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During the mid-Cretaceous, the Earth experienced several environmental perturbations, including an extremely warm climate and Oceanic Anoxic Events (OAEs). Submarine volcanic episodes associated with formation of large igneous provinces (LIPs) may have triggered these perturbations. The osmium isotopic ratio ( 187 Os/ 188 Os) is a suitable proxy for tracing hydrothermal activity associated with the LIPs formation, but 187 Os/ 188 Os data from the mid-Cretaceous are limited to short time intervals. Here we provide a continuous high-resolution marine 187 Os/ 188 Os record covering all mid-Cretaceous OAEs. Several OAEs (OAE1a, Wezel and Fallot events, and OAE2) correspond to unradiogenic 187 Os/ 188 Os shifts, suggesting that they were triggered by massive submarine volcanic episodes. However, minor OAEs (OAE1c and OAE1d), which do not show pronounced unradiogenic 187 Os/ 188 Os shifts, were likely caused by enhanced monsoonal activity. Because the subaerial LIPs volcanic episodes and Circum-Pacific volcanism correspond to the highest temperature and p CO 2 during the mid-Cretaceous, they may have caused the hot mid-Cretaceous climate. “Mid-Cretaceous experienced a series of drastic environmental perturbations called Oceanic Anoxic Events. Here, the authors asses high-resolution Os isotopic records which indicate that most of these events were associated with massive submarine volcanic episodes, but some minor ones were not.”

The Aptian–Albian boundary is marked by one of the major oceanic perturbations during the Cretaceous, called Oceanic Anoxic Event (OAE) 1b. Extensive volcanic episodes at the Southern Kerguelen Plateau has been suggested as the trigger of OAE1b, but compelling evidence remains lacking. Here, we reconstructed the temporal variations of marine Os isotopic ratios across the Aptian–Albian boundary in the Tethyan and Pacific pelagic sedimentary records to elucidate the causal links between OAE1b, the biotic turnover, and volcanic episodes. Our new Os isotopic records show two negative spikes that correlate with a period of planktonic foraminiferal turnover across the Aptian–Albian boundary during OAE1b and suggest multiple submarine volcanic events. By comparing our Os isotopic profile with carbon isotopic compositions of carbonate, CaCO 3 content, and the relative abundances of agglutinated foraminifera, we conclude that ocean acidification caused by the massive release of CO 2 through extensive volcanic episodes could have promoted the major planktonic foraminiferal turnover during OAE1b.

Large-igneous-province volcanic activity during the mid-Cretaceous triggered a global-scale episode of reduced marine oxygen levels known as Oceanic Anoxic Event 2 approximately 94.5 million years ago. It has been hypothesized that this geologically rapid degassing of volcanic carbon dioxide altered seawater carbonate chemistry, affecting marine ecosystems, geochemical cycles and sedimentation. Here we report on two sites drilled by the International Ocean Discovery Program offshore of southwest Australia that exhibit clear evidence for suppressed pelagic carbonate sedimentation in the form of a stratigraphic interval barren of carbonate minerals, recording ocean acidification during the event. We then use the osmium isotopic composition of bulk sediments to directly link this protracted ~600 kyr shoaling of the marine calcite compensation depth to the onset of volcanic activity. This decrease in marine pH was prolonged by biogeochemical feedbacks in highly productive regions where elevated heterotrophic respiration added carbon dioxide to the water column. A compilation of mid-Cretaceous marine stratigraphic records reveals a contemporaneous decrease of sedimentary carbonate content at continental slope sites globally. Thus, we contend that changes in marine carbonate chemistry are a primary ecological stress and important consequence of rapid emission of carbon dioxide during many large-igneous-province eruptions in the geologic past.Volcanic activity led to ocean acidification at the onset of Oceanic Anoxic Event 2, which then persisted for 600,000 years due to biogeochemical feedbacks, according to marine osmium isotope and carbonate sedimentation records offshore from southwest Australia.

Although siliceous sediments have the potential to reveal an enigmatic Miocene climate evolution, problems with age model construction are tough to beat. Cyclostratigraphy is a useful tool for the construction of a high-resolution age model. In the Japan Sea region, orbital-scale oscillations in the sedimentary environment of the Miocene sedimentary basins are reported, for example, the Onnagawa Formation in Akita Prefecture in northern Japan and the Nakayama Formation on Sado Island in central Japan. In this study, we constructed a high-resolution age model of the Miocene siliceous sediment in the Japan Sea, the Nakayama Formation, by cyclostratigraphy using the geochemical properties of the sediment. Ratios of the biogenic silica content to the detritus content in the sediment were determined based on the X-ray fluorescence (XRF) and X-ray diffraction (XRD) measurements. Orbital-scale oscillations were identified in the ratios of biogenic silica to detritus, and it was used for cyclostratigraphic correlation with the global oxygen stable isotope (δ 18 O) curve of benthic foraminifera. Our new cyclostratigraphic age model and method are expected to promote using the Miocene siliceous sediments for paleoceanographic and paleoclimatologic studies. Additionally, major element and mineral compositions determined by XRF and XRD analysis were used to reconstruct the sedimentary environment on which the East Asian Monsoon system may have an influence.

