Loss-of-function mutations in the retinoblastoma gene
are common in several treatment-refractory cancers such as small-cell lung cancer and triple-negative breast cancer. To identify drugs synthetic ...lethal with
mutation (
), we tested 36 cell-cycle inhibitors using a cancer cell panel profiling approach optimized to discern cytotoxic from cytostatic effects. Inhibitors of the Aurora kinases AURKA and AURKB showed the strongest
association in this assay. LY3295668, an AURKA inhibitor with over 1,000-fold selectivity versus AURKB, is distinguished by minimal toxicity to bone marrow cells at concentrations active against
cancer cells and leads to durable regression of
tumor xenografts at exposures that are well tolerated in rodents. Genetic suppression screens identified enforcers of the spindle-assembly checkpoint (SAC) as essential for LY3295668 cytotoxicity in RB1-deficient cancers and suggest a model in which a primed SAC creates a unique dependency on AURKA for mitotic exit and survival. SIGNIFICANCE: The identification of a synthetic lethal interaction between
and AURKA inhibition, and the discovery of a drug that can be dosed continuously to achieve uninterrupted inhibition of AURKA kinase activity without myelosuppression, suggest a new approach for the treatment of RB1-deficient malignancies, including patients progressing on CDK4/6 inhibitors.
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The IPBES Global Assessment: Pathways to Action Ruckelshaus, Mary H.; Jackson, Stephen T.; Mooney, Harold A. ...
Trends in ecology & evolution (Amsterdam),
20/May , Volume:
35, Issue:
5
Journal Article
Peer reviewed
Open access
The first Global Assessment of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) found widespread, accelerating declines in Earth’s biodiversity and ...associated benefits to people from nature. Addressing these trends will require science-based policy responses to reduce impacts, especially at national to local scales. Effective scaling of science-policy efforts, driven by global and national assessments, is a major challenge for turning assessment into action and will require unprecedented commitment by scientists to engage with communities of policy and practice. Fulfillment of science’s social contract with society, and with nature, will require strong institutional support for scientists’ participation in activities that transcend conventional research and publication.
The IPBES Global Assessment released in the spring of 2019 is a significant milestone for the international scientific community; the critical challenge now is to disseminate and apply its findings at national and local scales where most policy and management decisions affecting biodiversity and ecosystem services are made.Effective, enduring action from assessments requires collaborative, multidisciplinary science-policy processes that frame and cogenerate knowledge with decision makers and stakeholders from many sectors.Examples of assessments driving policy responses to recover biodiversity and ecosystem services highlight the need for significant, long-term commitments by governments, non-governmental organizations (NGOs), the private sector, civil society, and the scientific community.
Spaceflight instruments that measure the energy and intensity of gamma rays and neutrons emitted by the surfaces of planetary bodies have been included in planetary science missions since 1966. These ...instruments use nuclear techniques to determine the elemental composition and related information about planetary surface and near-surface materials from the analysis of these gamma ray and neutron data. This paper provides a short review of these nuclear techniques as they have been used in current and past orbital and landed missions. A description of the nuclear instrumentation on many such missions is provided. Finally, descriptions of future missions that will employ gamma ray and neutron instruments will be presented.
Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory ...4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach.
Abstract
NASA’s Dragonfly mission will send a rotorcraft lander to the surface of Titan in the mid-2030s. Dragonfly's science themes include investigation of Titan’s prebiotic chemistry, ...habitability, and potential chemical biosignatures from both water-based “life as we know it” (as might occur in the interior mantle ocean, potential cryovolcanic flows, and/or impact melt deposits) and potential “life, but not as we know it” that might use liquid hydrocarbons as a solvent (within Titan’s lakes, seas, and/or aquifers). Consideration of both of these solvents simultaneously led to our initial landing site in Titan’s equatorial dunes and interdunes to sample organic sediments and water ice, respectively. Ultimately, Dragonfly's traverse target is the 80 km diameter Selk Crater, at 7° N, where we seek previously liquid water that has mixed with surface organics. Our science goals include determining how far prebiotic chemistry has progressed on Titan and what molecules and elements might be available for such chemistry. We will also determine the role of Titan’s tropical deserts in the global methane cycle. We will investigate the processes and processing rates that modify Titan’s surface geology and constrain how and where organics and liquid water can mix on and within Titan. Importantly, we will search for chemical biosignatures indicative of past or extant biological processes. As such, Dragonfly, along with Perseverance, is the first NASA mission to explicitly incorporate the search for signs of life into its mission goals since the Viking landers in 1976.
