Abhd2, a Candidate Gene Regulating Airway Remodeling in COPD via TGF-ß.

Purpose: The typical characteristic of COPD is airway remodeling, affected by environmental and genetic factors. However, genetic studies on COPD have been limited. Currently, the Abhd2 gene is found to play a critical role in maintaining alveolar architecture and stability. The research aims to investigate the predictive value of Abhd2 for airway remodeling in COPD and its effect on TGF-ß regulation. Methods: In humans, Abhd2 protein was obtained from peripheral blood monocytes. Peripheral blood TGF-ß, pulmonary surfactant proteins (SPs), metalloproteinases, inflammatory indicators (WBC, NEU, NLR, EOS, CRP, PCT, D-Dimer), chest CT (airway diameter and airway wall thickness), pulmonary function, and blood gas analysis were used to assess airway remodeling. In animals, Abhd2 deficient mice (Abhd2Gt/Gt) using gene trapping and C57BL6 mice were injected intraperitoneally with CSE to construct COPD models. HE staining, Masson staining and immunohistochemistry were used to observe the pathological changes of airway in mice, and RT-PCR, WB, ELISA and immunofluorescence were used to detect the expression of secreted proteins and EMT markers. Results: COPD patients with worse pulmonary function and higher airway remodeling-related inflammatory factors had lower Abhd2 protein expression. Moreover, indicators followed the same trend for COPD patients grouped by prognosis (Group A vs Group B). Serum TGF-ß was negatively correlated with Abhd2 protein expression, FEV1/FVC, FEV1, and FEV1% PRED. In mice, Abhd2 depletion promoted deposition of TGF-ß, leading to more pronounced emphysema, airway thickening, increased alveolar macrophage infiltration, decreased AECII number and SPs, and EMT phenomenon. Conclusion: Downregulation of Abhd2 can promote airway remodeling in COPD by modulating repair after injury and EMT via TGF-ß. This study suggests that Abhd2 may serve as a biomarker for assessing airway remodeling and guiding prognosis in COPD.

Magnetic resonance imaging for evaluation of bowel inflammation and disease activity in Crohn's disease: A systematic review and meta-analysis / Imágenes por resonancia magnética para la evaluación de la inflamación intestinal y la actividad de la enfermedad en la enfermedad de Crohn: una revisión sistemática y un metaanálisis

Background: The aim of this systematic review and meta-analysis was to determine the performance of magnetic resonance imaging (MRI) in the diagnosis of bowel inflammation and disease activity in Crohn's disease (CD). Methods: MEDLINE, Embase and Web of Science databases of biomedical literature were systematically searched to identify studies that investigated the diagnostic accuracy of MRI in diagnosing bowel inflammation and disease activity in CD by comparing it with reference standards. Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality. The summary sensitivity and specificity were estimated using the bivariate model, and hierarchical summary receiver operating characteristic (HSROC) parameters were calculated and plotted. Results: Of 5492 citations of interest, 34 articles contained the diagnostic accuracy data. Of these, results for the small bowel and the colorectum were reported separately in 19 studies and jointly by 21 studies. The meta-analytic summary sensitivity and specificity under the bivariate model were 90.9% (95% CI, 85.8%–94.2%) and 90.2% (95% CI, 81.9%–95.0%), respectively. The sensitivities and specificities of individual studies ranged from 55% to 100% and 51% to 100%, respectively. Substantial heterogeneity was observed in both sensitivity (I2=84.9%) and specificity (I2=78.8%). The HSROC curve also showed considerable heterogeneity between studies. Conclusion: Although the meta-analytic summary accuracy of MRI was high for the diagnosis of bowel inflammation in CD, the summary estimates might be unreliable due to the presence of high heterogeneity.(AU)

Antecedentes: El objetivo de esta revisión sistemática y metaanálisis fue determinar el rendimiento de la resonancia magnética nuclear (RM) en el diagnóstico de la inflamación intestinal y la actividad de la enfermedad en la enfermedad de Crohn (EC). Métodos: Se realizaron búsquedas sistemáticas en las bases de datos de literatura biomédica de MEDLINE, Embase y Web of Science para identificar estudios que investigaran la precisión diagnóstica de la RM en el diagnóstico de la inflamación intestinal y la actividad de la enfermedad en la EC comparándola con estándares de referencia. Evaluación de la calidad de los estudios de precisión diagnóstica: se utilizó la herramienta 2 para evaluar la calidad del estudio. La sensibilidad y la especificidad resumidas se estimaron mediante el modelo bivariado, y se calcularon y trazaron los parámetros de características operativas del receptor resumidas jerárquicas (HSROC). Resultados: De 5.492 citas de interés, 34 artículos contenían datos de precisión diagnóstica. De estos, los resultados para el intestino delgado y el colorrectal se informaron por separado en 19 estudios y en forma conjunta en 21 estudios. La sensibilidad y la especificidad del resumen metanalítico bajo el modelo bivariado fueron del 90,9% (IC del 95%, 85,8%-94,2%) y el 90,2% (IC del 95%, 81,9%-95,0%), respectivamente. Las sensibilidades y especificidades de los estudios individuales variaron del 55 al 100% y del 51 al 100%, respectivamente. Se observó heterogeneidad sustancial tanto en la sensibilidad (I2=84,9%) como en la especificidad (I2=78,8%). La curva HSROC también mostró una considerable heterogeneidad entre los estudios. Conclusión: Aunque la precisión del resumen metaanalítico de la RM fue alta para el diagnóstico de inflamación intestinal en la EC, las estimaciones del resumen pueden no ser confiables debido a la presencia de una gran heterogeneidad.(AU)

