Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

BACKGROUND: Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. METHODS: To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. RESULTS: There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.80 and OR = 1.34, 95% CI: 1.00-1.79 respectively). CONCLUSION: This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.

BACKGROUND: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg-800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76-0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77-0·92; p<0·0001). INTERPRETATION: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

The Opdc missense mutation of Pax2 has a milder than loss-of-function phenotype

Renal-coloboma syndrome, also known as papillorenal syndrome, is an autosomal dominant human disorder in which optic disc coloboma is associated with kidney abnormalities. Mutations in the paired domain transcription factor PAX2 have been found to be the underlying cause of this disease. Disease severity varies between patients, and in some cases, renal hypoplasia has been found in the absence of any retinal defects. Here we report an N-ethyl-N-nitrosourea-induced mouse mutation, Opdc, which is an isoleucinetothreonine missense mutation, I40T, in the first α-helix of the Pax2 paired domain. The mutant protein binds target DNA sequences less strongly than the wild-type protein and acts poorly to transactivate target promoters in culture. The phenotypic consequence of this mutation on the development of the eye and ear is similar to that reported for null alleles of Pax2. However, in homozygotes, cerebellar development is normal on a genetic background in which loss of Pax2 results in failure of cerebellar formation. Moreover, there is a genetic background effect on the heterozygous phenotype such that on some strain backgrounds, kidney development is unaffected. Opdc is the first hypomorphic mutation reported for Pax2 that differs in phenotype from loss-of-function mutations. These results suggest that PAX2 is a strong candidate gene for cases in which human patients have optic disc coloboma not associated with renal dysplasia

Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention

National study of colorectal cancer genetics

Approximately, a third of all colorectal cancer (CRC) is due to inherited susceptibility. However, high-risk mutations in APC, the mismatch repair (MMR) genes, MUTYH/MYH, SMAD4, ALK3 and STK11/LKB1 are rare and account for <5% of cases. Much of the remaining variation in genetic risk is likely to be explained by combinations of more common gene variants that modestly increase risk. Reliable identification of such ‘low penetrance' alleles would provide insight into the aetiology of CRC and might highlight potential therapeutic and preventative interventions. In 2003, the National Study of Colorectal Cancer Genetics (NSCCG) was established with the aim of collecting DNA and clinicopathological data from 20 000 CRC cases and a series of spouse/partner controls, thereby creating a unique resource for identifying low-penetrance CRC susceptibility alleles. The National Cancer Research Network (NCRN) adopted NSCCG onto its portfolio of trials and 148 centres in the United Kingdom (UK) are now actively participating. Over 8700 cases and 2185 controls have so far been entered into NSCCG. Our experience in developing NSCCG serves to illustrate how world-class DNA databases for genetic analyses can be rapidly developed in the United Kingdom

The Development of Metabolomic Sampling Procedures for Pichia pastoris, and Baseline Metabolome Data

Metabolic profiling is increasingly being used to investigate a diverse range of biological questions. Due to the rapid turnover of intracellular metabolites it is important to have reliable, reproducible techniques for sampling and sample treatment. Through the use of non-targeted analytical techniques such as NMR and GC-MS we have performed a comprehensive quantitative investigation of sampling techniques for Pichia pastoris. It was clear that quenching metabolism using solutions based on the standard cold methanol protocol caused some metabolite losses from P. pastoris cells. However, these were at a low level, with the NMR results indicating metabolite increases in the quenching solution below 5% of their intracellular level for 75% of metabolites identified; while the GC-MS results suggest a slightly higher level with increases below 15% of their intracellular values. There were subtle differences between the four quenching solutions investigated but broadly, they all gave similar results. Total culture extraction of cells + broth using high cell density cultures typical of P. pastoris fermentations, was an efficient sampling technique for NMR analysis and provided a gold standard of intracellular metabolite levels; however, salts in the media affected the GC-MS analysis. Furthermore, there was no benefit in including an additional washing step in the quenching process, as the results were essentially identical to those obtained just by a single centrifugation step. We have identified the major high-concentration metabolites found in both the extra- and intracellular locations of P. pastoris cultures by NMR spectroscopy and GC-MS. This has provided us with a baseline metabolome for P. pastoris for future studies. The P. pastoris metabolome is significantly different from that of Saccharomyces cerevisiae, with the most notable difference being the production of high concentrations of arabitol by P. pastoris

Quantifying Microstructural Evolution in Moving Magma

Many of the grand challenges in volcanic and magmatic research are focused on understanding the dynamics of highly heterogeneous systems and the critical conditions that enable magmas to move or eruptions to initiate. From the formation and development of magma reservoirs, through propagation and arrest of magma, to the conditions in the conduit, gas escape, eruption dynamics, and beyond into the environmental impacts of that eruption, we are trying to define how processes occur, their rates and timings, and their causes and consequences. However, we are usually unable to observe the processes directly. Here we give a short synopsis of the new capabilities and highlight the potential insights that in situ observation can provide. We present the XRheo and Pele furnace experimental apparatus and analytical toolkit for the in situ X-ray tomography-based quantification of magmatic microstructural evolution during rheological testing. We present the first 3D data showing the evolving textural heterogeneity within a shearing magma, highlighting the dynamic changes to microstructure that occur from the initiation of shear, and the variability of the microstructural response to that shear as deformation progresses. The particular shear experiments highlighted here focus on the effect of shear on bubble coalescence with a view to shedding light on both magma transport and fragmentation processes. The XRheo system is intended to help us understand the microstructural controls on the complex and non-Newtonian evolution of magma rheology, and is therefore used to elucidate the many mobilization, transport, and eruption phenomena controlled by the rheological evolution of a multi-phase magmatic flows. The detailed, in situ characterization of sample textures presented here therefore represents the opening of a new field for the accurate parameterization of dynamic microstructural control on rheological behavior

Studies on CuCe0.75Zr0.25Ox preparation using bacterial cellulose and its application in toluene complete oxidation

A series of CuCe0.75Zr0.25Ox catalysts (CCZ) were synthesized based on the environmental‐friendly bacterial cellulose (BC) by using the sol‐gel method. The corresponding synthesis mechanism, physicochemical properties of the catalysts and catalytic performances for toluene oxidation were comprehensively studied. In the presence of BC without sugar, the CCZ−A synthesized by ethanol‐gel exhibits better catalytic activity than the CCZ−W synthesized by water‐gel, which may be due to the different roles of BC in different solvents. However, it is worth noting that the graft copolymerization between BC and active metal (Ce4+, Cu2+) is the same process in both water‐gel and ethanol‐gel. The activity of CCZ‐SW synthesized by water‐gel using BC with sugar is obviously higher than that of CCZ−W and CCZ−A. The temperature of complete degradation of toluene over CCZ‐SW is 205 °C, which is 35 °C lower than that of CCZ−W. The results from BET, Raman and H2‐TPR indicate that the larger the specific surface area, the more oxygen vacancies and better low‐temperature reducibility, that are mainly responsible for the excellent activity of CCZ‐SW. The existence of sugar in BC could hinder the agglomeration of active metal particles during the calcination process. Combined with the results of in situ DRIFT, the adsorbed toluene on the catalyst surface is oxidized into alkoxide, aldehydic and carboxylic acid species as intermediates before the complete oxidation into CO2 and H2O.