Search

UNLABELLED: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indica more...

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P <.001) and PARP inhibitor therapy (P <.001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P <.018) and WEE1 inhibitor (P <.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P <.001) but was not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy. more...

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy. more...

Many common diseases have a complex genetic basis in which large numbers of genetic variations combine with environmental factors to determine risk. However, quantifying such polygenic effects has been challenging. In order to address these difficulties we developed a global measure of the information content of an individual's genome relative to a reference population, which may be used to assess differences in global genome structure between cases and appropriate controls. Informally this measure, which we call relative genome information (RGI), quantifies the relative "disorder" of an individual's genome. In order to test its ability to predict disease risk we used RGI to compare single-nucleotide polymorphism genotypes from two independent samples of women with early-onset breast cancer with three independent sets of controls. We found that RGI was significantly elevated in both sets of breast cancer cases in comparison with all three sets of controls, with disease risk rising sharply with RGI. Furthermore, these differences are not due to associations with common variants at a small number of disease-associated loci, but rather are due to the combined associations of thousands of markers distributed throughout the genome. Our results indicate that the information content of an individual's genome may be used to measure the risk of a complex disease, and suggest that early-onset breast cancer has a strongly polygenic component. more...

In order to advance understanding of the role of seawater surfactants in the air-sea exchange of climatically active trace gases via suppression of the gas transfer velocity (k(w)), we constructed a fully automated, closed air-water gas exchange tank and coupled analytical system. The system allows water-side turbulence in the tank to be precisely controlled with an electronically operated baffle. Two coupled gas chromatographs and an integral equilibrator, connected to the tank in a continuous gas-tight system, allow temporal changes in the partial pressures of SF6, CH4 and N2O to be measured simultaneously in the tank water and headspace at multiple turbulence settings, during a typical experimental run of 3.25 h. PC software developed by the authors controls all operations and data acquisition, enabling the optimisation of experimental conditions with high reproducibility. The use of three gases allows three independent estimates of k(w) for each turbulence setting; these values are subsequently normalised to a constant Schmidt number for direct comparison. The normalised k(w) estimates show close agreement. Repeated experiments with Milli-Q water demonstrate a typical measurement accuracy of 4% for k(w). Experiments with natural seawater show that the system clearly resolves the effects on k(w) of spatial and temporal trends in natural surfactant activity. The system is an effective tool with which to probe the relationships between k(w), surfactant activity and biogeochemical indices of primary productivity, and should assist in providing valuable new insights into the air-sea gas exchange process., AuthorCount:3 more...

The sea surface microlayer (SML) is an important biogeochemical system whose physico-chemical analysis often necessitates some degree of sample storage. However, many SML components degrade with time so the development of optimal storage protocols is paramount. We here briefly review some commonly used treatment and storage protocols. Using freshwater and saline SML samples from a river estuary, we investigated temporal changes in surfactant activity (SA) and the absorbance and fluorescence of chromophoric dissolved organic matter (CDOM) over four weeks, following selected sample treatment and storage protocols. Some variability in the effectiveness of individual protocols most likely reflects sample provenance. None of the various protocols examined performed any better than dark storage at 4 degrees C without pre-treatment. We therefore recommend storing samples refrigerated in the dark., AuthorCount:4 more...

We report the results of an experiment in the Northeast Atlantic in which sulphur hexafluoride (SF6) was released within an eddy and the behaviour of trace gases, nutrients and productivity followed within a Lagrangian framework over a period of 24 days. Measurements were also made in the air above the eddy in order to estimate air–sea exchange rates for some components. The physical, biological and biogeochemical properties of the eddy resemble those of other eddies studied in this area, suggesting that the results we report may be applicable beyond the specific eddy studied. During a period of low wind speed at the start of the experiment, we are able to quantitatively describe and balance the nutrient and carbon budgets for the eddy. We also report concentrations of various trace gases in the region which are similar to those observed in other studies and we estimate exchange rates for several trace gases. We show that the importance of gas exchange over other loss terms varies with time and also varies for the different gases. We show that the various trace gases considered (CO2, dimethyl sulphide (DMS), N2O, CH4, non-methane-hydrocarbons, methyl bromide, methyl iodide and volatile selenium species) are all influenced by physical and biological processes, but the overall distribution and temporal variability of individual gases are different to one another. A storm disrupted the stratification in the eddy during the experiment, resulting in enhanced nutrient supply to surface waters, enhanced gas exchange rates and a change in plankton community, which we quantify, although overall productivity was little changed. Emphasis is placed on the regularity of storms in the temperate ocean and the importance of these stochastic processes in such systems. more...