► We assess foliar chemistry and flammability of mountain pine beetle-attacked trees. ► Attacked trees had 10 times less foliar moisture than unattacked trees. ► Crude fat and fiber content also ...varied significantly during an attack. ► Flammability was best predicted with moisture content, fiber and crude fat. ► Crown fire potential may be higher for attacked trees with intact crowns.
Very little is known about how foliar moisture and chemistry change after a mountain pine beetle attack and even less is known about how these intrinsic foliar characteristics alter foliage ignitability. Here, we examine the fuel characteristics and ignition potential of Pinus contorta (lodgepole pine) foliage during the early stages of a mountain pine beetle attack. Foliar samples were taken periodically from multiple trees identified as green (healthy, unattacked), recently attacked, or red (dead). The fuel moisture content, chemical composition, and time to ignition of needles from each attack category were quantified. Foliar moisture contents varied by an order of magnitude between the attack categories and were lowest for red needles (∼12% on average), highest for green needles (∼109% on average), and most variable for needles of recently attacked trees. Dry matter proportions of fiber in the needles of attacked and red trees were nearly twice that of green needles. Starch and sugar levels were much lower in the needles of attacked and red trees than green trees. Crude fat contents also differed between the attack categories. Time to ignition was strongly related to time since beetle attack. Ignition times varied from as little as 11s for red needles to 41s for green needles. A combined model of foliar moisture content, fiber, and crude fat explained 92% of the variation in the foliar time to ignition. Results show that decreased moisture contents and changes in foliar chemistry increase the foliar flammability of mountain pine beetle-attacked trees. This suggests that less heat would be required to ignite the foliage of attacked trees and thus crown fire potential may be higher in attacked stands as long as foliage is retained on the tree.
Background
Adolescents and young adults (AYAs) with public or no insurance experience later stage at diagnosis and worse overall survival compared with those with private insurance. However, prior ...studies have not distinguished the survival impact of continuous Medicaid coverage prior to diagnosis compared with gaining Medicaid coverage at diagnosis.
Methods
We linked a cohort of AYAs aged 15‐39 who were diagnosed with 13 common cancers from 2005 to 2014 in the California Cancer Registry with California Medicaid enrollment files to ascertain Medicaid enrollment, with other insurance determined from registry data. We used Cox proportional hazards regression to evaluate the impact of insurance on survival, adjusting for clinical and demographic characteristics.
Results
Among 62 218 AYAs, over 65% had private/military insurance, 10% received Medicaid at diagnosis, 13.2% had continuous Medicaid, 4.1% had discontinuous Medicaid, 1.7% had other public insurance, 3% were uninsured, and 2.6% had unknown insurance. Compared with those with private/military insurance, individuals with Medicaid insurance had significantly worse survival regardless of when coverage began (received Medicaid at diagnosis: hazard ratio 95% confidence interval: 1.51 1.42‐1.61; continuously Medicaid insured: 1.42 1.33‐1.52; discontinuous Medicaid: 1.64 1.49, 1.80). Analyses of those with Medicaid insurance only demonstrated slightly worse cancer‐specific survival among those with discontinuous Medicaid or enrollment at diagnosis compared with those with continuous enrollment, but results were not significant stratified by cancer site.
Conclusions and relevance
AYAs with Medicaid insurance experience worse cancer‐specific survival compared with those with private/military insurance, yet continuous enrollment demonstrates slight survival improvements, providing potential opportunities for future policy intervention.
Expression of eukaryotic translation initiation factor 4E (eIF4E) is commonly elevated in human and experimental cancers, promoting angiogenesis and tumor growth. Elevated eIF4E levels selectively ...increase translation of growth factors important in malignancy (e.g., VEGF, cyclin D1) and is thereby an attractive anticancer therapeutic target. Yet to date, no eIF4E-specific therapy has been developed. Herein we report development of eIF4E-specific antisense oligonucleotides (ASOs) designed to have the necessary tissue stability and nuclease resistance required for systemic anticancer therapy. In mammalian cultured cells, these ASOs specifically targeted the eIF4E mRNA for destruction, repressing expression of eIF4E-regulated proteins (e.g., VEGF, cyclin D1, survivin, c-myc, Bcl-2), inducing apoptosis, and preventing endothelial cells from forming vessel-like structures. Most importantly, intravenous ASO administration selectively and significantly reduced eIF4E expression in human tumor xenografts, significantly suppressing tumor growth. Because these ASOs also target murine eIF4E, we assessed the impact of eIF4E reduction in normal tissues. Despite reducing eIF4E levels by 80% in mouse liver, eIF4E-specific ASO administration did not affect body weight, organ weight, or liver transaminase levels, thereby providing the first in vivo evidence that cancers may be more susceptible to eIF4E inhibition than normal tissues. These data have prompted eIF4E-specific ASO clinical trials for the treatment of human cancers.
