Cardio-oncology Related to Heart Failure: Epidermal Growth Factor Receptor Target-Based Therapy.

PubMed

Kenigsberg, Benjamin; Jain, Varun; Barac, Ana

2017-04-01

Cancer therapy targeting the epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene B (ErbB)/human EGFR receptor (HER) family of tyrosine kinases has been successfully used in treatment of several malignancies. The ErbB pathways play a role in the maintenance of cardiac homeostasis. This article summarizes current knowledge about EGFR/ErbB/HER receptor-targeted cancer therapeutics focusing on their cardiotoxicity profiles, molecular mechanisms, and implications in clinical cardio-oncology. The article discusses challenges in predicting, monitoring, and treating cardiac dysfunction and heart failure associated with ErbB-targeted cancer therapeutics and highlights opportunities for researchers and clinical investigators. Copyright © 2016 Elsevier Inc. All rights reserved.

Geologic Controls on the Growth of Petroleum Reserves

USGS Publications Warehouse

Fishman, Neil S.; Turner, Christine E.; Peterson, Fred; Dyman, Thaddeus S.; Cook, Troy

2008-01-01

The geologic characteristics of selected siliciclastic (largely sandstone) and carbonate (limestone and dolomite) reservoirs in North America (largely the continental United States) were investigated to improve our understanding of the role of geology in the growth of petroleum reserves. Reservoirs studied were deposited in (1) eolian environments (Jurassic Norphlet Formation of the Gulf Coast and Pennsylvanian-Permian Minnelusa Formation of the Powder River Basin), (2) interconnected fluvial, deltaic, and shallow marine environments (Oligocene Frio Formation of the Gulf Coast and the Pennsylvanian Morrow Formation of the Anadarko and Denver Basins), (3) deeper marine environments (Mississippian Barnett Shale of the Fort Worth Basin and Devonian-Mississippian Bakken Formation of the Williston Basin), (4) marine carbonate environments (Ordovician Ellenburger Group of the Permian Basin and Jurassic Smackover Formation of the Gulf of Mexico Basin), (5) a submarine fan environment (Permian Spraberry Formation of the Midland Basin), and (6) a fluvial environment (Paleocene-Eocene Wasatch Formation of the Uinta-Piceance Basin). The connection between an oil reservoir's production history and geology was also evaluated by studying production histories of wells in disparate reservoir categories and wells in a single formation containing two reservoir categories. This effort was undertaken to determine, in general, if different reservoir production heterogeneities could be quantified on the basis of gross geologic differences. It appears that reserve growth in existing fields is most predictable for those in which reservoir heterogeneity is low and thus production differs little between wells, probably owing to relatively homogeneous fluid flow. In fields in which reservoirs are highly heterogeneous, prediction of future growth from infill drilling is notably more difficult. In any case, success at linking heterogeneity to reserve growth depends on factors in addition to

Marine Reserve Targets to Sustain and Rebuild Unregulated Fisheries.

PubMed

Krueck, Nils C; Ahmadia, Gabby N; Possingham, Hugh P; Riginos, Cynthia; Treml, Eric A; Mumby, Peter J

2017-01-01

Overfishing threatens the sustainability of coastal marine biodiversity, especially in tropical developing countries. To counter this problem, about 200 governments worldwide have committed to protecting 10%-20% of national coastal marine areas. However, associated impacts on fisheries productivity are unclear and could weaken the food security of hundreds of millions of people who depend on diverse and largely unregulated fishing activities. Here, we present a systematic theoretic analysis of the ability of reserves to rebuild fisheries under such complex conditions, and we identify maximum reserve coverages for biodiversity conservation that do not impair long-term fisheries productivity. Our analysis assumes that fishers have no viable alternative to fishing, such that total fishing effort remains constant (at best). We find that realistic reserve networks, which protect 10%-30% of fished habitats in 1-20 km wide reserves, should benefit the long-term productivity of almost any complex fishery. We discover a "rule of thumb" to safeguard against the long-term catch depletion of particular species: individual reserves should export 30% or more of locally produced larvae to adjacent fishing grounds. Specifically on coral reefs, where fishers tend to overexploit species whose dispersal distances as larvae exceed the home ranges of adults, decisions on the size of reserves needed to meet the 30% larval export rule are unlikely to compromise the protection of resident adults. Even achieving the modest Aichi Target 11 of 10% "effective protection" can then help rebuild depleted catch. However, strictly protecting 20%-30% of fished habitats is unlikely to diminish catch even if overfishing is not yet a problem while providing greater potential for biodiversity conservation and fishery rebuilding if overfishing is substantial. These findings are important because they suggest that doubling or tripling the only globally enforced marine reserve target will benefit

Marine Reserve Targets to Sustain and Rebuild Unregulated Fisheries

PubMed Central

Krueck, Nils C.; Ahmadia, Gabby N.; Possingham, Hugh P.; Riginos, Cynthia; Treml, Eric A.; Mumby, Peter J.

2017-01-01

Overfishing threatens the sustainability of coastal marine biodiversity, especially in tropical developing countries. To counter this problem, about 200 governments worldwide have committed to protecting 10%–20% of national coastal marine areas. However, associated impacts on fisheries productivity are unclear and could weaken the food security of hundreds of millions of people who depend on diverse and largely unregulated fishing activities. Here, we present a systematic theoretic analysis of the ability of reserves to rebuild fisheries under such complex conditions, and we identify maximum reserve coverages for biodiversity conservation that do not impair long-term fisheries productivity. Our analysis assumes that fishers have no viable alternative to fishing, such that total fishing effort remains constant (at best). We find that realistic reserve networks, which protect 10%–30% of fished habitats in 1–20 km wide reserves, should benefit the long-term productivity of almost any complex fishery. We discover a “rule of thumb” to safeguard against the long-term catch depletion of particular species: individual reserves should export 30% or more of locally produced larvae to adjacent fishing grounds. Specifically on coral reefs, where fishers tend to overexploit species whose dispersal distances as larvae exceed the home ranges of adults, decisions on the size of reserves needed to meet the 30% larval export rule are unlikely to compromise the protection of resident adults. Even achieving the modest Aichi Target 11 of 10% “effective protection” can then help rebuild depleted catch. However, strictly protecting 20%–30% of fished habitats is unlikely to diminish catch even if overfishing is not yet a problem while providing greater potential for biodiversity conservation and fishery rebuilding if overfishing is substantial. These findings are important because they suggest that doubling or tripling the only globally enforced marine reserve target will

Targeting Resources for Local Growth.

ERIC Educational Resources Information Center

Casto, James E.

2001-01-01

Focusing state and federal dollars on targeted areas, the Kentucky Appalachian Community Development Initiative helps communities in eastern Kentucky fund their own strategies for economic growth. In Hindman, the project focuses on creating the Kentucky School of Crafts, to train master artisans; supporting the Kentucky Appalachian Artisan Center;…

U.S. Geological Survey assessment of reserve growth outside of the United States

USGS Publications Warehouse

Klett, Timothy R.; Cook, Troy A.; Charpentier, Ronald R.; Tennyson, Marilyn E.; Le, Phuong A.

2015-12-21

The U.S. Geological Survey estimated volumes of technically recoverable, conventional petroleum resources resulting from reserve growth for discovered fields outside the United States that have reported in-place oil and gas volumes of 500 million barrels of oil equivalent or greater. The mean volumes of reserve growth were estimated at 665 billion barrels of crude oil; 1,429 trillion cubic feet of natural gas; and 16 billion barrels of natural gas liquids. These volumes constitute a significant portion of the world’s oil and gas resources and represent the potential future growth of current global reserves over time based on better assessment methodology, new technologies, and greater understanding of reservoirs.

Petroleum reserves and undiscovered resources in the total petroleum systems of Iraq: Reserve growth and production implications

USGS Publications Warehouse

Verma, M.K.; Ahlbrandt, T.S.; Al-Gailani, M.

2004-01-01

Iraq is one of the world's most petroleum-rich countries and, in the future, it could become one of the main producers. Iraq's petroleum resources are estimated to be 184 billion barrels, which include oil and natural gas reserves, and undiscovered resources. With its proved (or remaining) reserves of 113 billion barrels of oil (BBO) as of January 2003, Iraq ranks second to Saudi Arabia with 259 BBO in the Middle East. Iraq's proved reserves of 110 trillion cubic feet of gas (TCFG) rank tenth in the world. In addition to known reserves, the combined undiscovered hydrocarbon potential for the three Total Petroleum Systems (Paleozoic, Jurassic, and Cretaceous/Tertiary) in Iraq is estimated to range from 14 to 84 BBO (45 BBO at the mean), and 37 to 227 TCFG (120 TCFG at the mean). Additionally, of the 526 known prospective structures, some 370 remain undrilled. Petroleum migration models and associated geological and geochemical studies were used to constrain the undiscovered resource estimates of Iraq. Based on a criterion of recoverable reserves of between 1 and 5 BBO for a giant field, and more than 5 BBO for a super-giant, Iraq has 6 super-giant and 11 giant fields, accounting for 88% of its recoverable reserves, which include proved reserves and cumulative production. Of the 28 producing fields, 22 have recovery factors that range from 15 to 42% with an overall average of less than 30%. The recovery factor can be increased with water injection, improved and enhanced oil recovery methods (IOR and EOR) in various reservoirs, thus potentially increasing Iraq's reserves by an additional 50 to 70 BBO. Reserve growth is a significant factor that has been observed, to some extent, in nearly all Iraqi oil fields. Historically, producing fields have shown an average growth of 1.6 fold (or 60%) in their recoverable reserves over a 20-year period (1981-2001). With periodic assessments of reservoirs, application of available technology, and an upgrading of facilities

BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models.

PubMed

Morii, Takeshi; Ohtsuka, Kouki; Ohnishi, Hiroaki; Mochizuki, Kazuo; Yoshiyama, Akira; Aoyagi, Takayuki; Hornicek, Francis J; Ichimura, Shoichi

2014-11-01

Chondrosarcoma is refractory to conventional chemotherapy. BH-3 mimetics ABT-737 and ABT-263 are synthetic small-molecule inhibitors of anti-apoptotic proteins B-cell lymphoma-2 (Bcl2) and Bcl-xL, which play a critical role in survival of chondrosarcoma cells. Chondrosarcoma cell lines SW-1353 and CS-1 were used as the disease model. We used immunoblotting to assess the expression of target molecules Bcl2 and Bcl-xL, and the apoptotic inducers Bcl2-associated X (Bax) and Bcl2-antagonist/killer (Bak). In vitro growth inhibition by BH-3 mimetics was confirmed by photomicroscopic cell counting and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Apoptotic induction was confirmed by Enzyme-Linked ImmunoSorbent Assay (ELISA). In vivo growth inhibition was assessed in a non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model. Expression of the target and effector molecules was confirmed in chondrosarcoma cell lines. BH3 mimetics significantly inhibited cell growth and induced apoptosis in vitro. Administration of ABT-263 inhibited chondrosarcoma growth and improved survival in a mouse model. BH3 mimetics represent a novel treatment modality for chondrosarcoma. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Targeted delivery of growth factors in ischemic stroke animal models.

PubMed

Rhim, Taiyoun; Lee, Minhyung

2016-01-01

Ischemic stroke is caused by reduced blood supply and leads to loss of brain function. The reduced oxygen and nutrient supply stimulates various physiological responses, including induction of growth factors. Growth factors prevent neuronal cell death, promote neovascularization, and induce cell growth. However, the concentration of growth factors is not sufficient to recover brain function after the ischemic damage, suggesting that delivery of growth factors into the ischemic brain may be a useful treatment for ischemic stroke. In this review, various approaches for the delivery of growth factors to ischemic brain tissue are discussed, including local and targeting delivery systems. To develop growth factor therapy for ischemic stroke, important considerations should be taken into account. First, growth factors may have possible side effects. Thus, concentration of growth factors should be restricted to the ischemic tissues by local administration or targeted delivery. Second, the duration of growth factor therapy should be optimized. Growth factor proteins may be degraded too fast to have a high enough therapeutic effect. Therefore, delivery systems for controlled release or gene delivery may be useful. Third, the delivery systems to the brain should be optimized according to the delivery route.

Arginyltransferase ATE1 is targeted to the neuronal growth cones and regulates neurite outgrowth during brain development.

PubMed

Wang, Junling; Pavlyk, Iuliia; Vedula, Pavan; Sterling, Stephanie; Leu, N Adrian; Dong, Dawei W; Kashina, Anna

2017-10-01

Arginylation is an emerging protein modification mediated by arginyltransferase ATE1, shown to regulate embryogenesis and actin cytoskeleton, however its functions in different physiological systems are not well understood. Here we analyzed the role of ATE1 in brain development and neuronal growth by producing a conditional mouse knockout with Ate1 deletion in the nervous system driven by Nestin promoter (Nes-Ate1 mice). These mice were weaker than wild type, resulting in low postnatal survival rates, and had abnormalities in the brain that suggested defects in neuronal migration. Cultured Ate1 knockout neurons showed a reduction in the neurite outgrowth and the levels of doublecortin and F-actin in the growth cones. In wild type, ATE1 prominently localized to the growth cones, in addition to the cell bodies. Examination of the Ate1 mRNA sequence reveals the existence of putative zipcode-binding sequences involved in mRNA targeting to the cell periphery and local translation at the growth cones. Fluorescence in situ hybridization showed that Ate1 mRNA localized to the tips of the growth cones, likely due to zipcode-mediated targeting, and this localization coincided with spots of localization of arginylated β-actin, which disappeared in the presence of protein synthesis inhibitors. We propose that zipcode-mediated co-targeting of Ate1 and β-actin mRNA leads to localized co-translational arginylation of β-actin that drives the growth cone migration and neurite outgrowth. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Targeted manipulation of leaf form via local growth repression.

PubMed

Malinowski, Robert; Kasprzewska, Ania; Fleming, Andrew J

2011-06-01

A classical view is that leaf shape is the result of local promotion of growth linked to cell proliferation. However, an alternative hypothesis is that leaf form is the result of local repression of growth in an otherwise growing system. Here we show that leaf form can indeed be manipulated in a directed fashion by local repression of growth. We show that targeting expression of an inhibitor of a cyclin-dependent kinase (KRP1) to the sinus area of developing leaves of Arabidopsis leads to local growth repression and the formation of organs with extreme lobing, including generation of leaflet-like organs. Directing KRP1 expression to other regions of the leaf using an miRNA target sequence tagging approach also leads to predictable novel leaf forms, and repression of growth in the leaf margin blocks the outgrowth of lobes, leading to a smoother perimeter. In addition, we show that decreased growth around the perimeter and across the leaf abaxial surface leads to a change in 3D form, as predicted by mechanical models of leaf growth. Our analysis provides experimental evidence that local repression of growth influences leaf shape, suggesting that it could be part of the mechanism of morphogenesis in plants in the context of an otherwise growing system. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.

Optimizing clinical benefit with targeted treatment in mRCC: "Tumor growth rate" as an alternative clinical endpoint.

PubMed

Milella, Michele

2016-06-01

Tumor growth rate (TGR), usually defined as the ratio between the slope of tumor growth before the initiation of treatment and the slope of tumor growth during treatment, between the nadir and disease progression, is a measure of the rate at which tumor volume increases over time. In patients with metastatic renal cell carcinoma (mRCC), TGR has emerged as a reliable alternative parameter to allow a quantitative and dynamic evaluation of tumor response. This review presents evidence on the correlation between TGR and treatment outcomes and discusses the potential role of this tool within the treatment scenario of mRCC. Current evidence, albeit of retrospective nature, suggests that TGR might represent a useful tool to assess whether treatment is altering the course of the disease, and has shown to be significantly associated with progression-free survival and overall survival. Therefore, TGR may represent a valuable endpoint for clinical trials evaluating new molecularly targeted therapies. Most importantly, incorporation of TGR in the assessment of individual patients undergoing targeted therapies may help clinicians decide if a given agent is no longer able to control disease growth and whether continuing therapy beyond RECIST progression may still produce clinical benefit. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

An empirical model for transient crater growth in granular targets based on direct observations

NASA Astrophysics Data System (ADS)

Yamamoto, Satoru; Barnouin-Jha, Olivier S.; Toriumi, Takashi; Sugita, Seiji; Matsui, Takafumi

2009-09-01

The present paper describes observations of crater growth up to the time of transient crater formation and presents a new empirical model for transient crater growth as a function of time. Polycarbonate projectiles were impacted vertically into soda-lime glass sphere targets using a single-stage light-gas gun. Using a new technique with a laser sheet illuminating the target [Barnouin-Jha, O.S., Yamamoto, S., Toriumi, T., Sugita, S., Matsui, T., 2007. Non-intrusive measurements of the crater growth. Icarus, 188, 506-521], we measured the temporal change in diameter of crater cavities (diameter growth). The rate of increase in diameter at early times follows a power law relation, but the data at later times (before the end of transient crater formation) deviates from the power law relation. In addition, the power law exponent at early times and the degree of deviation from a power law at later times depend on the target. In order to interpret these features, we proposed to modify Maxwell's Z-model under the assumption that the strength of the excavation flow field decreases exponentially with time. We also derived a diameter growth model as: d(t)∝[1-exp(-βt)]γ, where d(t) is the apparent diameter of the crater cavity at time t after impact, and β and γ are constants. We demonstrated that the diameter growth model could represent well the experimental data for various targets with different target material properties, such as porosity or angle of repose. We also investigated the diameter growth for a dry sand target, which has been used to formulate previous scaling relations. The obtained results showed that the dry sand target has larger degree of deviation from a power law, indicating that the target material properties of the dry sand target have a significant effect on diameter growth, especially at later times. This may suggest that the previously reported scaling relations should be reexamined in order to account for the late-stage behavior with the

Growth history of oil reserves in major California oil fields during the twentieth century

USGS Publications Warehouse

Tennyson, Marilyn E.

2005-01-01

Oil reserves in 12 of California's 52 giant fields (fields with estimated recovery > 100 million barrels of oil) have continued to appreciate well past the age range at which most fields cease to show significant increases in ultimate recovery. Most of these fields were discovered between 1890 and 1920 and grew to volumes greater than 500 million barrels in their first two decades. Growth of reserves in these fields accelerated in th e1950s and 1960s and is mostly explained by application of secondary and tertiary recovery technicques, primarily waterflooding and thermal recovery. The remaining three-fourths of California's giant fields show a pattern of growth in which fields cease to grow significantly by 20-30 years following recovery. virtually all of these fields have estimated ultimate recoveries less than about 500 million barrels and most are in the 100-200 million barrel range. Three of six offshore giant fields, all discovered between 1966 and 1981, have shown decreases in their estimated ultimate sizes within about the first decade after production began, presumably because production volumes ailed to match initial projections. The data suggest that: 1. Only fields that attain an estimated ultimate size of several hundred million barrels shortly after discovery and have geologic characterisics that make them suceptible to advanced recovery techniques are likely to show substantial late growth. 2. Offshore fields are less likely to show significant growth, probably because projections based on modern seismic reflection and reservoir test data are unlikely to underestimate the volume of oil in the field. 3. Secondary and tertiary recovery programs rather than field extensions or new pool discoveries are responsible for most of the significant growth of reserves in California. 4. field size data collected ove rmany decades provide a more comprehensive context for inferring reasons for reserve appreciation than shorter data series such as the Oil and Gas

Priority target conditions for algorithms for monitoring children's growth: Interdisciplinary consensus.

PubMed

Scherdel, Pauline; Reynaud, Rachel; Pietrement, Christine; Salaün, Jean-François; Bellaïche, Marc; Arnould, Michel; Chevallier, Bertrand; Piloquet, Hugues; Jobez, Emmanuel; Cheymol, Jacques; Bichara, Emmanuelle; Heude, Barbara; Chalumeau, Martin

2017-01-01

Growth monitoring of apparently healthy children aims at early detection of serious conditions through the use of both clinical expertise and algorithms that define abnormal growth. Optimization of growth monitoring requires standardization of the definition of abnormal growth, and the selection of the priority target conditions is a prerequisite of such standardization. To obtain a consensus about the priority target conditions for algorithms monitoring children's growth. We applied a formal consensus method with a modified version of the RAND/UCLA method, based on three phases (preparatory, literature review, and rating), with the participation of expert advisory groups from the relevant professional medical societies (ranging from primary care providers to hospital subspecialists) as well as parent associations. We asked experts in the pilot (n = 11), reading (n = 8) and rating (n = 60) groups to complete the list of diagnostic classification of the European Society for Paediatric Endocrinology and then to select the conditions meeting the four predefined criteria of an ideal type of priority target condition. Strong agreement was obtained for the 8 conditions selected by the experts among the 133 possible: celiac disease, Crohn disease, craniopharyngioma, juvenile nephronophthisis, Turner syndrome, growth hormone deficiency with pituitary stalk interruption syndrome, infantile cystinosis, and hypothalamic-optochiasmatic astrocytoma (in decreasing order of agreement). This national consensus can be used to evaluate the algorithms currently suggested for growth monitoring. The method used for this national consensus could be re-used to obtain an international consensus.

miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A.

PubMed

Chang, Xiao; Zhang, Haiping; Lian, Shi; Zhu, Wei

2016-07-01

As an oncogene, aurora kinase A (AURKA) is overexpressed in various types of human cancers. However, the expression and roles of AURKA in malignant melanoma are largely unknown. In this study, a miR-137-AURKA axis was revealed to regulate melanoma growth. We found a significant increase in levels of AURKA in melanoma. Both genetic knockdown and pharmacologic inhibition of AURKA decreased tumor cell growth in vitro and in vivo. Further found that miR-137 reduced AURKA expression through interaction with its 3' untranslated region (3'UTR) and that miR-137 was negatively correlated with AURKA expression in melanoma specimens. Overexpression of miR-137 decreased cell proliferation and colony formation in vitro. Notably, re-expression of AURKA significantly rescued miR-137-mediated suppression of cell growth and clonality. In summary, these results reveal that miR-137 functions as a tumor suppressor by targeting AURKA, providing new insights into investigation of therapeutic strategies against malignant melanoma. Copyright © 2016 Elsevier Inc. All rights reserved.

