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The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes. The authors identify copy number signatures from shallow whole-genome sequencing of high-grade serous ovarian cancer (HGSOC) cases. HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in genomic aberration.

Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon.NuMA protein levels in normal and tumour tissues, ovarian cell lines and primary cultures of malignant cells derived from ovarian ascitic fluids were analysed by Affymetrix microarray analysis, immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF), with results correlated to associated clinical data. Aneuploidy status in primary cultures was determined by FACS analysis.Affymetrix microarray data indicated that NuMA was overexpressed in tumour tissue, primary cultures and cell lines compared to normal ovarian tissue. IHC revealed low to weak NuMA expression in normal tissues. Expression was upregulated in tumours, with a significant association with disease stage in mucinous EOC subtypes (p = 0.009), lymph node involvement (p = 0.03) and patient age (p = 0.04). Additional discontinuous data analysis revealed that high NuMA levels in tumours decreased with grade (p = 0.02) but increased with disease stage (p = 0.04) in serous EOC. NuMA expression decreased in late disease stage 4 endometrioid EOCs. High NuMA levels decreased with increased tumour invasion in all subtypes (p = 0.03). IF of primary cultures revealed that high NuMA levels at mitotic spindle poles were significantly associated with a decreased proportion of cells in cytokinesis (p = 0.05), increased binucleation (p = 0.021) and multinucleation (p = 0.007), and aneuploidy (p = 0.008).NuMA is highly expressed in EOC tumours and high NuMA levels correlate with increases in mitotic defects and aneuploidy in primary cultures.

Purpose To assess the significance of CA-125 regression as a prognostic indicator and predictor of optimal cytoreduction at interval debulking surgery (IDS) in women with ovarian or primary peritoneal carcinoma receiving neoadjuvant chemotherapy (NAC). Methods 63 women treated between 2004 and 2007 with neoadjuvant platinum-based chemotherapy followed by IDS were studied retrospectively. Pre-operative CA-125 values were used to calculate a regression coefficient (CA-125r) using exponential regression analysis. Outcome endpoints were overall survival (OS), time to CA-125 progression (TTC) by Rustin criteria and time to second-line treatment (TTS). Results Women with a CA-125 half-life greater than 18 days had a significantly worse OS compared to those with a half-life less than 12 days on univariate testing (HR 3.34, 95% CI 1.25–8.94, p  = 0.017). On multivariable analysis, CA-125r was an independent predictor of OS [HR 1.18 (per 0.01 increase in CA-125r), 95% CI 1.01–1.40, p  = 0.043]. CA-125r was independently predictive of TTC and TTS (HR 1.17, p  ≈ 0.03 for each). CA-125r was also predictive of achieving optimal cytoreduction at IDS (AUC 0.756, p  < 0.001). Conclusions CA-125 regression rate during pre-operative NAC is of independent prognostic value. CA-125 regression rate strongly predicts for optimal cytoreduction.

Epithelial ovarian cancer (EOC) remains a major source of cancer morbidity and mortality, despite advances in surgical and chemotherapeutic management. The molecular pathways that control angiogenesis have been demonstrated to be key to the pathogenesis of EOC, and have been shown to have prognostic significance. Increased understanding of the pathways and molecules involved in angiogenesis has allowed the identification of a number of targets for antiangiogenic therapies and the development of a variety of antiangiogenic drugs. There is now significant preclinical evidence, and a growing body of clinical data, demonstrating promising results with antiangiogenic drugs in the treatment of EOC. Single-agent VEGF inhibitor response rates in pretreated patients of between 15 and 20% have been reported, with much higher response rates when used in combination with chemotherapeutic agents. These benefits, however, must be balanced with the toxicities associated with these drugs, particularly the more serious ones, such as gastrointestinal perforation. The results of ongoing and future randomized clinical trials will confirm if, and how, antiangiogenic therapies should be integrated into the routine management of EOC. However, critical issues, such as the relative importance of combination remission induction regimens and maintenance therapy, remain poorly defined.

Genomic complexity from profound copy-number aberration has prevented effective molecular stratification of ovarian and other cancers. Here we present a method for copy-number signature identification that decodes this complexity. We derived eight signatures using 117 shallow whole-genome sequenced high-grade serous ovarian cancer cases, which were validated on a further 497 cases. Mutational processes underlying the copy-number signatures were identified, including breakage-fusion-bridge cycles, homologous recombination deficiency and whole-genome duplication. We show that most tumours are heterogeneous and harbour multiple signature exposures. We also demonstrate that copy number signatures predict overall survival and changes in signature exposure observed in response to chemotherapy suggest potential treatment strategies.

