nationwide incidence, prevalence, and pattern of medical service utilization of children's rare lung diseases in Korea. METHODS: We studied patients who were diagnosed with rare lung diseases coded per International Statistical Classification of Diseases and Related Health Problems, 10th Edition and registered in the national rare diseases database of confirmed patients. Data was extracted from the Korean National Health Insurance Service Claims database over 2019-2021. RESULTS: Average incidence rate was 12.9 new cases per million children per year, and average prevalence rate was 60.2 cases per million children during the study period of 2019-2021. We found that more than 65% of new cases were diagnosed before 2 years of age. ChILD, primary ciliary dyskinesia, and cystic fibrosis were usually diagnosed after 6 years of age. Congenital airway and lung anomalies were often diagnosed before 2 years of age. Busan and Gyeongsangnam-do residents tended to visit hospitals near their place of residence, while residents of other areas tended to visit hospitals in Seoul regardless of their area of residence. CONCLUSIONS: We examined the epidemiology of rare lung diseases in children in South Korea. Our estimation of the incidence and prevalence could be used for sustainable health care and equitable distribution of health care resources.

Six-Year Survival Outcomes for Patients with HER2-Positive Early Breast Cancer Treated with CT-P6 or Reference Trastuzumab: Observational Follow-Up Study of a Phase 3 Randomised Controlled Trial.

BACKGROUND: The Phase 3 CT-P6 3.2 study demonstrated equivalent efficacy and comparable safety between CT-P6 and reference trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer after up to 3 years' follow-up. OBJECTIVE: To investigate long-term survival with CT-P6 and reference trastuzumab. METHODS: In the CT-P6 3.2 study, patients with HER2-positive early breast cancer were randomised to neoadjuvant chemotherapy with CT-P6 or reference trastuzumab, surgery, and adjuvant CT-P6 or reference trastuzumab before a 3-year post-treatment follow-up. Patients who completed the study could enter a 3-year extension (CT-P6 4.2 study). Data were collected every 6 months to assess overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). RESULTS: Of 549 patients enrolled in the CT-P6 3.2 study, 216 (39.3%) patients continued in the CT-P6 4.2 study (CT-P6, 107; reference trastuzumab, 109) (intention-to-treat extension set). Median follow-up was 76.4 months for both groups. Medians were not reached for time-to-event parameters; estimated hazard ratios (95% confidence intervals) for CT-P6 versus reference trastuzumab were 0.59 (0.17-2.02) for OS, 1.07 (0.50-2.32) for DFS, and 1.08 (0.50-2.34) for PFS. Corresponding 6-year survival rates in the CT-P6 and reference trastuzumab groups, respectively, were 0.96 (0.90-0.99) and 0.94 (0.87-0.97), 0.87 (0.78-0.92) and 0.89 (0.81-0.94), and 0.87 (0.78-0.92) and 0.89 (0.82-0.94). CONCLUSIONS: Data from this extended follow-up of the CT-P6 3.2 study demonstrate the comparable long-term efficacy of CT-P6 and reference trastuzumab up to 6 years. EUDRACT NUMBER: 2019-003518-15 (retrospectively registered 10 March 2020).

Cognitive Function of Recipients of Primary or Secondary Defibrillator Therapy: A Comparative Study Involving Nondefibrillator Patients With Systolic Heart Failure.