Mold growth in on-reserve homes in Canada: the need for research, education, policy, and funding.

PubMed

Optis, Michael; Shaw, Karena; Stephenson, Peter; Wild, Peter

2012-01-01

The impact of mold growth in homes located on First Nations reserves in Canada is part of a national housing crisis that has not been adequately studied. Nearly half of the homes on reserves contain mold at levels of contamination associated with high rates of respiratory and other illnesses to residents. Mold thrives due to increased moisture levels in building envelopes and interior spaces. Increased moisture stems from several deficiencies in housing conditions, including structural damage to the building envelope, overcrowding and insufficient use of ventilation systems, and other moisture-control strategies. These deficiencies have developed due to a series of historical and socioeconomic factors, including disenfranchisement from traditional territory, environmentally inappropriate construction, high unemployment rates, lack of home ownership, and insufficient federal funding for on-reserve housing and socioeconomic improvements. The successful, long-term reduction of mold growth requires increased activity in several research and policy areas. First, the actual impacts on health need to be studied and associated with comprehensive experimental data on mold growth to understand the unique environmental conditions that permit the germination and growth of toxic mold species. Second, field data documenting the extent of mold growth in on-reserve homes do not exist but are essential in understanding the full extent of the crisis. Third, current government initiatives to educate homeowners in mold remediation and prevention techniques must be long lasting and effective. Finally, and most importantly, the federal government must make a renewed and lasting commitment to improve the socioeconomic conditions on reserves that perpetuate mold growth in homes. Without such improvement, the mold crisis will surely persist and likely worsen.

Targeting Epidermal Growth Factor Receptor in triple negative breast cancer: New discoveries and practical insights for drug development.

PubMed

Costa, Ricardo; Shah, Ami N; Santa-Maria, Cesar A; Cruz, Marcelo R; Mahalingam, Devalingam; Carneiro, Benedito A; Chae, Young Kwang; Cristofanilli, Massimo; Gradishar, William J; Giles, Francis J

2017-02-01

Triple negative breast cancer (TNBC) accounts for 10-20% of cases in breast cancer. Despite recent advances in the treatment of hormonal receptor+ and HER2+ breast cancers, there are no targeted therapies available for TNBC. Evidence supports that most patients with TNBC express the transmembrane Epidermal Growth Factor Receptor (EGFR). However, early phase clinical trials failed to demonstrate significant activity of EGFR-targeted monoclonal antibodies and/or tyrosine kinase inhibitors. Here, we review the recent discoveries related to the underlying biology of the EGFR pathway in TNBC, clinical progress to date and suggest rational future approaches for investigational therapies in TNBC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modeling determinants of growth: evidence for a community-based target in height?

PubMed

Aßmann, Christian; Hermanussen, Michael

2013-07-01

Human growth is traditionally envisaged as a target-seeking process regulated by genes, nutrition, health, and the state of an individual's social and economic environment; it is believed that under optimal physical conditions, an individual will achieve his or her full genetic potential. Using a panel data set on individual height increments, we suggest a statistical modeling approach that characterizes growth as first-order trend stationary and allows for controlling individual growth tempo via observable measures of individual maturity. A Bayesian framework and corresponding Markov-chain Monte Carlo techniques allowing for a conceptually stringent treatment of missing values are adapted for parameter estimation. The model provides evidence for the adjustment of the individual growth rate toward average height of the population. The increase in adult body height during the past 150 y has been explained by the steady improvement of living conditions that are now being considered to have reached an optimum in Western societies. The current investigation questions the notion that the traditional concept in the understanding of this target-seeking process is sufficient. We consider an additional regulator that possibly points at community-based target seeking in growth.

Growth Outcomes of Preterm Infants Exposed to Different Oxygen Saturation Target Ranges from Birth

PubMed Central

Navarrete, Cristina T.; Wrage, Lisa A.; Carlo, Waldemar A.; Walsh, Michele C.; Rich, Wade; Gantz, Marie G.; Das, Abhik; Schibler, Kurt; Newman, Nancy S.; Piazza, Anthony J.; Poindexter, Brenda B.; Shankaran, Seetha; Sánchez, Pablo J.; Morris, Brenda H.; Frantz, Ivan D.; Van Meurs, Krisa P.; Cotten, C. Michael; Ehrenkranz, Richard A.; Bell, Edward F.; Watterberg, Kristi L.; Higgins, Rosemary D.; Duara, Shahnaz

2017-01-01

Objective To test whether infants randomized to a lower oxygen saturation (SpO2) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA), and less growth failure at 36 weeks PMA and 18–22 months corrected age. Study design We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85–89%, n=402, GA 26 ± 1wk, BW 839 ± 186 g) or higher (91–95%, n=408, GA 26 ± 1wk, BW 840 ± 191 g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA, and 18–22 months corrected age. Growth velocities were estimated using the exponential method and analyzed using linear mixed models. Poor growth outcome, defined as weight < 10th percentile at 36 weeks PMA and 18–22 months corrected age, was compared across the two treatment groups using robust Poisson regression. Results Growth outcomes including growth at 36 weeks PMA and 18–22 months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups. Conclusion Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants. PMID:27344218

miR-137 inhibits glutamine catabolism and growth of malignant melanoma by targeting glutaminase.

PubMed

Luan, Wenkang; Zhou, Zhou; Zhu, Yan; Xia, Yun; Wang, Jinlong; Xu, Bin

2018-01-01

Glutamine catabolism is considered to be an important metabolic pathway for cancer cells. Glutaminase (GLS) is the important rate-limiting enzyme of glutamine catabolism. miR-137 functions as a tumor suppressor in many human malignant tumors. However, the role and molecular mechanism of miR-137 and GLS in malignant melanoma has not been reported. In this study, we showed that miR-137 was decreased in melanoma tissue, and the low miR-137 level and high GLS expression are independent risk factor in melanoma. miR-137 suppressed the proliferation and glutamine catabolism of melanoma cells. GLS is crucial for glutamine catabolism and growth of malignant melanoma. We also demonstrated that miR-137 acts as a tumor suppressor in melanoma by targeting GLS. This result elucidates a new mechanism for miR-137 in melanoma development and provides a survival indicator and potential therapeutic target for melanoma patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Tumor-specific RNA interference targeting Pokemon suppresses tumor growth and induces apoptosis in prostate cancer.

PubMed

Li, Yining; Xu, Shuxiong; Wang, Xiangwei; Shi, Hua; Sun, Zhaolin; Yang, Zhao

2013-02-01

To explore the exact mechanism of Pokemon in prostate cancer. Pokemon is a member of the POK family of transcriptional repressors. Its main function is suppression of the p14ARF (alternate reading frame) tumor suppressor gene. Although Pokemon expression has been found to be increased in various types of lymphoma, the exact mechanism of the gene in prostate cancer is not clear. In the present study, prostate cancer cells were transfected with the specific short hairpin ribonucleic acid (RNA) expression vector targeting Pokemon. The expression of Pokemon messenger RNA and its protein was detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cell growth and cell apoptosis were also examined using the methyl thiazolyl tetrazolium assay and flow cytometry. The results demonstrated that specific RNA interference (RNAi) could decrease the expression levels of Pokemon gene messenger RNA and protein in prostate cancer cells. In addition, that specific RNAi significantly inhibited the cell proliferation and increased the apoptotic rate. In vivo experiments showed that specific RNAi inhibited the tumorigenicity of prostate cancer cells and significantly suppressed tumor growth. Therefore, an RNAi-targeted Pokemon gene strategy could be a potential approach to prostate cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Growth of coast redwood and Douglas-fir following thinning in second-growth forests at Redwood National Park and Headwaters Forest Reserve

Treesearch

Phillip J. van Mantgem; Jason R. Teraoka; David H. LaFever; Laura B. Lalemand

2017-01-01

Managers of second-growth forests at Redwood National Park and the Bureau of Land Management’s Headwaters Forest Reserve encourage the development of late seral forest characteristics using mechanical thinning, where competing vegetation is removed to promote growth of residual trees. Yet the ability to quantify and reliably predict outcomes of treatments such...

Epidermal growth factor receptor and variant III targeted immunotherapy

PubMed Central

Congdon, Kendra L.; Gedeon, Patrick C.; Suryadevara, Carter M.; Caruso, Hillary G.; Cooper, Laurence J.N.; Heimberger, Amy B.; Sampson, John H.

2014-01-01

Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review, we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these approaches. PMID:25342601

Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth.

PubMed

Gururajan, Murali; Dasu, Trivikram; Shahidain, Seif; Jennings, C Darrell; Robertson, Darrell A; Rangnekar, Vivek M; Bondada, Subbarao

2007-01-01

Curcumin (diferuloylmethane), a component of dietary spice turmeric (Curcuma longa), has been shown in recent studies to have therapeutic potential in the treatment of cancer, diabetes, arthritis, and osteoporosis. We investigated the ability of curcumin to modulate the growth of B lymphomas. Curcumin inhibited the growth of both murine and human B lymphoma in vitro and murine B lymphoma in vivo. We also demonstrate that curcumin-mediated growth inhibition of B lymphoma is through inhibition of the survival kinase Akt and its key target Bad. However, in vitro kinase assays show that Akt is not a direct target of curcumin. We identified a novel target for curcumin in B lymphoma viz spleen tyrosine kinase (Syk). Syk is constitutively activated in primary tumors and B lymphoma cell lines and curcumin down-modulates Syk activity accompanied by down-regulation of Akt activation. Moreover, we show that overexpression of Akt, a target of Syk, or Bcl-x(L), a target of Akt can overcome curcumin-induced apoptosis of B lymphoma cells. These observations suggest a novel growth promoting role for Syk in lymphoma cells.

Targeting of a chlamydial protease impedes intracellular bacterial growth.

PubMed

Christian, Jan G; Heymann, Julia; Paschen, Stefan A; Vier, Juliane; Schauenburg, Linda; Rupp, Jan; Meyer, Thomas F; Häcker, Georg; Heuer, Dagmar

2011-09-01

Chlamydiae are obligate intracellular bacteria that propagate in a cytosolic vacuole. Recent work has shown that growth of Chlamydia induces the fragmentation of the Golgi apparatus (GA) into ministacks, which facilitates the acquisition of host lipids into the growing inclusion. GA fragmentation results from infection-associated cleavage of the integral GA protein, golgin-84. Golgin-84-cleavage, GA fragmentation and growth of Chlamydia trachomatis can be blocked by the peptide inhibitor WEHD-fmk. Here we identify the bacterial protease chlamydial protease-like activity factor (CPAF) as the factor mediating cleavage of golgin-84 and as the target of WEHD-fmk-inhibition. WEHD-fmk blocked cleavage of golgin-84 as well as cleavage of known CPAF targets during infection with C. trachomatis and C. pneumoniae. The same effect was seen when active CPAF was expressed in non-infected cells and in a cell-free system. Ectopic expression of active CPAF in non-infected cells was sufficient for GA fragmentation. GA fragmentation required the small GTPases Rab6 and Rab11 downstream of CPAF-activity. These results define CPAF as the first protein that is essential for replication of Chlamydia. We suggest that this role makes CPAF a potential anti-infective therapeutic target.

Whole Genome Re-Sequencing Identifies a Quantitative Trait Locus Repressing Carbon Reserve Accumulation during Optimal Growth in Chlamydomonas reinhardtii

PubMed Central

Goold, Hugh Douglas; Nguyen, Hoa Mai; Kong, Fantao; Beyly-Adriano, Audrey; Légeret, Bertrand; Billon, Emmanuelle; Cuiné, Stéphan; Beisson, Fred; Peltier, Gilles; Li-Beisson, Yonghua

2016-01-01

Microalgae have emerged as a promising source for biofuel production. Massive oil and starch accumulation in microalgae is possible, but occurs mostly when biomass growth is impaired. The molecular networks underlying the negative correlation between growth and reserve formation are not known. Thus isolation of strains capable of accumulating carbon reserves during optimal growth would be highly desirable. To this end, we screened an insertional mutant library of Chlamydomonas reinhardtii for alterations in oil content. A mutant accumulating five times more oil and twice more starch than wild-type during optimal growth was isolated and named constitutive oil accumulator 1 (coa1). Growth in photobioreactors under highly controlled conditions revealed that the increase in oil and starch content in coa1 was dependent on light intensity. Genetic analysis and DNA hybridization pointed to a single insertional event responsible for the phenotype. Whole genome re-sequencing identified in coa1 a >200 kb deletion on chromosome 14 containing 41 genes. This study demonstrates that, 1), the generation of algal strains accumulating higher reserve amount without compromising biomass accumulation is feasible; 2), light is an important parameter in phenotypic analysis; and 3), a chromosomal region (Quantitative Trait Locus) acts as suppressor of carbon reserve accumulation during optimal growth. PMID:27141848

USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance.

PubMed

Lee, Jin-Ku; Chang, Nakho; Yoon, Yeup; Yang, Heekyoung; Cho, Heejin; Kim, Eunhee; Shin, Yongjae; Kang, Wonyoung; Oh, Young Taek; Mun, Gyeong In; Joo, Kyeung Min; Nam, Do-Hyun; Lee, Jeongwu

2016-01-01

Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Potential Targets for Antifungal Drug Discovery Based on Growth and Virulence in Candida albicans

PubMed Central

Li, Xiuyun; Hou, Yinglong; Yue, Longtao; Liu, Shuyuan; Du, Juan

2015-01-01

Fungal infections, especially infections caused by Candida albicans, remain a challenging problem in clinical settings. Despite the development of more-effective antifungal drugs, their application is limited for various reasons. Thus, alternative treatments with drugs aimed at novel targets in C. albicans are needed. Knowledge of growth and virulence in fungal cells is essential not only to understand their pathogenic mechanisms but also to identify potential antifungal targets. This article reviews the current knowledge of the mechanisms of growth and virulence in C. albicans and examines potential targets for the development of new antifungal drugs. PMID:26195510

Gallium-Protoporphyrin IX Inhibits Pseudomonas aeruginosa Growth by Targeting Cytochromes.

PubMed

Hijazi, Sarah; Visca, Paolo; Frangipani, Emanuela

2017-01-01

Pseudomonas aeruginosa is a challenging pathogen due to both innate and acquired resistance to antibiotics. It is capable of causing a variety of infections, including chronic lung infection in cystic fibrosis (CF) patients. Given the importance of iron in bacterial physiology and pathogenicity, iron-uptake and metabolism have become attractive targets for the development of new antibacterial compounds. P. aeruginosa can acquire iron from a variety of sources to fulfill its nutritional requirements both in the environment and in the infected host. The adaptation of P. aeruginosa to heme iron acquisition in the CF lung makes heme utilization pathways a promising target for the development of new anti- Pseudomonas drugs. Gallium [Ga(III)] is an iron mimetic metal which inhibits P. aeruginosa growth by interfering with iron-dependent metabolism. The Ga(III) complex of the heme precursor protoporphyrin IX (GaPPIX) showed enhanced antibacterial activity against several bacterial species, although no inhibitory effect has been reported on P. aeruginosa . Here, we demonstrate that GaPPIX is indeed capable of inhibiting the growth of clinical P. aeruginosa strains under iron-deplete conditions, as those encountered by bacteria during infection, and that GaPPIX inhibition is reversed by iron. Using P. aeruginosa PAO1 as model organism, we show that GaPPIX enters cells through both the heme-uptake systems has and phu , primarily via the PhuR receptor which plays a crucial role in P. aeruginosa adaptation to the CF lung. We also demonstrate that intracellular GaPPIX inhibits the aerobic growth of P. aeruginosa by targeting cytochromes, thus interfering with cellular respiration.

Tumor suppressor miR-1 inhibits tumor growth and metastasis by simultaneously targeting multiple genes

PubMed Central

Liu, Cuilian; Zhang, Song; Wang, Qizhi; Zhang, Xiaobo

2017-01-01

Cancer progression depends on tumor growth and metastasis, which are activated or suppressed by multiple genes. An individual microRNA may target multiple genes, suggesting that a miRNA may suppress tumor growth and metastasis via simultaneously targeting different genes. However, thus far, this issue has not been explored. In the present study, the findings showed that miR-1 could simultaneously inhibit tumor growth and metastasis of gastric and breast cancers by targeting multiple genes. The results indicated that miR-1 was significantly downregulated in cancer tissues compared with normal tissues. The miR-1 overexpression led to cell cycle arrest in the G1 phase in gastric and breast cancer cells but not in normal cells. Furthermore, the miR-1 overexpression significantly inhibited the metastasis of gastric and breast cancer cells. An analysis of the underlying mechanism revealed that the simultaneous inhibition of tumor growth and metastasis mediated by miR-1 was due to the synchronous targeting of 6 miR-1 target genes encoding cyclin dependent kinase 4, twinfilin actin binding protein 1, calponin 3, coronin 1C, WAS protein family member 2 and thymosin beta 4, X-linked. In vivo assays demonstrated that miR-1 efficiently inhibited tumor growth and metastasis of gastric and breast cancers in nude mice. Therefore, our study contributed novel insights into the miR-1′s roles in tumorigenesis of gastric and breast cancers. PMID:28159933

Tumor suppressor miR-1 inhibits tumor growth and metastasis by simultaneously targeting multiple genes.

PubMed

Liu, Cuilian; Zhang, Song; Wang, Qizhi; Zhang, Xiaobo

2017-06-27

Cancer progression depends on tumor growth and metastasis, which are activated or suppressed by multiple genes. An individual microRNA may target multiple genes, suggesting that a miRNA may suppress tumor growth and metastasis via simultaneously targeting different genes. However, thus far, this issue has not been explored. In the present study, the findings showed that miR-1 could simultaneously inhibit tumor growth and metastasis of gastric and breast cancers by targeting multiple genes. The results indicated that miR-1 was significantly downregulated in cancer tissues compared with normal tissues. The miR-1 overexpression led to cell cycle arrest in the G1 phase in gastric and breast cancer cells but not in normal cells. Furthermore, the miR-1 overexpression significantly inhibited the metastasis of gastric and breast cancer cells. An analysis of the underlying mechanism revealed that the simultaneous inhibition of tumor growth and metastasis mediated by miR-1 was due to the synchronous targeting of 6 miR-1 target genes encoding cyclin dependent kinase 4, twinfilin actin binding protein 1, calponin 3, coronin 1C, WAS protein family member 2 and thymosin beta 4, X-linked. In vivo assays demonstrated that miR-1 efficiently inhibited tumor growth and metastasis of gastric and breast cancers in nude mice. Therefore, our study contributed novel insights into the miR-1's roles in tumorigenesis of gastric and breast cancers.

CO2 storage resources, reserves, and reserve growth: Toward a methodology for integrated assessment of the storage capacity of oil and gas reservoirs and saline formations

USGS Publications Warehouse

Burruss, R.C.

2009-01-01

Geologically based methodologies to assess the possible volumes of subsurface CO2 storage must apply clear and uniform definitions of resource and reserve concepts to each assessment unit (AU). Application of the current state of knowledge of geologic, hydrologic, geochemical, and geophysical parameters (contingencies) that control storage volume and injectivity allows definition of the contingent resource (CR) of storage. The parameters known with the greatest certainty are based on observations on known traps (KTs) within the AU that produced oil, gas, and water. The aggregate volume of KTs within an AU defines the most conservation volume of contingent resource. Application of the concept of reserve growth to CR volume provides a logical path for subsequent reevaluation of the total resource as knowledge of CO2 storage processes increases during implementation of storage projects. Increased knowledge of storage performance over time will probably allow the volume of the contingent resource of storage to grow over time, although negative growth is possible. ?? 2009 Elsevier Ltd. All rights reserved.

Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma

PubMed Central

Snuderl, Matija; Batista, Ana; Kirkpatrick, Nathaniel D.; de Almodovar, Carmen Ruiz; Riedemann, Lars; Walsh, Elisa C.; Anolik, Rachel; Huang, Yuhui; Martin, John D.; Kamoun, Walid; Knevels, Ellen; Schmidt, Thomas; Farrar, Christian T.; Vakoc, Benjamin J.; Mohan, Nishant; Chung, Euiheon; Roberge, Sylvie; Peterson, Teresa; Bais, Carlos; Zhelyazkova, Boryana H.; Yip, Stephen; Hasselblatt, Martin; Rossig, Claudia; Niemeyer, Elisabeth; Ferrara, Napoleone; Klagsbrun, Michael; Duda, Dan G.; Fukumura, Dai; Xu, Lei; Carmeliet, Peter; Jain, Rakesh K.