The Montreal Protocol was designed to protect the stratospheric ozone layer by enabling reductions in the abundance of ozone-depleting substances such as chlorofluorocarbons (CFCs) in the atmosphere 1 – 3 . The reduction in the atmospheric concentration of trichlorofluoromethane (CFC-11) has made the second-largest contribution to the decline in the total atmospheric concentration of ozone-depleting chlorine since the 1990s 1 . However, CFC-11 still contributes one-quarter of all chlorine reaching the stratosphere, and a timely recovery of the stratospheric ozone layer depends on a sustained decline in CFC-11 concentrations 1 . Here we show that the rate of decline of atmospheric CFC-11 concentrations observed at remote measurement sites was constant from 2002 to 2012, and then slowed by about 50 per cent after 2012. The observed slowdown in the decline of CFC-11 concentration was concurrent with a 50 per cent increase in the mean concentration difference observed between the Northern and Southern Hemispheres, and also with the emergence of strong correlations at the Mauna Loa Observatory between concentrations of CFC-11 and other chemicals associated with anthropogenic emissions. A simple model analysis of our findings suggests an increase in CFC-11 emissions of 13 ± 5 gigagrams per year (25 ± 13 per cent) since 2012, despite reported production being close to zero 4 since 2006. Our three-dimensional model simulations confirm the increase in CFC-11 emissions, but indicate that this increase may have been as much as 50 per cent smaller as a result of changes in stratospheric processes or dynamics. The increase in emission of CFC-11 appears unrelated to past production; this suggests unreported new production, which is inconsistent with the Montreal Protocol agreement to phase out global CFC production by 2010. Atmospheric CFC-11 concentrations have been declining less rapidly since 2012; evidence suggests that this finding is explained by an increase in the emission of CFC-11during these years.

ObjectivesTo estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer.MethodsWe employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England.ResultsDeclines in urgent referrals (median=−70.4%) and chemotherapy attendances (median=−41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=−44.5%) and chemotherapy attendances (median=−31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity.ConclusionsDramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.

The age of air is an important transport diagnostic that can be derived from trace gas measurements and compared to global chemistry climate model output. We describe a new technique to calculate the age of air, measuring transport times from the Earth's surface to any location in the atmosphere based on simultaneous in situ measurements of multiple key long-lived trace gases. The primary benefits of this new technique include (1) optimized ages of air consistent with simultaneously measured SF6 and CO2; (2) age of air from the upper troposphere through the stratosphere; (3) estimates of the second moment of age spectra that have not been well constrained from measurements; and (4) flexibility to be used with measurements across multiple instruments, platforms, and decades. We demonstrate the technique on aircraft and balloon measurements from the 1990s, the last period of extensive stratospheric in situ sampling, and several recent missions from the 2020s, and compare the results with previously published and modeled values.

UCATS (the UAS Chromatograph for Atmospheric Trace Species) was designed and built for observations of important atmospheric trace gases from unmanned aircraft systems (UAS) in the upper troposphere and lower stratosphere (UTLS). Initially it measured major chlorofluorocarbons (CFCs) and the stratospheric transport tracers nitrous oxide (N2O) and sulfur hexafluoride (SF6), using gas chromatography with electron capture detection. Compact commercial absorption spectrometers for ozone (O3) and water vapor (H2O) were added to enhance its capabilities on platforms with relatively small payloads. UCATS has since been reconfigured to measure methane (CH4), carbon monoxide (CO), and molecular hydrogen (H2) instead of CFCs and has undergone numerous upgrades to its subsystems. It has served as part of large payloads on stratospheric UAS missions to probe the tropical tropopause region and transport of air into the stratosphere; in piloted aircraft studies of greenhouse gases, transport, and chemistry in the troposphere; and in 2021 is scheduled to return to the study of stratospheric ozone and halogen compounds, one of its original goals. Each deployment brought different challenges, which were largely met or resolved. The design, capabilities, modifications, and some results from UCATS are shown and described here, including changes for future missions.

In this phase 3 trial, progesterone had no benefit as a neuroprotective agent in patients with blunt traumatic brain injury. Together with a second negative clinical trial of progesterone for acute TBI (SYNAPSE), the findings provide no support for this therapeutic approach. More than 2.4 million emergency department visits, hospitalizations, or deaths are related to traumatic brain injury (TBI) annually, and approximately 5.3 million Americans are living with disability from TBI. The aggregate annual cost of TBI in the United States now approaches $76.5 billion. 1 Survivors of severe TBI typically require 5 to 10 years of intensive therapy and are often left with substantial disability. 2 Despite decades of research, no pharmacologic agent has been shown to improve outcomes after TBI. Progesterone is a potent neurosteroid synthesized in the central nervous system. Preclinical studies in laboratory animals indicated that the early administration of . . .