Patients with BRCA-associated ovarian cancer (OC) have a survival advantage over those with sporadic OC. To further explore this, we examined the impact of prognostic factors on disease-free survival ...(DFS) and overall survival (OS) in patients with known BRCA mutation status.
We reviewed stage III–IV OC patients treated at our institution between 1 December 1996 and 30 September 2006 and also tested on protocol for BRCA mutations. Impact on DFS and OS was determined by Kaplan–Meier analysis and a Cox proportional hazards model.
Of the 110 patients, 36 had deleterious BRCA mutations BRCA (+) and 74 were BRCA wild type BRCA(-). Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (-) patients were platinum sensitive (P=0.60). Median OS was longer for BRCA (+) patients (not reached versus 67.8 months; P=0.02), but DFS was similar (26.9 versus 24.0, P=0.3). On multivariate analysis, OS correlated with primary platinum sensitivity HR=0.15; 95% CI (confidence interval) 0.06–0.34 and BRCA (+) mutation status (HR=0.33; 95% CI 0.12–0.86).
BRCA mutation status predicted OS independent of primary platinum sensitivity, suggesting that underlying tumor biology contributes to disease outcome and may be worthy of consideration in future clinical trial design.
Mutations at specific hotspots in non-coding regions of ADGRG6, PLEKHS1, WDR74, TBC1D12 and LEPROTL1 frequently occur in bladder cancer (BC). These mutations could function as biomarkers for the ...non-invasive detection of BC but this remains largely unexplored. Massively-parallel sequencing of non-coding hotspots was applied to 884 urine cell pellet DNAs: 591 from haematuria clinic patients (165 BCs, 426 non-BCs) and 293 from non-muscle invasive BC surveillance patients (29 with recurrence). Urine samples from 142 non-BC haematuria clinic patients were used to optimise variant calling. Non-coding mutations are readily detectable in the urine of BC patients and undetectable, or present at much lower frequencies, in the absence of BC. The mutations can be used to detect incident BC with 66% sensitivity (95% CI 58-75) at 92% specificity (95% CI 88-95) and recurrent disease with 55% sensitivity (95% CI 36-74) at 85% specificity (95% CI 80-89%) using a 2% variant allele frequency threshold. In the NMIBC surveillance setting, the detection of non-coding mutations in urine in the absence of clinically detectable disease was associated with an increased relative risk of future recurrence (RR = 4.62 (95% CI 3.75-5.48)). As urinary biomarkers, non-coding hotspot mutations behave similarly to driver mutations in BC-associated genes and could be included in biomarker panels for BC detection.
While marine sediments have been used to constrain a history of redox chemistry throughout the Precambrian, far fewer data have been generated from lakes. With major biological innovations thought to ...have occurred in Proterozoic lakes, understanding their chemistry is critical for understanding the evolution of eukaryotic life. We use sediment geochemistry to characterize the redox conditions of the Nonesuch Formation (~1.1 Ga) and a modern analogue for the Proterozoic: the Middle Island Sinkhole in Lake Huron (USA). Iron speciation, Mo contents, and Mo‐U covariation demonstrate oxic and anoxic—not euxinic—environments, with no clear indicators of enhanced biological productivity in the Nonesuch Formation. Moderate Mo enrichments observed in the Nonesuch Formation are not attributed to euxinia, but instead to an authigenic particulate shuttle. We suggest that the Fe and Mo sediment geochemistry of these lacustrine systems reflect only local water column and sediment burial conditions and not atmospheric oxygenation.
Plain Language Summary
Lakes are proposed to have been critical environments for the evolution of life during the Proterozoic (~2.5 to 0.5 billion years ago). However, relatively little is known about the chemistry of ancient lakes, including the availability of oxygen for biological productivity, and how local oxygen availability can be extrapolated to understand global oxygen availability. In addition, with no lakes remaining from the Proterozoic, the only way to study ancient lakes is to use the chemistry of the sediments left behind. This study uses the sediment chemistry of elements that are sensitive to oxygen to understand oxygen availability in a Proterozoic lake environment. These data were then compared to modern lake environments with known chemistry and oxygen levels in order to interpret the results better. We found that oxygen availability in the Proterozoic lake was variable, with no clear indicators of abundant biological productivity. We conclude that ancient lake sediments only constrain the chemistry of the local environment, with no major implications for global or even regional atmospheric oxygenation.