Recent studies have proved that high elevation environments, especially remote wetlands, are exceptional ecological sensors of global change. For example, European glaciers have retreated during the 20 th century while the Sierra Nevada National Park in southern Spain witnessed the first complete disappearance of modern glaciers in Europe. Given that the effects of climatic fluctuations on local ecosystems are complex in these sensitive alpine areas, it is crucial to identify their long-term natural trends, ecological thresholds, and responses to human impact. In this study, the geochemical records from two adjacent alpine bogs in the protected Sierra Nevada National Park reveal different sensitivities and long-term environmental responses, despite similar natural forcings, such as solar radiation and the North Atlantic Oscillation, during the late Holocene. After the Industrial Revolution both bogs registered an independent, abrupt and enhanced response to the anthropogenic forcing, at the same time that the last glaciers disappeared. The different response recorded at each site suggests that the National Park and land managers of similar regions need to consider landscape and environmental evolution in addition to changing climate to fully understand implications of climate and human influence.

INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux‐M), as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second‐line arms, patients with EGFR‐amplified recurrent WHO grade III/IV glioma received Depatux‐M plus chemotherapy (temozolomide) or Depatux‐M alone regardless of EGFR status. In first‐line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux‐M plus chemoradiotherapy. The study was halted following lack of survival benefit with first‐line Depatux‐M in the global trial INTELLANCE‐1. The primary endpoint was 6‐month progression‐free survival (PFS) in patients with EGFR‐amplified tumors receiving second‐line Depatux‐M plus chemotherapy. Common nonocular treatment‐emergent adverse events (TEAEs) with both second‐line and first‐line Depatux‐M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second‐line Depatux‐M plus chemotherapy and all patients receiving second‐line Depatux‐M alone or first‐line Depatux‐M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6‐month PFS estimate was 25.6% (95% confidence interval [CI] 11.4‒42.6), and median PFS was 2.1 months (95% CI 1.9‒3.9) with second‐line Depatux‐M plus chemotherapy in the EGFR‐amplified subgroup. This study showed acceptable safety profile of Depatux‐M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263). INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin, as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in Japanese patients with World Health Organization grade III/IV glioma. The results of this trial demonstrate an acceptable safety profile of depatuxizumab mafodotin, with ocular side effects being the most common adverse events that were mostly reversible. Second‐line depatuxizumab mafodotin in combination with temozolomide resulted in a 6‐month progression‐free survival estimate of 25.6% (95% confidence interval 11.4‒42.6) in patients with EGFR‐amplified tumors and showed encouraging antitumor activity in this subgroup of patients (NCT02590263).

Purpose To analyze the efficacy of adaptive radiotherapy (ART) for glioblastoma. Methods Sixty-one glioblastoma patients who received ART were prospectively evaluated. The initial clinical target volume (CTVinitial) was represented by T2 hyperintensity on postoperative MRIs (pre-RT MRI [MRIpre])plus 10 mm. The initial planning target volume (PTVinitial) was the CTVinitial plus a 5-mm margin. The PTVinitial received 40 Gy. An MRI and a second planning CT were performed during radiotherapy (MRImid). Two types of boost CTVs (the resection cavity and residual tumor on enhanced T1-weighted MRI plus 10 mm) were created based on the MRIpre and MRImid (CTVboost-pre and -mid). The boost PTV (PTVboost) was the CTVboost plus 5 mm. Two types of boost plans (fixed and adaptive boost plans in the first and second planning CT, respectively) of 20 Gy were created. The PTV based on the post-RT MRI (PTVboost-post) was created, and the dose-volume histograms of the PTVboost-post in the fixed and adaptive boost plans were compared. Additionally, the conformity indices (CIs) of the fixed and adaptive boost plans were compared. Results The median V95 of the PTVboost-post of the fixed and adaptive boost plans (V95pre and V95mid) were 95.6% and 98.3%, respectively ( P  < 0.01). The median V95pre and V95mid of patients after gross total resection (GTR) were 97.4% and 98.8%, respectively ( P  = 0.41); in contrast, the median values of patients after non-GTR were 91.9% and 98.2%, respectively ( P  < 0.01). The median CIs of the fixed and adaptive boost plans in all patients were 1.45 and 1.47, respectively ( P  = 0.31). The median CIs of the fixed and adaptive boost plans in patients after GTR were 1.61 and 1.48, respectively ( P  = 0.01); in contrast, those in patients after non-GTR were 1.36 and 1.44, respectively ( P  = 0.13). Conclusion ART for glioblastoma improved the target coverage and dose reduction for the normal brain. By analyzing the results according to the resection rate, we can expect a decrease in normal brain dose in patients with GTR and an increase in coverage in those with partial resection or biopsy.

