Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1  week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.

Alpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from variations in SERPINA1. Many individuals affected by AATD are thought to be undiagnosed, leading to poor patient outcomes. The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world.

Testing for the epidermal growth factor receptor (EGFR) gene mutations requires considerable multidisciplinary experience of clinicians (for appropriate patient selection), pathologists (for selection of appropriate cytological or histological material) and geneticists (for performing and reporting reliable molecular tests). We present our experience on the efficacy of routine EGFR testing in various types of tumor samples and the frequency of EGFR mutations in a large series of Polish non-small cell lung cancer (NSCLC) patients.

Differentiating between chronic obstructive pulmonary disease (COPD) patients with normal (PiMM) or deficient (PiZZ) genetic variants of alpha-1 antitrypsin (A1AT) is important not only for understanding the pathobiology of disease progression but also for improving personalized therapies. This pilot study aimed to investigate whether urinary peptides reflect the A1AT-related phenotypes of COPD. Urine samples from 19 clinically stable COPD cases (7 PiMM and 12 PiZZ A1AT) were analyzed by capillary electrophoresis coupled to mass spectrometry. We identified 66 peptides (corresponding to 36 unique proteins) that differed between PiZZ and PiMM COPD. Among these, peptides from the collagen family were the most abundant and divergent. A logistic regression model based on COL1A1 or COL5A3 peptides enabled differentiation between PiMM and PiZZ groups, with a sensitivity of 100% and specificity of 85.71% for COL1A1 and a sensitivity of 91.67% and specificity of 85.71% for COL5A3. Furthermore, patients with PiZZ presented low levels of urinary peptides involved in lipoproteins/lipids and retinoic acid metabolism, such as apolipoprotein A-I and C4, retinol-binding protein 4 and prostaglandin-H2 D-isomerase. However, peptides of MDS1 and EVII complex locus, gelsolin and hemoglobin alpha were found in the urine of COPD cases with PiZZ, but not with PiMM. These capillary electrophoresis coupled to mass spectrometry-based results provide the first evidence that urinary peptide content differs between PiMM and PiZZ patients with COPD.

Multiple sclerosis (MS) has a significant inflammatory component and may have significant gray matter (GM) pathophysiology. Brain oxygenation is a sensitive measurement of the balance between metabolic need and oxygen delivery. There is evidence that inflammation and hypoxia are interdependent. In this paper, we applied novel, implanted PO2 sensors to measure hypoxia in cortical and cerebellar GM, in an inflammation-induced mouse model of MS.

Atrophy has become a clinically relevant marker of progressive neurodegeneration in multiple sclerosis (MS). To better understand atrophy, mouse models that feature atrophy along with other aspects of MS are needed. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS was used to determine the extent of atrophy in a model of inflammation-associated central nervous system pathology. High-resolution magnetic resonance imaging (MRI) and atlas-based volumetric analysis were performed to measure brain regional volumes in EAE mice. EAE brains were larger at peak clinical disease (days 14-16) compared to controls, with affected regions including the cerebellum, hippocampus, and corpus callosum. Following peak clinical disease, EAE mice exhibited significant loss of volume at chronic long-term disease duration (day 66+). Atrophy was identified in both white and grey matter regions including the cerebral cortex, cerebellum, hippocampus, corpus callosum, basal forebrain, midbrain, optic tract, and colliculus. Histological analysis of the atrophied cortex, cerebellum, and hippocampus showed demyelination, and axonal/neuronal loss. We hypothesize this atrophy could be a result of inflammatory associated neurodegenerative processes, which may also be involved in MS. Using MRI and atlas-based volumetrics, EAE has the potential to be a test bed for treatments aimed at reducing progressive neurological deterioration in MS.

Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples.

