Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.Olga Kondrashova … M.K. Oehler … [et al.] (Australian Ovarian Cancer Study (AOCS)

Mineral deficiency and the presence of Pinus sylvestris on mires during the mid- to late Holocene: Palaeoecological data from Cadogan's Bog, Mizen Peninsula, Co. Cork, southwest Ireland

Pollen records across parts of Ireland, England and northern Scotland show a dramatic collapse in Pinus pollen percentages at approximately 4000 radiocarbon years BP. This phenomenon has attracted much palaeoecological interest and several hypotheses have been put forward to account for this often synchronous and rapid reduction in pine from mid-Holocene woodland. Explanations for the 'pine decline' include prehistoric human activity, climatic change, in particular a substantial increase in precipitation resulting in increased mire wetness, and airborne pollution associated with the deposition of tephra. Hitherto, one largely untested hypothesis is that mineral deficiency could adversely affect pine growth and regeneration on mire surfaces. The discovery of pine-tree remains (wood pieces, stumps and trunks) within a peat located at Cadogan's Bog on the Mizen Peninsula, southwest Ireland, provided an opportunity to investigate the history of Pinus sylvestris and also to assess the importance of mineral nutrition in maintaining pine growth on mires. Pollen, plant macrofossils, microscopic charcoal and geochemical data are presented from a radiocarbon dated monolith extracted from this peat together with tree ring-width data and radiocarbon dated age estimates from subfossil wood. Analyses of these data suggest that peat accumulation commenced at the site around 6000 years BP when pine was the dominant local tree. Thereafter Pinus pollen percentages diminish in two stages, with the second decline taking place around 4160 ± 50 years BP. Concomitant with this decline in Pinus pollen, there is a noticeable, short-lived increase in wet-loving mire taxa and a decrease in the concentration of phosphorus, potassium, magnesium, calcium, sodium, iron and zinc. These results suggest that increased mire surface wetness, possibly the result of a change in climate, created conditions unsuitable for pine growth c. 4000 years BP. Mire surface wetness, coupled with a period of associated nutrient deficiency, appears to be a possible explanation for a lack of subsequent pine-seedling establishment for most of the later Holocene

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

The biosynthesis and metabolic role of chloromethane in fungi

SIGLEAvailable from British Library Document Supply Centre- DSC:DXN1385 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Severe γ-sarcoglycanopathy caused by a novel missense mutation and a large deletion

We report two siblings with a relatively severe limb-girdle muscular dystrophy. The elder sister presented at 8 years of age with inability to climb and abnormal gait. At 12 years she was barely ambulant. Her sister followed a similar course. Serum creatine kinase was 8500–10 000 IU (N 25–200) in the elder sister and 17 000–19 000 IU in the younger sister. Muscle biopsy of the elder sister at 8 years showed chronic myopathic changes with loss of muscle fibres, active necrosis and regeneration. Immunocytochemistry demonstrated normal spectrin and dystrophin, reduced α-sarcoglycan and absent γ-sarcoglycan – indicating a γ-sarcoglycanopathy. Haplotype analysis for the markers D13S115, D13S232, D13S292, D13S787, D13S1243 and D13S283 internal to and flanking the γ-sarcoglycan gene showed the affected sisters shared haplotypes, indicating it was possible they were suffering from a γ-sarcoglycanopathy. Non-inheritance of paternal alleles for D13S232, D13S292 and D13S1243 suggested the inheritance of a deletion, which was confirmed by FISH, using a genomic probe from the γ-sarcoglycan gene. The γ-sarcoglycan cDNA was amplified by reverse transcriptase PCR from the muscle biopsy of the elder sister and sequenced. A missense mutation changing codon 69 from GGC glycine to CGC arginine was identified. HhaI digestion of exon 3 genomic PCR products showed the two affected sisters were hemizygous for the mutation, while the mother and grandmother were heterozygotes. The mutation, identified by SSCP analysis, was not observed in 116 unrelated, unaffected individuals. Previously, only two other missense mutations, the Cys283Tyr missense mutation in Gypsies and the Leu193Ser mutation in a Dutch family, have been described in the γ-sarcoglycan gene. The fact that the affected individuals in the current and Gypsy families are γ-sarcoglycan negative may indicate that codons 69 and 283 are important in γ-sarcoglycan function

Dispatcher-assisted bystander cardiopulmonary resuscitation in a metropolitan city: A before-after population-based study

10.1016/j.resuscitation.2013.06.004Resuscitation85134-41RSUS

Recommendations on ambulance cardiopulmonary resuscitation in basic life support systems

10.3109/10903127.2013.818176Prehospital Emergency Care174491-500PEMC