Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding.

The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2 that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30.

cGAS-STING drives the IL-6-dependent survival of chromosomally instable cancers.

Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance.

Tumor-educated T drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche.

Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (T) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive T during primary tumor growth.

Pro-mutagenic effects of the gut microbiota in a Lynch syndrome mouse model.

The gut microbiota strongly impacts the development of sporadic colorectal cancer (CRC), but it is largely unknown how the microbiota affects the pathogenesis of mismatch-repair-deficient CRC in the context of Lynch syndrome. In a mouse model for Lynch syndrome, we found a nearly complete loss of intestinal tumor development when animals were transferred from a conventional "open" animal facility to specific-pathogen-free (SPF) conditions. Using 16S sequencing we detected large changes in microbiota composition between the two facilities.

Multidimensional outcome assessment of pulmonary rehabilitation in traits-based clusters of COPD patients.

Background: Clusters of COPD patients have been reported in order to individualize the treatment program. Neither co-morbidity clusters, nor integrated respiratory physiomics clusters contributed to a better prediction of outcomes. Based on a thoroughly assessed set of pulmonary and extra-pulmonary traits at the start of a pulmonary rehabilitation (PR) program, we recently described seven clusters of COPD patients.

Safe-by-Design in Engineering: An Overview and Comparative Analysis of Engineering Disciplines.

In this paper, we provide an overview of how Safe-by-Design is conceived and applied in practice in a large number of engineering disciplines. We discuss the differences, commonalities, and possibilities for mutual learning found in those practices and identify several ways of putting those disciplinary outlooks in perspective. The considered engineering disciplines in the order of historically grown technologies are construction engineering, chemical engineering, aerospace engineering, urban engineering, software engineering, bio-engineering, nano-engineering, and finally cyber space engineering.

The Widely Used Antihelmintic Drug Albendazole is a Potent Inducer of Loss of Heterozygosity.

The antihelmintic drug ABZ and its metabolites belong to the chemical family of benzimidazoles (BZM) that act as potent tubulin polymerization inhibitors, suggesting a potential re-direction of BZMs for cancer therapy. Applying UV-Vis spectrometry we here demonstrate ABZ as a DNA intercalator. This insight led us to determine the primary mode of ABZ action in mammalian cells.

Retrograde flushing collection and freezing of dromedary camel epididymal spermatozoa with seminal plasma.

The objectives of this study were to describe the parameters of dromedary camel epididymal spermatozoa collected by retrograde flushing (RF) technique and to evaluate the freezability of the collected sperm, diluted with and without the supplementation of seminal plasma (SP). Two experiments were conducted: in Experiment 1, ES were recovered within 6-8 h after castration; selected samples were diluted with a Tris-citrate egg-yolk glycerolated buffer and frozen. In Experiment 2, epididymides were stored for 24 h at 4 °C before RF and semen samples were frozen after dilution with a Tris-lactose egg-yolk glycerolated extender with and without 15% SP.

Extensive trimming of short single-stranded DNA oligonucleotides during replication-coupled gene editing in mammalian cells.

Through transfection of short single-stranded oligodeoxyribonucleotides (ssODNs) small genomic alterations can be introduced into mammalian cells with high precision. ssODNs integrate into the genome during DNA replication, but the resulting heteroduplex is prone to detection by DNA mismatch repair (MMR), which prevents effective gene modification. We have previously demonstrated that the suppressive action of MMR can be avoided when the mismatching nucleotide in the ssODN is a locked nucleic acid (LNA).

Three-step site-directed mutagenesis screen identifies pathogenic variants associated with Lynch syndrome.

Background: Inactivating mutations in the MLH1 DNA mismatch repair (MMR) gene underlie 42% of Lynch syndrome (LS) cases. LS is a cancer predisposition causing early onset colorectal and endometrial cancer. Nonsense and frameshift alterations unambiguously cause LS.

An Adversarial Risk Analysis Framework for Cybersecurity.

Risk analysis is an essential methodology for cybersecurity as it allows organizations to deal with cyber threats potentially affecting them, prioritize the defense of their assets, and decide what security controls should be implemented. Many risk analysis methods are present in cybersecurity models, compliance frameworks, and international standards. However, most of them employ risk matrices, which suffer shortcomings that may lead to suboptimal resource allocations.

Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells.

In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of DNA damage. We show that abrogation of the G1/S-checkpoint allowed cells to enter S-phase under growth-restricting conditions at the expense of severe replication stress manifesting as decelerated DNA replication, reduced origin firing and accumulation of DNA double-strand breaks.

Effectiveness of Pulmonary Rehabilitation in Patients With Chronic Obstructive Pulmonary Disease With Different Degrees of Static Lung Hyperinflation.

Objective: To evaluate the effect of pulmonary rehabilitation (PR) on exercise performance and quality of life in patients with chronic obstructive pulmonary disease (COPD) with different degrees of static lung hyperinflation (LH).

Design: Retrospective cohort study.

Setting: PR network.

THE ACUTE-PHASE AND HEMOSTATIC RESPONSE IN DROMEDARY CAMELS ( CAMELUS DROMEDARIUS).

  Acute-phase reactants indicate inflammation and are increasingly used in veterinary medicine to indicate and to monitor progression of disease. Hemostasis and inflammation have interconnected pathophysiologic pathways and influence each other on different levels. This study established observed normal ranges for acute-phase reactants and for coagulation and thromboelastographic (TEG) parameters in 49 dromedary camels ( Camelus dromedarius) and assessed the response to chronic and acute inflammation.