2013-01-01

SUMMARY Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastases, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1—and not vascular endothelial growth factor receptor 1 (VEGFR1)—to promote tumor cell survival. This critical tumor-stroma interaction—mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes—supports the development of therapies targeting PlGF/Nrp1 pathway. PMID:23452854

MicroRNA-375 inhibits colorectal cancer growth by targeting PIK3CA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yihui; Tang, Qingchao; Li, Mingqi

2014-02-07

Highlights: • miR-375 is downregulated in colorectal cancer cell lines and tissues. • miR-375 inhibits colorectal cancer cell growth by targeting PIK3CA. • miR-375 inhibits colorectal cancer cell growth in xenograft nude mice model. - Abstract: Colorectal cancer (CRC) is the second most common cause of death from cancer. MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression by triggering RNA degradation or interfering with translation. Aberrant miRNA expression is involved in human disease including cancer. Herein, we showed that miR-375 was frequently down-regulated in human colorectal cancer cell lines and tissues when compared to normalmore » human colon tissues. PIK3CA was identified as a potential miR-375 target by bioinformatics. Overexpression of miR-375 in SW480 and HCT15 cells reduced PIK3CA protein expression. Subsequently, using reporter constructs, we showed that the PIK3CA untranslated region (3′-UTR) carries the directly binding site of miR-375. Additionally, miR-375 suppressed CRC cell proliferation and colony formation and led to cell cycle arrest. Furthermore, miR-375 overexpression resulted in inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. SiRNA-mediated silencing of PIK3CA blocked the inhibitory effect of miR-375 on CRC cell growth. Lastly, we found overexpressed miR-375 effectively repressed tumor growth in xenograft animal experiments. Taken together, we propose that overexpression of miR-375 may provide a selective growth inhibition for CRC cells by targeting PI3K/Akt signaling pathway.« less

Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth

USDA-ARS?s Scientific Manuscript database

Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make canc...

Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

PubMed Central

Loewith, Robbie; Hall, Michael N.

2011-01-01

TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae. PMID:22174183

Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors

NASA Astrophysics Data System (ADS)

Niederman, Thomas M. J.; Ghogawala, Zoher; Carter, Bob S.; Tompkins, Hillary S.; Russell, Margaret M.; Mulligan, Richard C.

2002-05-01

The demonstration that angiogenesis is required for the growth of solid tumors has fueled an intense interest in the development of new therapeutic strategies that target the tumor vasculature. Here we report the development of an immune-based antiangiogenic strategy that is based on the generation of T lymphocytes that possess a killing specificity for cells expressing vascular endothelial growth factor receptors (VEGFRs). To target VEGFR-expressing cells, recombinant retroviral vectors were generated that encoded a chimeric T cell receptor comprised of VEGF sequences linked to intracellular signaling sequences derived from the chain of the T cell receptor. After transduction of primary murine CD8 lymphocytes by such vectors, the transduced cells were shown to possess an efficient killing specificity for cells expressing the VEGF receptor, Flk-1, as measured by in vitro cytotoxicity assays. After adoptive transfer into tumor-bearing mice, the genetically modified cytotoxic T lymphocytes strongly inhibited the growth of a variety of syngeneic murine tumors and human tumor xenografts. An increased effect on in vivo tumor growth inhibition was seen when this therapy was combined with the systemic administration of TNP-470, a conventional angiogenesis inhibitor. The utilization of the immune system to target angiogenic markers expressed on tumor vasculature may prove to be a powerful means for controlling tumor growth.

Gallium-Protoporphyrin IX Inhibits Pseudomonas aeruginosa Growth by Targeting Cytochromes

PubMed Central

Hijazi, Sarah; Visca, Paolo; Frangipani, Emanuela

2017-01-01

Pseudomonas aeruginosa is a challenging pathogen due to both innate and acquired resistance to antibiotics. It is capable of causing a variety of infections, including chronic lung infection in cystic fibrosis (CF) patients. Given the importance of iron in bacterial physiology and pathogenicity, iron-uptake and metabolism have become attractive targets for the development of new antibacterial compounds. P. aeruginosa can acquire iron from a variety of sources to fulfill its nutritional requirements both in the environment and in the infected host. The adaptation of P. aeruginosa to heme iron acquisition in the CF lung makes heme utilization pathways a promising target for the development of new anti-Pseudomonas drugs. Gallium [Ga(III)] is an iron mimetic metal which inhibits P. aeruginosa growth by interfering with iron-dependent metabolism. The Ga(III) complex of the heme precursor protoporphyrin IX (GaPPIX) showed enhanced antibacterial activity against several bacterial species, although no inhibitory effect has been reported on P. aeruginosa. Here, we demonstrate that GaPPIX is indeed capable of inhibiting the growth of clinical P. aeruginosa strains under iron-deplete conditions, as those encountered by bacteria during infection, and that GaPPIX inhibition is reversed by iron. Using P. aeruginosa PAO1 as model organism, we show that GaPPIX enters cells through both the heme-uptake systems has and phu, primarily via the PhuR receptor which plays a crucial role in P. aeruginosa adaptation to the CF lung. We also demonstrate that intracellular GaPPIX inhibits the aerobic growth of P. aeruginosa by targeting cytochromes, thus interfering with cellular respiration. PMID:28184354

Natural product (-)-gossypol inhibits colon cancer cell growth by targeting RNA-binding protein Musashi-1.

PubMed

Lan, Lan; Appelman, Carl; Smith, Amber R; Yu, Jia; Larsen, Sarah; Marquez, Rebecca T; Liu, Hao; Wu, Xiaoqing; Gao, Philip; Roy, Anuradha; Anbanandam, Asokan; Gowthaman, Ragul; Karanicolas, John; De Guzman, Roberto N; Rogers, Steven; Aubé, Jeffrey; Ji, Min; Cohen, Robert S; Neufeld, Kristi L; Xu, Liang

2015-08-01

Musashi-1 (MSI1) is an RNA-binding protein that acts as a translation activator or repressor of target mRNAs. The best-characterized MSI1 target is Numb mRNA, whose encoded protein negatively regulates Notch signaling. Additional MSI1 targets include the mRNAs for the tumor suppressor protein APC that regulates Wnt signaling and the cyclin-dependent kinase inhibitor P21(WAF-1). We hypothesized that increased expression of NUMB, P21 and APC, through inhibition of MSI1 RNA-binding activity might be an effective way to simultaneously downregulate Wnt and Notch signaling, thus blocking the growth of a broad range of cancer cells. We used a fluorescence polarization assay to screen for small molecules that disrupt the binding of MSI1 to its consensus RNA binding site. One of the top hits was (-)-gossypol (Ki = 476 ± 273 nM), a natural product from cottonseed, known to have potent anti-tumor activity and which has recently completed Phase IIb clinical trials for prostate cancer. Surface plasmon resonance and nuclear magnetic resonance studies demonstrate a direct interaction of (-)-gossypol with the RNA binding pocket of MSI1. We further showed that (-)-gossypol reduces Notch/Wnt signaling in several colon cancer cell lines having high levels of MSI1, with reduced SURVIVIN expression and increased apoptosis/autophagy. Finally, we showed that orally administered (-)-gossypol inhibits colon cancer growth in a mouse xenograft model. Our study identifies (-)-gossypol as a potential small molecule inhibitor of MSI1-RNA interaction, and suggests that inhibition of MSI1's RNA binding activity may be an effective anti-cancer strategy. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer.

PubMed

Brown, Wells S; Tan, Li; Smith, Andrew; Gray, Nathanael S; Wendt, Michael K

2016-09-01

Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096-106. ©2016 AACR. ©2016 American Association for Cancer Research.

Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia.

PubMed

Cho, Jay Y; Guo, Changsheng; Torello, Monica; Lunstrum, Gregory P; Iwata, Tomoko; Deng, Chuxia; Horton, William A

2004-01-13

Mutations of fibroblast growth factor receptor 3 (FGFR3) are responsible for achondroplasia (ACH) and related dwarfing conditions in humans. The pathogenesis involves constitutive activation of FGFR3, which inhibits proliferation and differentiation of growth plate chondrocytes. Here we report that activating mutations in FGFR3 increase the stability of the receptor. Our results suggest that the mutations disrupt c-Cbl-mediated ubiquitination that serves as a targeting signal for lysosomal degradation and termination of receptor signaling. The defect allows diversion of actively signaling receptors from lysosomes to a recycling pathway where their survival is prolonged, and, as a result, their signaling capacity is increased. The lysosomal targeting defect is additive to other mechanisms proposed to explain the pathogenesis of ACH.

The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways.

PubMed

Rengarajan, Thamaraiselvan; Yaacob, Nik Soriani

2016-10-15

Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeted therapies in the treatment of urothelial cancers.

PubMed

Aragon-Ching, Jeanny B; Trump, Donald L

2017-07-01

Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

Reserve growth of the world's giant oil fields

USGS Publications Warehouse

Klett, T.R.; Schmoker, J.W.

2005-01-01

Analysis of estimated total recoverable oil volume (field size) of 186 well-known giant oil fields of the world (>0.5 billion bbl of oil, discovered prior to 1981), exclusive of the United States and Canada, demonstrates general increases in field sizes through time. Field sizes were analyzed as a group and within subgroups of the Organization of Petroleum Exporting Countries (OPEC) and non-OPEC countries. From 1981 through 1996, the estimated volume of oil in the 186 fields for which adequate data were available increased from 617 billion to 777 billion bbl of oil (26%). Processes other than new field discoveries added an estimated 160 billion bbl of oil to known reserves in this subset of the world's oil fields. Although methods for estimating field sizes vary among countries, estimated sizes of the giant oil fields of the world increased, probably for many of the same reasons that estimated sizes of oil fields in the United States increased over the same time period. Estimated volumes in OPEC fields increased from a total of 550 billion to 668 billion bbl of oil and volumes in non-OPEC fields increased from 67 billion to 109 billion bbl of oil. In terms of percent change, non-OPEC field sizes increased more than OPEC field sizes (63% versus 22%). The changes in estimated total recoverable oil volumes that occurred within three 5-year increments between 1981 and 1996 were all positive. Between 1981 and 1986, the increase in estimated total recoverable oil volume within the 186 giant oil fields was 11 billion bbl of oil; between 1986 and 1991, the increase was 120 billion bbl of oil; and between 1991 and 1996, the increase was 29 billion bbl of oil. Fields in both OPEC and non-OPEC countries followed trends of substantial reserve growth.

Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function

PubMed Central

Gonzalez, Eric J.; Merrill, Liana

2014-01-01

Urinary bladder dysfunction presents a major problem in the clinical management of patients suffering from pathological conditions and neurological injuries or disorders. Currently, the etiology underlying altered visceral sensations from the urinary bladder that accompany the chronic pain syndrome, bladder pain syndrome (BPS)/interstitial cystitis (IC), is not known. Bladder irritation and inflammation are histopathological features that may underlie BPS/IC that can change the properties of lower urinary tract sensory pathways (e.g., peripheral and central sensitization, neurochemical plasticity) and contribute to exaggerated responses of peripheral bladder sensory pathways. Among the potential mediators of peripheral nociceptor sensitization and urinary bladder dysfunction are neuroactive compounds (e.g., purinergic and neuropeptide and receptor pathways), sensory transducers (e.g., transient receptor potential channels) and target-derived growth factors (e.g., nerve growth factor). We review studies related to the organization of the afferent limb of the micturition reflex and discuss neuroplasticity in an animal model of urinary bladder inflammation to increase the understanding of functional bladder disorders and to identify potential novel targets for development of therapeutic interventions. Given the heterogeneity of BPS/IC and the lack of consistent treatment benefits, it is unlikely that a single treatment directed at a single target in micturition reflex pathways will have a mass benefit. Thus, the identification of multiple targets is a prudent approach, and use of cocktail treatments directed at multiple targets should be considered. PMID:24760999

miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Xiao; Zhang, Haiping; Lian, Shi

2016-07-01

As an oncogene, aurora kinase A (AURKA) is overexpressed in various types of human cancers. However, the expression and roles of AURKA in malignant melanoma are largely unknown. In this study, a miR-137-AURKA axis was revealed to regulate melanoma growth. We found a significant increase in levels of AURKA in melanoma. Both genetic knockdown and pharmacologic inhibition of AURKA decreased tumor cell growth in vitro and in vivo. Further found that miR-137 reduced AURKA expression through interaction with its 3′ untranslated region (3′UTR) and that miR-137 was negatively correlated with AURKA expression in melanoma specimens. Overexpression of miR-137 decreased cell proliferation andmore » colony formation in vitro. Notably, re-expression of AURKA significantly rescued miR-137-mediated suppression of cell growth and clonality. In summary, these results reveal that miR-137 functions as a tumor suppressor by targeting AURKA, providing new insights into investigation of therapeutic strategies against malignant melanoma. -- Highlights: •First reported overexpression of AURKA in melanoma. •Targeting AURKA inhibits melanoma growth in vitro and in vivo. •Further found miR-137 suppressed cell growth by binding to AURKA 3′UTR. •Re-expression of AURKA rescued miR-137-mediated suppression. •miR-137-AURKA axis may be potential therapeutic targets of melanoma.« less

Targeting of glutamine transporter ASCT2 and glutamine synthetase suppresses gastric cancer cell growth.

PubMed

Ye, Jianxin; Huang, Qiang; Xu, Jie; Huang, Jinsheng; Wang, Jinzhou; Zhong, Wenjing; Chen, Wannan; Lin, Xinjian; Lin, Xu

2018-05-01

Glutamine (Gln) is essential for the proliferation of most cancer cells, making it an appealing target for cancer therapy. However, the role of Gln in gastric cancer (GC) metabolism is unknown and Gln-targeted therapy against GC remains scarce. The aim of this study was to investigate the relevance of Gln in GC growth and targeting. Expression of Gln transporter ASCT2 and glutamine synthetase (GS) in the parental and molecularly engineered GC cells or in human GC specimens was determined by RT-PCR and western blot analysis or immunohistochemistry. Cell proliferation and survival was assessed by CCK-8 assay and colony formation assay. Intracellular Gln content was measured by a HPLC system. Effects of ASCT2 and/or GS inhibitor on tumor growth were investigated in xenograft models. A significant heterogeneity of GC cells was observed with respect to their response to the treatment of ASCT2 inhibitor benzylserine (BenSer). Gln deprivation did not affect the BenSer-resistant cell growth due to endogenous GS expression, whose inhibition remarkably reduced cell proliferation. The differential in vitro sensitivity correlated with overall intracellular Gln content. Combined therapy with both ASCT2 and GS inhibitors produced a greater therapeutic efficacy than the treatment of either inhibitor alone. Furthermore, 77% human GC tissues were found to express moderate and high levels of ASCT2, 12% of which also co-expressed relatively high levels of GS. Gln mediates GC growth and the therapeutic efficacy of Gln-targeted treatment relies on distinct ASCT2 and GS expression pattern in specific gastric cancer groups.

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

PubMed

Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

2017-11-01

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Understanding and Targeting Cell Growth Networks in Breast Cancer

DTIC Science & Technology

2010-04-01

both monitoring and preventing the outbreak of cancer cells. A common target of ARF is the NPM/B23 oncogene, an abundant protein of the nucleolus ...phenotype is dependent on NPM and p68DDX5 expression in the nucleolus , with loss of either capable of completely reversing the phenotype back to...ARF, DDX5, and NPM in the nucleolus of breast epithelial cells and how they impact both ribosome biogenesis and cell growth to prevent and/or promote

Predicting the dynamics of bacterial growth inhibition by ribosome-targeting antibiotics

NASA Astrophysics Data System (ADS)

Greulich, Philip; Doležal, Jakub; Scott, Matthew; Evans, Martin R.; Allen, Rosalind J.

2017-12-01

Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance—yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding (‘low-affinity antibiotic’) or, in contrast, irreversible transport and/or high affinity ribosome binding (‘high-affinity antibiotic’). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance.

Predicting the dynamics of bacterial growth inhibition by ribosome-targeting antibiotics

PubMed Central

Greulich, Philip; Doležal, Jakub; Scott, Matthew; Evans, Martin R; Allen, Rosalind J

2017-01-01

Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance—yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding (‘low-affinity antibiotic’) or, in contrast, irreversible transport and/or high affinity ribosome binding (‘high-affinity antibiotic’). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance. PMID:28714461

Targeting the fibroblast growth factor receptors for the treatment of cancer.

PubMed

Lemieux, Steven M; Hadden, M Kyle

2013-06-01

Receptor tyrosine kinases (RTKs) are transmembrane proteins that play a critical role in stimulating signal transduction cascades to influence cell proliferation, growth, and differentiation and they have also been shown to promote angiogenesis when they are up-regulated or mutated. For this reason, their dysfunction has been implicated in the development of human cancer. Over the past decade, much attention has been devoted to developing inhibitors and antibodies against several classes of RTKs, including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptors (EGFRs), and platelet-derived growth factor receptors (PDGFRs). More recently, interest in the fibroblast growth factor receptor (FGFR) class of RTKs as a drug target for the treatment of cancer has emerged. Signaling through FGFRs is critical for normal cellular function and their dysregulation has been linked to various malignancies such as breast and prostate cancer. This review will focus on the current state of both small molecules and antibodies as FGFR inhibitors to provide insight into their development and future potential as anti-cancer agents.

Evidence for protection of targeted reef fish on the largest marine reserve in the Caribbean

PubMed Central

Pina-Amargós, Fabián; González-Sansón, Gaspar; Martín-Blanco, Félix

2014-01-01

Marine reserves can restore fish abundance and diversity in areas impacted by overfishing, but the effectiveness of reserves in developing countries where resources for enforcement are limited, have seldom been evaluated. Here we assess whether the establishment in 1996 of the largest marine reserve in the Caribbean, Gardens of the Queen in Cuba, has had a positive effect on the abundance of commercially valuable reef fish species in relation to neighboring unprotected areas. We surveyed 25 sites, including two reef habitats (reef crest and reef slope), inside and outside the marine reserve, on five different months, and over a one-and-a-half year period. Densities of the ten most frequent, highly targeted, and relatively large fish species showed a significant variability across the archipelago for both reef habitats that depended on the month of survey. These ten species showed a tendency towards higher abundance inside the reserve in both reef habitats for most months during the study. Average fish densities pooled by protection level, however, showed that five out of these ten species were at least two-fold significantly higher inside than outside the reserve at one or both reef habitats. Supporting evidence from previously published studies in the area indicates that habitat complexity and major benthic communities were similar inside and outside the reserve, while fishing pressure appeared to be homogeneous across the archipelago before reserve establishment. Although poaching may occur within the reserve, especially at the boundaries, effective protection from fishing was the most plausible explanation for the patterns observed. PMID:24688853

Evidence for protection of targeted reef fish on the largest marine reserve in the Caribbean.

PubMed

Pina-Amargós, Fabián; González-Sansón, Gaspar; Martín-Blanco, Félix; Valdivia, Abel

2014-01-01

Marine reserves can restore fish abundance and diversity in areas impacted by overfishing, but the effectiveness of reserves in developing countries where resources for enforcement are limited, have seldom been evaluated. Here we assess whether the establishment in 1996 of the largest marine reserve in the Caribbean, Gardens of the Queen in Cuba, has had a positive effect on the abundance of commercially valuable reef fish species in relation to neighboring unprotected areas. We surveyed 25 sites, including two reef habitats (reef crest and reef slope), inside and outside the marine reserve, on five different months, and over a one-and-a-half year period. Densities of the ten most frequent, highly targeted, and relatively large fish species showed a significant variability across the archipelago for both reef habitats that depended on the month of survey. These ten species showed a tendency towards higher abundance inside the reserve in both reef habitats for most months during the study. Average fish densities pooled by protection level, however, showed that five out of these ten species were at least two-fold significantly higher inside than outside the reserve at one or both reef habitats. Supporting evidence from previously published studies in the area indicates that habitat complexity and major benthic communities were similar inside and outside the reserve, while fishing pressure appeared to be homogeneous across the archipelago before reserve establishment. Although poaching may occur within the reserve, especially at the boundaries, effective protection from fishing was the most plausible explanation for the patterns observed.

Targeting Insulin-Like Growth Factor 1 Receptor Inhibits Pancreatic Cancer Growth and Metastasis

PubMed Central

Subramani, Ramadevi; Lopez-Valdez, Rebecca; Arumugam, Arunkumar; Nandy, Sushmita; Boopalan, Thiyagarajan; Lakshmanaswamy, Rajkumar

2014-01-01

Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer. PMID:24809702

When Is Spillover from Marine Reserves Likely to Benefit Fisheries?

PubMed Central

Buxton, Colin D.; Hartmann, Klaas; Kearney, Robert; Gardner, Caleb

2014-01-01

The net movement of individuals from marine reserves (also known as no-take marine protected areas) to the remaining fishing grounds is known as spillover and is frequently used to promote reserves to fishers on the grounds that it will benefit fisheries. Here we consider how mismanaged a fishery must be before spillover from a reserve is able to provide a net benefit for a fishery. For our model fishery, density of the species being harvested becomes higher in the reserve than in the fished area but the reduction in the density and yield of the fished area was such that the net effect of the closure was negative, except when the fishery was mismanaged. The extent to which effort had to exceed traditional management targets before reserves led to a spillover benefit varied with rates of growth and movement of the model species. In general, for well-managed fisheries, the loss of yield from the use of reserves was less for species with greater movement and slower growth. The spillover benefit became more pronounced with increasing mis-management of the stocks remaining available to the fishery. This model-based result is consistent with the literature of field-based research where a spillover benefit from reserves has only been detected when the fishery is highly depleted, often where traditional fisheries management controls are absent. We conclude that reserves in jurisdictions with well-managed fisheries are unlikely to provide a net spillover benefit. PMID:25188380

When is spillover from marine reserves likely to benefit fisheries?

PubMed

Buxton, Colin D; Hartmann, Klaas; Kearney, Robert; Gardner, Caleb

2014-01-01

The net movement of individuals from marine reserves (also known as no-take marine protected areas) to the remaining fishing grounds is known as spillover and is frequently used to promote reserves to fishers on the grounds that it will benefit fisheries. Here we consider how mismanaged a fishery must be before spillover from a reserve is able to provide a net benefit for a fishery. For our model fishery, density of the species being harvested becomes higher in the reserve than in the fished area but the reduction in the density and yield of the fished area was such that the net effect of the closure was negative, except when the fishery was mismanaged. The extent to which effort had to exceed traditional management targets before reserves led to a spillover benefit varied with rates of growth and movement of the model species. In general, for well-managed fisheries, the loss of yield from the use of reserves was less for species with greater movement and slower growth. The spillover benefit became more pronounced with increasing mis-management of the stocks remaining available to the fishery. This model-based result is consistent with the literature of field-based research where a spillover benefit from reserves has only been detected when the fishery is highly depleted, often where traditional fisheries management controls are absent. We conclude that reserves in jurisdictions with well-managed fisheries are unlikely to provide a net spillover benefit.

Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy.

PubMed

Szlachcic, Anna; Zakrzewska, Malgorzata; Lobocki, Michal; Jakimowicz, Piotr; Otlewski, Jacek

2016-01-01

Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody-drug conjugates. The FGF1V-valine-citrulline-MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V-vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality.

Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy

PubMed Central

Szlachcic, Anna; Zakrzewska, Malgorzata; Lobocki, Michal; Jakimowicz, Piotr; Otlewski, Jacek

2016-01-01

Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality. PMID:27563235

CO2 storage resources, reserves, and reserve growth: Toward a methodology for integrated assessment of the storage capacity of oil and gas reservoirs and saline formations

USGS Publications Warehouse

Burruss, Robert

2009-01-01

Geologically based methodologies to assess the possible volumes of subsurface CO2 storage must apply clear and uniform definitions of resource and reserve concepts to each assessment unit (AU). Application of the current state of knowledge of geologic, hydrologic, geochemical, and geophysical parameters (contingencies) that control storage volume and injectivity allows definition of the contingent resource (CR) of storage. The parameters known with the greatest certainty are based on observations on known traps (KTs) within the AU that produced oil, gas, and water. The aggregate volume of KTs within an AU defines the most conservation volume of contingent resource. Application of the concept of reserve growth to CR volume provides a logical path for subsequent reevaluation of the total resource as knowledge of CO2 storage processes increases during implementation of storage projects. Increased knowledge of storage performance over time will probably allow the volume of the contingent resource of storage to grow over time, although negative growth is possible.

Radionuclide therapy using ¹³¹I-labeled anti-epidermal growth factor receptor-targeted nanoparticles suppresses cancer cell growth caused by EGFR overexpression.

PubMed

Li, Wei; Liu, Zhongyun; Li, Chengxia; Li, Ning; Fang, Lei; Chang, Jin; Tan, Jian

2016-03-01

Anti-epidermal growth factor receptor (EGFR)-targeted nanoparticles can be used to deliver a therapeutic and imaging agent to EGFR-overexpressing tumor cells. (131)I-labeled anti-EGFR nanoparticles derived from cetuximab were used as a tumor-targeting vehicle in radionuclide therapy. This paper describes the construction of the anti-EGFR nanoparticle EGFR-BSA-PCL. This nanoparticle was characterized for EGFR-targeted binding and cellular uptake in EGFR-overexpressing cancer cells by using flow cytometry and confocal microscopy. Anti-EGFR and non-targeted nanoparticles were labeled with (131)I using the chloramine-T method. Analyses of cytotoxicity and targeted cell killing with (131)I were performed using the MTT assay. The time-dependent cellular uptake of (131)I-labeled anti-EGFR nanoparticles proved the slow-release effects of nanoparticles. A radioiodine therapy study was also performed in mice. The EGFR-targeted nanoparticle EGFR-BSA-PCL and the non-targeted nanoparticle BSA-PCL were constructed; the effective diameters were approximately 100 nm. The results from flow cytometry and confocal microscopy revealed significant uptake of EGFR-BSA-PCL in EGFR-overexpressing tumor cells. Compared with EGFR-BSA-PCL, BSA-PCL could also bind to cells, but tumor cell retention was minimal and weak. In MTT assays, the EGFR-targeted radioactive nanoparticle (131)I-EGFR-BSA-PCL showed greater cytotoxicity and targeted cell killing than the non-targeted nanoparticle (131)I-BSA-PCL. The radioiodine uptake of both (131)I-labeled nanoparticles, (131)I-EGFR-BSA-PCL and (131)I-BSA-PCL, was rapid and reached maximal levels 4 h after incubation, but the (131)I uptake of (131)I-EGFR-BSA-PCL was higher than that of (131)I-BSA-PCL. On day 15, the average tumor volumes of the (131)I-EGFR-BSA-PCL and (131)I-BSA-PCL groups showed a slow growth relationship compared with that of the control group. The EGFR-targeted nanoparticle EGFR-BSA-PCL demonstrated superior cellular binding and uptake

Targeting GH-1 splicing as a novel pharmacological strategy for growth hormone deficiency type II.

PubMed

Miletta, Maria Consolata; Flück, Christa E; Mullis, Primus-E

2017-01-15

Isolated growth hormone deficiency type II (IGHD II) is a rare genetic splicing disorder characterized by reduced growth hormone (GH) secretion and short stature. It is mainly caused by autosomal dominant-negative mutations within the growth hormone gene (GH-1) which results in missplicing at the mRNA level and the subsequent loss of exon 3, producing the 17.5-kDa GH isoform: a mutant and inactive GH protein that reduces the stability and the secretion of the 22-kDa GH isoform, the main biologically active GH form. At present, patients suffering from IGHD II are treated with daily injections of recombinant human GH (rhGH) in order to reach normal height. However, this type of replacement therapy, although effective in terms of growth, does not prevent the toxic effects of the 17.5-kDa mutant on the pituitary gland, which may eventually lead to other hormonal deficiencies. As the severity of the disease inversely correlates with the 17.5-kDa/22-kDa ratio, increasing the inclusion of exon 3 is expected to ameliorate disease symptoms. This review focuses on the recent advances in experimental and therapeutic strategies applicable to treat IGHD II in clinical and preclinical contexts. Several avenues for alternative IGHD II therapy will be discussed including the use of small interfering RNA (siRNA) and short hairpin RNA (shRNA) constructs that specifically target the exon 3-deleted transcripts as well as the application of histone deacetylase inhibitors (HDACi) and antisense oligonucleotides (AONs) to enhance full-length GH-1 transcription, correct GH-1 exon 3 splicing and manipulate GH pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis.

PubMed

Lee, Changki; Whang, Young Mi; Campbell, Preston; Mulcrone, Patrick L; Elefteriou, Florent; Cho, Sun Wook; Park, Serk In

2018-02-01

Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NFκB ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis. Insulin-like growth factor-1 (IGF1) also increased RANKL and M-CSF via c-Met transactivation. The conditioned media from IGF1-, HGF-, or VEGFA-treated osteoblasts promoted osteoclastogenesis that was reversed by inhibiting c-Met and/or VEGFR2 in osteoblasts. In vivo experiments used cabozantinib-resistant prostate cancer cells (PC-3 and C4-2B) to test the effects of c-Met/VEGFR2 inhibition specifically in osteoblasts. Cabozantinib (60 mg/kg, 3 weeks) suppressed tumor growth in bone and reduced expression of RANKL and M-CSF and subsequent tumor-induced osteolysis. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduced RANKL and M-CSF expression, and associated with reduction of tumor-induced osteolysis, suggesting that c-Met and VEGFR2 are promising therapeutic targets in bone metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

Targeted inhibition of EG-1 blocks breast tumor growth.

PubMed

Lu, Ming; Sartippour, Maryam R; Zhang, Liping; Norris, Andrew J; Brooks, Mai N

2007-06-01

EG-1 is a gene product that is significantly elevated in human breast cancer tissues. Previously, we have shown that EG-1 overexpression stimulates cellular proliferation both in vitro and in vivo. Here, we ask whether this molecule can be targeted for experimental therapeutic purpose. siRNA lentivirus and polyclonal antibodies were designed to suppress EG-1 expression. These agents were then used in cell culture proliferation assays and breast tumor xenograft models. Serum and urine from breast cancer patients were also analyzed for the presence of EG-1 peptide. We report here for the first time that endogenous EG-1 can be targeted to inhibit breast tumor growth. This inhibition, whether delivered via siRNA lentivirus or polyclonal antibody, resulted in decreased cellular proliferation in culture and smaller xenografts in mice. The effects were shown in both ER (estrogen receptor)-positive human breast cancer MCF-7 cells, as well as in ER-negative MDA-MB-231 cells. Furthermore, we detected soluble EG-1 in serum and urine of breast cancer patients. These observations demonstrate that EG-1 is relevant to human breast cancer, and is a molecular target worthy of translational efforts into effective breast cancer therapy.

Identification of Host-Targeted Small Molecules That Restrict Intracellular Mycobacterium tuberculosis Growth

PubMed Central

Silvis, Melanie R.; Luo, Samantha S.; Sogi, Kimberly; Vokes, Martha; Bray, Mark-Anthony; Carpenter, Anne E.; Moore, Christopher B.; Siddiqi, Noman; Rubin, Eric J.; Hung, Deborah T.

2014-01-01

Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if appropriately activated. The outcome of infection is determined at least in part by the host-pathogen interaction within the macrophage; however, we lack a complete understanding of which host pathways are critical for bacterial survival and replication. To add to our understanding of the molecular processes involved in intracellular infection, we performed a chemical screen using a high-content microscopic assay to identify small molecules that restrict mycobacterial growth in macrophages by targeting host functions and pathways. The identified host-targeted inhibitors restrict bacterial growth exclusively in the context of macrophage infection and predominantly fall into five categories: G-protein coupled receptor modulators, ion channel inhibitors, membrane transport proteins, anti-inflammatories, and kinase modulators. We found that fluoxetine, a selective serotonin reuptake inhibitor, enhances secretion of pro-inflammatory cytokine TNF-α and induces autophagy in infected macrophages, and gefitinib, an inhibitor of the Epidermal Growth Factor Receptor (EGFR), also activates autophagy and restricts growth. We demonstrate that during infection signaling through EGFR activates a p38 MAPK signaling pathway that prevents macrophages from effectively responding to infection. Inhibition of this pathway using gefitinib during in vivo infection reduces growth of M. tuberculosis in the lungs of infected mice. Our results support the concept that screening for inhibitors using intracellular models results in the identification of tool compounds for probing pathways during in vivo infection and may also result in the identification of new anti-tuberculosis agents that work by

The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases?

PubMed

Garcia-Huerta, Paula; Troncoso-Escudero, Paulina; Jerez, Carolina; Hetz, Claudio; Vidal, Rene L

2016-10-15

One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

Insulin-Like Growth Factor System in Cancer: Novel Targeted Therapies

PubMed Central

Brahmkhatri, Varsha P.; Prasanna, Chinmayi; Atreya, Hanudatta S.

2015-01-01

Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies. PMID:25866791

Significant reduction in energy for plant-growth lighting in space using targeted LED lighting and spectral manipulation

NASA Astrophysics Data System (ADS)

Poulet, L.; Massa, G. D.; Morrow, R. C.; Bourget, C. M.; Wheeler, R. M.; Mitchell, C. A.

2014-07-01

Bioregenerative life-support systems involving photoautotrophic organisms will be necessary to sustain long-duration crewed missions at distant space destinations. Since sufficient sunlight will not always be available for plant growth at many space destinations, efficient electric-lighting solutions are greatly needed. The present study demonstrated that targeted plant lighting with light-emitting diodes (LEDs) and optimizing spectral parameters for close-canopy overhead LED lighting allowed the model crop leaf lettuce (Lactuca sativa L. cv. 'Waldmann's Green') to be grown using significantly less electrical energy than using traditional electric-lighting sources. Lettuce stands were grown hydroponically in a growth chamber controlling temperature, relative humidity, and CO2 level. Several red:blue ratios were tested for growth rate during the lag phase of lettuce growth. In addition, start of the exponential growth phase was evaluated. Following establishment of a 95% red + 5% blue spectral balance giving the best growth response, the energy efficiency of a targeted lighting system was compared with that of two total coverage (untargeted) LED lighting systems throughout a crop-production cycle, one using the same proportion of red and blue LEDs and the other using white LEDs. At the end of each cropping cycle, whole-plant fresh and dry mass and leaf area were measured and correlated with the amount of electrical energy (kWh) consumed for crop lighting. Lettuce crops grown with targeted red + blue LED lighting used 50% less energy per unit dry biomass accumulated, and the total coverage white LEDs used 32% less energy per unit dry biomass accumulated than did the total coverage red + blue LEDs. An energy-conversion efficiency of less than 1 kWh/g dry biomass is possible using targeted close-canopy LED lighting with spectral optimization. This project was supported by NASA grant NNX09AL99G.

Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer.

PubMed

Philip, Philip A; Lutz, Manfred P

2015-10-01

Pancreatic cancer is aggressive, chemoresistant, and characterized by complex and poorly understood molecular biology. The epidermal growth factor receptor (EGFR) pathway is frequently activated in pancreatic cancer; therefore, it is a rational target for new treatments. However, the EGFR tyrosine kinase inhibitor erlotinib is currently the only targeted therapy to demonstrate a very modest survival benefit when added to gemcitabine in the treatment of patients with advanced pancreatic cancer. There is no molecular biomarker to predict the outcome of erlotinib treatment, although rash may be predictive of improved survival; EGFR expression does not predict the biologic activity of anti-EGFR drugs in pancreatic cancer, and no EGFR mutations are identified as enabling the selection of patients likely to benefit from treatment. Here, we review clinical studies of EGFR-targeted therapies in combination with conventional cytotoxic regimens or multitargeted strategies in advanced pancreatic cancer, as well as research directed at molecules downstream of EGFR as alternatives or adjuncts to receptor targeting. Limitations of preclinical models, patient selection, and trial design, as well as the complex mechanisms underlying resistance to EGFR-targeted agents, are discussed. Future clinical trials must incorporate translational research end points to aid patient selection and circumvent resistance to EGFR inhibitors.

Cu-Chitosan Nanoparticle Mediated Sustainable Approach To Enhance Seedling Growth in Maize by Mobilizing Reserved Food.

PubMed

Saharan, Vinod; Kumaraswamy, R V; Choudhary, Ram Chandra; Kumari, Sarita; Pal, Ajay; Raliya, Ramesh; Biswas, Pratim

2016-08-10

Food crop seedlings often have susceptibility to various abiotic and biotic stresses. Therefore, in the present study, we investigated the impact of Cu-chitosan nanoparticles (NPs) on physiological and biochemical changes during maize seedling growth. Higher values of percent germination, shoot and root length, root number, seedling length, fresh and dry weight, and seed vigor index were obtained at 0.04-0.12% concentrations of Cu-chitosan NPs as compared to water, CuSO4, and bulk chitosan treatments. Cu-chitosan NPs at the same concentrations induced the activities of α-amylase and protease enzymes and also increased the total protein content in germinating seeds. The increased activities of α-amylase and protease enzymes corroborated with decreased content of starch and protein, respectively, in the germinating seeds. Cu-chitosan NPs at 0.16% and CuSO4 at 0.01% concentrations showed inhibitory effect on seedling growth. The observed results on seedling growth could be explained by the toxicity of excess Cu and growth promotory effect of Cu-chitosan NPs. Physiological and biochemical studies suggest that Cu-chitosan NPs enhance the seedling growth of maize by mobilizing the reserved food, primarily starch, through the higher activity of α-amylase.

Genome-scale reconstruction of the Streptococcus pyogenes M49 metabolic network reveals growth requirements and indicates potential drug targets.

PubMed

Levering, Jennifer; Fiedler, Tomas; Sieg, Antje; van Grinsven, Koen W A; Hering, Silvio; Veith, Nadine; Olivier, Brett G; Klett, Lara; Hugenholtz, Jeroen; Teusink, Bas; Kreikemeyer, Bernd; Kummer, Ursula

2016-08-20

Genome-scale metabolic models comprise stoichiometric relations between metabolites, as well as associations between genes and metabolic reactions and facilitate the analysis of metabolism. We computationally reconstructed the metabolic network of the lactic acid bacterium Streptococcus pyogenes M49. Initially, we based the reconstruction on genome annotations and already existing and curated metabolic networks of Bacillus subtilis, Escherichia coli, Lactobacillus plantarum and Lactococcus lactis. This initial draft was manually curated with the final reconstruction accounting for 480 genes associated with 576 reactions and 558 metabolites. In order to constrain the model further, we performed growth experiments of wild type and arcA deletion strains of S. pyogenes M49 in a chemically defined medium and calculated nutrient uptake and production fluxes. We additionally performed amino acid auxotrophy experiments to test the consistency of the model. The established genome-scale model can be used to understand the growth requirements of the human pathogen S. pyogenes and define optimal and suboptimal conditions, but also to describe differences and similarities between S. pyogenes and related lactic acid bacteria such as L. lactis in order to find strategies to reduce the growth of the pathogen and propose drug targets. Copyright © 2016 Elsevier B.V. All rights reserved.

Marine reserves: fish life history and ecological traits matter.

PubMed

Claudet, J; Osenberg, C W; Domenici, P; Badalamenti, F; Milazzo, M; Falcón, J M; Bertocci, I; Benedetti-Cecchi, L; García-Charton, J A; Goñi, R; Borg, J A; Forcada, A; De Lucia, G A; Perez-Ruzafa, A; Afonso, P; Brito, A; Guala, I; Le Diréach, L; Sanchez-Jerez, P; Somerfield, P J; Planes, S

2010-04-01

Marine reserves are assumed to protect a wide range of species from deleterious effects stemming from exploitation. However, some species, due to their ecological characteristics, may not respond positively to protection. Very little is known about the effects of life history and ecological traits (e.g., mobility, growth, and habitat) on responses of fish species to marine reserves. Using 40 data sets from 12 European marine reserves, we show that there is significant variation in the response of different species of fish to protection and that this heterogeneity can be explained, in part, by differences in their traits. Densities of targeted size-classes of commercial species were greater in protected than unprotected areas. This effect of protection increased as the maximum body size of the targeted species increased, and it was greater for species that were not obligate schoolers. However, contrary to previous theoretical findings, even mobile species with wide home ranges benefited from protection: the effect of protection was at least as strong for mobile species as it was for sedentary ones. Noncommercial bycatch and unexploited species rarely responded to protection, and when they did (in the case of unexploited bentho-pelagic species), they exhibited the opposite response: their densities were lower inside reserves. The use of marine reserves for marine conservation and fisheries management implies that they should ensure protection for a wide range of species with different life-history and ecological traits. Our results suggest this is not the case, and instead that effects vary with economic value, body size, habitat, depth range, and schooling behavior.

A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment

PubMed Central

Nör, Jacques Eduardo

2018-01-01

Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth. PMID:29351275

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation.

PubMed

Unkelbach, Jan; Menze, Bjoern H; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A

2014-02-07

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

NASA Astrophysics Data System (ADS)

Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A.

2014-02-01

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Targeting mutant fibroblast growth factor receptors in cancer.

PubMed

Greulich, Heidi; Pollock, Pamela M

2011-05-01

Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutations has been associated with human cancers. Many of these somatic mutations are gain-of-function and oncogenic and create dependencies in tumor cell lines harboring such mutations. A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti-FGFR activity and a new generation of specific pan-FGFR inhibitors. Copyright © 2011. Published by Elsevier Ltd.

MicroRNA-510 promotes cell and tumor growth by targeting peroxiredoxin1 in breast cancer

PubMed Central

2013-01-01

Introduction MicroRNAs are small non-coding RNAs that are involved in the post-transcriptional negative regulation of mRNAs. MicroRNA 510 (miR-510) was initially shown to have a potential oncogenic role in breast cancer by the observation of its elevated levels in human breast tumor samples when compared to matched non-tumor samples. Few targets have been identified for miR-510. However, as microRNAs function through the negative regulation of their direct targets, the identification of those targets is critical for the understanding of their functional role in breast cancer. Methods Breast cancer cell lines were transfected with pre-miR-510 or antisense miR-510 and western blotting and quantitative real time PCR were performed. Functional assays performed included cell growth, migration, invasion, colony formation, cytotoxicity and in vivo tumor growth. We performed a PCR assay to identify novel direct targets of miR-510. The study focused on peroxiredoxin 1 (PRDX1) as it was identified through our screen and was bioinformatically predicted to contain a miR-510 seed site in its 3' untranslated region (3'UTR). Luciferase reporter assays and site-directed mutagenesis were performed to confirm PRDX1 as a direct target. The Student's two-sided, paired t-test was used and a P-value less than 0.05 was considered significant. Results We show that miR-510 overexpression in non-transformed and breast cancer cells can increase their cell growth, migration, invasion and colony formation in vitro. We also observed increased tumor growth when miR-510 was overexpressed in vivo. We identified PRDX1 through a novel PCR screen and confirmed it as a direct target using luciferase reporter assays. The reintroduction of PRDX1 into breast cancer cell lines without its regulatory 3'UTR confirmed that miR-510 was mediating its migratory phenotype at least in part through the negative regulation of PRDX1. Furthermore, the PI3K/Akt pathway was identified as a positive regulator of miR-510

MicroRNA-510 promotes cell and tumor growth by targeting peroxiredoxin1 in breast cancer.