BACKGROUND: The extent to which cognitive function differs between patients who receive implantable cardioverter-defibrillator (ICD) therapy and patients with heart failure (HF) who do not receive ICD therapy remains to be elucidated. OBJECTIVES: The aim of this study was to compare the cognitive function between patients with primary or secondary ICDs and patients with HF without an ICD. METHODS: This descriptive, comparative study included 116 patients who received ICDs and 74 patients with HF who did not receive ICDs. Patients underwent neuropsychological assessment for general cognition, memory, and executive function. RESULTS: Immediate recall memory loss (18.9%) occurred more often in patients with HF without an ICD than in patients with primary (3.1%) and secondary (7.1%) ICDs (P = .018). After adjusting for age and education, delayed recall memory of patients with HF without ICDs was significantly worse than that of patients with primary ICDs (4.0 vs 6.5; P < .001), whereas delayed recall memory of patients with primary ICDs was better than that of patients with secondary ICDs (6.0 vs 6.5; P = .006). Executive function of patients with HF without ICDs was significantly worse than that of patients with primary (35 vs 58 seconds; P < .001) and secondary (28 vs 58 seconds; P = .0012) ICDs. CONCLUSIONS: Patients with ICDs, regardless of primary or secondary indication, had less impairment of memory and executive function than patients with HF without ICDs, implying that ICD therapy did not interfere with cognitive performance. Cognitive screening as a part of routine care could be helpful for identifying impairment and implementing early cognitive training, especially in patients with HF.

Review and Hypothesis: A Potential Common Link Between Glial Cells, Calcium Changes, Modulation of Synaptic Transmission, Spreading Depression, Migraine, and Epilepsy-H.

There is significant evidence to support the notion that glial cells can modulate the strength of synaptic connections between nerve cells, and it has further been suggested that alterations in intracellular calcium are likely to play a key role in this process. However, the molecular mechanism(s) by which glial cells modulate neuronal signaling remains contentiously debated. Recent experiments have suggested that alterations in extracellular H+ efflux initiated by extracellular ATP may play a key role in the modulation of synaptic strength by radial glial cells in the retina and astrocytes throughout the brain. ATP-elicited alterations in H+ flux from radial glial cells were first detected from Müller cells enzymatically dissociated from the retina of tiger salamander using self-referencing H+-selective microelectrodes. The ATP-elicited alteration in H+ efflux was further found to be highly evolutionarily conserved, extending to Müller cells isolated from species as diverse as lamprey, skate, rat, mouse, monkey and human. More recently, self-referencing H+-selective electrodes have been used to detect ATP-elicited alterations in H+ efflux around individual mammalian astrocytes from the cortex and hippocampus. Tied to increases in intracellular calcium, these ATP-induced extracellular acidifications are well-positioned to be key mediators of synaptic modulation. In this article, we examine the evidence supporting H+ as a key modulator of neurotransmission, review data showing that extracellular ATP elicits an increase in H+ efflux from glial cells, and describe the potential signal transduction pathways involved in glial cell-mediated H+ efflux. We then examine the potential role that extracellular H+ released by glia might play in regulating synaptic transmission within the vertebrate retina, and then expand the focus to discuss potential roles in spreading depression, migraine, epilepsy, and alterations in brain rhythms, and suggest that alterations in extracellular H+ may be a unifying feature linking these disparate phenomena.

Extracellular ATP-Induced Alterations in Extracellular H+ Fluxes From Cultured Cortical and Hippocampal Astrocytes.

Small alterations in the level of extracellular H+ can profoundly alter neuronal activity throughout the nervous system. In this study, self-referencing H+-selective microelectrodes were used to examine extracellular H+ fluxes from individual astrocytes. Activation of astrocytes cultured from mouse hippocampus and rat cortex with extracellular ATP produced a pronounced increase in extracellular H+ flux. The ATP-elicited increase in H+ flux appeared to be independent of bicarbonate transport, as ATP increased H+ flux regardless of whether the primary extracellular pH buffer was 26 mM bicarbonate or 1 mM HEPES, and persisted when atmospheric levels of CO2 were replaced by oxygen. Adenosine failed to elicit any change in extracellular H+ fluxes, and ATP-mediated increases in H+ flux were inhibited by the P2 inhibitors suramin and PPADS suggesting direct activation of ATP receptors. Extracellular ATP also induced an intracellular rise in calcium in cultured astrocytes, and ATP-induced rises in both calcium and H+ efflux were significantly attenuated when calcium re-loading into the endoplasmic reticulum was inhibited by thapsigargin. Replacement of extracellular sodium with choline did not significantly reduce the size of the ATP-induced increases in H+ flux, and the increases in H+ flux were not significantly affected by addition of EIPA, suggesting little involvement of Na+/H+ exchangers in ATP-elicited increases in H+ flux. Given the high sensitivity of voltage-sensitive calcium channels on neurons to small changes in levels of free H+, we hypothesize that the ATP-mediated extrusion of H+ from astrocytes may play a key role in regulating signaling at synapses within the nervous system.

