Although biophysical yield responses to local warming have been studied, we know little about how crop yield growth-a function of climate and technology-responds to global temperature and ...socioeconomic changes. Here, we present the yield growth of major crops under warming conditions from preindustrial levels as simulated by a global gridded crop model. The results revealed that global mean yields of maize and soybean will stagnate with warming even when agronomic adjustments are considered. This trend is consistent across socioeconomic assumptions. Low-income countries located at low latitudes will benefit from intensive mitigation and from associated limited warming trends (1.8 °C), thus preventing maize, soybean and wheat yield stagnation. Rice yields in these countries can improve under more aggressive warming trends. The yield growth of maize and soybean crops in high-income countries located at mid and high latitudes will stagnate, whereas that of rice and wheat will not. Our findings underpin the importance of ambitious climate mitigation targets for sustaining yield growth worldwide.
Increased glucose metabolism is now recognized as an emerging hallmark of cancer. Recent studies have shown that glucose metabolism is even more active in cancer stem cells (CSCs), a rare population ...of cancer cells with the capacity to self-renew and initiate tumors, and that CSCs are dependent on glycolysis for their survival/growth. However, the role of glucose metabolism in the control of their self-renewal and tumor-initiating capacity per se still remains obscure. Moreover, much remains unknown as to which of the numerous molecules involved in the glucose metabolism is suitable as a target to control CSCs. Here we demonstrate that the facilitative glucose transporter GLUT1 is essential for the maintenance of pancreatic, ovarian, and glioblastoma CSCs. Notably, we found that WZB117, a specific GLUT1 inhibitor, could inhibit the self-renewal and tumor-initiating capacity of the CSCs without compromising their proliferative potential in vitro. In vivo, systemic WZB117 administration inhibited tumor initiation after implantation of CSCs without causing significant adverse events in host animals. Our findings indicate GLUT1-dependent glucose metabolism has a pivotal role not only in the growth and survival of CSCs but also in the maintenance of their stemness and suggest GLUT1 as a promising target for CSC-directed cancer therapy.
Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence ...in GBM, therapies targeting GSCs are considered to be effective for long‐term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings. In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA‐coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration‐approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne®), a drug approved for macular degeneration, was a novel GSC‐specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC50 of approximately 200 nm was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC‐specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC‐specific cytotoxic agents.
The OXPHOS activity and expression of mtDNA‐related proteins were higher in glioma stem cells (GSCs) than in differentiated GSCs. Moreover, GSC survival was dependent on OXPHOS activity. We identified verteporfin (VPF; a drug that is used clinically for macular degeneration) as a GSC‐OXPHOS‐targeting drug. VPF induced the death of GSCs selectively possibly due to mitochondrial dysfunction. Thus, VPF may be a potential therapeutic option for glioblastoma by targeting mitochondrial OXPHOS.
Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of ...GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.
Annual recruitment data of new graduates are manually analyzed by human resources (HR) specialists in industries, which signifies the need to evaluate the recruitment strategy of HR specialists. ...Different job seekers send applications to companies every year. The relationships between applicants' attributes (e.g., English skill or academic credentials) can be used to analyze the changes in recruitment trends across multiple years. However, most attributes are unnormalized and thus require thorough preprocessing. Such unnormalized data hinder effective comparison of the relationship between applicants in the early stage of data analysis. Thus, a visual exploration system is highly needed to gain insight from the overview of the relationship among applicant qualifications across multiple years. In this study, we propose the Polarizing Attributes for Network Analysis of Correlation on Entities Association (Panacea) visualization system. The proposed system integrates a time-varying graph model and dynamic graph visualization for heterogeneous tabular data. Using this system, HR specialists can interactively inspect the relationships between two attributes of prospective employees across multiple years. Further, we demonstrate the usability of Panacea with representative examples for finding hidden trends in real-world datasets, and we discuss feedback from HR specialists obtained throughout Panacea's development. The proposed Panacea system enables HR specialists to visually explore the annual recruitment of new graduates.
Control of the cancer stem/initiating cell population is considered key to realizing the long‐term survival of glioblastoma patients. Recently, we demonstrated that FOXO3 activation is sufficient to ...induce differentiation of glioma‐initiating cells having stem‐like properties and inhibit their tumor‐initiating potential. Here we identified metformin, an antidiabetic agent, as a therapeutic activator of FOXO3. Metformin activated FOXO3 and promoted differentiation of such stem‐like glioma‐initiating cells into nontumorigenic cells. Furthermore, metformin promoted FOXO3 activation and differentiation via AMP‐activated protein kinase (AMPK) activation, which was sensitive to extracellular glucose availability. Importantly, transient, systemic administration of metformin depleted the self‐renewing and tumor‐initiating cell population within established tumors, inhibited tumor formation by stem‐like glioma‐initiating cells in the brain, and provided a substantial survival benefit. Our findings demonstrate that targeting glioma‐initiating cells via the AMPK‐FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma‐initiating cells. Our results also establish a novel, direct link between glucose metabolism and cancer stem/initiating cells.
