Strengths and challenges in current lung cancer care: Timeliness and diagnostic procedures in six Dutch hospitals.

Objectives: Timely diagnosis of lung cancer (LC) is crucial to achieve optimal patient care and outcome. Moreover, the number of procedures required to obtain a definitive diagnosis can have a large influence on the life expectancy of a patient. Here, adherence with existing Dutch guidelines for timeliness and type and number of invasive and imaging procedures was assessed.

Liquid biopsy-based decision support algorithms for diagnosis and subtyping of lung cancer.

Objectives: Pathologic subtyping of tissue biopsies is the gold standard for the diagnosis of lung cancer (LC), which could be complicated in cases of e.g. inconclusive tissue biopsies or unreachable tumors.

Up-front mutation detection in circulating tumor DNA by droplet digital PCR has added diagnostic value in lung cancer.

Identification of actionable mutations in advanced stage non-squamous non-small-cell lung cancer (NSCLC) patients is recommended by guidelines as it enables treatment with targeted therapies. In current practice, mutations are identified by next-generation sequencing of tumor DNA (tDNA-NGS), which requires tissue biopsies of sufficient quality. Alternatively, circulating tumor DNA (ctDNA) could be used for mutation analysis.

Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients.

Liquid biopsies have become of interest as minimally invasive ways to monitor treatment response in lung cancer patients. Circulating tumor DNA (ctDNA) and protein biomarkers are evaluated for their added value in monitoring therapy response and early detection of disease progression. Plasma and serum samples of non-small cell or small cell lung cancer patients were analyzed for driver mutations in ctDNA (EGFR, KRAS or BRAF) using droplet digital PCR and protein biomarkers (CA125, CEA, CA15.

Pragmatic trial on inhaled corticosteroid withdrawal in patients with COPD in general practice.

The therapeutic value of inhaled corticosteroids (ICSs) for COPD is limited. In published RCTs, ICS could be withdrawn in COPD patients without increasing exacerbation risk when bronchodilator treatment is optimized. Here we report on the feasibility and risks of ICS withdrawal in Dutch general practice for COPD patients without an indication for ICSs.

Correction of the NSE concentration in hemolyzed serum samples improves its diagnostic accuracy in small-cell lung cancer.

Neuron-specific enolase (NSE) is a well-known biomarker for the diagnosis, prognosis and treatment monitoring of small-cell lung cancer (SCLC). Nevertheless, its clinical applicability is limited since serum NSE levels are influenced by hemolysis, leading to falsely elevated results. Therefore, this study aimed to develop a hemolysis correction equation and evaluate its role in SCLC diagnostics.

CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN.

ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated with clinical data in a prospective study of patients with renal ANCA disease.

CXCL5 drives neutrophil recruitment in TH17-mediated GN.

Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in TH17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen- and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic TH17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury.

The CTLA-4 +49GG genotype is associated with susceptibility for nephrotic kidney diseases.

Background: The pathogenesis of primary nephrotic kidney diseases is not completely understood. As T-cell involvement is suspected, cytotoxic T-lymphocyte antigen 4 (CTLA-4) expressed on activated T cells could play a role in the immune response. Single-nucleotide polymorphisms (SNPs) in the CTLA-4 gene are associated with several autoimmune-related diseases.

MicroRNA-155 drives TH17 immune response and tissue injury in experimental crescentic GN.

CD4(+) T cells play a pivotal role in the pathogenesis of autoimmune disease, including human and experimental crescentic GN. Micro-RNAs (miRs) have emerged as important regulators of immune cell development, but the impact of miRs on the regulation of the CD4(+) T cell immune response remains to be fully clarified. Here, we report that miR-155 expression is upregulated in the kidneys of patients with ANCA-associated crescentic GN and a murine model of crescentic GN (nephrotoxic nephritis).

Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.

