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

Induction chemotherapy followed by chemoradiation in locally advanced pancreatic cancer: an effective and well-tolerated treatment

Aims The treatment of locally advanced pancreatic cancer varies enormously both within the UK and internationally. Although chemoradiation is the treatment of choice in the USA, in the UK this modality is used infrequently because of concerns regarding both its efficacy and its toxicity. We reviewed our experience with induction chemotherapy and selective chemoradiation in an attempt to show that it is a well-tolerated treatment that may be superior to chemotherapy alone. Materials and methods Case notes of patients with locally advanced pancreatic cancer referred to the Velindre Cancer Centre between 1 March 2005 and 31 October 2007 were reviewed. Data on patient demographics, tumour characteristics, treatment and overall survival were collected retrospectively. Toxicity data during chemoradiation were collected prospectively. Patients who had non-progressive disease after 3 months of chemotherapy were planned for chemoradiation using three-dimensional conformal radiotherapy to a total dose of 4500–5040 cGy in 25–28 daily fractions with gemcitabine as a radiosensitiser. Results Of the 91 referrals, 69 (76%) were fit for active oncological treatment; 43/69 (62%) patients were considered for induction chemotherapy followed by chemoradiation and 16/43 (37%) patients received chemoradiation. The median overall survival for patients receiving primary chemotherapy (n = 26) was 9.2 (6.8–11.9) months and was 15.3 (11.6–upper limit not reached) months for patients who received chemoradiation (n = 16). During the induction chemotherapy 8/16 (50%) patients experienced grade 3/4 toxicity and there were five hospital admissions. During chemoradiation there were 6/16 (37.5%) cases of grade 3/4 toxicity and two hospital admissions. There were no treatment-related deaths. Overall, 94.5% of the intended radiotherapy dose and 84% of the concurrent chemotherapy dose was delivered. Conclusions In this UK network, about half of patients were considered for chemoradiation, but only 18% received it. Survival and treatment-related toxicity are consistent with data from other chemoradiation trials and in our series chemoradiation was tolerated better than chemotherapy alone. This supports the view that ‘consolidation’ chemoradiation is a viable treatment option that should be considered in selected patients with locally advanced non-metastatic pancreatic cancer

Targeting of Rough Endoplasmic Reticulum Membrane Proteins and Ribosomes in Invertebrate Neurons

The endoplasmic reticulum (ER) is divided into rough and smooth domains (RER and SER). The two domains share most proteins, but RER is enriched in some membrane proteins by an unknown mechanism. We studied RER protein targeting by expressing fluorescent protein fusions to ER membrane proteins in Caenorhabditis elegans. In several cell types RER and general ER proteins colocalized, but in neurons RER proteins were concentrated in the cell body, whereas general ER proteins were also found in neurites. Surprisingly RER membrane proteins diffused rapidly within the cell body, indicating they are not localized by immobilization. Ribosomes were also concentrated in the cell body, suggesting they may be in part responsible for targeting RER membrane proteins