We report the results of an experiment in the Northeast Atlantic in which sulphur hexafluoride (SF6) was released within an eddy and the behaviour of trace gases, nutrients and productivity followed within a Lagrangian framework over a period of 24 days. Measurements were also made in the air above the eddy in order to estimate air–sea exchange rates for some components. The physical, biological and biogeochemical properties of the eddy resemble those of other eddies studied in this area, suggesting that the results we report may be applicable beyond the specific eddy studied. During a period of low wind speed at the start of the experiment, we are able to quantitatively describe and balance the nutrient and carbon budgets for the eddy. We also report concentrations of various trace gases in the region which are similar to those observed in other studies and we estimate exchange rates for several trace gases. We show that the importance of gas exchange over other loss terms varies with time and also varies for the different gases. We show that the various trace gases considered (CO2, dimethyl sulphide (DMS), N2O, CH4, non-methane-hydrocarbons, methyl bromide, methyl iodide and volatile selenium species) are all influenced by physical and biological processes, but the overall distribution and temporal variability of individual gases are different to one another. A storm disrupted the stratification in the eddy during the experiment, resulting in enhanced nutrient supply to surface waters, enhanced gas exchange rates and a change in plankton community, which we quantify, although overall productivity was little changed. Emphasis is placed on the regularity of storms in the temperate ocean and the importance of these stochastic processes in such systems. more...

The aims of the Atlantic Meridional Transect (AMT) programme [www.amt-uk.org] are to quantify the nature and causes of ecological and biogeochemical variability in the planktonic ecosystems of the Atlantic Ocean, and to assess the effects of this variability on biological carbon cycling and air–sea exchange of radiatively active gases and aerosols. Marine and atmospheric data have been collected twice a year along a 13,500 km transect in the Atlantic Ocean between 50°N and 52°S since 1995. The cruise track enables biogeochemical measurements to be made within the poorly studied North and South Atlantic oligotrophic gyres as well as within equatorial and coastal upwelling regions. The range of ecosystems sampled during AMT has facilitated the calibration and validation of newly developed optical, microbiological, molecular and analytical techniques and provided a testbed for comparative ecology and the development of atmospheric and oceanographic models. This paper describes the rationale and methodology of the programme. Upper-ocean measurements of density, nitrate and chlorophyll a (Chl a) are presented to illustrate seasonal, inter-annual and decadal variability in hydrography. Seasonal distributions of dissolved nitrous oxide (N2O) and methane (CH4) are used to derive estimates of the sea–air flux of these gases in the South Atlantic Gyre. Observations made during AMT and published since 2000 are reviewed, and the key findings are highlighted. The extent to which the programme aims have been achieved is discussed and improvements for the future suggested. more...

The aims of the Atlantic Meridional Transect (AMT) programme [www.amt-uk.org] are to quantify the nature and causes of ecological and biogeochemical variability in the planktonic ecosystems of the Atlantic Ocean, and to assess the effects of this variability on biological carbon cycling and air–sea exchange of radiatively active gases and aerosols. Marine and atmospheric data have been collected twice a year along a 13,500 km transect in the Atlantic Ocean between 50°N and 52°S since 1995. The cruise track enables biogeochemical measurements to be made within the poorly studied North and South Atlantic oligotrophic gyres as well as within equatorial and coastal upwelling regions. The range of ecosystems sampled during AMT has facilitated the calibration and validation of newly developed optical, microbiological, molecular and analytical techniques and provided a testbed for comparative ecology and the development of atmospheric and oceanographic models. This paper describes the rationale and methodology of the programme. Upper-ocean measurements of density, nitrate and chlorophyll a (Chl a) are presented to illustrate seasonal, inter-annual and decadal variability in hydrography. Seasonal distributions of dissolved nitrous oxide (N2O) and methane (CH4) are used to derive estimates of the sea–air flux of these gases in the South Atlantic Gyre. Observations made during AMT and published since 2000 are reviewed, and the key findings are highlighted. The extent to which the programme aims have been achieved is discussed and improvements for the future suggested. more...

Transfers of some important biogenic atmospheric constituents, carbon dioxide (CO2), methane (CH4), molecular nitrogen (N2), nitrous oxide (N2O), nitrate View the MathML source(NO3-), ammonia (NH3), methylamines (MAs) and dimethylsulphide (DMS), across the air–sea interface are investigated using published data generated mostly during the Arabian Sea Process Study (1992–1997) of the Joint Global Ocean Flux Study (JGOFS). The most important contribution of the region to biogeochemical fluxes is through the production of N2 and N2O facilitated by an acute, mid-water deficiency of dissolved oxygen (O2); emissions of these gases to the atmosphere from the Arabian Sea are globally significant. For the other constituents, especially CO2, even though the surface concentrations and atmospheric fluxes exhibit extremely large variations both in space and time, arising from the unique physical forcing and associated biogeochemical environment, the overall significance in terms of their global fluxes is not much because of the relatively small area of the Arabian Sea. Distribution and air–sea exchanges of some of these constituents are likely to be greatly influenced by alterations of the subsurface O2 field forced by human-induced eutrophication and/or modifications to the regional hydrography. more...