The M-type phospholipase A2 receptor (PLA2R) is the major target antigen in idiopathic membranous nephropathy with detectable autoantibodies in the serum of up to 70% of patients. In retrospective studies, the PLA2R-autoantibody titer in the serum was sometimes negative indicating their measurement alone may be inconclusive. In order to better differentiate between primary and secondary membranous nephropathy, we conducted a prospective study that included 88 patients with a histologic diagnosis of membranous nephropathy.

Manual vs. automated analysis of polysomnographic recordings in patients with chronic obstructive pulmonary disease.

Purpose: The sleep quality, as assessed by polysomnography (PSG), of patients with chronic obstructive pulmonary disease (COPD) can be severely disturbed. The manual analysis of PSGs is time-consuming, and computer systems have been developed to automatically analyze PSGs. Studies on the reliability of automated analyses in healthy subjects show varying results, and the purpose of this study was to assess whether automated analysis of PSG by one certain automatic system in patients with COPD provide accurate outcomes when compared to manual analysis.

Temazepam 10mg does not affect breathing and gas exchange in patients with severe normocapnic COPD.

Background: Benzodiazepines can improve sleep quality, but are also thought to cause respiratory depression in patients with chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the effects of temazepam on indices of circadian respiratory function, dyspnea, sleep quality, and sleepiness in patients with severe COPD and insomnia.

Methods: In a double-blind, randomized, placebo-controlled, cross-over study in 14 stable patients with COPD (mean FEV(1) 0.

Accuracy of transcutaneous carbon dioxide tension measurements during cardiopulmonary exercise testing.

Background: Measurements of transcutaneous carbon dioxide tension (PtcCO(2)) with current devices are proven to provide clinically acceptable agreement with measurements of partial arterial carbon dioxide tension (PaCO(2)) in several settings but not during cardiopulmonary exercise testing (CPET).

Objectives: The primary objective of this study was to investigate the agreement between PaCO(2) and PtcCO(2) measurements (using a Tosca 500 with a Tosca sensor 92) during CPET. A secondary objective was to investigate the agreement between arterial and transcutaneous oxygen saturation (SaO(2), SpO(2)) as measured with this sensor during CPET.

Sleep, hypnotics and chronic obstructive pulmonary disease.

The quality of sleep is significantly compromised in many patients with chronic obstructive pulmonary disease (COPD) and may be further diminished when certain comorbidities are present. A reduced sleep quality is associated with daytime consequences like fatigue, psychiatric problems and an impaired quality of life. Sleep induces physiologic alterations in respiratory function, which can become pathologic and may provoke or worsen hypoxemia and hypercapnia in COPD.

Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia.

Objective: Reported survival in congenital diaphragmatic hernia (CDH) fails to allow for case selection bias. This study reports the incidence of CDH in a geographically defined population over 11 years and assesses the effect of new therapies (high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, inhaled nitric oxide, and delayed surgery) on survival when case selection is avoided.

Methods: A retrospective review of cases from a regional case registry, the Northern Region Congenital Anomaly Survey, was conducted.

Nuclear staining for the small heat shock protein alphaB-crystallin colocalizes with splicing factor SC35.

AlphaB-Crystallin has for a long time been considered a specific eye lens protein. Later on it appeared that this protein belongs to the family of the small heat shock proteins and that it occurs also extra-lenticularly in many different cell types. AlphaB-Crystallin is mainly present in the cytoplasm, but there are some indications that it might have a function in the nucleus too.

Differential expression of stress proteins in human adult astrocytes in response to cytokines.

Various lines of evidence suggest a close relationship between heat shock proteins (hsp) and several autoimmune diseases such as arthritis, diabetes and multiple sclerosis. While enhanced expression of hsp in autoimmune diseases is often regarded as a non-specific bystander effect of the inflammatory process, surprisingly little is known on hsp regulation by inflammatory mediators such as cytokines. In this study cytokine-induced expression of hsp60, hsp27 and alphaB-crystallin was studied in cultures of primary human adult astrocytes at the mRNA as well as at the protein level.