Magnetic resonance imaging for evaluation of bowel inflammation and disease activity in Crohn's disease: A systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to determine the performance of magnetic resonance imaging (MRI) in the diagnosis of bowel inflammation and disease activity in Crohn's disease (CD). METHODS: MEDLINE, Embase and Web of Science databases of biomedical literature were systematically searched to identify studies that investigated the diagnostic accuracy of MRI in diagnosing bowel inflammation and disease activity in CD by comparing it with reference standards. Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality. The summary sensitivity and specificity were estimated using the bivariate model, and hierarchical summary receiver operating characteristic (HSROC) parameters were calculated and plotted. RESULTS: Of 5492 citations of interest, 34 articles contained the diagnostic accuracy data. Of these, results for the small bowel and the colorectum were reported separately in 19 studies and jointly by 21 studies. The meta-analytic summary sensitivity and specificity under the bivariate model were 90.9% (95% CI, 85.8%-94.2%) and 90.2% (95% CI, 81.9%-95.0%), respectively. The sensitivities and specificities of individual studies ranged from 55% to 100% and 51% to 100%, respectively. Substantial heterogeneity was observed in both sensitivity (I2=84.9%) and specificity (I2=78.8%). The HSROC curve also showed considerable heterogeneity between studies. CONCLUSION: Although the meta-analytic summary accuracy of MRI was high for the diagnosis of bowel inflammation in CD, the summary estimates might be unreliable due to the presence of high heterogeneity.

Hyperpolarized 3 helium MRI measured apparent diffusion coefficient and its correlations with pulmonary functions tests in patients with chronic obstructive pulmonary disease: A meta-analysis.

BACKGROUND: This study evaluates role of hyperpolarized 3 helium (3 He) MRI measured apparent diffusion coefficient (ADC) in examining pulmonary function of chronic obstructive pulmonary disease (COPD) patients. METHODS: After literature search in electronic databases, studies were selected by following precise eligibility criteria. Meta-analyses were performed to estimate mean difference in ADC between COPD patients and healthy individuals and to seek correlations between lung ADC and pulmonary function. Metaregression analyses were performed to seek relationships between ADC and age, gender, BMI, cigarette pack-years, and pulmonary function tests. RESULTS: Twenty-five studies (622 COPD patients and 469 healthy controls) were included. Lung ADC was 0.402 (95% confidence interval [CI]: 0.374, 0.429) in COPD patients and 0.228 (95% CI: 0.205, 0.252) in healthy individuals (mean difference 0.160 [95% CI: 0.127, 0.193]; p < 0.001). In metaregression, age (coefficient: 0.006; p = 0.004), pack-years (coefficient: 0.005; p = 0.018), forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (coefficient: -1.815; p = 0.007), percent predicted diffusion capacity of carbon monoxide (DLCO) (coefficient: -0.004; p = 0.008), and percent predicted inspiratory capacity (coefficient: -0.004; p = 0.012) were significantly associated with ADC in COPD patients. In meta-analysis of correlation coefficients, ADC was significantly correlated with FEV1 (r = -0.62; p < 0.00001), FEV1/FVC (r = -0.80; p < 0.00001), DLCO (r = -0.85; p < 0.00001), functional residual capacity (r = 0.71; p < 0.00001), reserve volume (r = 0.53; p = 0.0001), and emphysema index (r = 0.89; p < 0.00001). CONCLUSION: Hyperpolarized 3 He MRI measured ADC was higher in COPD patients than in healthy individuals and was inversely associated with FEV1, FEV1/FVC, DLCO, and inspiratory capacity.

miR129-1 regulates protein phosphatase 1D protein expression under hypoxic conditions in non-small cell lung cancer cells harboring a TP53 mutation.