Key Points
Fe, Mo, and U sediment geochemistry of the Nonesuch Formation (~1.1 Ga; USA) indicate fluctuating oxic and anoxic redox chemistry
Mo and U covariation in the Nonesuch Formation and modern analogue sediments confirm euxinia is not necessary for moderate Mo burial
Comparison of Nonesuch Formation and modern analogue indicates that Proterozoic lakes are unlikely to constrain atmospheric oxygen
We measured and took blood samples from large tiger sharks in the wild to determine if their body condition (a metric of health) was related to energy stores (fatty acids). Our results revealed that ...body condition and fatty acids were positively and significantly correlated. This is important for understanding how large, highly mobile apex predators such as tiger sharks store and use energy required for migration and mating.
Animal condition typically reflects the accumulation of energy stores (e.g. fatty acids), which can influence an individual's decision to undertake challenging life-history events, such as migration and reproduction. Accordingly, researchers often use measures of animal body size and/or weight as an index of condition. However, values of condition, such as fatty acid levels, may not always reflect the physiological state of animals accurately. While the relationships between condition indices and energy stores have been explored in some species (e.g. birds), they have yet to be examined in top predatory fishes, which often undertake extensive and energetically expensive migrations. We used an apex predatory shark (Galeocerdo cuvier, the tiger shark) as a model species to evaluate the relationship between triglycerides (energy metabolite) and a metric of overall body condition. We captured, blood sampled, measured and released 28 sharks (size range 125–303 cm pre-caudal length). In the laboratory, we assayed each plasma sample for triglyceride values. We detected a positive and significant relationship between condition and triglyceride values (P < 0.02). This result may have conservation implications if the largest and highest-condition sharks are exploited in fisheries, because these individuals are likely to have the highest potential for successful reproduction. Our results suggest that researchers may use either plasma triglyceride values or an appropriate measure of body condition for assessing health in large sharks.
Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is ...associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.
Summary
The incidence and spectrum of non‐Hodgkin lymphoma (NHL) differ between the Chinese and Caucasian populations. Using population‐based registries, we studied the pattern of NHL in Chinese ...migrants to British Columbia (BC). The records of all NHL cases of Chinese descent diagnosed between 1980 and 1997 were retrieved. Age‐standardized incidences were calculated by 5‐year intervals in terms of age and calendar years and the relative rates were compared between the migrant, Hong Kong and BC populations. The histological distribution of NHL was compared with 4500 consecutive NHL cases diagnosed in the two populations. A total of 211 cases of migrant NHL were identified, with an age‐standardized incidence rate of 7·11 per 100 000 per year, compared with the Hong Kong and BC rates of 7·91 standardized incidence ratio (SIR) = 0·86, P = 0·01 and 11·88 (SIR = 0·56, P < 0·01). The standardized rates of follicular lymphoma remained low, but the incidence of gastric and nasal natural killer/T lymphomas in migrants were lower than expected. Genetic factors appeared to be stronger than environmental factors in governing the overall incidence of NHL in Chinese. However, certain subtypes of lymphoma may show decreased rates in migrants because of environmental factors.
