Enhanced ocean carbon storage during the Pleistocene ice ages lowered atmospheric CO2 concentrations by 80 to 100 ppm relative to interglacial levels. Leading hypotheses to explain this phenomenon ...invoke a greater efficiency of the ocean's biological pump, in which case carbon storage in the deep sea would have been accompanied by a corresponding reduction in dissolved oxygen. We exploit the sensitivity of organic matter preservation in marine sediments to bottom water oxygen concentration to constrain the level of dissolved oxygen in the deep central equatorial Pacific Ocean during the last glacial period (18,000–28,000 years BP) to have been within the range of 20–50 μmol/kg, much less than the modern value of ~168 μmol/kg. We further demonstrate that reduced oxygen levels characterized the water column below a depth of ~1,000 m. Converting the ice age oxygen level to an equivalent concentration of respiratory CO2, and extrapolating globally, we estimate that deep‐sea CO2 storage during the last ice age exceeded modern values by as much as 850 Pg C, sufficient to balance the loss of carbon from the atmosphere (~200 Pg C) and from the terrestrial biosphere (~300–600 Pg C). In addition, recognizing the enhanced preservation of organic matter in ice age sediments of the deep Pacific Ocean helps reconcile previously unexplained inconsistencies among different geochemical and micropaleontological proxy records used to assess past changes in biological productivity of the ocean.
Plain Language Summary
Carbon dioxide (CO2) in Earth's atmosphere was lower during cold glacial periods of the last 800,000 years than during warm interglacial periods, by an amount equivalent to about one third of the preindustrial CO2 content of the atmosphere. It is thought that the ocean absorbed the CO2 missing from the atmosphere, but determining where and how the CO2 was stored in the ocean has remained a challenge. Photosynthesis in the surface ocean converts CO2 to organic matter, a portion of which sinks into the deep sea, where it is subsequently converted back to CO2 by respiration of the organisms that consume the organic matter. Stimulation of the biological uptake of CO2 in surface water, inhibition of the physical processes that raise deep waters back to the surface where they exchange gases with the atmosphere, or any combination of the two would enhance the storage of CO2 in the deep ocean while also reducing the concentration there of dissolved oxygen. Here we show that the oxygen concentration in deep waters of the Pacific Ocean was much lower during the last glacial period than today. The difference is sufficient to accommodate the CO2 removed from the atmosphere during the ice ages.
Key Points
Deep Pacific dissolved oxygen was much lower than today during the last glacial period (focusing on the interval 18,000–28,000 years BP)
Ice age ocean storage of carbon was sufficient to explain low atmospheric CO2 levels
Enhanced preservation in sediments of organic compounds under low dissolved oxygen reconciles paleoproductivity proxies
Unmet needs in prostate cancer drug development and patient management are the ability to monitor treatment effects and to identify therapeutic targets in a tumor at the time treatment is being ...considered. This review focuses on establishing analytically valid biomarkers for specific contexts of use in patients with castration-resistant prostate cancer (CRPC), emphasizing a biomarker currently in clinical use, circulating tumor cells (CTC). The FDA Critical Path provides a road map for these investigations, which, if followed, will facilitate the incorporation of these types of assays into clinical decision-making. CTC enumeration at baseline and post-treatment is prognostic of survival, with no threshold effect, and the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. The clinical utility of monitoring CTC changes with treatment, as an efficacy-response surrogate biomarker of survival, is currently being tested in large phase III trials, with the novel antiandrogen therapies abiraterone acetate and MDV3100. Molecular determinants can be identified and characterized in CTCs as potential predictive biomarkers of tumor sensitivity to a therapeutic modality. Additionally, we discuss novel technologies to enrich and characterize CTCs from more patients, the potential clinical uses of CTCs in determining prognosis and monitoring treatment effects, and CTCs as a source of tissue to identify predictive markers of drug sensitivity to guide treatment selection. Prospective studies, designed around the biomarker itself and the specific clinical context for which it is applied, are needed to further assess the role of these and novel markers in clinical practice.
Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of ...limited access to tumor tissue.
We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.
We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.
The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.
One of the primary sources of micronutrients to the sea surface in remote ocean regions is the deposition of atmospheric dust. Geographic patterns in biogeochemical processes such as primary ...production and nitrogen fixation that require micronutrients like iron (Fe) are modulated in part by the spatial distribution of dust supply. Global models of dust deposition rates are poorly calibrated in the open ocean, owing to the difficulty of determining dust fluxes in sparsely sampled regions. We present new estimates of dust and Fe input rates from measurements of dissolved and particulate thorium isotopes 230Th and 232Th on the FS Sonne SO245 section (GEOTRACES process study GPpr09) in the South Pacific. We first discuss high‐resolution upper water column profiles of Th isotopes and the implications for the systematics of dust flux reconstructions from seawater Th measurements. We find dust fluxes in the center of the highly oligotrophic South Pacific Gyre that are the lowest of any mean annual dust input rates measured in the global oceans, but that are 1–2 orders of magnitude higher than those estimated by global dust models. We also determine dust‐borne Fe fluxes and reassess the importance of individual Fe sources to the surface South Pacific Gyre, finding that dust dissolution, not vertical or lateral diffusion, is the primary Fe source. Finally, we combine our estimates of Fe flux in dust with previously published cellular and enzymatic quotas to determine theoretical upper limits on annual average nitrogen fixation rates for a given Fe deposition rate.