Rate of central corneal thickness changes in primary angle closure eyes: long-term follow-up results.

BACKGROUND: Central corneal thickness (CCT) and its association with intraocular pressure, which is a pivotal parameter in glaucoma management, has previously been reported. In this study, we intended to investigate the long-term change of CCT in terms of rate in eyes with primary angle-closure (PAC). Additionally, we aimed to analyze events that could affect CCT. METHODS: In this retrospective study, 26 patients with PAC who had a follow-up period of more than 5 years were analyzed. The rate of CCT changes from baseline was evaluated from the serial CCT measurements over the average follow-up period. The pattern of CCT change rate according to modes of treatment and history of angle-closure attack was analyzed using the repeated linear mixed model analysis. RESULTS: A total of 52 eyes were enrolled. The CCT reduction rate of the entire study population was - 0.72 ± 0.22 µm/yr (P = 0.001) with statistical significance. The CCT thinning rate of the laser peripheral iridotomy (PI) group was - 0.53 ± 0.25 µm/yr (P = 0.034) and that of the surgical trabeculectomy group was - 1.32 ± 0.43 µm/yr (P = 0.002), and it was not statistically significant (P = 0.112). The rate of CCT thinning in patients with a history of acute angle-closure attack was - 0.81 ± 0.31 µm/yr (P = 0.009) and that in patients without an attack was - 0.63 ± 0.30 µm/yr (P = 0.001), and it was not statistically significant (P = 0.680). Baseline CCT appeared to be the only significant factor affecting the rate of CCT changes (P < 0.001). CONCLUSIONS: We found a significant reduction in CCT over a long observation period in PAC eyes. We also found that the rates of CCT reduction were not affected by different treatment modalities or acute angle-closure attacks. The analysis of long-term CCT changes in conjunction with baseline CCT would also be helpful in the clinical evaluation of the PAC patients.

Do advance directive attitudes and perceived susceptibility and end-of-life life-sustaining treatment preferences between patients with heart failure and cancer differ?

There is limited evidence on the relationships of preference for end-of-life life-sustaining treatments [LSTs] and diagnostic contexts like heart failure [HF] or cancer, and patient attitudes toward and perceived susceptibility to use advance directives [ADs]. Thus, this study aimed to compare attitudes and perceived susceptibility between HF patients and community-dwelling patients with cancer, and examine the associations of these variables with their preference for each LST (cardiopulmonary resuscitation [CPR], ventilation support, hemodialysis, and hospice care). Secondary data were obtained from 36 outpatients with HF (mean age, 65.44 years; male, 69.4%) and 107 cancer patients (mean age, 67.39 years; male, 32.7%). More patients with HF preferred CPR than cancer patients (41.7% and 15.9%, χ2 = 8.88, P = 0.003). Attitudes and perceived susceptibility were similar between the two diagnostic cohorts. HF patients and those with more positive attitudes had greater odds of preferring CPR (odds ratio [OR] = 3.02, confidence interval [CI] = 1.19, 7.70) and hospice care (OR = 1.14, CI = 1.06, 1.23), respectively. HF diagnosis and AD attitudes increased the preference for CPR and hospice care, respectively. This suggests that it is important to gain positive attitudes toward ADs and consider diagnostic context to facilitate informed decision-making for LSTs.

Effect of physical and psychocognitive function and perceived health status on 12-month adverse cardiac events among implantable cardioverter-defibrillator recipients.