Deficiencies in Epstein-Barr virus (EBV)-specific T cell immunosurveillance appear to precede the development of endemic Burkitt lymphoma (eBL), a malaria-associated pediatric cancer common in ...sub-Saharan Africa. However, T cell contributions to eBL disease progression and survival have not been characterized. Our objective was to investigate regulatory and inflammatory T cell responses in eBL patients associated with clinical outcomes. By multi-parameter flow cytometry, we examined peripheral blood mononuclear cells from 38 eBL patients enrolled in a prospective cohort study in Kisumu, Kenya from 2008-2010, and 14 healthy age-matched Kenyan controls. Children diagnosed with eBL were prospectively followed and outcomes categorized as 2-year event-free survivors, cases of relapses, or those who died. At the time of diagnosis, eBL children with higher CD25+Foxp3+ regulatory T (Treg) cell frequencies were less likely to survive than patients with lower Treg frequencies (p = 0·0194). Non-survivors also had higher absolute counts of CD45RA+Foxp3lo naïve and CD45RA-Foxp3hi effector Treg subsets compared to survivors and healthy controls. Once patients went into clinical remission, Treg frequencies remained low in event-free survivors. Patients who relapsed, however, showed elevated Treg frequencies months prior to their adverse event. Neither concurrent peripheral blood EBV load nor malaria infection could explain higher Treg cell frequencies. CD8+ T cell PD-1 expression was elevated in all eBL patients at time of diagnosis, but relapse patients tended to have persistently high PD-1 expression compared to long-term survivors. Non-survivors produced more CD4+ T-cell IL-10 in response to both Epstein-Barr Nuclear Antigen-1 (EBNA-1) (p = 0·026) and the malaria antigen Plasmodium falciparum Schizont Egress Antigen-1 (p = 0·0158) compared to survivors, and were concurrently deficient in (EBNA-1)-specific CD8+ T-cell derived IFN-γ production (p = 0·002). In addition, we identified the presence of Foxp3-IL10+ regulatory Type 1 cells responding to EBNA-1 in contrast to the malaria antigen tested. These novel findings suggest that poor outcomes in eBL patients are associated with a predominantly immuno-regulatory environment. Therefore, Treg frequencies could be a predictive biomarker of disease progression and manipulation of Treg activity has potential as a therapeutic target to improve eBL survival.
Elevated eukaryotic translation initiation factor 4E (eIF4E) function induces malignancy in experimental models by selectively enhancing translation of key malignancy-related mRNAs (c-myc and BCL-2). ...eIF4E activation may reflect increased eIF4E expression or phosphorylation of its inhibitory binding proteins (4E-BP). By immunohistochemical analyses of 148 tissues from 89 prostate cancer patients, we now show that both eIF4E expression and 4E-BP1 phosphorylation (p4E-BP1) are increased significantly, particularly in advanced prostate cancer versus benign prostatic hyperplasia tissues. Further, increased eIF4E and p4E-BP1 levels are significantly related to reduced patient survival, whereas uniform 4E-BP1 expression is significantly related to better patient survival. Both immunohistochemistry and Western blotting reveal that elevated eIF4E and p4E-BP1 are evident in the same prostate cancer tissues. In two distinct prostate cancer cell models, the progression to androgen independence also involves increased eIF4E activation. In these prostate cancer cells, reducing eIF4E expression with an eIF4E-specific antisense oligonucleotide currently in phase I clinical trials robustly induces apoptosis, regardless of cell cycle phase, and reduces expression of the eIF4E-regulated proteins BCL-2 and c-myc. Collectively, these data implicate eIF4E activation in prostate cancer and suggest that targeting eIF4E may be attractive for prostate cancer therapy.
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