PubMed

Guo, Qi J; Mills, Jamie N; Bandurraga, Savannah G; Nogueira, Lourdes M; Mason, Natalie J; Camp, E Ramsay; Larue, Amanda C; Turner, David P; Findlay, Victoria J

2013-01-01

MicroRNAs are small non-coding RNAs that are involved in the post-transcriptional negative regulation of mRNAs. MicroRNA 510 (miR-510) was initially shown to have a potential oncogenic role in breast cancer by the observation of its elevated levels in human breast tumor samples when compared to matched non-tumor samples. Few targets have been identified for miR-510. However, as microRNAs function through the negative regulation of their direct targets, the identification of those targets is critical for the understanding of their functional role in breast cancer. Breast cancer cell lines were transfected with pre-miR-510 or antisense miR-510 and western blotting and quantitative real time PCR were performed. Functional assays performed included cell growth, migration, invasion, colony formation, cytotoxicity and in vivo tumor growth. We performed a PCR assay to identify novel direct targets of miR-510. The study focused on peroxiredoxin 1 (PRDX1) as it was identified through our screen and was bioinformatically predicted to contain a miR-510 seed site in its 3' untranslated region (3'UTR). Luciferase reporter assays and site-directed mutagenesis were performed to confirm PRDX1 as a direct target. The Student's two-sided, paired t-test was used and a P-value less than 0.05 was considered significant. We show that miR-510 overexpression in non-transformed and breast cancer cells can increase their cell growth, migration, invasion and colony formation in vitro. We also observed increased tumor growth when miR-510 was overexpressed in vivo. We identified PRDX1 through a novel PCR screen and confirmed it as a direct target using luciferase reporter assays. The reintroduction of PRDX1 into breast cancer cell lines without its regulatory 3'UTR confirmed that miR-510 was mediating its migratory phenotype at least in part through the negative regulation of PRDX1. Furthermore, the PI3K/Akt pathway was identified as a positive regulator of miR-510 both in vitro and in vivo

Epidermal Growth Factor Receptor targeting in non-small cell lung cancer: revisiting different strategies against the same target.

PubMed

Castañón, Eduardo; Martín, Patricia; Rolfo, Christian; Fusco, Juan P; Ceniceros, Lucía; Legaspi, Jairo; Santisteban, Marta; Gil-Bazo, Ignacio

2014-01-01

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the paradigm of treatment in non-small cell lung cancer (NSCLC). The molecular biology study of EGFR has led to clinical trials that select patients more accurately, regarding the presence of EGFR activating mutations. Nonetheless, a lack of response or a temporary condition of the response has been detected in patients on EGFR TKIs. This has urged to study potential resistance mechanisms underneath. The most important ones are the presence of secondary mutations in EGFR, such as T790M, or the overexpression of mesenchymal-epithelial transition factor (MET) that may explain why patients who initially respond to EGFR TKIs, may ultimately become refractory. Several approaches have been taken and new drugs both targeting EGFR resistance-mutation or MET are currently being developed. Here we review and update the EGFR biological pathway as well as the clinical data leading to approval of the EGFR TKIs currently in the market. New compounds under investigation targeting resistance mutations or dually targeting EGFR and other relevant receptors are also reviewed and discussed.

Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

PubMed

Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

2012-07-15

Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

Phthalocyanine-Peptide Conjugates for Epidermal Growth Factor Receptor Targeting1

PubMed Central

Ongarora, Benson G.; Fontenot, Krystal R.; Hu, Xiaoke; Sehgal, Inder; Satyanarayana-Jois, Seetharama D.; Vicente, M. Graça H.

2012-01-01

Four phthalocyanine (Pc)-peptide conjugates designed to target the epidermal growth factor receptor (EGFR) were synthesized and evaluated in vitro using four cell lines: human carcinoma A431 and HEp2, human colorectal HT-29, and kidney Vero (negative control) cells. Two peptide ligands for EGFR were investigated: EGFR-L1 and -L2, bearing 6 and 13 amino acid residues, respectively. The peptides and Pc-conjugates were shown to bind to EGFR using both theoretical (Autodock) and experimental (SPR) investigations. The Pc-EGFR-L1 conjugates 5a and 5b efficiently targeted EGFR and were internalized, in part due to their cationic charge, whereas the uncharged Pc-EGFR-L2 conjugates 4b and 6a poorly targeted EGFR maybe due to their low aqueous solubility. All conjugates were non-toxic (IC50 > 100 µM) to HT-29 cells, both in the dark and upon light activation (1 J/cm2). Intravenous (iv) administration of conjugate 5b into nude mice bearing A431 and HT-29 human tumor xenografts resulted in a near-IR fluorescence signal at ca. 700 nm, 24 h after administration. Our studies show that Pc-EGFR-L1 conjugates are promising near-IR fluorescent contrast agents for CRC, and potentially other EGFR over-expressing cancers. PMID:22468711

Prediction of pilot reserve attention capacity during air-to-air target tracking

NASA Technical Reports Server (NTRS)

Onstott, E. D.; Faulkner, W. H.

1977-01-01

Reserve attention capacity of a pilot was calculated using a pilot model that allocates exclusive model attention according to the ranking of task urgency functions whose variables are tracking error and error rate. The modeled task consisted of tracking a maneuvering target aircraft both vertically and horizontally, and when possible, performing a diverting side task which was simulated by the precise positioning of an electrical stylus and modeled as a task of constant urgency in the attention allocation algorithm. The urgency of the single loop vertical task is simply the magnitude of the vertical tracking error, while the multiloop horizontal task requires a nonlinear urgency measure of error and error rate terms. Comparison of model results with flight simulation data verified the computed model statistics of tracking error of both axes, lateral and longitudinal stick amplitude and rate, and side task episodes. Full data for the simulation tracking statistics as well as the explicit equations and structure of the urgency function multiaxis pilot model are presented.

Epidermal growth factor receptor-targeted lipid nanoparticles retain self-assembled nanostructures and provide high specificity

NASA Astrophysics Data System (ADS)

Zhai, Jiali; Scoble, Judith A.; Li, Nan; Lovrecz, George; Waddington, Lynne J.; Tran, Nhiem; Muir, Benjamin W.; Coia, Gregory; Kirby, Nigel; Drummond, Calum J.; Mulet, Xavier

2015-02-01

Next generation drug delivery utilising nanoparticles incorporates active targeting to specific sites. In this work, we combined targeting with the inherent advantages of self-assembled lipid nanoparticles containing internal nano-structures. Epidermal growth factor receptor (EGFR)-targeting, PEGylated lipid nanoparticles using phytantriol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-maleimide amphiphiles were created. The self-assembled lipid nanoparticles presented here have internal lyotropic liquid crystalline nano-structures, verified by synchrotron small angle X-ray scattering and cryo-transmission electron microscopy, that offer the potential of high drug loading and enhanced cell penetration. Anti-EGFR Fab' fragments were conjugated to the surface of nanoparticles via a maleimide-thiol reaction at a high conjugation efficiency and retained specificity following conjugation to the nanoparticles. The conjugated nanoparticles were demonstrated to have high affinity for an EGFR target in a ligand binding assay.Next generation drug delivery utilising nanoparticles incorporates active targeting to specific sites. In this work, we combined targeting with the inherent advantages of self-assembled lipid nanoparticles containing internal nano-structures. Epidermal growth factor receptor (EGFR)-targeting, PEGylated lipid nanoparticles using phytantriol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-maleimide amphiphiles were created. The self-assembled lipid nanoparticles presented here have internal lyotropic liquid crystalline nano-structures, verified by synchrotron small angle X-ray scattering and cryo-transmission electron microscopy, that offer the potential of high drug loading and enhanced cell penetration. Anti-EGFR Fab' fragments were conjugated to the surface of nanoparticles via a maleimide-thiol reaction at a high conjugation efficiency and retained specificity following conjugation to the nanoparticles. The conjugated nanoparticles

Particulate reduction in ternary-compound film growth via pulsed laser deposition from segmented binary-targets

NASA Astrophysics Data System (ADS)

Grant-Jacob, James A.; Prentice, Jake J.; Beecher, Stephen J.; Shepherd, David P.; Eason, Robert W.; Mackenzie, Jacob I.

2018-03-01

We present the hetero-epitaxial growth of high-quality crystalline Y3Ga5O12 onto a 〈100〉-oriented YAG substrate via pulsed laser deposition, using mixed ternary-compound and segmented binary-compound targets. We observe that a Y3Ga5O12 film fabricated using a segmented target (Y2O3/Ga2O3) contained ∼100 times fewer scattering points than a film grown using a mixed Y3Ga5O12 target. We show that following ablation, the surface of the mixed compound (ternary) target had laser-induced cone structures, whereas the surface of single compound (binary) targets did not. It is concluded that the different ablation dynamics of the oxide constituents in the respective targets plays a significant role in the origin of the scattering points in the resultant films.

Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.

PubMed

Yang, Guang-Wei; Jiang, Jin-Song; Lu, Wei-Qin

2015-10-12

Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.

One-week 96-well soft agar growth assay for cancer target validation.

PubMed

Ke, Ning; Albers, Aaron; Claassen, Gisela; Yu, De-hua; Chatterton, Jon E; Hu, Xiuyuan; Meyhack, Bernd; Wong-Staal, Flossie; Li, Qi-Xiang

2004-05-01

Soft agar growth, used to measure cell anchorage-independent proliferation potential, is one of the most important and most commonly used assays to detect cell transformation. However, the traditional soft agar assay is time-consuming, labor-intensive, and plagued with inconsistencies due to individual subjectivity. It does not, therefore, meet the increasing demands of today's oncology drug target screening or validation processes. This report describes an alternative 96-well soft agar growth assay that can function as a replacement for the traditional method and overcomes the aforementioned limitations. It offers the following advantages: a shortened assay duration (1 week instead of 4 weeks) that makes transient transfection or treatment possible; plate reader quantification of soft agar growth (measuring cloning efficiency and colony size); and a significant reduction in required labor. Higher throughput also makes it possible to process large numbers of samples and treatments simultaneously and in a much more efficient manner, while saving precious workspace and overall cost.

The EML4-ALK oncogene: targeting an essential growth driver in human cancer.

PubMed

Mano, Hiroyuki

2015-01-01

Targeting of essential growth drivers represents an ideal approach to cancer treatment. To identify such molecules in clinical specimens, we developed a highly sensitive functional screening system based on the preparation of retroviral cDNA expression libraries. By screening such a library of lung adenocarcinoma with a focus formation assay, we discovered the EML4-ALK fusion-type oncogene. A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for EML4-ALK-positive lung cancer, three of which (crizotinib, ceritinib, and alectinib) have already been approved for clinical use. An overall clinical response rate of 93.5% for alectinib has shown that agents that target essential growth drivers can become magic bullets for cancer treatment.

The EML4-ALK oncogene: targeting an essential growth driver in human cancer

PubMed Central

MANO, Hiroyuki

2015-01-01

Targeting of essential growth drivers represents an ideal approach to cancer treatment. To identify such molecules in clinical specimens, we developed a highly sensitive functional screening system based on the preparation of retroviral cDNA expression libraries. By screening such a library of lung adenocarcinoma with a focus formation assay, we discovered the EML4-ALK fusion-type oncogene. A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for EML4-ALK–positive lung cancer, three of which (crizotinib, ceritinib, and alectinib) have already been approved for clinical use. An overall clinical response rate of 93.5% for alectinib has shown that agents that target essential growth drivers can become magic bullets for cancer treatment. PMID:25971657

Seed reserve composition in 19 tree species of a tropical deciduous forest in Mexico and its relationship to seed germination and seedling growth

PubMed Central

Soriano, Diana; Orozco-Segovia, Alma; Márquez-Guzmán, Judith; Kitajima, Kaoru; Gamboa-de Buen, Alicia; Huante, Pilar

2011-01-01

Background and Aims The size and composition of seed reserves may reflect the ecological strategy and evolutionary history of a species and also temporal variation in resource availability. The seed mass and composition of seed reserves of 19 co-existing tree species were studied, and we examined how they varied among species in relation to germination and seedling growth rates, as well as between two years with contrasting precipitation (652 and 384 mm). Methods Seeds were collected from a tropical deciduous forest in the northwest of Mexico (Chamela Biological Station). The seed dry mass, with and without the seed coat, and the concentrations of lipids, nitrogen and non-structural carbohydrates for the seed minus seed coat were determined. The anatomical localization of these reserves was examined using histochemical analysis. The germination capacity, rate and lag time were determined. The correlations among these variables, and their relationship to previously reported seedling relative growth rates, were evaluated with and without phylogenetic consideration. Key Results There were interannual differences in seed mass and reserve composition. Seed was significantly heavier after the drier year in five species. Nitrogen concentration was positively correlated with seed coat fraction, and was significantly higher after the drier year in 12 species. The rate and lag time of germination were negatively correlated with each other. These trait correlations were also supported for phylogenetic independent contrasts. Principal component analysis supported these correlations, and indicated a negative association of seedling relative growth rate with seed size, and a positive association of germination rate with nitrogen and lipid concentrations. Conclusions Nitrogen concentration tended to be higher after the drier year and, while interannual variations in seed size and reserve composition were not sufficient to affect interspecific correlations among seed and seedling

Gene Targets in Prostate Tumor Cells that Mediate Aberrant Growth and Invasiveness

DTIC Science & Technology

2005-02-01

Craig A. Hauser , Ph.D. Gabriele Foos, Ph.D. CONTRACTING ORGANIZATION: The Burnham Institute La Jolla, California 92037 REPORT DATE: February 2005 TYPE...NUMBERS Gene Targets in Prostate Tumor Cells that Mediate DAMD17-02-1-0019 Aberrant Growth and Invasiveness 6. AUTHOR(S) Craig A. Hauser , Ph.D. Gabriele...REPORTABLE OUTCOMES Foos G, Hauser CA (2004) The role of Ets transcription factors in mediating cellular transformation. In: Handbook of Experimental

Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase

PubMed Central

Gao, Suyu; Cheng, Li; Hao, Bin; Li, Jiacheng; Chen, Yao; Hou, Xuemei; Chen, Lixia; Li, Hua

2017-01-01

T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole. Results of an in vivo study demonstrated that gavage of ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after ilaprazole treatment. Our results suggested that ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo. PMID:28388576

Target of rapamycin signaling orchestrates growth-defense trade-offs in plants.

PubMed

De Vleesschauwer, David; Filipe, Osvaldo; Hoffman, Gena; Seifi, Hamed Soren; Haeck, Ashley; Canlas, Patrick; Van Bockhaven, Jonas; De Waele, Evelien; Demeestere, Kristof; Ronald, Pamela; Hofte, Monica

2018-01-01

Plant defense to microbial pathogens is often accompanied by significant growth inhibition. How plants merge immune system function with normal growth and development is still poorly understood. Here, we investigated the role of target of rapamycin (TOR), an evolutionary conserved serine/threonine kinase, in the plant defense response. We used rice as a model system and applied a combination of chemical, genetic, genomic and cell-based analyses. We demonstrate that ectopic expression of TOR and Raptor (regulatory-associated protein of mTOR), a protein previously demonstrated to interact with TOR in Arabidopsis, positively regulates growth and development in rice. Transcriptome analysis of rice cells treated with the TOR-specific inhibitor rapamycin revealed that TOR not only dictates transcriptional reprogramming of extensive gene sets involved in central and secondary metabolism, cell cycle and transcription, but also suppresses many defense-related genes. TOR overexpression lines displayed increased susceptibility to both bacterial and fungal pathogens, whereas plants with reduced TOR signaling displayed enhanced resistance. Finally, we found that TOR antagonizes the action of the classic defense hormones salicylic acid and jasmonic acid. Together, these results indicate that TOR acts as a molecular switch for the activation of cell proliferation and plant growth at the expense of cellular immunity. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Survival, growth, and target canker infection of black walnut families 15 years after establishment in West Virginia

Treesearch

Thomas M. Schuler; Thomas M. Schuler

1993-01-01

The survival, growth, and rate of target canker infection of 34 black walnut (Juglans nigra L.) families were evaluated 15 years after establishment in north-central West Virginia. The progenies originated at locations in Pennsylvania, West Virginia, Tennessee, and North Carolina. There were significant differences between families in survival, incidence of target...

Developing a novel therapeutic strategy targeting Kallikrein-4 to inhibit prostate cancer growth and metastasis

DTIC Science & Technology

Kallikrein-related peptidase 4 (KLK4) is a rational therapeutic target for prostate cancer (PCa) as it is up-regulated in both localised and bone ...in PCa homing to bone . We therefore hypothesize that blockade of KLK4 activity will inhibit PCa growth and prevent metastasis to secondary sites like... bone . This project aims to develop a novel therapeutic strategy targeting KLK4 specifically in PCa. KLK4 siRNA is incorporated into a novel polymeric

Forest structure, stand composition, and climate-growth response in montane forests of Jiuzhaigou National Nature Reserve, China.

PubMed

Schwartz, Mark W; Dolanc, Christopher R; Gao, Hui; Strauss, Sharon Y; Schwartz, Ari C; Williams, John N; Tang, Ya

2013-01-01

Montane forests of western China provide an opportunity to establish baseline studies for climate change. The region is being impacted by climate change, air pollution, and significant human impacts from tourism. We analyzed forest stand structure and climate-growth relationships from Jiuzhaigou National Nature Reserve in northwestern Sichuan province, along the eastern edge of the Tibetan plateau. We conducted a survey to characterize forest stand diversity and structure in plots occurring between 2050 and 3350 m in elevation. We also evaluated seedling and sapling recruitment and tree-ring data from four conifer species to assess: 1) whether the forest appears in transition toward increased hardwood composition; 2) if conifers appear stressed by recent climate change relative to hardwoods; and 3) how growth of four dominant species responds to recent climate. Our study is complicated by clear evidence of 20(th) century timber extraction. Focusing on regions lacking evidence of logging, we found a diverse suite of conifers (Pinus, Abies, Juniperus, Picea, and Larix) strongly dominate the forest overstory. We found population size structures for most conifer tree species to be consistent with self-replacement and not providing evidence of shifting composition toward hardwoods. Climate-growth analyses indicate increased growth with cool temperatures in summer and fall. Warmer temperatures during the growing season could negatively impact conifer growth, indicating possible seasonal climate water deficit as a constraint on growth. In contrast, however, we found little relationship to seasonal precipitation. Projected warming does not yet have a discernible signal on trends in tree growth rates, but slower growth with warmer growing season climates suggests reduced potential future forest growth.

Forest Structure, Stand Composition, and Climate-Growth Response in Montane Forests of Jiuzhaigou National Nature Reserve, China

PubMed Central

Schwartz, Mark W.; Dolanc, Christopher R.; Gao, Hui; Strauss, Sharon Y.; Schwartz, Ari C.; Williams, John N.; Tang, Ya

2013-01-01

Montane forests of western China provide an opportunity to establish baseline studies for climate change. The region is being impacted by climate change, air pollution, and significant human impacts from tourism. We analyzed forest stand structure and climate-growth relationships from Jiuzhaigou National Nature Reserve in northwestern Sichuan province, along the eastern edge of the Tibetan plateau. We conducted a survey to characterize forest stand diversity and structure in plots occurring between 2050 and 3350 m in elevation. We also evaluated seedling and sapling recruitment and tree-ring data from four conifer species to assess: 1) whether the forest appears in transition toward increased hardwood composition; 2) if conifers appear stressed by recent climate change relative to hardwoods; and 3) how growth of four dominant species responds to recent climate. Our study is complicated by clear evidence of 20th century timber extraction. Focusing on regions lacking evidence of logging, we found a diverse suite of conifers (Pinus, Abies, Juniperus, Picea, and Larix) strongly dominate the forest overstory. We found population size structures for most conifer tree species to be consistent with self-replacement and not providing evidence of shifting composition toward hardwoods. Climate-growth analyses indicate increased growth with cool temperatures in summer and fall. Warmer temperatures during the growing season could negatively impact conifer growth, indicating possible seasonal climate water deficit as a constraint on growth. In contrast, however, we found little relationship to seasonal precipitation. Projected warming does not yet have a discernible signal on trends in tree growth rates, but slower growth with warmer growing season climates suggests reduced potential future forest growth. PMID:23951188

Targeting the tumour microenvironment in ovarian cancer.

PubMed

Hansen, Jean M; Coleman, Robert L; Sood, Anil K

2016-03-01

The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers.

PubMed

Song, W; Hwang, Y; Youngblood, V M; Cook, R S; Balko, J M; Chen, J; Brantley-Sieders, D M

2017-10-05

Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.

Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers

PubMed Central

Song, W; Hwang, Y; Youngblood, V M; Cook, R S; Balko, J M; Chen, J; Brantley-Sieders, D M

2017-01-01

Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC. PMID:28581527

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer.

PubMed

Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T

2017-04-01

Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.

Accounting for system dynamics in reserve design.

PubMed

Leroux, Shawn J; Schmiegelow, Fiona K A; Cumming, Steve G; Lessard, Robert B; Nagy, John

2007-10-01

Systematic conservation plans have only recently considered the dynamic nature of ecosystems. Methods have been developed to incorporate climate change, population dynamics, and uncertainty in reserve design, but few studies have examined how to account for natural disturbance. Considering natural disturbance in reserve design may be especially important for the world's remaining intact areas, which still experience active natural disturbance regimes. We developed a spatially explicit, dynamic simulation model, CONSERV, which simulates patch dynamics and fire, and used it to evaluate the efficacy of hypothetical reserve networks in northern Canada. We designed six networks based on conventional reserve design methods, with different conservation targets for woodland caribou habitat, high-quality wetlands, vegetation, water bodies, and relative connectedness. We input the six reserve networks into CONSERV and tracked the ability of each to maintain initial conservation targets through time under an active natural disturbance regime. None of the reserve networks maintained all initial targets, and some over-represented certain features, suggesting that both effectiveness and efficiency of reserve design could be improved through use of spatially explicit dynamic simulation during the planning process. Spatial simulation models of landscape dynamics are commonly used in natural resource management, but we provide the first illustration of their potential use for reserve design. Spatial simulation models could be used iteratively to evaluate competing reserve designs and select targets that have a higher likelihood of being maintained through time. Such models could be combined with dynamic planning techniques to develop a general theory for reserve design in an uncertain world.

Epidermal growth factor targeting of bacteriophage to the choroid plexus for gene delivery to the central nervous system via cerebrospinal fluid.