BACKGROUND: Post-implant recovery in patients with implantable cardioverter-defibrillators (ICDs) is often compromised because of reduced physical and psycho-cognitive function and poor health perception, leading to short event-free survival. OBJECTIVES: To examine the effects of psychocognitive function, health perception, and ICD-related factors on 12-month cardiac events among ICD patients. METHODS: Using a prospective study design, ICD patients underwent baseline assessment and were followed for 12 months to assess cardiac events. RESULTS: Cardiac events occurred in 14 patients (18.9%) (N = 74: age, 58 years; primary ICDs, 45.9%). Time after ICD implant (odds ratio [OR] = 1.002; p = .028) and executive function (OR = 1.021; p = .027) were significant predictors of 12-month cardiac events, while other physical and psychological indices were not. CONCLUSIONS: Reduced executive function and longer time after implant predicted the events. Healthcare professionals need to assess executive function and provide treatment and support to improve executive function.

Changes in the Physical Function and Psychological Distress from Pre-Implant to 1, 6, and 12 Months Post-Implant in Patients Undergoing Implantable Cardioverter Defibrillator Therapy.

Recipients of implantable cardioverter-defibrillator (ICD) therapy in Western countries often experience distressful physical and psychological adjustments. Sociocultural influences on post-implant recovery are likely; however, evidence from other ethnic/cultural backgrounds is lacking. This study aimed to examine the changes in physical function and psychological distress (anxiety and depressive symptoms) from pre-implant to one, six, and 12 months post-implant in Korean patients undergoing ICD therapy. A total of 34 patients underwent pre- to post-implant longitudinal assessments of physical and psychological function using mixed modeling procedures. Physical function significantly declined from pre-implant to one month post-implant (B = -10.05, p = 0.004) and then nearly returned to the pre-implant level at six months post-implant (B = 8.34, p = 0.028). This level of improvement continued through 12 months post-implant. In psychological distress, significant improvements were observed from pre-implant to one month (anxiety (B = -1.20, p = 0.020) and in depressive symptoms (B = -1.15, p = 0.037)), which then plateaued without significant changes from one to 12 months. We concluded that physical function recovery occurred six months post-implant, but function remained poor until 12 months post-implant. Psychological distress improved one month post-implant and it was maintained. Clinicians must provide more intensive interventions to improve long-term physical function after ICD therapy.

The utility of histological subtype for predicting survival of lung cancer patients with rheumatoid arthritis.

BACKGROUND: This study determined whether the survival of lung cancer (LC) patients with rheumatoid arthritis (RA) is differed by histological subtype. MATERIALS: This observational, retrospective study compared the LC survival rate of 34 RA patients with that of 132 age- and sex-matched patients without RA who received medical care from 2011 to 2016. Survival curves were generated using the Kaplan-Meier method. Cox proportional hazards regression analyses were used to estimate hazard ratios and determine risk factors predicting mortality according to histological subtype, including small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC). RESULTS: The predominant histological subtype was adenocarcinoma in both groups, however, a larger proportion of SCLC patients was noted in patients with both LC and RA, compared to those with LC but without RA (26.5% vs. 12.9%, respectively; P=0.0317). LC patients with RA had a significantly lower body mass index (P=0.0488), and a higher proportion of interstitial lung disease (P<0.0001), compared to patients without RA. There was no statistical difference in the distribution of smoking status, stage, or comorbidity index between groups. Overall survival did not differ between LC patients with and without RA. Mortality was significantly worse for RA patients with SCLC than those with NSCLC (P=0.0404), and RA was associated with a 3.26-fold increase in mortality for SCLC patients with versus without RA (P=0.0350; 95% confidence interval: 1.05-9.56). However, RA was not a risk factor for mortality in NSCLC and, even in histological subtypes including lung adenocarcinoma and squamous cell carcinoma. CONCLUSIONS: RA was not associated with a lower overall survival rate for LC patients, irrespective of histological subtype. Because the effects of RA on LC mortality might differ between SCLC and NSCLC patients, future studies should recognize that the histological subtype may affect the outcome.