Protein phosphatase 1D (PPM1D), which functions as an oncogene, is a known target of the tumor suppressor p53 and is involved in p53-regulated genomic surveillance mechanisms. PPM1D dephosphorylates both p53 and its ubiquitin ligase mouse double minute 2 homolog, as well as the RNA-binding protein (RBM)38, which turns RBM38 from an inducer to inhibitor of TP53 translation. In addition, RBM38 induces PPM1D translation. Hence, the PPM1D-RBM38-p53 axis is important in maintaining genomic integrity and is often altered during tumorigenesis. TP53, which encodes p53, is deleted or mutated in >50% of cancer types, including lung cancer. Mutant p53 has been revealed to complex with hypoxia-inducible factor 1α (HIF1α) and upregulate transcription of pro-metastatic genes. However, the mechanism underlying the action of the PPM1D-RBM38-p53 axis in the context of mutant p53 under normoxic and hypoxic conditions is yet to be elucidated. In the present study, using non-small cell lung cancer (NSCLC) cell lines harboring wild-type (A549 cells) or hot-spot mutant (NCI-H1770 and R249WΔ-TP53-A549 cells) TP53, it was demonstrated that in cells harboring mutant p53, RBM38 was not the primary regulator of PPM1D translation under hypoxic conditions. Knockdown of RBM38 in TP53 mutant cells did not affect the PPM1D protein expression under hypoxic conditions. Instead, in NCI-H1770 cells maintained under normoxic conditions, PPM1D was revealed as a target of micro RNA (miR)-129-1-3p, a known tumor suppressor in lung cancer. Hypoxia resulted in the downregulation of miR-129-1-3p expression, and thus, in the downregulation of PPM1D messenger RNA (mRNA) translation. In NCI-H1770 cells grown under hypoxic conditions, the transient transfection of miR-129-1-3p mimic, and not control mimic, repressed the expression of a reporter containing wild-type, but not miR-129-1-3p binding mutant, of the PPM1D 3'-untranslated region (UTR). Analysis of NSCLC cell lines from the Broad Institute Cancer Cell Encyclopedia and patients with NSCLC from The Cancer Genome Atlas dataset revealed significant co-occurrence of PPM1D/RBM38 and PPM1D/HIF1A mutations. However, there was no significant difference in the overall survival of patients with NSCLC with or without genomic alterations in TP53, RBM38, PPM1D and HIF1A. In summary, the current study demonstrated hypoxia-dependent miR-129-1-3p-mediated regulation of PPM1D protein expression in NSCLC cell line harboring mutant TP53.

RBM38 induces SIRT1 expression during hypoxia in non-small cell lung cancer cells by suppressing MIR34A expression.

OBJECTIVE: The study is to research how miR-34-SIRT1 is regulated during hypoxia in lung cancer cells. RESULTS: Analysis of publicly available datasets from patients with NSCLC did not reveal significant genomic alterations in RBM38, SIRT1, HIF1A, MIR34A, MIR34B, and MIR34C, but expectedly revealed alterations in TP53. Overall survival in NSCLC patients with or without alterations in these genes was not significantly different. When expanded to include all lung cancer patients, overall survival was significantly lower in patients with genomic alterations in these genes. CONCLUSIONS: Cumulatively, our results reveal a novel mechanism of RBM38-mediated regulation of the HIF1A/miR-34a/SIRT1/p53 axis under hypoxia in NSCLC cells.

Prevalence of comorbidities in chronic obstructive pulmonary disease patients: A meta-analysis.

BACKGROUND: This study compares the prevalence rates of comorbidities between chronic obstructive pulmonary disease (COPD) and non-COPD control patients reported in literature. METHOD: Literature was searched in several electronic databases. After the selection of studies by following précised eligibility criteria, meta-analyses of odds ratios (ORs) were carried out with subgroup and sensitivity analyses under random effects model. RESULTS: Eleven studies (47,695,183 COPD and 47,924,876 non-COPD control patients' data) were used for meta-analysis. Average age of COPD patients was 66.66 ±â€Š8.72 years of whom 55.4 ±â€Š11.9% were males. The prevalence of cardiovascular comorbidities [OR 1.90, 95% confidence interval (95% CI) 1.59-2.28; P < .00001], cerebrovascular comorbidities (OR 1.84, 95% CI 1.47-2.31; P < .00001), hypertension (OR 1.45, 95% CI 1.31-1.61; P < .00001), diabetes mellitus (OR 1.22, 95% CI 1.07-1.38; P = .003), neurological and psychiatric disorders (OR 1.78, 95% CI 1.48-2.14; P < .00001), gut and renal disorders (OR 1.96, 95% CI 1.43-2.68; P < .00001), musculoskeletal disorders (OR 1.51, 95% CI 1.27-1.78; P < .00001), non-COPD respiratory comorbidities (OR 2.81, 95% CI 2.52-3.14; P < .00001), and cancer (OR 1.67, 95% CI 1.25-2.23; P = .0005) were significantly higher in COPD patients than in non-COPD controls. CONCLUSION: COPD is associated with significantly higher comorbidities than in other diseases that should be taken into consideration in COPD control strategies.