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

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

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

Wildlife Underpass Use and Environmental Impact Assessment: A Southern California Case Study

Environmental planners often rely on transportation structures (i.e., underpasses, bridges) to provide connectivity for animals across developed landscapes. Environmental assessments of predicted environmental impacts from proposed developments often rely on literature reviews or other indirect measures to establish the importance of wildlife crossings. Literature-based evaluations of wildlife crossings may not be accurate, and result in under-estimation of impacts or establishment of inappropriate mitigation measures. To investigate the adequacy of literature-based evaluations, we monitored wildlife use of a freeway underpass that had been identified as critically important to wildlife connectivity, and which was evaluated in an environmental review document. Photographs were obtained from a network of trail cameras over 3 years. Six mid- to large-sized native mammal species used the underpass and two other mammal species were photographed near the underpass but not using it. American badger (Taxidea taxus) was photographed at a higher rate in the underpass than in the surrounding area. Gray fox (Urocyon cinereoargenteus) was rarely detected in the underpass relative to surrounding habitats, whereas the absence of mule deer (Odocoileus hemionus) in the underpass was unexpected, given relatively frequent detection in adjacent habitats. These results differed from the environmental assessment in that American badger was listed as potentially present while mule deer were expected to use the underpass. Results underscore importance of gathering data to document wildlife use of corridors, because some species do not or rarely take advantage of apparently suitable corridors, while others may be present when assumed to be absent

Analysis of haplotypes of CAT, TLR4, and IL10 genes in bronchial asthma patients comorbid with arterial hypertension

Co-occurrence of cardiovascular diseases is significantly common among patients with bronchial asthma. Genetic factors can have a significant effect on the development of hypertension in patients with asthma. Objective of the study was to investigate the associations of polymorphic variants relating to quantitative changes in the expression profile (eQTL) of the CAT, TLR4, and IL10 genes with the development of bronchial asthma co-morbid with arterial hypertension.Material and methods. Genotyping of 48 eQTL SNPs of the CAT, TLR4, and IL10 genes was performed using MALDI-TOF mass spectrometry in patients with «isolated» asthma (n = 145) and arterial hypertension (n = 144) and their combination (n = 146), as well as in the control group of healthy individuals (n = 152). Using logistic regression, an analysis of the associations of haplotypes with the studied diseases was carried out.Results. An association of bronchial asthma in combination with arterial hypertension with haplotypes formed by eQTL SNPs of the CAT and TLR4 genes was established. The spectrum of haplotypes associated with comorbidity of asthma and hypertension differs from the haplotypes associated with “isolated” asthma.Conclusion. The molecular base of asthma and hypertension comorbidity can be associated with variants that control the expression of TLR4 and CAT genes

Acute molecular changes in synovial fluid following human knee injury: association with early clinical outcomes

Objective To investigate whether molecules found to be up-regulated within hours of surgical joint destabilization in the mouse are also elevated in the analogous human setting of acute knee injury, how this molecular response varies between individuals, and whether it is related to patient-reported outcomes in the 3 months after injury. Methods Seven candidate molecules were analyzed in blood and synovial fluid (SF) from 150 participants with recent structural knee injury at baseline (<8 weeks from injury) and in blood at 14 days and 3 months following baseline. Knee Injury and Osteoarthritis Outcome Score 4 (KOOS4) was obtained at baseline and 3 months. Patient and control samples were compared using Meso Scale Discovery platform assays or enzyme-linked immunosorbent assay. Results Six of the 7 molecules were significantly elevated in human SF immediately after injury: interleukin-6 (IL-6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), activin A, and tumor necrosis factor–stimulated gene 6 (TSG-6). There was low-to-moderate correlation with blood measurements. Three of the 6 molecules were significantly associated with baseline KOOS4 (those with higher SF IL-6, TIMP-1, or TSG-6 had lower KOOS4). These 3 molecules, MMP-3, and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, after adjustment for other relevant factors. Of these, IL-6 alone significantly accounted for the molecular contribution to baseline KOOS4 and change in KOOS4 over 3 months. Conclusion Our findings validate relevant human biomarkers of tissue injury identified in a mouse model. Analysis of SF rather than blood more accurately reflects this response. The response is associated with patient-reported outcomes over this early period, with SF IL-6 acting as a single representative marker. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent disease risk

Geo-social gradients in predicted COVID-19 prevalence in Great Britain: results from 1 960 242 users of the COVID-19 Symptoms Study app

Understanding the geographical distribution of COVID-19 through the general population is key to the provision of adequate healthcare services. Using self-reported data from 1 960 242 unique users in Great Britain (GB) of the COVID-19 Symptom Study app, we estimated that, concurrent to the GB government sanctioning lockdown, COVID-19 was distributed across GB, with evidence of ’urban hotspots’. We found a geo-social gradient associated with predicted disease prevalence suggesting urban areas and areas of higher deprivation are most affected. Our results demonstrate use of self-reported symptoms data to provide focus on geographical areas with identified risk factors

Geo-social gradients in predicted COVID-19 prevalence in Great Britain: results from 1 960 242 users of the COVID-19 Symptoms Study app

Understanding the geographical distribution of COVID-19 through the general population is key to the provision of adequate healthcare services. Using self-reported data from 1 960 242 unique users in Great Britain (GB) of the COVID-19 Symptom Study app, we estimated that, concurrent to the GB government sanctioning lockdown, COVID-19 was distributed across GB, with evidence of ’urban hotspots’. We found a geo-social gradient associated with predicted disease prevalence suggesting urban areas and areas of higher deprivation are most affected. Our results demonstrate use of self-reported symptoms data to provide focus on geographical areas with identified risk factors

Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy

Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesised that a previously reported dark skin mouse mutant (Dsk7), which has a germline hypermorphic Gα11 mutation, Ile62Val, may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant Dsk7/+ and Dsk7/Dsk7 mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11 to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain-offunction. Treatment with NPS-2143, a calcilytic compound, normalised these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations in Dsk7/Dsk7 and Dsk7/+ mice, which became normocalcemic. Thus, these studies have established Dsk7 mice, which harbor a germline gain-of-function Gα11 mutation, as a model for ADH2; and demonstrated calcilytics as a potential targeted therapy