Key Points
Dust fluxes to the South Pacific Gyre are quantified using measurements of dissolved and particulate thorium isotopes
Global models underestimate dust flux to the South Pacific Gyre by 1–2 orders of magnitude
Dust deposition is the most important source of dissolved iron to the surface of the South Pacific Ocean
Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome ...measure.
Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.
A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.
A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.
Particulate organic carbon (POC) produced in the surface ocean sinks through the water column and is respired at depth, acting as a primary vector sequestering carbon in the abyssal ocean. ...Atmospheric carbon dioxide levels are sensitive to the length (depth) scale over which respiration converts POC back to inorganic carbon, because shallower waters exchange with the atmosphere more rapidly than deeper ones. However, estimates of this carbon regeneration length scale and its spatiotemporal variability are limited, hindering the ability to characterize its sensitivity to environmental conditions. Here, we present a zonal section of POC fluxes at high vertical and spatial resolution from the GEOTRACES GP16 transect in the eastern tropical South Pacific, based on normalization to the radiogenic thorium isotope 230Th. We find shallower carbon regeneration length scales than previous estimates for the oligotrophic South Pacific gyre, indicating less efficient carbon transfer to the deep ocean. Carbon regeneration is strongly inhibited within suboxic waters near the Peru coast. Canonical Martin curve power laws inadequately capture POC flux profiles at suboxic stations. We instead fit these profiles using an exponential function with flux preserved at depth, finding shallow regeneration but high POC sequestration below 1,000 m. Both regeneration length scales and POC flux at depth closely track the depths at which oxygen concentrations approach zero. Our findings imply that climate warming will result in reduced ocean carbon storage due to expanding oligotrophic gyres, but opposing effects on ocean carbon storage from expanding suboxic waters will require modeling and future work to disentangle.
Dust plays a critical role in Earth's climate system and serves as a natural source of iron and other micronutrients to remote regions of the ocean. We have generated records of dust deposition over ...the past 500,000 years at three sites spanning the breadth of the equatorial Pacific Ocean. Equatorial Pacific dust fluxes are highly correlated with global ice volume and with dust fluxes to Antarctica, which suggests that dust generation in interhemispheric source regions exhibited a common response to climate change over late-Pleistocene glacial cycles. Our results provide quantitative constraints on the variability of aeolian iron supply to the equatorial Pacific Ocean and, more generally, on the potential contribution of dust to past climate change and to related changes in biogeochemical cycles.
Summary Background MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ...ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. Methods This phase 1–2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov , number NCT00510718. Findings We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased18 F-fluoro-5α-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20–100%). The median time to progression was 47 weeks (95% CI 34–not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3–4 adverse event was dose-dependent fatigue (16 11% patients), which generally resolved after dose reduction. Interpretation We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1–2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease. Funding Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium.
Summary Background Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for ...survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy. Methods We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance probability estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival. Findings Variables associated with high risk of death were high LDH concentration (hazard ratio 6·44, 95% CI 4·24–9·79), high CTC count (1·58, 1·41–1·77), and high PSA titre (1·26, 1·10–1·45), low albumin (0·10, 0·03–0·39), and low haemoglobin (0·72, 0·64–0·81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0·04). The most predictive factors for survival were LDH concentration and CTC counts (concordance probability estimate 0·72–0·75). Interpretation CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted. Funding The Prostate Cancer Foundation, Immunicon Corporation, Memorial Sloan-Kettering Cancer Center.
Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in organ-specific metastasis ...remain poorly defined despite their well-appreciated role in matrix degradation and tumor invasion. Here, we show a mechanism whereby two distinct metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1) and matrix metalloproteinase-1 (MMP1), orchestrate a paracrine signaling cascade to modulate the bone microenvironment in favor of osteoclastogenesis and bone metastasis. Proteolytic release of membrane-bound epidermal growth factor (EGF)-like growth factors, including Amphiregulin (AREG), heparin-binding EGF (HB-EGF), and transforming growth factor alpha (TGFalpha) from tumor cells suppress the expression of osteoprotegerin (OPG) in osteoblasts and subsequently potentiate osteoclast differentiation. EGF receptor (EGFR) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells. Furthermore, elevated MMP1 and ADAMTS1 expression is associated with increased risk of bone metastasis in breast cancer patients. This study established MMP1 and ADAMTS1 in tumor cells, as well as EGFR signaling in osteoblasts, as promising therapeutic targets for inhibiting bone metastasis of breast cancer.
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