PubMed

Gonzalez, Ana Maria; Leadbeater, Wendy; Podvin, Sonia; Borboa, Alexandra; Burg, Michael; Sawada, Ritsuko; Rayner, James; Sims, Karen; Terasaki, Tetsuya; Johanson, Conrad; Stopa, Edward; Eliceiri, Brian; Baird, Andrew

2010-11-04

Because the choroid plexus normally controls the production and composition of cerebrospinal fluid and, as such, its many functions of the central nervous system, we investigated whether ligand-mediated targeting could deliver genes to its secretory epithelium. We show here that when bacteriophages are targeted with epidermal growth factor, they acquire the ability to enter choroid epithelial cells grown in vitro as cell cultures, ex vivo as tissue explants or in vivo by intracerebroventricular injection. The binding and internalization of these particles activate EGF receptors on targeted cells, and the dose- and time-dependent internalization of particles is inhibited by the presence of excess ligand. When the phage genome is further reengineered to contain like green fluorescent protein or firefly luciferase under control of the cytomegalovirus promoter, gene expression is detectable in the choroid plexus and ependymal epithelium by immunohistochemistry or by noninvasive imaging, respectively. Taken together, these data support the hypothesis that reengineered ligand-mediated gene delivery should be considered a viable strategy to increase the specificity of gene delivery to the central nervous system and bypass the blood-brain barrier so as to exploit the biological effectiveness of the choroid plexus as a portal of entry into the brain. Copyright © 2010 Elsevier B.V. All rights reserved.

miRNA-497 Negatively Regulates the Growth and Motility of Chondrosarcoma Cells by Targeting Cdc25A.

PubMed

Lu, Yandong; Li, Fangguo; Xu, Tao; Sun, Jie

2016-01-01

Chondrosarcoma (CHS) is the second most common malignant bone sarcoma with increased risk of invasion and metastasis. However, the regulatory mechanisms of CHS tumorigenesis remain unknown. Here we investigated the novel role of miR-497 in regulating chondrosarcoma cell growth and cell cycle arrest. RT-PCR analysis showed that the expression of miR-497 is aberrantly downregulated in human chondrosarcoma samples and cells. After transfection with miR-497 mimic or antagomir, the proliferation and apoptosis of JJ012 and OUMS-27 chondrosarcoma cells were determined by CCK-8 assay and flow cytometric analysis, respectively. Results showed that the proliferation capacity of JJ012 and OUMS-27 cells was significantly decreased by miR-497 overexpression but increased by miR-497 repression. Apoptosis in both cell types was remarkably enhanced by miR-497 mimic but inhibited by miR-497 antagomir. By bioinformatics and luciferase reporter analysis, Cdc25A was proven to be a direct target of miR-497 in chondrosarcoma cells. Further studies indicated that miR-497 modulates the growth of chondrosarcoma cells by targeting Cdc25A, in which the cell cycle inhibitor p21 is involved through a p53-independent pathway. In conclusion, we demonstrated that miR-497 represents a potential tumor suppressor in human chondrosarcoma that regulates the growth of chondrosarcoma cells by targeting Cdc25A. This may provide a novel therapeutic target for chondrosarcoma.

Impact of targeting insulin-like growth factor signaling in head and neck cancers.

PubMed

Limesand, Kirsten H; Chibly, Alejandro Martinez; Fribley, Andrew

2013-10-01

The IGF system has been shown to have either negative or negligible impact on clinical outcomes of tumor development depending on specific tumor sites or stages. This review focuses on the clinical impact of IGF signaling in head and neck cancer, the effects of IGF targeted therapies, and the multi-dimensional role of IRS 1/2 signaling as a potential mechanism in resistance to targeted therapies. Similar to other tumor sites, both negative and positive correlations between levels of IGF-1/IGF-1-R and clinical outcomes in head and neck cancer have been reported. In addition, utilization of IGF targeted therapies has not demonstrated significant clinical benefit; therefore the prognostic impact of the IGF system on head and neck cancer remains uncertain. Copyright © 2013 Elsevier Ltd. All rights reserved.

Assessment of potential additions to conventional oil and gas resources in discovered fields of the United States from reserve growth, 2012

USGS Publications Warehouse

,

2012-01-01

The U.S. Geological Survey estimated volumes of technically recoverable, conventional petroleum resources that have the potential to be added to reserves from reserve growth in 70 discovered oil and gas accumulations of the United States, excluding Federal offshore areas. The mean estimated volumes are 32 billion barrels of crude oil, 291 trillion cubic feet of natural gas, and 10 billion barrels of natural gas liquids.

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer

PubMed Central

Siena, S; Sartore-Bianchi, A; Marsoni, S; Hurwitz, H I; McCall, S J; Penault-Llorca, F; Srock, S; Bardelli, A; Trusolino, L

2018-01-01

Abstract Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients. PMID:29659677

Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram

NASA Astrophysics Data System (ADS)

Duan, Xiaopin; Xiao, Jisheng; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Mao, Shirui; Li, Yaping

2014-03-01

Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.

A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth

NASA Astrophysics Data System (ADS)

Holmgren, Lars; Ambrosino, Elena; Birot, Olivier; Tullus, Carl; Veitonmäki, Niina; Levchenko, Tetyana; Carlson, Lena-Maria; Musiani, Piero; Iezzi, Manuela; Curcio, Claudia; Forni, Guido; Cavallo, Federica; Kiessling, Rolf

2006-06-01

Endogenous angiogenesis inhibitors have shown promise in preclinical trials, but clinical use has been hindered by low half-life in circulation and high production costs. Here, we describe a strategy that targets the angiostatin receptor angiomotin (Amot) by DNA vaccination. The vaccination procedure generated antibodies that detected Amot on the endothelial cell surface. Purified Ig bound to the endothelial cell membrane and inhibited endothelial cell migration. In vivo, DNA vaccination blocked angiogenesis in the matrigel plug assay and prevented growth of transplanted tumors for up to 150 days. We further demonstrate that a combination of DNA vaccines encoding Amot and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice. No toxicity or impairment of normal blood vessels could be detected. This work shows that DNA vaccination targeting Amot may be used to mimic the effect of angiostatin. cancer vaccines | neoplasia | neovascularization | breast cancer | angiostatin

Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis.

PubMed

Chiu, Christopher W; Nozawa, Hiroaki; Hanahan, Douglas

2010-10-10

Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET. Rapamycin and erlotinib, inhibitors of mTOR and EGFR, respectively, were used to treat RIP-Tag2 transgenic mice bearing advanced multifocal PNET. Tumor growth and survival were monitored, and tumors were surveyed for potential biomarkers of response to the therapeutics. Rapamycin monotherapy was notably efficacious, prolonging survival concomitant with tumor stasis (stable disease). However, the tumors developed resistance, as evidenced by eventual relapse to progressive tumor growth. Erlotinib monotherapy slowed tumor growth and elicited a marginal survival benefit. In combination, there was an unprecedented survival benefit in the face of this aggressive multifocal cancer and, in contrast to either monotherapy, the development of adaptive resistance was not apparent. Additionally, the antiapoptotic protein survivin was implicated as a biomarker of sensitivity and beneficial responses to the dual targeted therapy. Preclinical trials in a mouse model of endogenous PNET suggest that combined targeting of the mTOR and EGFR signaling pathways could have potential clinical benefit in treating PNET. These results have encouraged development of an ongoing phase II clinical trial aimed to evaluate the efficacy of this treatment regimen in human neuroendocrine tumors.

Growth hormone is a cellular senescence target in pituitary and nonpituitary cells

PubMed Central

Chesnokova, Vera; Zhou, Cuiqi; Ben-Shlomo, Anat; Zonis, Svetlana; Tani, Yuji; Ren, Song-Guang; Melmed, Shlomo

2013-01-01

Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin-induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence. PMID:23940366

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

PubMed Central

Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T.

2018-01-01

Introduction Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted. PMID:28271910

Growth and reproductive performance of sambar deer in Sabal Forest Reserve of Sarawak, Malaysia.

PubMed

Dahlan, Ismail; Dawend, Jiwan

2013-10-01

We examined the growth, reproduction, rutting behavior, and health status of sambar deer (Cervus unicolor brookei) in secondary Acacia mangium plantation. The data were collected over 11 years from a breeding herd of 21 stags and 33 hinds in Sabal Forest Reserve, Sarawak, Malaysia. Brody's growth model of the pooled data is Y t  = 148.56 (1 - 0.98e(-0.023t)), which estimates that maximum weights of adults are 184 and 115 kg for males and females respectively. Sambar deer are nonseasonal breeders with the breeding peak in February. Although the earliest age at which a female reached sexual maturity was 11 months, the mean age was 23 ± 7 months. Mean age of first fawning was 32 ± 8 months. Mean gestation period was 259 ± 12 days (n = 82). Stags shed antlers mostly between March and July. Velvet hardens at 103 ± 27 days (n = 23), and velvet harvesting is best at 7-9 weeks when antler length is 25-30 cm. Sambar deer are suitable as a farm species in forest plantations and have a vast potential to uplift rural living standards.

Effect of deoxyribozymes targeting c-Jun on solid tumor growth and angiogenesis in rodents.

PubMed

Zhang, Guishui; Dass, Crispin R; Sumithran, Eric; Di Girolamo, Nick; Sun, Lun-Quan; Khachigian, Levon M

2004-05-05

The basic region-leucine zipper protein c-Jun has been linked to cell proliferation, transformation, and apoptosis. However, a direct role for c-Jun in angiogenesis has not been shown. We used human microvascular endothelial cells (HMEC-1) transfected with a DNAzyme targeting the c-Jun mRNA (Dz13), related oligonucleotides, or vehicle in in vitro models of microvascular endothelial cell proliferation, migration, chemoinvasion, and tubule formation, a rat model of corneal neovascularization, and a mouse model of solid tumor growth and vascular endothelial growth factor (VEGF)-induced angiogenesis. All statistical tests were two-sided. Compared with mock-transfected cells, HMEC-1 cells transfected with Dz13 expressed less c-Jun protein and possessed lower DNA-binding activity. Dz13 blocked endothelial cell proliferation, migration, chemoinvasion, and tubule formation. Dz13 inhibited the endothelial cell expression and proteolytic activity of MMP-2, a c-Jun-dependent gene. Dz13 inhibited VEGF-induced neovascularization in the rat cornea compared with vehicle control (Dz13 versus vehicle: 4.0 neovessels versus 30.7 neovessels, difference = 26.7 neovessels; P =.004; area occupied by new blood vessels for Dz13 versus vehicle: 0.35 mm2 versus 1.52 mm2, difference = 1.17 mm2; P =.005) as well as solid melanoma growth in mice (Dz13 versus vehicle at 14 days: 108 mm3 versus 283 mm3, difference = 175 mm3; P =.006) with greatly reduced vascular density (Dz13 versus vehicle: 30% versus 100%, difference = 70%; P<.001). DNAzymes targeting c-Jun may have therapeutic potential as inhibitors of tumor angiogenesis and growth.

Epidermal Growth Factor Receptor Tyrosine Kinase: A Potential Target in Treatment of Non-Small-Cell Lung Carcinoma.

PubMed

Prabhu, Venugopal Vinod; Devaraj, Niranjali

2017-01-01

Lung cancer is responsible for 1.6 million deaths. Approximately 80%-85% of lung cancers are of the non-small-cell variety, which includes squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. Knowing the stage of cancer progression is a requisite for determining which management approach-surgery, chemotherapy, radiotherapy, and/or immunotherapy-is optimal. Targeted therapeutic approaches with antiangiogenic monoclonal antibodies or tyrosine kinase inhibitors are one option if tumors harbor oncogene mutations. Another, newer approach is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. This approach targets the epidermal growth factor receptor (EGFR, HER-1/ErbB1), a receptor tyrosine kinase of the ErbB family, which consists of four closely related receptors: HER-1/ErbB1, HER-2/neu/ErbB2, HER-3/ErbB3, and HER-4/ErbB4. Because EGFR is expressed at high levels on the surface of some cancer cells, it has been recognized as an effective anticancer target. EGFR-targeted therapies include monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review highlights various classes of synthetically derived molecules that have been reported in the last few years as potential EGFR-TK inhibitors (TKIs) and their targeted therapies in NSCLC, along with effective strategies for overcoming EGFR-TKI resistance and efforts to develop a novel potent EGFR-TKI as an efficient target of NSCLC treatment in the foreseeable future.

Optimization of vascular-targeting drugs in a computational model of tumor growth

NASA Astrophysics Data System (ADS)

Gevertz, Jana

2012-04-01

A biophysical tool is introduced that seeks to provide a theoretical basis for helping drug design teams assess the most promising drug targets and design optimal treatment strategies. The tool is grounded in a previously validated computational model of the feedback that occurs between a growing tumor and the evolving vasculature. In this paper, the model is particularly used to explore the therapeutic effectiveness of two drugs that target the tumor vasculature: angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs). Using sensitivity analyses, the impact of VDA dosing parameters is explored, as is the effects of administering a VDA with an AI. Further, a stochastic optimization scheme is utilized to identify an optimal dosing schedule for treatment with an AI and a chemotherapeutic. The treatment regimen identified can successfully halt simulated tumor growth, even after the cessation of therapy.

Monoclonal Antibody Fragments for Targeting Therapeutics to Growth Plate Cartilage | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at The Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD) have discovered monoclonal antibodies that bind to matrilin-3, a protein specifically expressed in cartilage tissue, that could be used for treating or inhibiting growth plate disorders, such as a skeletal dysplasia or short stature. The monoclonal antibodies can also be used to target therapeutic agents, such as anti-arthritis agents, to cartilage tissue. NICHD seeks statements of capability or interest from parties interested in collaborative research to co-develop, evaluate, or commercialize treatment of skeletal disorders using targeting antibodies.

Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis.

PubMed

Sun, Maxine; Marconi, Lorenzo; Eisen, Tim; Escudier, Bernard; Giles, Rachel H; Haas, Naomi B; Harshman, Lauren C; Quinn, David I; Larkin, James; Pal, Sumanta K; Powles, Thomas; Ryan, Christopher W; Sternberg, Cora N; Uzzo, Robert; Choueiri, Toni K; Bex, Axel

2018-05-18

-dose regimen, DFS was improved in patients who received adjuvant therapy (HR random : 0.83, 95% CI: 0.73-0.95, p=0.005). This pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs. Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects. Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

MicroRNA-100 regulates pancreatic cancer cells growth and sensitivity to chemotherapy through targeting FGFR3.

PubMed

Li, Zhipeng; Li, Xu; Yu, Chao; Wang, Min; Peng, Feng; Xiao, Jie; Tian, Rui; Jiang, Jianxin; Sun, Chengyi

2014-12-01

We intended to investigate the role of microRNA 100 (miR-100) in regulating pancreatic cancer cells' growth in vitro and tumor development in vivo. QTR-PCR was used to examine the expression of miR-100 in pancreatic cancer cell lines and tumor cells from human patients. Lentivirual vector containing miR-100 mimics (lv-miR-100) was used to overexpress miR-100 in MIA PaCa-2 and FCPAC-1 cells. The effects of overexpressing miR-100 on pancreatic cancer cell proliferation and chemosensitivity to cisplatin were examined by cell proliferation essay in vitro. MIA PaCa-2 cells with endogenously overexpressed miR-100 were transplanted into null mice to examine tumor growth in vivo. The predicted target of miR-100, fibroblast growth factor receptor 3 (FGFR3), was downregulated by siRNA to examine its effect on pancreatic cancer cells. We found miR-100 was markedly underexpressed in both pancreatic cancer cell lines and tumor cells from patients. In cancer cells, transfection of lv-miR-100 was able to upregulate endogenous expression of miR-100, inhibited cancer cell proliferation, and increased sensitivities to cisplatin. Overexpressing miR-100 led to significant inhibition on tumor formation in vivo. Luciferase essay showed FGFR3 was direct target of miR-100. FGFR3 was significantly downregulated by overexpressing miR-100 in pancreatic cancer cells and knocking down FGFR3 by siRNA exerted similar effect as miR-100. Our study demonstrated that miR-100 played an important role in pancreatic cancer development, possibly through targeting FGFR3. It may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer.

Understanding and Targeting Cell Growth Networks in Breast Cancer

DTIC Science & Technology

2009-04-01

cells.   A common target of ARF  is the NPM/B23 oncogene, an abundant protein of  the  nucleolus .    NPM  normally  responds  to  growth  factors  and...p68DDX5 expression  in  the  nucleolus , with  loss of  either  capable  of  completely  reversing  the  phenotype  back  to  normal.    This  exciting...determine  the complex roles of ARF, DDX5, and NPM in the  nucleolus  of breast epithelial cells and how they impact  both ribosome biogenesis and cell

The outer epidermis of Avena and maize coleoptiles is not a unique target for auxin in elongation growth

NASA Technical Reports Server (NTRS)

Cleland, R. E.

1991-01-01

A controversy exists as to whether or not the outer epidermis in coleoptiles is a unique target for auxin in elongation growth. The following evidence indicates that the outer epidermis is not the only auxin-responsive cell layer in either Avena sativa L. or Zea mays L. coleoptiles. Coleoptile sections from which the epidermis has been removed by peeling elongate in response to auxin. The magnitude of the response is similar to that of intact sections provided the incubation solution contains both auxin and sucrose. The amount of elongation is independent of the amount of epidermis removed. Sections of oat coleoptiles from which the epidermis has been removed from one side are nearly straight after 22 h in auxin and sucrose, despite extensive growth of the sections. These data indicate that the outer epidermis is not a unique target for auxin in elongation growth, at least in Avena and maize coleoptiles.

Cannabinoid CB2 receptor as a new phototherapy target for the inhibition of tumor growth.

PubMed

Jia, Ningyang; Zhang, Shaojuan; Shao, Pin; Bagia, Christina; Janjic, Jelena M; Ding, Ying; Bai, Mingfeng

2014-06-02

The success of targeted cancer therapy largely relies upon the selection of target and the development of efficient therapeutic agents that specifically bind to the target. In the current study, we chose a cannabinoid CB2 receptor (CB2R) as a new target and used a CB2R-targeted photosensitizer, IR700DX-mbc94, for phototherapy treatment. IR700DX-mbc94 was prepared by conjugating a photosensitizer, IR700DX, to mbc94, whose binding specificity to CB2R has been previously demonstrated. We found that phototherapy treatment using IR700DX-mbc94 greatly inhibited the growth of CB2R positive tumors but not CB2R negative tumors. In addition, phototherapy treatment with nontargeted IR700DX did not show significant therapeutic effect. Similarly, treatment with IR700DX-mbc94 without light irradiation or light irradiation without the photosensitizer showed no tumor-inhibitory effect. Taken together, IR700DX-mbc94 is a promising phototherapy agent with high target-specificity. Moreover, CB2R appears to have great potential as a phototherapeutic target for cancer treatment.

MiR-590-3p suppresses hepatocellular carcinoma growth by targeting TEAD1.

PubMed

Ge, Xin; Gong, Liansheng

2017-03-01

MicroRNA signature is altered in different disease states including cancer, and some microRNAs act as oncogenes or tumor suppressors. MiR-590-3p has been shown to be involved in human cancer progression. However, its role in hepatocellular carcinoma remains unknown. In this study, miR-590-3p level was measured, and clinicopathological features were determined in hepatocellular carcinoma tissues. The function of miR-590-3p was examined in vitro and in vivo. Real-time reverse transcription polymerase chain reaction analysis demonstrated downregulation of miR-590-3p in hepatocellular carcinoma tissues, and its downregulation was associated with a poor overall survival of hepatocellular carcinoma patients. Ectopic expression of miR-590-3p promoted growth of hepatocellular carcinoma cells, whereas its depletion inhibited cell growth. Transcriptional enhancer activator domain 1 was identified as a validated miR-590-3p target. Upregulation of transcriptional enhancer activator domain 1 was found in hepatocellular carcinoma tissues and inversely correlated with miR-590-3p. Our results indicate a tumor suppressor role of miR-590-3p in hepatocellular carcinoma through targeting transcriptional enhancer activator domain 1 and suggest its use in the diagnosis and prognosis of liver cancer.

Population Connectivity Measures of Fishery-Targeted Coral Reef Species to Inform Marine Reserve Network Design in Fiji.

PubMed

Eastwood, Erin K; López, Elora H; Drew, Joshua A

2016-01-25

Coral reef fish serve as food sources to coastal communities worldwide, yet are vulnerable to mounting anthropogenic pressures like overfishing and climate change. Marine reserve networks have become important tools for mitigating these pressures, and one of the most critical factors in determining their spatial design is the degree of connectivity among different populations of species prioritized for protection. To help inform the spatial design of an expanded reserve network in Fiji, we used rapidly evolving mitochondrial genes to investigate connectivity patterns of three coral reef species targeted by fisheries in Fiji: Epinephelus merra (Serranidae), Halichoeres trimaculatus (Labridae), and Holothuria atra (Holothuriidae). The two fish species, E. merra and Ha. trimaculatus, exhibited low genetic structuring and high amounts of gene flow, whereas the sea cucumber Ho. atra displayed high genetic partitioning and predominantly westward gene flow. The idiosyncratic patterns observed among these species indicate that patterns of connectivity in Fiji are likely determined by a combination of oceanographic and ecological characteristics. Our data indicate that in the cases of species with high connectivity, other factors such as representation or political availability may dictate where reserves are placed. In low connectivity species, ensuring upstream and downstream connections is critical.

Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth.