Transfers of some important biogenic atmospheric constituents, carbon dioxide (CO2), methane (CH4), molecular nitrogen (N2), nitrous oxide (N2O), nitrate View the MathML source(NO3-), ammonia (NH3), methylamines (MAs) and dimethylsulphide (DMS), across the air–sea interface are investigated using published data generated mostly during the Arabian Sea Process Study (1992–1997) of the Joint Global Ocean Flux Study (JGOFS). The most important contribution of the region to biogeochemical fluxes is through the production of N2 and N2O facilitated by an acute, mid-water deficiency of dissolved oxygen (O2); emissions of these gases to the atmosphere from the Arabian Sea are globally significant. For the other constituents, especially CO2, even though the surface concentrations and atmospheric fluxes exhibit extremely large variations both in space and time, arising from the unique physical forcing and associated biogeochemical environment, the overall significance in terms of their global fluxes is not much because of the relatively small area of the Arabian Sea. Distribution and air–sea exchanges of some of these constituents are likely to be greatly influenced by alterations of the subsurface O2 field forced by human-induced eutrophication and/or modifications to the regional hydrography. more...

We computed high-resolution (1º latitude x 1º longitude) seasonal and annual nitrous oxide (N2O) concentration fields for the Arabian Sea surface layer using a database containing more than 2400 values measured between December 1977 and July 1997. N2O concentrations are highest during the southwest (SW) monsoon along the southern Indian continental shelf. Annual emissions range from 0.33 to 0.70 Tg N2O and are dominated by fluxes from coastal regions during the SW and northeast monsoons. Our revised estimate for the annual N2O flux from the Arabian Sea is much more tightly constrained than the previous consensus derived using averaged in-situ data from a smaller number of studies. However, the tendency to focus on measurements in locally restricted features in combination with insufficient seasonal data coverage leads to considerable uncertainties of the concentration fields and thus in the flux estimates, especially in the coastal zones of the northern and eastern Arabian Sea. The overall mean relative error of the annual N2O emissions from the Arabian Sea was estimated to be at least 65%. more...

We computed high-resolution (1º latitude x 1º longitude) seasonal and annual nitrous oxide (N2O) concentration fields for the Arabian Sea surface layer using a database containing more than 2400 values measured between December 1977 and July 1997. N2O concentrations are highest during the southwest (SW) monsoon along the southern Indian continental shelf. Annual emissions range from 0.33 to 0.70 Tg N2O and are dominated by fluxes from coastal regions during the SW and northeast monsoons. Our revised estimate for the annual N2O flux from the Arabian Sea is much more tightly constrained than the previous consensus derived using averaged in-situ data from a smaller number of studies. However, the tendency to focus on measurements in locally restricted features in combination with insufficient seasonal data coverage leads to considerable uncertainties of the concentration fields and thus in the flux estimates, especially in the coastal zones of the northern and eastern Arabian Sea. The overall mean relative error of the annual N2O emissions from the Arabian Sea was estimated to be at least 65%. more...

We computed high-resolution (1º latitude x 1º longitude) seasonal and annual nitrous oxide (N2O) concentration fields for the Arabian Sea surface layer using a database containing more than 2400 values measured between December 1977 and July 1997. N2O concentrations are highest during the southwest (SW) monsoon along the southern Indian continental shelf. Annual emissions range from 0.33 to 0.70 Tg N2O and are dominated by fluxes from coastal regions during the SW and northeast monsoons. Our revised estimate for the annual N2O flux from the Arabian Sea is much more tightly constrained than the previous consensus derived using averaged in-situ data from a smaller number of studies. However, the tendency to focus on measurements in locally restricted features in combination with insufficient seasonal data coverage leads to considerable uncertainties of the concentration fields and thus in the flux estimates, especially in the coastal zones of the northern and eastern Arabian Sea. The overall mean relative error of the annual N2O emissions from the Arabian Sea was estimated to be at least 65%. more...

We report the results of an experiment in the Northeast Atlantic in which sulphur hexafluoride (SF6) was released within an eddy and the behaviour of trace gases, nutrients and productivity followed within a Lagrangian framework over a period of 24 days. Measurements were also made in the air above the eddy in order to estimate air–sea exchange rates for some components. The physical, biological and biogeochemical properties of the eddy resemble those of other eddies studied in this area, suggesting that the results we report may be applicable beyond the specific eddy studied. During a period of low wind speed at the start of the experiment, we are able to quantitatively describe and balance the nutrient and carbon budgets for the eddy. We also report concentrations of various trace gases in the region which are similar to those observed in other studies and we estimate exchange rates for several trace gases. We show that the importance of gas exchange over other loss terms varies with time and also varies for the different gases. We show that the various trace gases considered (CO\(_2\), dimethyl sulphide (DMS), N\(_2\)O, CH\(_4\), non-methane-hydrocarbons, methyl bromide, methyl iodide and volatile selenium species) are all influenced by physical and biological processes, but the overall distribution and temporal variability of individual gases are different to one another. A storm disrupted the stratification in the eddy during the experiment, resulting in enhanced nutrient supply to surface waters, enhanced gas exchange rates and a change in plankton community, which we quantify, although overall productivity was little changed. Emphasis is placed on the regularity of storms in the temperate ocean and the importance of these stochastic processes in such systems. more...

