Inertia based microfluidic capture and characterisation of circulating tumour cells for the diagnosis of lung cancer

Background: Routine clinical application of circulating tumour cells (CTCs) for blood based diagnostics is yet to be established. Despite growing evidence of their clinical utility for diagnosis, prognosis and treatment monitoring, the efficacy of a robust platform and universally accepted diagnostic criteria remain uncertain. We evaluate the diagnostic performance of a microfluidic CTC isolation platform using cytomorphologic criteria in patients undergoing lung cancer surgery. Methods: Blood was processed from 51 patients undergoing surgery for known or suspected lung cancer using the ClearBridge ClearCell FX systemTM (ClearBridge Biomedics, Singapore). Captured cells were stained on slides with haematoxylin and eosin (H&E) and independently assessed by two pathologist teams. Diagnostic performance was evaluated against the pathologists reported diagnosis of cancer from surgically obtained specimens. Results: Cancer was diagnosed in 43.1% and 54.9% of all cases. In early stage primary lung cancer, between the two reporting teams, a positive diagnosis of CTCs was made for 50% and 66.7% of patients. The agreement between the reporting teams was 80.4%, corresponding to a kappa-statistic of 0.61±0.11 (P<0.001), indicating substantial agreement. Sensitivity levels for the two teams were calculated as 59% (95% CI, 41–76%) and 41% (95% CI, 24–59%), with a specificity of 53% for both. Conclusions: The performance of the tested microfluidic antibody independent device to capture CTCs using standard cytomorphological criteria provides the potential of a diagnostic blood test for lung cancer

The ‘Galilean Style in Science’ and the Inconsistency of Linguistic Theorising

Chomsky’s principle of epistemological tolerance says that in theoretical linguistics contradictions between the data and the hypotheses may be temporarily tolerated in order to protect the explanatory power of the theory. The paper raises the following problem: What kinds of contradictions may be tolerated between the data and the hypotheses in theoretical linguistics? First a model of paraconsistent logic is introduced which differentiates between week and strong contradiction. As a second step, a case study is carried out which exemplifies that the principle of epistemological tolerance may be interpreted as the tolerance of week contradiction. The third step of the argumentation focuses on another case study which exemplifies that the principle of epistemological tolerance must not be interpreted as the tolerance of strong contradiction. The reason for the latter insight is the unreliability and the uncertainty of introspective data. From this finding the author draws the conclusion that it is the integration of different data types that may lead to the improvement of current theoretical linguistics and that the integration of different data types requires a novel methodology which, for the time being, is not available

The ‘Galilean Style in Science’ and the Inconsistency of Linguistic Theorising

Chomsky’s principle of epistemological tolerance says that in theoretical linguistics contradictions between the data and the hypotheses may be temporarily tolerated in order to protect the explanatory power of the theory. The paper raises the following problem: What kinds of contradictions may be tolerated between the data and the hypotheses in theoretical linguistics? First a model of paraconsistent logic is introduced which differentiates between week and strong contradiction. As a second step, a case study is carried out which exemplifies that the principle of epistemological tolerance may be interpreted as the tolerance of week contradiction. The third step of the argumentation focuses on another case study which exemplifies that the principle of epistemological tolerance must not be interpreted as the tolerance of strong contradiction. The reason for the latter insight is the unreliability and the uncertainty of introspective data. From this finding the author draws the conclusion that it is the integration of different data types that may lead to the improvement of current theoretical linguistics and that the integration of different data types requires a novel methodology which, for the time being, is not available

Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response

The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low-dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti-TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization

ISSLS Prize in Clinical Science 2020. Examining causal effects of body mass index on back pain:a Mendelian randomization study

PURPOSE: Measures of body fat accumulation are associated with back pain, but a causal association is unclear. We hypothesized that BMI would have causal effects on back pain. We conducted a two-sample Mendelian randomization (MR) study to assess the causal effect of body mass index (BMI) on the outcomes of (1) back pain and (2) chronic back pain (duration &gt; 3 months).METHODS: We identified genetic instrumental variables for BMI (n = 60 variants) from a meta-analysis of genome-wide association studies (GWAS) conducted by the Genetic Investigation of ANthropometric Traits consortium in individuals of European ancestry (n = 322,154). We conducted GWAS of back pain and chronic back pain (n = 453,860) in a non-overlapping sample of individuals of European ancestry. We used inverse-variance weighted (IVW) meta-analysis as the primary method to estimate causal effects.RESULTS: The IVW analysis showed evidence supporting a causal association of BMI on back pain, with a 1-standard deviation (4.65 kg/m2) increase in BMI conferring 1.15 times the odds of back pain (95% confidence interval [CI]: 1.06-1.25, p = 0.001]; effects were directionally consistent in secondary analysis and sensitivity analyses. The IVW analysis supported a causal association of BMI on chronic back pain (OR 1.20 per 1 SD deviation increase in BMI [95% CI 1.09-1.32; p = 0.0002]), and effects were directionally consistent in secondary analysis and sensitivity analyses.CONCLUSION: In this first MR study of BMI and back pain, we found a significant causal effect of BMI on both back pain and chronic back pain. These slides can be retrieved under Electronic Supplementary Material.</p