In this study metformin, an antidiabetic agent, is identified as a therapeutic activator of FOXO3. The study demonstrates that targeting glioma‐initiating cells via the AMP‐activated protein kinase‐ FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma‐initiating cells.
In the present paper, we propose an extension of the Deep Planning Network (PlaNet), also referred to as PlaNet of the Bayesians (PlaNet-Bayes). There has been a growing demand in model predictive ...control (MPC) in partially observable environments in which complete information is unavailable because of, for example, lack of expensive sensors. PlaNet is a promising solution to realize such latent MPC, as it is used to train state-space models via model-based reinforcement learning (MBRL) and to conduct planning in the latent space. However, recent state-of-the-art strategies mentioned in MBRR literature, such as involving uncertainty into training and planning, have not been considered, significantly suppressing the training performance. The proposed extension is to make PlaNet uncertainty-aware on the basis of Bayesian inference, in which both model and action uncertainty are incorporated. Uncertainty in latent models is represented using a neural network ensemble to approximately infer model posteriors. The ensemble of optimal action candidates is also employed to capture multimodal uncertainty in the optimality. The concept of the action ensemble relies on a general variational inference MPC (VI-MPC) framework and its instance, probabilistic action ensemble with trajectory sampling (PaETS). In this paper, we extend VI-MPC and PaETS, which have been originally introduced in previous literature, to address partially observable cases. We experimentally compare the performances on continuous control tasks, and conclude that our method can consistently improve the asymptotic performance compared with PlaNet.
Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) ...endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.
Use of epidermal growth factor receptor (EGFR) inhibitors represented by gefitinib and erlotinib has become the standard of treatment for non-small-cell lung cancers (NSCLCs) with activating EGFR ...mutations. However, the majority of NSCLCs, which overexpress EGFR without such mutations, are resistant to EGFR inhibitors, and the mechanism(s) behind such primary resistance of NSCLCs without activating EGFR mutations to EGFR inhibitors still remains poorly understood. Here in this study, we show that glucose metabolism mediated by GLUT1, a facilitative glucose transporter, is involved in gefitinib resistance of NSCLC cells. We found that GLUT1 expression and glucose uptake were increased in resistant NSCLC cells after gefitinib treatment and that genetic as well as pharmacological inhibition of GLUT1 sensitized not only NSCLC cells with primary resistance but also those with acquired resistance to gefitinib.
, the combination of systemic gefitinib and a GLUT1 inhibitor, both of which failed to inhibit tumor growth when administered alone, significantly inhibited the growth of xenograft tumors formed by the implantation of NSCLC cells with wild-type EGFR (wt-EGFR). Since our data indicated that GLUT1 was similarly involved in erlotinib resistance, our findings suggest that the activity of GLUT1-mediated glucose metabolism could be a critical determinant for the sensitivity of NSCLC cells to EGFR inhibitors and that concurrent GLUT1 inhibition may therefore be a mechanism-based approach to treating NSCLCs resistant to EGFR inhibitors, including those with wt-EGFR.
Givinostat is a pan-histone deacetylase (HDAC) inhibitor that has demonstrated excellent tolerability as well as efficacy in patients with polycythemia vera. Accumulating in vitro and in vivo ...evidence suggests givinostat is also promising as a therapeutic agent targeting glioma stem cells (GSCs), the cancer stem cells of glioblastoma (GBM) considered responsible for its intractable nature. However, it remains to be shown how givinostat impacts the therapeutic effects of temozolomide, a DNA-alkylating agent and the key component of GBM treatment given not only during postoperative radiotherapy but also thereafter as maintenance chemotherapy.
The effects of givinostat and knockdown of O
-methylguanine-DNA methyltransferase (MGMT) or Sp1 on the mRNA and protein expression of relevant genes in human GSC lines were examined by RT-PCR and western blot analyses. The dye exclusion method was used to evaluate cell viability.
Givinostat enhanced the cytotoxic activity of temozolomide in GSC lines expressing MGMT, in which the MGMT expression was shown to contribute to their temozolomide resistance. Givinostat inhibited MGMT expression in GSCs and, in parallel, the expression of Sp1, a transcription factor involved in the control of MGMT promoter activity. Knockdown experiments demonstrated Sp1 expression was indeed required for MGMT expression in GSCs.
Givinostat, in addition to its own cytotoxic activity, sensitizes GSCs to temozolomide by inhibiting Sp1-dependent MGMT expression in GSCs. Combining givinostat with temozolomide could therefore be a rational therapeutic strategy to effectively eliminate GSCs and thus help overcome the therapy resistance of GBM.
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