Circulating levels of anti-angiogenic VEGF-A isoform (VEGF-Axxxb) in colorectal cancer patients predicts tumour VEGF-A ratios

Purpose: Bevacizumab as an adjunct to chemotherapy improves survival for some patients with metastatic colorectal cancer. Immunohistochemical staining of samples from the registration ECOG E3200 trial of bevacizumab with FOLFOX demonstrated that only patients with carcinomas expressing low levels of VEGF-A(165)b, an anti-angiogenic splice variant of the Vascular Endothelial Growth Factor family of proteins, benefited from bevacizumab treatment. To identify a more useful biomarker of response we tested the hypothesis that circulating VEGF-A(165)b levels correlate with immunohistochemical staining. Experimental Design: 17 patients with biopsy proven colorectal adenocarcinoma had pre-operative blood samples drawn. They underwent resection and had post-resection blood drawn. The plasma was analysed for levels of VEGF-A(xxx)b using enzyme-linked immunosorbent assay (ELISA) and the tumour blocks stained for VEGF-A(xxx)b and pan-VEGF-A. The normalised ratio of VEGF-A(xxx)b expression to that of panVEGF-A expression scored by IHC was calculated and correlated with plasma VEGF-A(165)b levels. Results: Plasma levels of VEGF-A(xxx)b significantly correlated with the VEGF-A(xxx)b:panVEGF-A ratio (r=0.594, P<0.02) in colorectal cancers. Median plasma VEGF-A(xxx)b levels were 151 pg/ml. The mean (1.5±0.17) and median, IQR (1.8, 1-2) IHC scores of the patients with greater than median plasma VEGF-A(xxx)b were significantly greater than those with less than median plasma VEGF-A(xxx)b levels (mean ± SEM=0.85±10.12, median, IQR=1, 0.54-1). Conclusion: These results suggest that plasma VEGF-A(xxx)b levels could be an effective biomarker of response to Bevacizumab. These results indicate that a prospective trial is warranted to explore the use of plasma VEGF-A(xxx)b levels to stratify patients for colorectal cancer treatment by bevacizumab

A clinician’s guide to management of intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways

The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been fully elucidated. Although genetic, acquired diseases and environmental influences may play a role, it is also possible that motile cilia can influence this disease process. We hypothesized that deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia, resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88, and airway remodeling and pulmonary function were evaluated. In IFT88− mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and hyperplasia. IFT88− mice exhibited increased airway reactivity to a methacholine challenge and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With deletion of respiratory cilia there was a marked increase in the number of club cells as seen by scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the presence of club cells, since these cells are involved in airway repair. Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium. This monocilium is a prerequisite for these progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play an important role in controlling airway structure and function

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Needle bevel geometry influences the flexural deflection magnitude in ultrasound-enhanced fine-needle biopsy

Funding Information: Business Finland (grant 5607/31/2018), the Academy of Finland (grants 311586, 314286, and 335799), and the Finnish Cultural Foundation (personal grant 00210248) are acknowledged for financial support. The authors would like to give thanks to Yohann Le Bourlout and Dr. Gösta Ehnholm for fabrication and design of needle constructs, RF amplifier, and SWR meter. We are grateful to Dr. Maxime Fauconnier for his valuable comments, and we would like to thank all members of the Medical Ultrasonics Laboratory (MEDUSA) at Aalto University (Finland), for the insightful discussions. In addition, the authors would like to thank senior lecturer Kari Santaoja (Aalto University) for the constructive discussions.It has been recently demonstrated that use of ultrasound increases the tissue yield in ultrasound-enhanced fine-needle aspiration biopsy (USeFNAB) as compared to conventional fine-needle aspiration biopsy (FNAB). To date, the association between bevel geometry and needle tip action has not been widely explored. In this study, we studied the needle resonance characteristics and deflection magnitude of various needle bevel geometries with varying bevel lengths. With a conventional lancet, having a 3.9 mm long bevel, the tip deflection-to-power ratio (DPR) in air and water was 220 and 105 µm/W, respectively. This was higher in comparison to an axi-symmetric tip, having a bevel length of 4 mm, which achieved a DPR of 180 and 80 µm/W in air and water, respectively. This study emphasised the importance of relationship between flexural stiffness of bevel geometry in the context of various insertion media and, thus, could provide understanding on approaches to control post-puncture cutting action by modifying the needle bevel geometry, essential for the USeFNAB application.Peer reviewe