Susceptibility-weighted imaging (SWI) detects hypointensities due to iron deposition and deoxyhemoglobin. Previously it was shown that SWI detects hypointensities in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), most of which are due to intravascular deoxyhemoglobin, with a small proportion being due to iron deposition in the central nervous system parenchyma and demyelination. However, animals had to be sacrificed to differentiate these two types of lesions which is impractical for time course studies or for human application. Here, we proposed altering the inspired oxygen concentration during imaging to identify deoxyhemoglobin-based hypointensities in vivo. SWI was performed on lumbar spinal cords of naive control and EAE mice using 30% O2 then 100% O2. Some mice were imaged using 30% O2, 100% O2 and after perfusion. Most SWI-visible hypointensities seen with 30% O2 changed in appearance upon administration of 100% O2, and were not visible after perfusion. That hypointensities changed with hyperoxygenation indicates that they were caused by deoxyhemoglobin. We show that increasing the inspired oxygen concentration identifies deoxyhemoglobin-based hypointensities in vivo. This could be applied in future studies to investigate the contribution of vascular-based hypointensities with SWI in EAE and MS over time.

MicroRNAs (miRNAs), key regulators of gene expression at the post-transcriptional level, are grossly misregulated in some human cancers, including non-small-cell lung carcinoma (NSCLC). The aberrant expression of specific miRNAs results in the abnormal regulation of key components of signalling pathways in tumour cells. MiRNA levels and the activity of the gene targets, including oncogenes and tumour suppressors, produce feedback that changes miRNA expression levels and indicates the cell's genetic activity. In this study, we measured the expression of five circulating miRNAs (miR-195, miR-504, miR-122, miR-10b and miR-21) and evaluated their association with EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) mutation status in 66 NSCLC patients. Moreover, we examined the discriminative power of circulating miRNAs for EGFR mutant-positive and -negative NSCLC patients using two different data normalisation approaches. We extracted total RNA from the plasma of 66 non-squamous NSCLC patients (31 of whom had tumours with EGFR mutations) and measured circulating miRNA levels using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The miRNA expression levels were normalised using two endogenous controls: miR-191 and miR-16. We found significant associations between the expression of circulating miR-504 and EGFR-activating mutations in NSCLC patients regardless of the normalisation approach used (p = 0.0072 and 0.0236 for miR-16 and miR-191 normalisation, respectively). The greatest discriminative power of circulating miR-504 was observed in patients with EGFR exon 19 deletions versus wild-type EGFR normalised to miR-191 (area under the curve (AUC) = 0.81, p < 0.0001). Interestingly, circulating miR-504 levels were significantly reduced in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated subgroup compared to EGFR-mutated patients (p < 0.0030) and those with EGFR/KRAS wild-type tumours (p < 0.0359). Our study demonstrated the feasibility and potential diagnostic value of plasma miR-504 expression analysis to distinguish between EGFR-mutated and wild-type NSCLC patients. However, quality control and normalisation strategies are very important and have a major impact on the outcomes of circulating miRNA analyses.

Cumulating reports suggest that acute phase proteins (APPs) have diagnostic and prognostic value in different clinical conditions. Among others, APPs are proposed to serve as markers that help to control the outcome of transplant recipients. Here, we questioned whether plasma concentrations of APPs mirror the development of chronic lung allograft dysfunction (CLAD). We performed blinded analysis of serial plasma samples retrospectively collected from 35 lung transplanted patients, of whom 25 developed CLAD and 10 remained stable during the follow-up period of 3 to 4.5 years. Albumin (ALB), alpha1-antitrypsin (AAT), high sensitivity C-reactive protein (CRPH), antithrombin-3 (AT3), ceruloplasmin (CER), and alpha2-macroglobulin (A2MG) were measured by the nephelometric method. We found that within the first six months post-transplantation, levels of A2MG, CER and AAT were higher in stable patients relative to those who later developed CLAD. Moreover, in stable patient's plasma CRPH levels decreased during the follow-up period whereas opposite, in those developing CLAD, the CRPH gradually increased. The ALB levels became significantly lower at the end of the follow-up period in CLAD relative to a stable group. A logistic regression model based on A2MG, CER and AT3 at cut-offs levels of ≥175.5 mg/dL, ≥37.8 mg/dL and ≥27.35 mg/dL enabled to discriminate between stable and CLAD patients with a sensitivity of 87.5%, 100% and 62.5%, and specificity of 65.9%, 72.7% and 79.5%, respectively. We identified A2MG (below 175.5 mg/dL) as an independent predictor of CLAD (hazard ratio 11.5, 95% CI (1.5-91.3), p<0.021). Our findings suggest that profiles of certain APPs may help to predict the development of lung dysfunction at the very early stages after transplantation.