We report the results of an experiment in the Northeast Atlantic in which sulphur hexafluoride (SF6) was released within an eddy and the behaviour of trace gases, nutrients and productivity followed within a Lagrangian framework over a period of 24 days. Measurements were also made in the air above the eddy in order to estimate air–sea exchange rates for some components. The physical, biological and biogeochemical properties of the eddy resemble those of other eddies studied in this area, suggesting that the results we report may be applicable beyond the specific eddy studied. During a period of low wind speed at the start of the experiment, we are able to quantitatively describe and balance the nutrient and carbon budgets for the eddy. We also report concentrations of various trace gases in the region which are similar to those observed in other studies and we estimate exchange rates for several trace gases. We show that the importance of gas exchange over other loss terms varies with time and also varies for the different gases. We show that the various trace gases considered (CO\(_2\), dimethyl sulphide (DMS), N\(_2\)O, CH\(_4\), non-methane-hydrocarbons, methyl bromide, methyl iodide and volatile selenium species) are all influenced by physical and biological processes, but the overall distribution and temporal variability of individual gases are different to one another. A storm disrupted the stratification in the eddy during the experiment, resulting in enhanced nutrient supply to surface waters, enhanced gas exchange rates and a change in plankton community, which we quantify, although overall productivity was little changed. Emphasis is placed on the regularity of storms in the temperate ocean and the importance of these stochastic processes in such systems. more...

We report the results of an experiment in the Northeast Atlantic in which sulphur hexafluoride (SF6) was released within an eddy and the behaviour of trace gases, nutrients and productivity followed within a Lagrangian framework over a period of 24 days. Measurements were also made in the air above the eddy in order to estimate air–sea exchange rates for some components. The physical, biological and biogeochemical properties of the eddy resemble those of other eddies studied in this area, suggesting that the results we report may be applicable beyond the specific eddy studied. During a period of low wind speed at the start of the experiment, we are able to quantitatively describe and balance the nutrient and carbon budgets for the eddy. We also report concentrations of various trace gases in the region which are similar to those observed in other studies and we estimate exchange rates for several trace gases. We show that the importance of gas exchange over other loss terms varies with time and also varies for the different gases. We show that the various trace gases considered (CO\(_2\), dimethyl sulphide (DMS), N\(_2\)O, CH\(_4\), non-methane-hydrocarbons, methyl bromide, methyl iodide and volatile selenium species) are all influenced by physical and biological processes, but the overall distribution and temporal variability of individual gases are different to one another. A storm disrupted the stratification in the eddy during the experiment, resulting in enhanced nutrient supply to surface waters, enhanced gas exchange rates and a change in plankton community, which we quantify, although overall productivity was little changed. Emphasis is placed on the regularity of storms in the temperate ocean and the importance of these stochastic processes in such systems. more...

We report the results of an experiment in the Northeast Atlantic in which sulphur hexafluoride (SF6) was released within an eddy and the behaviour of trace gases, nutrients and productivity followed within a Lagrangian framework over a period of 24 days. Measurements were also made in the air above the eddy in order to estimate air–sea exchange rates for some components. The physical, biological and biogeochemical properties of the eddy resemble those of other eddies studied in this area, suggesting that the results we report may be applicable beyond the specific eddy studied. During a period of low wind speed at the start of the experiment, we are able to quantitatively describe and balance the nutrient and carbon budgets for the eddy. We also report concentrations of various trace gases in the region which are similar to those observed in other studies and we estimate exchange rates for several trace gases. We show that the importance of gas exchange over other loss terms varies with time and also varies for the different gases. We show that the various trace gases considered (CO\(_2\), dimethyl sulphide (DMS), N\(_2\)O, CH\(_4\), non-methane-hydrocarbons, methyl bromide, methyl iodide and volatile selenium species) are all influenced by physical and biological processes, but the overall distribution and temporal variability of individual gases are different to one another. A storm disrupted the stratification in the eddy during the experiment, resulting in enhanced nutrient supply to surface waters, enhanced gas exchange rates and a change in plankton community, which we quantify, although overall productivity was little changed. Emphasis is placed on the regularity of storms in the temperate ocean and the importance of these stochastic processes in such systems. more...