PubMed

Bryson, Paul D; Han, Xiaolu; Truong, Norman; Wang, Pin

2017-10-13

Breast cancer immunotherapy is a potent treatment option, with antibody therapies such as trastuzumab increasing 2-year survival rates by 50%. However, active immunotherapy through vaccination has generally been clinically ineffective. One potential means of improving vaccine therapy is by delivering breast cancer antigens to dendritic cells (DCs) for enhanced antigen presentation. To accomplish this in vivo, we pseudotyped lentiviral vector (LV) vaccines with a modified Sindbis Virus glycoprotein so that they could deliver genes encoding the breast cancer antigen alpha-lactalbumin (Lalba) or erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) directly to resident DCs. We hypothesized that utilizing these DC-targeting lentiviral vectors asa breast cancer vaccine could lead to an improved immune response against self-antigens found in breast cancer tumors. Indeed, single injections of the vaccine vectors were able to amplify antigen-specific CD8T cells 4-6-fold over naïve mice, similar to the best published vaccine regimens. Immunization of these mice completely inhibited tumor growth in a foreign antigen environment (LV-ERBB2 in wildtype mice), and it reduced the rate of tumor growth in a self-antigen environment (LV-Lalba in wildtype or LV-ERBB2 in MMTV-huHER2 transgenic). These results show that a single injection with targeted lentiviral vectors can be an effective immunotherapy for breast cancer. Furthermore, they could be combined with other immunotherapeutic regimens to improve outcomes for patients with breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

PANC-1 pancreatic cancer cell growth inhibited by cucurmosin alone and in combination with an epidermal growth factor receptor-targeted drug.

PubMed

Wang, Congfei; Yang, Aiqin; Zhang, Baoming; Yin, Qiang; Huang, Heguang; Chen, Minghuang; Xie, Jieming

2014-03-01

To investigate the inhibition of PANC-1 pancreatic cancer cell growth by cucurmosin (CUS) and its possible mechanism. We observed the inhibition of PANC-1 cell growth by sulforhodamine B and colony-forming experiments in vitro and established nonobese diabetic/severe combined immunodeficiency mouse subcutaneous tumor models in vivo. We used Western blot to analyze protein levels related to apoptosis and epidermal growth factor receptor (EGFR) signaling pathways after drug intervention, whereas the messenger RNA expression of EGFR was analyzed by quantitative real-time polymerase chain reaction. Sulforhodamine B and colony-forming experiments indicated that CUS inhibited PANC-1 cell proliferation in a dose- and time-dependent manner. A stronger inhibitory effect was observed when CUS was combined with gefitinib. The subcutaneous tumor growth was also inhibited. Western blot showed that all the examined proteins decreased, except for 4E-BP1 and the active fragments of caspase 3 and caspase 9 increased. Epidermal growth factor receptor expression did not change significantly in quantitative real-time polymerase chain reaction. Cucurmosin can strongly inhibit the growth of PANC-1 cells in vitro and in vivo. Cucurmosin can down-regulate EGFR protein expression, but not at the messenger RNA level. Cucurmosin can also inhibit the ras/raf and phosphatidylinositol 3-kinase/Akt downstream signaling pathways and enhance the sensitivity of the EGFR-targeted drug gefitinib.

Bacterial Cell Growth Inhibitors Targeting Undecaprenyl Diphosphate Synthase and Undecaprenyl Diphosphate Phosphatase.

PubMed

Wang, Yang; Desai, Janish; Zhang, Yonghui; Malwal, Satish R; Shin, Christopher J; Feng, Xinxin; Sun, Hong; Liu, Guizhi; Guo, Rey-Ting; Oldfield, Eric

2016-10-19

We synthesized a series of benzoic acids and phenylphosphonic acids and investigated their effects on the growth of Staphylococcus aureus and Bacillus subtilis. One of the most active compounds, 5-fluoro-2-(3-(octyloxy)benzamido)benzoic acid (7, ED 50 ∼0.15 μg mL -1 ) acted synergistically with seven antibiotics known to target bacterial cell-wall biosynthesis (a fractional inhibitory concentration index (FICI) of ∼0.35, on average) but had indifferent effects in combinations with six non-cell-wall biosynthesis inhibitors (average FICI∼1.45). The most active compounds were found to inhibit two enzymes involved in isoprenoid/bacterial cell-wall biosynthesis: undecaprenyl diphosphate synthase (UPPS) and undecaprenyl diphosphate phosphatase (UPPP), but not farnesyl diphosphate synthase, and there were good correlations between bacterial cell growth inhibition, UPPS inhibition, and UPPP inhibition. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diffusion tensor magnetic resonance imaging driven growth modeling for radiotherapy target definition in glioblastoma.

PubMed

Jensen, Morten B; Guldberg, Trine L; Harbøll, Anja; Lukacova, Slávka; Kallehauge, Jesper F

2017-11-01

The clinical target volume (CTV) in radiotherapy is routinely based on gadolinium contrast enhanced T1 weighted (T1w + Gd) and T2 weighted fluid attenuated inversion recovery (T2w FLAIR) magnetic resonance imaging (MRI) sequences which have been shown to over- or underestimate the microscopic tumor cell spread. Gliomas favor spread along the white matter fiber tracts. Tumor growth models incorporating the MRI diffusion tensors (DTI) allow to account more consistently for the glioma growth. The aim of the study was to investigate the potential of a DTI driven growth model to improve target definition in glioblastoma (GBM). Eleven GBM patients were scanned using T1w, T2w FLAIR, T1w + Gd and DTI. The brain was segmented into white matter, gray matter and cerebrospinal fluid. The Fisher-Kolmogorov growth model was used assuming uniform proliferation and a difference in white and gray matter diffusion of a ratio of 10. The tensor directionality was tested using an anisotropy weighting parameter set to zero (γ0) and twenty (γ20). The volumetric comparison was performed using Hausdorff distance, Dice similarity coefficient (DSC) and surface area. The median of the standard CTV (CTVstandard) was 180 cm 3 . The median surface area of CTVstandard was 211 cm 2 . The median surface area of respective CTV γ0 and CTV γ20 significantly increased to 338 and 376 cm 2 , respectively. The Hausdorff distance was greater than zero and significantly increased for both CTV γ0 and CTV γ20 with respective median of 18.7 and 25.2 mm. The DSC for both CTV γ0 and CTV γ20 were significantly below one with respective median of 0.74 and 0.72, which means that 74 and 72% of CTVstandard were included in CTV γ0 and CTV γ20, respectively. DTI driven growth models result in CTVs with a significantly increased surface area, a significantly increased Hausdorff distance and decreased overlap between the standard and model derived volume.

Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaylani, Samer Z.; Xu, Jianmin; Srivastava, Ritesh K.

Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissuemore » sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

Isorhapontigenin induced cell growth inhibition and apoptosis by targeting EGFR-related pathways in prostate cancer.

PubMed

Zhu, Cuicui; Zhu, Qingyi; Wu, Zhaomeng; Yin, Yingying; Kang, Dan; Lu, Shan; Liu, Ping

2018-02-01

Isorhapontigenin (ISO), a naturally phytopolyphenol compound existing in Chinese herb, apples, and various vegetables, has attracted extensive interest in recent years for its diverse pharmacological characteristics. Increasing evidences reveal that ISO can inhibit cancer cell growth by induced apoptosis, however, the molecular mechanisms is not fully understood. In this study, we found for the first time that ISO apparently induced cell growth inhibition and apoptosis by targeting EGFR and its downstream signal pathways in prostate cancer (PCa) cells both in vitro and in vivo, whereas no obviously effect on normal prostate cells. From the results, we found that ISO competitively targeted EGFR with EGF and inhibited EGFR auto-phosphorylation, and then decreased the levels of p-Erk1/2, p-PI3 K, and p-AKT, and further induced down-regulation of p-FOXO1 and promoted FOXO1 nuclear translocation; and finally resulted in a significantly up-regulation of Bim/p21/27/Bax/cleaved Caspase-3/cleaved PARP-1 and a markedly down-regulation of Sp1/Bcl-2/XIAP/Cyclin D1. Moreover, our experimental data demonstrated that treatment of ISO decreased protein level of AR via both inhibiting the expression of AR gene and promoting the ubiquitination/degradation of AR proteins in proteasome. In vivo, we also found that ISO inhibited the growth of subcutaneous xenotransplanted tumor in nude mice by inducing PCa cell growth inhibition and apoptosis. Taken together, all findings here clearly implicated that EGFR-related signal pathways, including EGFR-PI3K-Akt and EGFR-Erk1/2 pathways, were involved in ISO-induced cell growth inhibition and apoptosis in PCa cells, providing a more solid theoretical basis for the application of ISO to treat patients with prostate cancer in clinic. © 2017 Wiley Periodicals, Inc.

Therapeutic silence of pleiotrophin by targeted delivery of siRNA and its effect on the inhibition of tumor growth and metastasis.

PubMed

Zha, Lisha; He, Lichun; Xie, Weidong; Cheng, Jin; Li, Tong; Mohsen, Mona O; Lei, Fan; Storni, Federico; Bachmann, Martin; Chen, Hongquan; Zhang, Yaou

2017-01-01

Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene. However, efficient delivery of small interfering RNA (siRNA) in vivo remains a significant hurdle for its successful therapeutic application. In this study, we first identified, on a cell-based experiment, applying a 1:1 mixture of two PTN specific siRNA engenders a higher silencing efficiency on both mRNA and protein level than using any of them discretely at the same dose. As a consequence, slower melanoma cells growth was also observed for using two specific siRNA combinatorially. To establish a robust way for siRNA delivery in vivo and further investigate how silence of PTN affects tumor growth, we tested three different methods to deliver siRNA in vivo: first non-targeted in-vivo delivery of siRNA via jetPEI; second lung targeted delivery of siRNA via microbubble coated jetPEI; third tumor cell targeted delivery of siRNA via transferrin-polyethylenimine (Tf-PEI). As a result, we found that all three in-vivo siRNAs delivery methods led to an evident inhibition of melanoma growth in non-immune deficiency C57BL/6 mice without a measureable change of ALT and AST activities. Both targeted delivery methods showed more significant curative effect than jetPEI. The lung targeted delivery by microbubble coated jetPEI revealed a comparable therapeutic effect with Tf-PEI, indicating its potential application for target delivery of siRNA in vivo.

Therapeutic silence of pleiotrophin by targeted delivery of siRNA and its effect on the inhibition of tumor growth and metastasis

PubMed Central

Xie, Weidong; Cheng, Jin; Li, Tong; Mohsen, Mona O.; Lei, Fan; Storni, Federico; Bachmann, Martin; Chen, Hongquan; Zhang, Yaou

2017-01-01

Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene. However, efficient delivery of small interfering RNA (siRNA) in vivo remains a significant hurdle for its successful therapeutic application. In this study, we first identified, on a cell-based experiment, applying a 1:1 mixture of two PTN specific siRNA engenders a higher silencing efficiency on both mRNA and protein level than using any of them discretely at the same dose. As a consequence, slower melanoma cells growth was also observed for using two specific siRNA combinatorially. To establish a robust way for siRNA delivery in vivo and further investigate how silence of PTN affects tumor growth, we tested three different methods to deliver siRNA in vivo: first non-targeted in-vivo delivery of siRNA via jetPEI; second lung targeted delivery of siRNA via microbubble coated jetPEI; third tumor cell targeted delivery of siRNA via transferrin-polyethylenimine (Tf-PEI). As a result, we found that all three in-vivo siRNAs delivery methods led to an evident inhibition of melanoma growth in non-immune deficiency C57BL/6 mice without a measureable change of ALT and AST activities. Both targeted delivery methods showed more significant curative effect than jetPEI. The lung targeted delivery by microbubble coated jetPEI revealed a comparable therapeutic effect with Tf-PEI, indicating its potential application for target delivery of siRNA in vivo. PMID:28562667

The Role of Target of Rapamycin Signaling Networks in Plant Growth and Metabolism1

PubMed Central

Sheen, Jen

2014-01-01

The target of rapamycin (TOR) kinase, a master regulator that is evolutionarily conserved among yeasts (Saccharomyces cerevisiae), plants, animals, and humans, integrates nutrient and energy signaling to promote cell proliferation and growth. Recent breakthroughs made possible by integrating chemical, genetic, and genomic analyses have greatly increased our understanding of the molecular functions and dynamic regulation of the TOR kinase in photosynthetic plants. TOR signaling plays fundamental roles in embryogenesis, meristem activation, root and leaf growth, flowering, senescence, and life span determination. The molecular mechanisms underlying TOR-mediated ribosomal biogenesis, translation promotion, readjustment of metabolism, and autophagy inhibition are now being uncovered. Moreover, monitoring photosynthesis-derived Glc and bioenergetics relays has revealed that TOR orchestrates unprecedented transcriptional networks that wire central metabolism and biosynthesis for energy and biomass production. In addition, these networks integrate localized stem/progenitor cell proliferation through interorgan nutrient coordination to control developmental transitions and growth. PMID:24385567

HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

PubMed

Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

2016-08-01

The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

A sunflower WRKY transcription factor stimulates the mobilization of seed-stored reserves during germination and post-germination growth.

PubMed

Raineri, Jesica; Hartman, Matías D; Chan, Raquel L; Iglesias, Alberto A; Ribichich, Karina F

2016-09-01

The sunflower transcription factor HaWRKY10 stimulates reserves mobilization in Arabidopsis. Gene expression and enzymes activity assays indicated that lipolysis and gluconeogenesis were increased. Microarray results suggested a parallelism in sunflower. Germinating oilseeds converts stored lipids into sugars, and thereafter in metabolic energy that is used in seedling growth and establishment. During germination, the induced lipolysis linked to the glyoxylate pathway and gluconeogenesis produces sucrose, which is then transported to the embryo and driven through catabolic routes. Herein, we report that the sunflower transcription factor HaWRKY10 regulates carbon partitioning by reducing carbohydrate catabolism and increasing lipolysis and gluconeogenesis. HaWRKY10 was regulated by abscisic acid and gibberellins in the embryo leaves 48 h after seed imbibition and highly expressed during sunflower seed germination and seedling growth, concomitantly with lipid mobilization. Sunflower leaf disks overexpressing HaWRKY10 showed repressed expression of genes related to sucrose cleavage and glycolysis compared with controls. Moreover, HaWRKY10 constitutive expression in Arabidopsis seeds produced higher decrease in lipid reserves, whereas starch and sucrose were more preserved compared with wild type. Gene transcripts abundance and enzyme activities involved in stored lipid mobilization and gluconeogenesis increased more in transgenic than in wild type seeds 36 h after imbibition, whereas the negative regulator of lipid mobilization, ABI4, was repressed. Altogether, the results point out a functional parallelism between tissues and plant species, and reveal HaWRKY10 as a positive regulator of storage reserve mobilization in sunflower.

Deptor Is a Novel Target of Wnt/β-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth.

PubMed

Wang, Qingding; Zhou, Yuning; Rychahou, Piotr; Harris, Jennifer W; Zaytseva, Yekaterina Y; Liu, Jinpeng; Wang, Chi; Weiss, Heidi L; Liu, Chunming; Lee, Eun Y; Evers, B Mark

2018-06-15

Activation of the Wnt/β-catenin signaling pathway drives colorectal cancer growth by deregulating expression of downstream target genes, including the c-myc proto-oncogene. The critical targets that mediate the functions of oncogenic c-Myc in colorectal cancer have yet to be fully elucidated. Previously, we showed that activation of PI3K/Akt/mTOR contributes to colorectal cancer growth and metastasis. Here, we show that Deptor, a suppressor of mTOR, is a direct target of Wnt/β-catenin/c-Myc signaling in colorectal cancer cells. Inhibition of Wnt/β-catenin or knockdown of c-Myc decreased, while activation of Wnt/β-catenin or overexpression of c-Myc increased the expression of Deptor. c-Myc bound the promoter of Deptor and transcriptionally regulated Deptor expression. Inhibition of Wnt/β-catenin/c-Myc signaling increased mTOR activation, and the combination of Wnt and Akt/mTOR inhibitors enhanced inhibition of colorectal cancer cell growth in vitro and in vivo Deptor expression was increased in colorectal cancer cells; knockdown of Deptor induced differentiation, decreased expression of B lymphoma Mo-MLV insertion region 1 (Bmi1), and decreased proliferation in colorectal cancer cell lines and primary human colorectal cancer cells. Importantly, our work identifies Deptor as a downstream target of the Wnt/β-catenin/c-Myc signaling pathway, acting as a tumor promoter in colorectal cancer cells. Moreover, we provide a molecular basis for the synergistic combination of Wnt and mTOR inhibitors in treating colorectal cancer with elevated c-Myc. Significance: The mTOR inhibitor DEPTOR acts as a tumor promoter and could be a potential therapeutic target in colorectal cancer. Cancer Res; 78(12); 3163-75. ©2018 AACR . ©2018 American Association for Cancer Research.

Phospholipase C-mediated hydrolysis of phosphatidylcholine is a target of transforming growth factor beta 1 inhibitory signals.

PubMed Central

Diaz-Meco, M T; Dominguez, I; Sanz, L; Municio, M M; Berra, E; Cornet, M E; Garcia de Herreros, A; Johansen, T; Moscat, J

1992-01-01

Cell growth and tumor transformation can be restrained in certain cell systems by the action of transforming growth factor beta (TGF-beta). It has been established that the mechanism whereby TGF-beta 1 inhibits cell growth does not interfere with the triggering of early mitogenic signal transduction mechanisms. Phospholipase C-catalyzed hydrolysis of phosphatidylcholine (PC) is a relatively late step in the cascade activated by growth factors. Therefore, conceivably activation of phospholipase C-catalyzed hydrolysis of PC could be the target of TGF-beta 1 action. In the study reported here, we demonstrate that TGF-beta 1 inhibits the coupling of ras p21 to the activation of PC hydrolysis, which appears to be critical for the antiproliferative effects of TGF-beta 1. Images PMID:1309592

Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. | Office of Cancer Genomics

Cancer.gov

Amplification of epidermal growth factor receptor (EGFR) and its active mutant EGFRvIII occurs frequently in glioblastoma (GBM). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has only shown limited efficacy in patients. Here we discuss signaling pathways mediated by EGFR/EGFRvIII, current therapeutics, and novel strategies to target EGFR/EGFRvIII-amplified GBM.

Prioritizing plant defence over growth through WRKY regulation facilitates infestation by non-target herbivores.

PubMed

Li, Ran; Zhang, Jin; Li, Jiancai; Zhou, Guoxin; Wang, Qi; Bian, Wenbo; Erb, Matthias; Lou, Yonggen

2015-06-17

Plants generally respond to herbivore attack by increasing resistance and decreasing growth. This prioritization is achieved through the regulation of phytohormonal signaling networks. However, it remains unknown how this prioritization affects resistance against non-target herbivores. In this study, we identify WRKY70 as a specific herbivore-induced, mitogen-activated protein kinase-regulated rice transcription factor that physically interacts with W-box motives and prioritizes defence over growth by positively regulating jasmonic acid (JA) and negatively regulating gibberellin (GA) biosynthesis upon attack by the chewing herbivore Chilo suppressalis. WRKY70-dependent JA biosynthesis is required for proteinase inhibitor activation and resistance against C. suppressalis. In contrast, WRKY70 induction increases plant susceptibility against the rice brown planthopper Nilaparvata lugens. Experiments with GA-deficient rice lines identify WRKY70-dependent GA signaling as the causal factor in N. lugens susceptibility. Our study shows that prioritizing defence over growth leads to a significant resistance trade-off with important implications for the evolution and agricultural exploitation of plant immunity.

Quantifying the Importance of MSP1-19 as a Target of Growth-Inhibitory and Protective Antibodies against Plasmodium falciparum in Humans

PubMed Central

Wilson, Danny W.; Fowkes, Freya J. I.; Gilson, Paul R.; Elliott, Salenna R.; Tavul, Livingstone; Michon, Pascal; Dabod, Elija; Siba, Peter M.; Mueller, Ivo; Crabb, Brendan S.; Beeson, James G.

2011-01-01

Background Antibodies targeting blood stage antigens are important in protection against malaria, but the key targets and mechanisms of immunity are not well understood. Merozoite surface protein 1 (MSP1) is an abundant and essential protein. The C-terminal 19 kDa region (MSP1-19) is regarded as a promising vaccine candidate and may also be an important target of immunity. Methodology/Findings Growth inhibitory antibodies against asexual-stage parasites and IgG to recombinant MSP1-19 were measured in plasma samples from a longitudinal cohort of 206 children in Papua New Guinea. Differential inhibition by samples of mutant P. falciparum lines that expressed either the P. falciparum or P. chabaudi form of MSP1-19 were used to quantify MSP1-19 specific growth-inhibitory antibodies. The great majority of children had detectable IgG to MSP1-19, and high levels of IgG were significantly associated with a reduced risk of symptomatic P. falciparum malaria during the 6-month follow-up period. However, there was little evidence of PfMSP1-19 specific growth inhibition by plasma samples from children. Similar results were found when testing non-dialysed or dialysed plasma, or purified antibodies, or when measuring growth inhibition in flow cytometry or microscopy-based assays. Rabbit antisera generated by immunization with recombinant MSP1-19 demonstrated strong MSP1-19 specific growth-inhibitory activity, which appeared to be due to much higher antibody levels than human samples; antibody avidity was similar between rabbit antisera and human plasma. Conclusions/Significance These data suggest that MSP1-19 is not a major target of growth inhibitory antibodies and that the protective effects of antibodies to MSP1-19 are not due to growth inhibitory activity, but may instead be mediated by other mechanisms. Alternatively, antibodies to MSP1-19 may act as a marker of protective immunity. PMID:22110733

Population Connectivity Measures of Fishery-Targeted Coral Reef Species to Inform Marine Reserve Network Design in Fiji

PubMed Central

Eastwood, Erin K.; López, Elora H.; Drew, Joshua A.