Comparison and Validation of 10 Equations Including a Novel Method for Estimation of LDL-cholesterol in a 168,212 Asian Population.

Low-density lipoprotein cholesterol (LDL-C) is frequently estimated using the empirical Friedewald equation. We compared the accuracy of the novel equation named as the 180-cell method (180-c), which estimates LDL-C using a stratification approach, to those of 9 previously suggested formulas, including the Friedewald equation.We compared the accuracy of 10 equations by calculating intraclass correlation coefficient (ICC) and weighted kappa index in relation to direct LDL-C measurement values. Two independent populations used in the validation were the Severance Hospital LDL-C (SHL) registry (n = 164,358) and the Korea National Health and Nutrition Examination Survey (KNHANES) 2009 to 2010 (n = 3,854), each representing the hospital patient population and the general Korean population, respectively.The 180-c and DeLong equations showed the highest ICCs, indicating the best agreement with direct LDL-C measurement. The 180-c and Chen equations showed the highest kappa indices. For the hypertriglyceridemic subpopulation from SHL, the 180-c equation showed the best agreement with direct LDL-C measurement in terms of ICC.We compared the novel 180-c method for LDL-C estimation with 9 previous formulas in a non-US population as the first external validation. The 180-c equation, with Chen equation, appeared to be more accurate than the Friedewald equation. Although the DeLong equation showed better performance in the hypertriglyceridemic subpopulation, the 180-c equation performed appropriately in Asian population.

Radiation dose and image quality in pediatric chest CT: effects of iterative reconstruction in normal weight and overweight children.

BACKGROUND: New CT reconstruction techniques may help reduce the burden of ionizing radiation. OBJECTIVE: To quantify radiation dose reduction when performing pediatric chest CT using a low-dose protocol and 50% adaptive statistical iterative reconstruction (ASIR) compared with age/gender-matched chest CT using a conventional dose protocol and reconstructed with filtered back projection (control group) and to determine its effect on image quality in normal weight and overweight children. MATERIALS AND METHODS: We retrospectively reviewed 40 pediatric chest CT (M:F = 21:19; range: 0.1-17 years) in both groups. Radiation dose was compared between the two groups using paired Student's t-test. Image quality including noise, sharpness, artifacts and diagnostic acceptability was subjectively assessed by three pediatric radiologists using a four-point scale (superior, average, suboptimal, unacceptable). RESULTS: Eight children in the ASIR group and seven in the control group were overweight. All radiation dose parameters were significantly lower in the ASIR group (P < 0.01) with a greater than 57% dose reduction in overweight children. Image noise was higher in the ASIR group in both normal weight and overweight children. Only one scan in the ASIR group (1/40, 2.5%) was rated as diagnostically suboptimal and there was no unacceptable study. CONCLUSION: In both normal weight and overweight children, the ASIR technique is associated with a greater than 57% mean dose reduction, without significantly impacting diagnostic image quality in pediatric chest CT examinations. However, CT scans in overweight children may have a greater noise level, even when using the ASIR technique.

Prediction of transplant-free survival in idiopathic pulmonary fibrosis patients using joint models for event times and mixed multivariate longitudinal data.

We implement a joint model for mixed multivariate longitudinal measurements, applied to the prediction of time until lung transplant or death in idiopathic pulmonary fibrosis. Specifically, we formulate a unified Bayesian joint model for the mixed longitudinal responses and time-to-event outcomes. For the longitudinal model of continuous and binary responses, we investigate multivariate generalized linear mixed models using shared random effects. Longitudinal and time-to-event data are assumed to be independent conditional on available covariates and shared parameters. A Markov chain Monte Carlo (MCMC) algorithm, implemented in OpenBUGS, is used for parameter estimation. To illustrate practical considerations in choosing a final model, we fit 37 different candidate models using all possible combinations of random effects and employ a Deviance Information Criterion (DIC) to select a best fitting model. We demonstrate the prediction of future event probabilities within a fixed time interval for patients utilizing baseline data, post-baseline longitudinal responses, and the time-to-event outcome. The performance of our joint model is also evaluated in simulation studies.