Approximately 34 million years ago across the Eocene–Oligocene transition (EOT), Earth’s climate tipped from a largely unglaciated state into one that sustained large ice sheets on Antarctica. Antarctic glaciation is attributed to a threshold response to slow decline in atmospheric CO 2 but our understanding of the feedback processes triggered and of climate change on the other contents is limited. Here we present new geochemical records of terrigenous dust accumulating on the sea floor across the EOT from a site in the central equatorial Pacific. We report a change in dust chemistry from an Asian affinity to a Central-South American provenance that occurs geologically synchronously with the initiation of stepwise global cooling, glaciation of Antarctica and aridification on the northern continents. We infer that the inter-tropical convergence zone of intense precipitation extended to our site during late Eocene, at least four degrees latitude further south than today, but that it migrated northwards in step with global cooling and initiation of Antarctic glaciation. Our findings point to an atmospheric teleconnection between extratropical cooling and rainfall climate in the tropics and the mid-latitude belt of the westerlies operating across the most pivotal transition in climate state of the Cenozoic Era.

The most common age constraint for the diatomaceous sediments is biostratigraphy of siliceous microfossils. Although biostratigraphy is a powerful tool to establish stratigraphy and correlate with sedimentary sequences in other sites, biostratigraphy generally includes uncertainties difficult to evaluate. In this study, we measured zircon U–Pb ages of eight tuff beds intercalated with diatomaceous mudstone of the Nakayama Formation on Sado Island in Central Japan and integrated the U–Pb ages with diatom and radiolarian biostratigraphy, whose ages and errors were re-evaluated by this study, to establish an age model precisely representing the sedimentary age. Two tuff beds in the upper and middle part of the formation offered zircon U–Pb ages of 6.7 ± 0.2 Ma and 10.87 ± 0.07 Ma, which are consistent with biostratigraphy, and provided a good example of effective integration of zircon U–Pb ages with the biostratigraphy. On the other hand, zircon U–Pb ages of the other six tuff beds in the lower part are around 12 Ma and not distinguishable from each other. In addition, older zircon grains in the 6 tuff beds are assembled in the interval from 30 to 20 Ma, which is consistent with the age of the volcanic basement rocks forming most part of Sado Island. Similarities in chemical compositions of glass shards and age distributions of zircon grains indicate that the volcaniclastic components in the tuff beds should originate from single or associated magmatic activities.

We report a newly developed method for analyzing the sulfur isotope ratio ( 34 S/ 32 S) of trace amounts of sulfate. This method consists of two steps: 1) isolation of sulfate via anion chromatography with fraction collection (IC-FC), and 2) precipitation of nanomolar-scale sulfate as barite within a tin capsule (nano-BP) for isotope measurement. In the first step of anion chromatography with fraction collection, the sulfate ion is isolated from other components with baseline resolution on the chromatogram. In the second nanomolar barite precipitation step, microcrystalline barite precipitates through reaction with BaCl 2 , followed by evaporation through heating. By conducting this reaction in a tin capsule for isotope ratio measurement, the collection or filtration of barite precipitates is not required. With our nano-EA/IRMS, sulfur content and isotope ratio can be determined in the 5–125 nmol sulfur content range. In this study, we further applied this method to carbonate-associated sulfate (CAS) extracted from natural samples, including foraminiferal shells from marine sediments and geological carbonates such as coral, limestone, and dolostone. Reliable δ 34 S values were obtained from as little as 5–10 nmol of sulfur, with standard deviations typically within ± 0.2–1.0‰ , reflecting differences in material homogeneity. The method successfully resolved δ 34 S variations among size fractions and stratigraphic layers in foraminifera and distinguished between carbonate types of different origins. These results demonstrate the method’s precision and robustness for analyzing CAS δ 34 S in diverse natural materials.