DNA topoisomerase I and II expression in drug resistantgerm cell tumours

A small number of testicular germ cell tumours are refractory to current chemotherapy regimens. DNA topoisomerase I is the target for several new drugs and a potential candidate treatment for chemorefractory germ cell tumours. DNA topoisomerase IIα is the target for etoposide, which is currently used regularly in germ cell tumour treatment. The expression of DNA topoisomerase I and IIα were therefore assessed immunohistochemically in a range of testicular tumours, especially those with persistent malignant elements on retroperitoneal lymph node dissection. Pre-chemotherapy orchidectomy specimens were matched with post-chemotherapy retroperitoneal lymph node dissections to examine changes in expression. There was considerable variation in the expression of topoisomerase I in different tumour types. Both yolk sac tumours and teratoma, mature showed universal expression of topoisomerase I, while 38% of seminomas and 30% of embryonal carcinomas were positive. Strong topoisomerase IIα expression was found in embryonal carcinoma. There was a negative correlation between topoisomerase I and IIα expression (P=0.004) and downregulation of topoisomerase IIα after chemotherapy (P=0.02). Topoisomerase I expression appears to increase in those cases with residual teratoma, mature, but is largely unchanged in those cases remaining as embryonal carcinoma. These results suggest that topoisomerase I inhibitors may be useful in chemorefractory germ cell tumours, especially yolk sac tumours and where there are unresectable residual teratoma, mature deposits

Climate change and the rise of the central Asian Silk Roads

The final centuries BCE (Before Common Era) saw the main focus of trade between the Far East and Europe switch from the so called Northern Route across the Asian steppes to the classical silk roads. The cities across central Asia flourished and grew in size and importance. While clearly there were political, economic and cultural drivers for these changes, there may also have been a role for changes in climate in this relatively arid region of Asia. Analysis of a new ensemble of snapshot global climate model simulations, run every 250 years over the last 6000 years, allows us to assess the long term climatological changes seen across the central Asian arid region through which the classical Silk Roads run. While the climate is comparatively stable through the Holocene, the fluctuations seen in these simulations match significant cultural developments in the region. From 1500 BCE the deterioration of climate from a transient precipitation peak, along with technological development and the immigration of Aryan nomads, drove a shift towards urbanization and probably irrigation, culminating in the founding of the major cities of Bukhara and Samarkand around 700–500 BCE. Between 1000 and 250 BCE the modelled precipitation in the central Asian arid region undergoes a transition towards wetter climates. The changes in the Western Disturbances, which is the key weather system for central Asian precipitation, provides 10% more precipitation and the increased hydrological resources may provide the climatological foundation for the golden era of Silk Road trade

Carbon isotope records reveal precise timing of enhanced Southern Ocean upwelling during the last deglaciation

The Southern Ocean plays a prominent role in the Earth’s climate and carbon cycle. Changes in the Southern Ocean circulation may have regulated the release of CO2 to the atmosphere from a deep-ocean reservoir during the last deglaciation. However, the path and exact timing of this deglacial CO2 release are still under debate. Here we present measurements of deglacial surface reservoir 14C age changes in the eastern Pacific sector of the Southern Ocean, obtained by 14C dating of tephra deposited over the marine and terrestrial regions. These results, along with records of foraminifera benthic–planktic 14C age and δ13C difference, provide evidence for three periods of enhanced upwelling in the Southern Ocean during the last deglaciation, supporting the hypothesis that Southern Ocean upwelling contributed to the deglacial rise in atmospheric CO2. These independently dated marine records suggest synchronous changes in the Southern Ocean circulation and Antarctic climate during the last deglaciation

Independent variations of CH4 emissions and isotopic composition over the past 160,000 years

During the last glacial cycle, greenhouse gas concentrations fluctuated on decadal and longer timescales. Concentrations of methane, as measured in polar ice cores, show a close connection with Northern Hemisphere temperature variability, but the contribution of the various methane sources and sinks to changes in concentration is still a matter of debate. Here we assess changes in methane cycling over the past 160,000 years by measurements of the carbon isotopic composition δ13C of methane in Antarctic ice cores from Dronning Maud Land and Vostok. We find that variations in the δ13C of methane are not generally correlated with changes in atmospheric methane concentration, but instead more closely correlated to atmospheric CO2 concentrations. We interpret this to reflect a climatic and CO2-related control on the isotopic signature of methane source material, such as ecosystem shifts in the seasonally inundated tropical wetlands that produce methane. In contrast, relatively stable δ13C values occurred during intervals of large changes in the atmospheric loading of methane. We suggest that most methane sources—most notably tropical wetlands—must have responded simultaneously to climate changes across these periods

Upper-ocean-to-atmosphere radiocarbon offsets imply fast deglacial carbon dioxide release

Radiocarbon in the atmosphere is regulated largely by ocean circulation, which controls the sequestration of carbon dioxide (CO(2)) in the deep sea through atmosphere-ocean carbon exchange. During the last glaciation, lower atmospheric CO(2) levels were accompanied by increased atmospheric radiocarbon concentrations that have been attributed to greater storage of CO(2) in a poorly ventilated abyssal ocean. The end of the ice age was marked by a rapid increase in atmospheric CO(2) concentrations that coincided with reduced (14)C/(12)C ratios (Delta(14)C) in the atmosphere, suggesting the release of very 'old' ((14)C-depleted) CO(2) from the deep ocean to the atmosphere. Here we present radiocarbon records of surface and intermediate-depth waters from two sediment cores in the southwest Pacific and Southern oceans. We find a steady 170 per mil decrease in Delta(14)C that precedes and roughly equals in magnitude the decrease in the atmospheric radiocarbon signal during the early stages of the glacial-interglacial climatic transition. The atmospheric decrease in the radiocarbon signal coincides with regionally intensified upwelling and marine biological productivity, suggesting that CO(2) released by means of deep water upwelling in the Southern Ocean lost most of its original depleted-(14)C imprint as a result of exchange and isotopic equilibration with the atmosphere. Our data imply that the deglacial (14)C depletion previously identified in the eastern tropical North Pacific must have involved contributions from sources other than the previously suggested carbon release by way of a deep Southern Ocean pathway, and may reflect the expanded influence of the (14)C-depleted North Pacific carbon reservoir across this interval. Accordingly, shallow water masses advecting north across the South Pacific in the early deglaciation had little or no residual (14)C-depleted signals owing to degassing of CO(2) and biological uptake in the Southern Ocean