Multivariate generalized multifactor dimensionality reduction to detect gene-gene interactions.

BACKGROUND: Recently, one of the greatest challenges in genome-wide association studies is to detect gene-gene and/or gene-environment interactions for common complex human diseases. Ritchie et al. (2001) proposed multifactor dimensionality reduction (MDR) method for interaction analysis. MDR is a combinatorial approach to reduce multi-locus genotypes into high-risk and low-risk groups. Although MDR has been widely used for case-control studies with binary phenotypes, several extensions have been proposed. One of these methods, a generalized MDR (GMDR) proposed by Lou et al. (2007), allows adjusting for covariates and applying to both dichotomous and continuous phenotypes. GMDR uses the residual score of a generalized linear model of phenotypes to assign either high-risk or low-risk group, while MDR uses the ratio of cases to controls. METHODS: In this study, we propose multivariate GMDR, an extension of GMDR for multivariate phenotypes. Jointly analysing correlated multivariate phenotypes may have more power to detect susceptible genes and gene-gene interactions. We construct generalized estimating equations (GEE) with multivariate phenotypes to extend generalized linear models. Using the score vectors from GEE we discriminate high-risk from low-risk groups. We applied the multivariate GMDR method to the blood pressure data of the 7,546 subjects from the Korean Association Resource study: systolic blood pressure (SBP) and diastolic blood pressure (DBP). We compare the results of multivariate GMDR for SBP and DBP to the results from separate univariate GMDR for SBP and DBP, respectively. We also applied the multivariate GMDR method to the repeatedly measured hypertension status from 5,466 subjects and compared its result with those of univariate GMDR at each time point. RESULTS: Results from the univariate GMDR and multivariate GMDR in two-locus model with both blood pressures and hypertension phenotypes indicate best combinations of SNPs whose interaction has significant association with risk for high blood pressures or hypertension. Although the test balanced accuracy (BA) of multivariate analysis was not always greater than that of univariate analysis, the multivariate BAs were more stable with smaller standard deviations. CONCLUSIONS: In this study, we have developed multivariate GMDR method using GEE approach. It is useful to use multivariate GMDR with correlated multiple phenotypes of interests.

Cytokine-like factor 1 gene expression is enriched in idiopathic pulmonary fibrosis and drives the accumulation of CD4+ T cells in murine lungs: evidence for an antifibrotic role in bleomycin injury.

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into the pathogenesis of IPF, we reanalyzed our previously published gene expression data profiling IPF lungs. Cytokine receptor-like factor 1 (CRLF1) was among the most highly up-regulated genes in IPF lungs, compared with normal controls. The protein product (CLF-1) and its partner, cardiotrophin-like cytokine (CLC), function as members of the interleukin 6 (IL-6) family of cytokines. Because of earlier work implicating IL-6 family members in IPF pathogenesis, we tested whether CLF-1 expression contributes to inflammation in experimental pulmonary fibrosis. In IPF, we detected CLF-1 expression in both type II alveolar epithelial cells and macrophages. We found that the receptor for CLF-1/CLC signaling, ciliary neurotrophic factor receptor (CNTFR), was expressed only in type II alveolar epithelial cells. Administration of CLF-1/CLC to both uninjured and bleomycin-injured mice led to the pulmonary accumulation of CD4(+) T cells. We also found that CLF-1/CLC administration increased inflammation but decreased pulmonary fibrosis. CLF-1/CLC leads to significantly enriched expression of T-cell-derived chemokines and cytokines, including the antifibrotic cytokine interferon-γ. We propose that, in IPF, CLF-1 is a selective stimulus of type II alveolar epithelial cells and may potentially drive an antifibrotic response by augmenting both T-helper-1-driven and T-regulatory-cell-driven inflammatory responses in the lung.

Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course. OBJECTIVES: The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF. METHODS: Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested. MEASUREMENTS AND MAIN RESULTS: High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort. CONCLUSIONS: Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.