Despite the special working environment and exposures of airline pilots, data on risk of death and cancer incidence in this occupational group are limited. The authors investigated a cohort of 2,740 ...Air Canada pilots who contributed 62,449 person-years of observation. All male pilots employed for at least 1 year on and since January 1, 1950, were studied. The cutoff date for outcome information was December 31, 1992. Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were used to compare mortality rates and cancer incidence rates of the cohort with the respective Canadian population rates. Ninety percent confidence intervals of the SMR and SIR were calculated. Statistically significant decreased mortality was observed for all causes (SMR = 0.63, 90% confidence interval (CI) 0.56–0.70), for all cancers (SMR = 0.61, 90% CI 0.48–0.76), and for all noncancer diseases (SMR = 0.53, 90% CI 0.45–0.62). Mortality from aircraft accidents was significantly raised (SMR = 26.57, 90% CI 19.3–35.9). Significantly decreased cancer incidence was observed for all cancers (SIR = 0.71, 90% CI 0.61–0.82), rectal cancer (SIR = 0.42, 90% CI 0.14–0.96), lung cancer (SIR = 0.28, 90% CI 0.16–0.46), and bladder cancer (SIR = 0.36, 90% CI 0.12–0.82). Prostate cancer (SIR = 1.87, 90% CI 1.38–2.49) and acute myeloid leukemia (SIR = 4.72, 90% CI 2.05–9.31) were significantly increased. The preferred relative risk model for radiation-induced nonchronic lymphoid leukemia (Beir V report) was applied to the cohort by using published estimates of in-flight radiation exposures. The estimated relative risk ranged from 1.001 to 1.06 and did not differ significantly from the observed SIR (SIR = 1.88, 90% CI 0.80–3.53). However, the incidence rate of acute myeloid leukemia was significantly increased. Monitoring of in-flight radiation exposure and long-term follow-up of civil aviation crew members is needed to further assess cancer incidence and leukemia risk in this special occupational group. Am J Epidemiol 1996;143:137–43
Autosomal-dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) causes sudden cardiac death and is characterized by clinical and genetic heterogeneity. Fifteen unrelated ARVC ...families with a disease-associated haplotype on chromosome 3p (ARVD5) were ascertained from a genetically isolated population. Identification of key recombination events reduced the disease region to a 2.36 Mb interval containing 20 annotated genes. Bidirectional resequencing showed one rare variant in transmembrane protein 43 (TMEM43 1073C→T, S358L), was carried on all recombinant ARVD5 ancestral haplotypes from affected subjects and not found in population controls. The mutation occurs in a highly conserved transmembrane domain of TMEM43 and is predicted to be deleterious. Clinical outcomes in 257 affected and 151 unaffected subjects were compared, and penetrance was determined. We concluded that ARVC at locus ARVD5 is a lethal, fully penetrant, sex-influenced morbid disorder. Median life expectancy was 41 years in affected males compared to 71 years in affected females (relative risk 6.8, 95% CI 1.3–10.9). Heart failure was a late manifestation in survivors. Although little is known about the function of the TMEM43 gene, it contains a response element for PPARγ (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC.
Wind-driven redistribution of snow on sea ice alters its
topography and microstructure, yet the impact of these processes on radar
signatures is poorly understood. Here, we examine the effects of ...snow
redistribution over Arctic sea ice on radar waveforms and backscatter
signatures obtained from a surface-based, fully polarimetric Ka- and Ku-band
radar at incidence angles between 0∘ (nadir) and 50∘.
Two wind events in November 2019 during the Multidisciplinary drifting Observatory for
the Study of Arctic Climate (MOSAiC) expedition are evaluated. During both events, changes in Ka- and
Ku-band radar waveforms and backscatter coefficients at nadir are observed,
coincident with surface topography changes measured by a terrestrial laser
scanner. At both frequencies, redistribution caused snow densification at
the surface and the uppermost layers, increasing the scattering at the
air–snow interface at nadir and its prevalence as the dominant radar scattering surface. The waveform data also detected the presence of previous
air–snow interfaces, buried beneath newly deposited snow. The additional
scattering from previous air–snow interfaces could therefore affect the
range retrieved from Ka- and Ku-band satellite altimeters. With increasing
incidence angles, the relative scattering contribution of the air–snow
interface decreases, and the snow–sea ice interface scattering increases.
Relative to pre-wind event conditions, azimuthally averaged backscatter at
nadir during the wind events increases by up to 8 dB (Ka-band) and 5 dB (Ku-band). Results show substantial backscatter variability within the scan
area at all incidence angles and polarizations, in response to increasing
wind speed and changes in wind direction. Our results show that snow
redistribution and wind compaction need to be accounted for to interpret
airborne and satellite radar measurements of snow-covered sea ice.
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