Cortical Bone Size Deficit in Adult Patients With Type 1 Diabetes Mellitus.

Context: The increased fracture risk associated with type 1 diabetes mellitus (T1DM) remains unexplained by traditional risk factors such as low areal bone mineral density (aBMD). Nonetheless, few data exist on other determinants of bone strength in T1DM, including volumetric bone mineral density (vBMD) and bone geometry.

Objective: We compared areal and volumetric bone parameters and cortical bone geometry in adult T1DM patients and sex- and age-matched controls.

Insulin-like growth factor axis targeting in cancer and tumour angiogenesis - the missing link.

Numerous molecular players in the process of tumour angiogenesis have been shown to offer potential for therapeutic targeting. Initially denoted to be involved in malignant transformation and tumour progression, the insulin-like growth factor (IGF) signalling axis has been subject to therapeutic interference, albeit with limited clinical success. More recently, IGFs and their receptors have received attention for their contribution to tumour angiogenesis, which offers novel therapeutic opportunities.

Differential response to pulmonary rehabilitation in COPD: multidimensional profiling.

The aim of the present study was to profile a multidimensional response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD).Dyspnoea, exercise performance, health status, mood status and problematic activities of daily life were assessed before and after a 40-session pulmonary rehabilitation programme in 2068 patients with COPD (mean forced expiratory volume in 1 s of 49% predicted). Patients were ordered by their overall similarity concerning their multidimensional response profile, which comprises the overall response on MRC dyspnoea grade, 6MWD, cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression, and St George's Respiratory Questionnaire total score, using a novel non-parametric regression technique.

Security-by-Experiment: Lessons from Responsible Deployment in Cyberspace.

Conceiving new technologies as social experiments is a means to discuss responsible deployment of technologies that may have unknown and potentially harmful side-effects. Thus far, the uncertain outcomes addressed in the paradigm of new technologies as social experiments have been mostly safety-related, meaning that potential harm is caused by the design plus accidental events in the environment. In some domains, such as cyberspace, adversarial agents (attackers) may be at least as important when it comes to undesirable effects of deployed technologies.

Fatal Ichthyocotylurus erraticus infestation in Inca terns (Larosterna inca) in a zoological collection.

In a breeding group of Inca terns (Larosterna inca), 14 birds died without antemortem signs of illness. Other than a poor body condition and a bloody cloaca, no symptoms were observed. Gross necropsy revealed severe segmental hemorrhagic enteritis with intralesional trematodes in most birds.

Using the DOSE index to predict changes in health status of patients with COPD: a prospective cohort study.

Background: The severity of chronic obstructive pulmonary disease (COPD) should not be based on the level of airflow limitation alone. A multicomponent index such as the DOSE index (dyspnoea score (D), level of airflow obstruction (O), current smoking status (S), and exacerbations (E)) has the potential to predict important future outcomes in patients with COPD more effectively than the forced expiratory volume in one second. Health status deterioration should be prevented in COPD patients.

Effect of e-learning and repeated performance feedback on spirometry test quality in family practice: a cluster trial.

Purpose: Spirometry has become an indispensable tool in primary care to exclude, diagnose, and monitor chronic respiratory conditions, but the quality of spirometry tests in family practices is a reason for concern. Aim of this study was to investigate whether a combination of e-learning and bimonthly performance feedback would improve spirometry test quality in family practices in the course of 1 year.

Methods: Our study was a cluster trial with 19 family practices allocated to intervention or control conditions through minimization.

Quality of routine spirometry tests in Dutch general practices.

Background: Spirometry is an indispensable tool for diagnosis and monitoring of chronic airways disease in primary care.

Aim: To establish the quality of routine spirometry tests in general practice, and explore associations between test quality and patient characteristics.

Design Of Study: Analysis of routine spirometry test records.

Prevalence of nutritional depletion in a large out-patient population of patients with COPD.

Objective: The present study focuses on the prevalence of nutritional depletion in relation to functional performance, airflow limitation, experienced dyspnoea and health status in a large multi-center out-patient population with chronic obstructive pulmonary disease (COPD).

Methods: In 39 out-patient centers in The Netherlands, 389 patients with moderate to severe COPD (217 men) were recruited. The study evaluated on the baseline characteristics of the COSMIC study.

Salmeterol/fluticasone propionate versus fluticasone propionate plus montelukast: a cost-effective comparison for asthma.

Introduction And Objective: Asthma, owing to its chronic nature, is associated with a substantial economic burden. Healthcare providers need to compare the cost effectiveness of alternative asthma treatment options to ensure that they obtain the best value for money from the resources they control. The objective of the current study was to compare the cost effectiveness of salmeterol/fluticasone propionate in combination with fluticasone propionate plus montelukast in patients with symptomatic asthma uncontrolled with inhaled corticosteroid (ICS) monotherapy.

Measuring the success of treatment for chronic obstructive pulmonary disease--patient, physician and healthcare payer perspectives.

The success of treatments for chronic obstructive pulmonary disease (COPD) is evaluated by measuring the impact on a range of health outcomes. However, outcome measures differ in their relative importance to the various stakeholder groups. Patients are most interested in the impact on quality of life and on mortality, while physicians also value information about the effect of treatments on lung function and disease progression.