The short 5' untranslated region of the betaA3/A1-crystallin mRNA is responsible for leaky ribosomal scanning.

Leaky ribosomal scanning allows the expression of multiple proteins from a single mRNA by occasionally skipping the first start codon, and initiating translation at a subsequent one. BetaA3- and betaA1-crystallin, two members of the beta-crystallin family of vertebrate eye lens proteins, are produced via this mechanism, of which, until now, only very few examples have been found in eukaryotic genes. Since the two start codons on the betaA3/A1 messenger lie in the same reading frame, the two translated proteins are identical, except for the 17 residues shorter N-terminal extension of betaA1-crystallin.

The molecular chaperone alphaB-crystallin enhances amyloid beta neurotoxicity.

Amyloid beta (Abeta) is a 40- to 42-residue peptide that is implicated in the pathogenesis of Alzheimer's Disease (AD). As a result of conformational changes, Abeta assembles into neurotoxic fibrils deposited as 'plaques' in the diseased brain. In AD brains, the small heat shock proteins (sHsps) alphaB-crystallin and Hsp27 occur at increased levels and colocalize with these plaques.

Dementia, gliosis and expression of the small heat shock proteins hsp27 and alpha B-crystallin in Parkinson's disease.

Cognitive impairment and dementia are common in the later stages of Parkinson's disease (PD). Neuropathological examination of demented PD (PDD) patients often reveals changes that are typical of Alzheimer's disease (AD). In AD, there is a massive reactive gliosis and increased expression of the small heat shock proteins (hsp) hsp27 and alpha B-crystallin.

The biochemistry of Alzheimer's disease.

In the course of the biochemical efforts devoted to elucidation of the cause(s) and mechanism(s) of neurodegeneration in Alzheimer's disease (AD), much attention has been given to the processes by which amyloid is generated from amyloid precursor protein, notwithstanding the finding that mutations in 2 other proteins, presenilin 1 and 2, are associated with early-onset, familial AD in the majority of patients. In addition, the reason why the apolipoprotein E epsilon4 allele is over-represented in patients with the sporadic form of AD is unknown. Furthermore, the degree of dementia is clearly associated more with the degree of neurofibrillary pathology than with the amyloid plaque burden.

Rat Hsp20 confers thermoresistance in a clonal survival assay, but fails to protect coexpressed luciferase in Chinese hamster ovary cells.

Hsp20 is a mammalian small heat shock protein with some deviating in vitro characteristics. We now compare the in vivo cellular thermoprotective abilities of Hsp20 with those of its direct relative, alphaB-crystallin. In a clonal survival assay Chinese hamster ovary (CHO) cells stably overexpressing Hsp20 survive equally well as alphaB-crystallin-expressing cells, after a heat shock.

Heat shock, but not the reactive state per se, induces increased expression of the small stress proteins hsp25 and alpha B-crystallin in glial cells in vitro.

The stress proteins hsp25 and alpha B-crystallin are found in increased concentrations in reactive astrocytes of brains undergoing neurodegeneration. In order to characterize this reaction, we investigated the expression of hsp25 and alpha B-crystallin during growth and after stress (heat shock) in glial cells in vitro. In primary rat brain cultures, hsp25 was present in actively dividing astrocytes that were positive for glial fibrillary acidic protein.

Thermotolerance and nuclear protein aggregation: protection against initial damage or better recovery?

Heat-induced nuclear protein aggregation and subsequent disaggregation were measured in nonpreheated and preheated (thermotolerant) HeLa S3 cells. The effect of thermotolerance on the formation of and recovery from heat-induced nuclear protein aggregates was related to the cellular levels of hsp27, hsp60, hsp70, hsc70, and hsp90. Cells heated at different time points after the thermotolerance trigger showed various levels of protection against heat-induced nuclear protein aggregation.