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Background: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. Methods: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. Results: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). Conclusion: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection

Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium.

BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma

Genetics of «atopic march» syntropy

The study of the phenomenon of a combination of several diseases at the same time in an individual, actualized in the second half of the 19th century, is being actively analyzed 150 years later using genetic approaches. We present an overview of the results of such studies in relation to allergic diseases, in particular, a special variant, the so-called «atopic march», the sequential development of eczema, allergic rhinitis and asthma («atopic march» syntropy). The data of genetic and epidemiological studies were summarized, the analysis of genome-wide associative studies was carried out, and the role of mutations in the filaggrin gene (FLG) in the development of the «atopic march» syntropy was considered

Genome-Wide Association Analysis of Over 170,000 Individuals from the UK Biobank Identifies Seven Loci Associated with Dietary Approaches to Stop Hypertension (DASH) Diet

Diet is a modifiable risk factor for common chronic diseases and mental health disorders, and its effects are under partial genetic control. To estimate the impact of diet on individual health, most epidemiological and genetic studies have focused on individual aspects of dietary intake. However, analysing individual food groups in isolation does not capture the complexity of the whole diet pattern. Dietary indices enable a holistic estimation of diet and account for the intercorrelations between food and nutrients. In this study we performed the first ever genome-wide association study (GWA) including 173,701 individuals from the UK Biobank to identify genetic variants associated with the Dietary Approaches to Stop Hypertension (DASH) diet. DASH was calculated using the 24 h-recall questionnaire collected by UK Biobank. The GWA was performed using a linear mixed model implemented in BOLT-LMM. We identified seven independent single-nucleotide polymorphisms (SNPs) associated with DASH. Significant genetic correlations were observed between DASH and several educational traits with a significant enrichment for genes involved in the AMP-dependent protein kinase (AMPK) activation that controls the appetite by regulating the signalling in the hypothalamus. The colocalization analysis implicates genes involved in body mass index (BMI)/obesity and neuroticism (ARPP21, RP11-62H7.2, MFHAS1, RHEBL1). The Mendelian randomisation analysis suggested that increased DASH score, which reflect a healthy diet style, is causal of lower glucose, and insulin levels. These findings further our knowledge of the pathways underlying the relationship between diet and health outcomes. They may have significant implications for global public health and provide future dietary recommendations for the prevention of common chronic diseases

Impact of the polymorphism of the PACRG and CD80 genes on the development of the different stages of tuberculosis infection

Background: Tuberculosis (TB) is one of the most significant health-care problems worldwide. The host’s genetics play an important role in the development of TB in humans. The disease progresses through several stages, each of which can be under the control of different genes. The precise genes influencing the different stages of the disease are not yet identified. The aim of the current study was to determine the associations between primary and secondary TB and the polymorphisms of novel candidate genes for TB susceptibility, namely CD79A, HCST, CXCR4, CD4, CD80, CP, PACRG, and CD69.Methods: A total of 357 patients with TB (130 cases with primary TB and 227 cases with secondary TB) from the Siberian region of Russia as well as 445 healthy controls were studied. The study was performed at the Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russia, between July 2015 and November 2016. Genotyping was carried out using MALDI-TOF mass spectrometry and PCR-RFLP. The associations between the single-nucleotide polymorphisms and TB were assessed using logistic regression adjusting for covariates (age and gender). Multiple testing was addressed via the experiment-wise permutation approach. The statistical significance threshold was a P value less than 0.05 for the permutation P values. The analyses were done in R 3.2 statistical software.Results: An association was established between the rs1880661 variant of the CD80 gene and secondary TB and the rs10945890 variant of the PACRG gene and both primary and secondary TB. However, the same allele of PACRG appeared to be both a risk factor for reactivation (secondary TB) and a protector against primary infection. Conclusion: The results suggested that the CD80 and PACRG genes were associated with susceptibility to different forms of TB infection in the Russian population