2016-01-01

Coral reef fish serve as food sources to coastal communities worldwide, yet are vulnerable to mounting anthropogenic pressures like overfishing and climate change. Marine reserve networks have become important tools for mitigating these pressures, and one of the most critical factors in determining their spatial design is the degree of connectivity among different populations of species prioritized for protection. To help inform the spatial design of an expanded reserve network in Fiji, we used rapidly evolving mitochondrial genes to investigate connectivity patterns of three coral reef species targeted by fisheries in Fiji: Epinephelus merra (Serranidae), Halichoeres trimaculatus (Labridae), and Holothuria atra (Holothuriidae). The two fish species, E. merra and Ha. trimaculatus, exhibited low genetic structuring and high amounts of gene flow, whereas the sea cucumber Ho. atra displayed high genetic partitioning and predominantly westward gene flow. The idiosyncratic patterns observed among these species indicate that patterns of connectivity in Fiji are likely determined by a combination of oceanographic and ecological characteristics. Our data indicate that in the cases of species with high connectivity, other factors such as representation or political availability may dictate where reserves are placed. In low connectivity species, ensuring upstream and downstream connections is critical. PMID:26805954

miR-182 targets CHL1 and controls tumor growth and invasion in papillary thyroid carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Hongling; Fang, Jin; Zhang, Jichen

2014-07-18

Highlights: • miR-182 and CHL1 expression patterns are negatively correlated. • CHL1 is a direct target of miR-182 in PTC cells. • miR-182 suppression inhibits PTC cell growth and invasion. • CHL1 is involved in miR-182-mediated cell behavior. - Abstract: In this study, we investigated the role and underlying mechanism of action of miR-182 in papillary thyroid carcinoma (PTC). Bioinformatics analysis revealed close homolog of LI (CHL1) as a potential target of miR-182. Upregulation of miR-182 was significantly correlated with CHL1 downregulation in human PTC tissues and cell lines. miR-182 suppressed the expression of CHL1 mRNA through direct targeting ofmore » the 3′-untranslated region (3′-UTR). Downregulation of miR-182 suppressed growth and invasion of PTC cells. Silencing of CHL1 counteracted the effects of miR-182 suppression, while its overexpression mimicked these effects. Our data collectively indicate that miR-182 in PTC promotes cell proliferation and invasion through direct suppression of CHL1, supporting the potential utility of miR-182 inhibition as a novel therapeutic strategy against PTC.« less

CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth.

PubMed

Lee, Eunjung; Son, Joe Eun; Byun, Sanguine; Lee, Seung Joon; Kim, Yeong A; Liu, Kangdong; Kim, Jiyoung; Lim, Soon Sung; Park, Jung Han Yoon; Dong, Zigang; Lee, Ki Won; Lee, Hyong Joo

2013-10-01

Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phase cell cycle transition and the accumulation of p27(kip1). The elevated p27(kip1) expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Regulations on growth and development in tomato cotyledon, flower and fruit via destruction of miR396 with short tandem target mimic.

PubMed

Cao, Dongyan; Wang, Jiao; Ju, Zheng; Liu, Qingqing; Li, Shan; Tian, Huiqin; Fu, Daqi; Zhu, Hongliang; Luo, Yunbo; Zhu, Benzhong

2016-06-01

Despite many studies about functions of miR396 were concentrated on cotyledon and leaf growth and development, only few researches were focused on flower and fruit, especially for fleshy fruit, for example, tomato fruit. Here, the roles of miR396 throughout the growth and development of tomato plant were explored with combining bioinformatics and transgene-mediated methods. In tomato, miR396 had two mature types (miR396a and miR396b), and miR396a expressed significantly higher than miR396b in cotyledon, flower, sepal and fruit. Generally, plant growth and development were regulated by miR396 via growth-regulating factors (GRFs). In tomato, all 13 SlGRFs were analyzed comprehensively, including phylogeny, domain and expression patterns. To investigate the roles of miR396 further, STTM396a/396a-88 was over-expressed in tomato, which induced miR396a and miR396b both dramatical down-regulation, and the target GRFs general up-regulation. As a result, the flowers, sepals and fruits all obviously became bigger. Most significantly, the sepal length of transgenic lines #3 and #4 at 39 days post-anthesis was separately increased 75% and 81%, and the fruit weight was added 45% and 39%, respectively. Overall, these results revealed novel roles of miR396 in regulating flower and fruit development, and provided a new potential way for improving tomato fruit yield. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

PubMed Central

Olmos, David; Martins, Ana Sofia; Jones, Robin L.; Alam, Salma; Scurr, Michelle; Judson, Ian R.

2011-01-01

Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response. PMID:21647361

Bioinsecticidal activity of Talisia esculenta reserve protein on growth and serine digestive enzymes during larval development of Anticarsia gemmatalis.

PubMed

Macedo, Maria Lígia R; Freire, Maria das Graças M; Kubo, Carlos Eduardo G; Parra, José Roberto P

2011-01-01

Plants synthesize a variety of molecules to defend themselves against an attack by insects. Talisin is a reserve protein from Talisia esculenta seeds, the first to be characterized from the family Sapindaceae. In this study, the insecticidal activity of Talisin was tested by incorporating the reserve protein into an artificial diet fed to the velvetbean caterpillar Anticarsia gemmatalis, the major pest of soybean crops in Brazil. At 1.5% (w/w) of the dietary protein, Talisin affected larval growth, pupal weight, development and mortality, adult fertility and longevity, and produced malformations in pupae and adult insects. Talisin inhibited the trypsin-like activity of larval midgut homogenates. The trypsin activity in Talisin-fed larvae was sensitive to Talisin, indicating that no novel protease-resistant to Talisin was induced in Talisin-fed larvae. Affinity chromatography showed that Talisin bound to midgut proteinases of the insect A. gemmatalis, but was resistant to enzymatic digestion by these larval proteinases. The transformation of genes coding for this reserve protein could be useful for developing insect resistant crops. Copyright © 2010 Elsevier Inc. All rights reserved.

Target of Rapamycin Signaling Regulates Metabolism, Growth, and Life Span in Arabidopsis[W][OA

PubMed Central

Ren, Maozhi; Venglat, Prakash; Qiu, Shuqing; Feng, Li; Cao, Yongguo; Wang, Edwin; Xiang, Daoquan; Wang, Jinghe; Alexander, Danny; Chalivendra, Subbaiah; Logan, David; Mattoo, Autar; Selvaraj, Gopalan; Datla, Raju

2012-01-01

Target of Rapamycin (TOR) is a major nutrition and energy sensor that regulates growth and life span in yeast and animals. In plants, growth and life span are intertwined not only with nutrient acquisition from the soil and nutrition generation via photosynthesis but also with their unique modes of development and differentiation. How TOR functions in these processes has not yet been determined. To gain further insights, rapamycin-sensitive transgenic Arabidopsis thaliana lines (BP12) expressing yeast FK506 Binding Protein12 were developed. Inhibition of TOR in BP12 plants by rapamycin resulted in slower overall root, leaf, and shoot growth and development leading to poor nutrient uptake and light energy utilization. Experimental limitation of nutrient availability and light energy supply in wild-type Arabidopsis produced phenotypes observed with TOR knockdown plants, indicating a link between TOR signaling and nutrition/light energy status. Genetic and physiological studies together with RNA sequencing and metabolite analysis of TOR-suppressed lines revealed that TOR regulates development and life span in Arabidopsis by restructuring cell growth, carbon and nitrogen metabolism, gene expression, and rRNA and protein synthesis. Gain- and loss-of-function Ribosomal Protein S6 (RPS6) mutants additionally show that TOR function involves RPS6-mediated nutrition and light-dependent growth and life span in Arabidopsis. PMID:23275579

MiRNA-101 inhibits oral squamous-cell carcinoma growth and metastasis by targeting zinc finger E-box binding homeobox 1

PubMed Central

Wu, Baolei; Lei, Delin; Wang, Lei; Yang, Xinjie; Jia, Sen; Yang, Zihui; Shan, Chun; Yang, Xi; Zhang, Chenping; Lu, Bin

2016-01-01

MicroRNAs (miRNAs) are implicated in the pathogenesis of oral squamous-cell carcinoma (OSCC). miR-101 is involved in the development and progression of OSCC, but the biological functions and underlying molecular mechanisms of this miRNA remain largely unknown. In this study, we showed that miR-101 was underexpressed in OSCC tissues and cell lines. miR-101 downregulation was inversely correlated with zinc finger E-box binding homeobox 1 (ZEB1) expression, lymph-node metastasis, and poor prognosis in OSCC patients. Enhanced expression of miR-101 significantly inhibited OSCC cell proliferation, apoptosis resistance, migration and invasion in vitro, and suppressed tumor growth and lung metastasis in vivo. Bioinformatics analyses showed that miR-101 directly targeted ZEB1, as confirmed by a dual-luciferase reporter assay. The inhibitory effects of miR-101 on OSCC growth and metastasis were attenuated and phenocopied by ZEB1 overexpression and knockdown, respectively. Overall, our findings indicated that miRNA-101 reduced OSCC growth and metastasis by targeting ZEB1 and provided new evidence of miR-101 as a potential therapeutic target for OSCC patients. PMID:27429852

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways.

PubMed

Newton, Herbert B

2003-10-01

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clinical trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clinical trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.

Regional price targets appropriate for advanced coal extraction

NASA Technical Reports Server (NTRS)

Terasawa, K. L.; Whipple, D. M.

1980-01-01

A methodology is presented for predicting coal prices in regional markets for the target time frames 1985 and 2000 that could subsequently be used to guide the development of an advanced coal extraction system. The model constructed is a supply and demand model that focuses on underground mining since the advanced technology is expected to be developed for these reserves by the target years. Coal reserve data and the cost of operating a mine are used to obtain the minimum acceptable selling price that would induce the producer to bring the mine into production. Based on this information, market supply curves can be generated. Demand by region is calculated based on an EEA methodology that emphasizes demand by electric utilities and demand by industry. The demand and supply curves are then used to obtain the price targets. The results show a growth in the size of the markets for compliance and low sulphur coal regions. A significant rise in the real price of coal is not expected even by the year 2000. The model predicts heavy reliance on mines with thick seams, larger block size and deep overburden.

Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy.

PubMed

Dharmawardana, Pathirage G; Peruzzi, Benedetta; Giubellino, Alessio; Burke, Terrence R; Bottaro, Donald P

2006-01-01

Growth factor receptor-bound 2 (Grb2) is a ubiquitously expressed adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. As such, it has been implicated in the oncogenesis of several important human malignancies. In addition to this function, research over the last decade has revealed other fundamental roles for Grb2 in cell motility and angiogenesis--processes that also contribute to tumor growth, invasiveness and metastasis. This functional profile makes Grb2 a high priority target for anti-cancer drug development. Knowledge of Grb2 protein structure, its component Src homology domains and their respective structure-function relationships has facilitated the rapid development of sophisticated drug candidates that can penetrate cells, bind Grb2 with high affinity and potently antagonize Grb2 signaling. These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics.

FGFR a promising druggable target in cancer: Molecular biology and new drugs.

PubMed

Porta, Rut; Borea, Roberto; Coelho, Andreia; Khan, Shahanavaj; Araújo, António; Reclusa, Pablo; Franchina, Tindara; Van Der Steen, Nele; Van Dam, Peter; Ferri, Jose; Sirera, Rafael; Naing, Aung; Hong, David; Rolfo, Christian

2017-05-01

The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations. Copyright © 2017 Elsevier B.V. All rights reserved.

The use of stored carbon reserves in growth of temperate tree roots and leaf buds: Analyses using radiocarbon measurements and modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaudinski, J.B.; Torn, M.S.; Riley, W.J.

2009-02-01

Characterizing the use of carbon (C) reserves in trees is important for understanding regional and global C cycles, stress responses, asynchrony between photosynthetic activity and growth demand, and isotopic exchanges in studies of tree physiology and ecosystem C cycling. Using an inadvertent, whole-ecosystem radiocarbon ({sup 14}C) release in a temperate deciduous oak forest and numerical modeling, we estimated that the mean age of stored C used to grow both leaf buds and new roots is 0.7 years and about 55% of new-root growth annually comes from stored C. Therefore, the calculated mean age of C used to grow new-root tissuemore » is {approx}0.4 years. In short, new roots contain a lot of stored C but it is young in age. Additionally, the type of structure used to model stored C input is important. Model structures that did not include storage, or that assumed stored and new C mixed well (within root or shoot tissues) before being used for root growth, did not fit the data nearly as well as when a distinct storage pool was used. Consistent with these whole-ecosystem labeling results, the mean age of C in new-root tissues determined using 'bomb-{sup 14}C' in three additional forest sites in North America and Europe (one deciduous, two coniferous) was less than 1-2 years. The effect of stored reserves on estimated ages of fine roots is unlikely to be large in most natural abundance isotope studies. However, models of root C dynamics should take stored reserves into account, particularly for pulse-labeling studies and fast-cycling roots (<1 years).« less

Intricate Puzzle of Oil and Gas Reserves Growth

EIA Publications

1997-01-01

This article begins with a background discussion of the methods used to estimate proved oil and gas reserves and ultimate recovery, which is followed by a discussion of the factors that affect the ultimate recovery estimates of a field or reservoir.

MicroRNA-340 suppresses osteosarcoma tumor growth and metastasis by directly targeting ROCK1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Xin; Wei, Min; Wang, Wei, E-mail: rjwangwei@126.com

2013-08-09

Highlights: •miR-340 is downregulated in OS cell lines and tissues. •miR-340 suppresses OS cell proliferation, migration and invasion. •miR-340 suppresses tumor growth and metastasis of OS cells in nude mice. •ROCK1 is a target gene of miR-340. •ROCK1 is involved in miR-340-induced suppression of OS cell proliferation, migration and invasion. -- Abstract: MicroRNAs (miRNAs) play key roles in cancer development and progression. In the present study, we investigated the role of miR-340 in the progression and metastasis of osteosarcoma (OS). Our results showed that miR-340 was frequently downregulated in OS tumors and cell lines. Overexpression of miR-340 in OS cellmore » lines significantly inhibited cell proliferation, migration, and invasion in vitro, and tumor growth and metastasis in a xenograft mouse model. ROCK1 was identified as a target of miR-340, and ectopic expression of miR-340 downregulated ROCK1 by direct binding to its 3′ untranslated region. siRNA-mediated silencing of ROCK1 phenocopied the effects of miR-340 overexpression, whereas restoration of ROCK1 in miR-340-overexpressing OS cells reversed the suppressive effects of miR-340. Together, these findings indicate that miR-340 acts as a tumor suppressor and its downregulation in tumor tissues may contribute to the progression and metastasis of OS through a mechanism involving ROCK1, suggesting miR-340 as a potential new diagnostic and therapeutic target for the treatment of OS.« less

Effects of sex change on the implications of marine reserves for fisheries.

PubMed

Chan, Neil C S; Connolly, Sean R; Mapstone, Bruce D

2012-04-01

Marine reserves have become widely used in biodiversity conservation and are increasingly proposed as fisheries management tools. Previous modeling studies have found that reserves may increase or decrease yields, depending on local environmental conditions and on the specific life-history traits of the fishery species. Sex-changing (female-to-male) fish are targets of some of the most important commercial and recreational fisheries in the world. The potential for disproportionate removal of the larger, older sex of such species requires new theory to facilitate our understanding of how reserves will affect the yields of surrounding fisheries, relative to fishes with separate sexes. We investigated this question by modeling the effects of marine reserves on a non-sex-changing and a sex-changing population. We used demographic parameter estimates for the common coral trout as a baseline, and we conducted extensive sensitivity analyses to determine how sustainable yields of sex-changing species are likely to be affected by reserves across a broad range of life-history parameters. Our findings indicate that fisheries for sex-changing species are unlikely to receive the same yield-enhancing benefit that non-sex-changing fisheries enjoy from marine reserves, and that often reserves tend to reduce sustainable yields for a given overall population size. Specifically, the increased egg production and high fertilization success within reserves is more than offset by the reduced egg production and fertilization success in the fished areas, relative to a system in which fishing mortality is distributed more evenly over the entire system. A key reason for this appears to be that fertilization success is reduced, on average, when males are unevenly distributed among subpopulations, as is the case when reserves are present. These findings suggests that, for sex-changing populations, reserves are more suited to rebuilding overfished populations and sustaining fishery viability

USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance

PubMed Central

Lee, Jin-Ku; Chang, Nakho; Yoon, Yeup; Yang, Heekyoung; Cho, Heejin; Kim, Eunhee; Shin, Yongjae; Kang, Wonyoung; Oh, Young Taek; Mun, Gyeong In; Joo, Kyeung Min; Nam, Do-Hyun; Lee, Jeongwu

2016-01-01

Background Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. Methods We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. Results USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. Conclusion USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM. PMID:26032834

Targeting fibroblast growth factor receptor in breast cancer: a promise or a pitfall?

PubMed

Bedussi, Francesca; Bottini, Alberto; Memo, Maurizio; Fox, Stephen B; Sigala, Sandra; Generali, Daniele

2014-06-01

Fibroblast growth factors (FGFs) along with their receptors (FGFRs) are involved in several cellular functions, from embryogenesis to metabolism. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival in cancer, these have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. New evidences indicate that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial-to-mesenchymal transition, invasion and tumour angiogenesis. This review focuses on the predictive and prognostic role of FGFRs, the role of FGFR signalling and how it may be most appropriately therapeutically targeted in breast cancer. Activation of the FGFR pathway is a common event in many cancer types and for this reason FGFR is an important potential target in cancer treatment. Relevant literature was reviewed to identify current and future role of FGFR family as a possible guide for selecting those patients who would be poor or good responders to the available or the upcoming target therapies for breast cancer treatment. The success of a personalised medicine approach using targeted therapies ultimately depends on being capable of identifying the patients who will benefit the most from any given drug. Outlining the molecular mechanisms of FGFR signalling and discussing the role of this pathway in breast cancer, we would like to endorse the incorporation of specific patient selection biomakers with the rationale for therapeutic intervention with FGFR-targeted therapy in breast cancer.

Axon Targeting of the Alpha 7 Nicotinic Receptor in Developing Hippocampal Neurons by Gprin1 Regulates Growth

PubMed Central

Nordman, Jacob C.; Philips, Wiktor S.; Kodama, Nathan; Clark, Sarah G.; Negro, Christopher Del; Kabbani, Nadine

2015-01-01

Cholinergic signaling plays an important role in regulating the growth and regeneration of axons in the nervous system. The α7 nicotinic receptor (α7) can drive synaptic development and plasticity in the hippocampus. Here we show that activation of α7 significantly reduces axon growth in hippocampal neurons by coupling to G protein regulated inducer of neurite outgrowth 1 (Gprin1), which targets it to the growth cone (GC). Knockdown of Gprin1 expression using RNAi is found sufficient to abolish the localization and calcium signaling of α7 at the GC. In particular, α7/Gprin1 interaction appears intimately linked to a Gαo, GAP-43, and CDC42 cytoskeletal regulatory pathway within the developing axon. These findings demonstrate that α7 regulates axon growth in hippocampal neurons, thereby likely contributing to synaptic formation in the developing brain. PMID:24350810

Prioritizing plant defence over growth through WRKY regulation facilitates infestation by non-target herbivores

PubMed Central

Li, Ran; Zhang, Jin; Li, Jiancai; Zhou, Guoxin; Wang, Qi; Bian, Wenbo; Erb, Matthias; Lou, Yonggen

2015-01-01

Plants generally respond to herbivore attack by increasing resistance and decreasing growth. This prioritization is achieved through the regulation of phytohormonal signaling networks. However, it remains unknown how this prioritization affects resistance against non-target herbivores. In this study, we identify WRKY70 as a specific herbivore-induced, mitogen-activated protein kinase-regulated rice transcription factor that physically interacts with W-box motifs and prioritizes defence over growth by positively regulating jasmonic acid (JA) and negatively regulating gibberellin (GA) biosynthesis upon attack by the chewing herbivore Chilo suppressalis. WRKY70-dependent JA biosynthesis is required for proteinase inhibitor activation and resistance against C. suppressalis. In contrast, WRKY70 induction increases plant susceptibility against the rice brown planthopper Nilaparvata lugens. Experiments with GA-deficient rice lines identify WRKY70-dependent GA signaling as the causal factor in N. lugens susceptibility. Our study shows that prioritizing defence over growth leads to a significant resistance trade-off with important implications for the evolution and agricultural exploitation of plant immunity. DOI: http://dx.doi.org/10.7554/eLife.04805.001 PMID:26083713

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

PubMed Central

Yashiro, Masakazu; Matsuoka, Tasuku

2016-01-01

Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer. PMID:26937130

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer.

PubMed

Yashiro, Masakazu; Matsuoka, Tasuku

2016-02-28

Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.

Nutrient reserve dynamics of breeding canvasbacks

USGS Publications Warehouse

Barzen, Jeb A.; Serie, Jerome R.

1990-01-01

We compared nutrients in reproductive and nonreproductive tissues of breeding Canvasbacks (Aythya valisineria) to assess the relative importance of endogenous reserves and exogenous foods. Fat reserves of females increased during rapid follicle growth and varied more widely in size during the early phase of this period. Females began laying with ca. 205 g of fat in reserve and lost 1.8 g of carcass fat for every 1 g of fat contained in their ovary and eggs. Females lost body mass (primarily fat) at a declining rate as incubation advanced. Protein reserves increased directly with dry oviduct mass during rapid follicle growth. This direct relationship was highly dependent upon data from 2 birds and likely biased by structural size. During laying, protein reserves did not vary with the combined mass of dry oviduct and dry egg protein. Between laying and incubation, mean protein reserves decreased by an amount equal to the protein found in 2.1 Canvasback eggs. Calcium reserves did not vary with the cumulative total of calcium deposited in eggs. Mean calcium reserve declined by the equivalent content of 1.2 eggs between laying and incubation. We believe that protein and calcium were stored in small amounts during laying, and that they were supplemented continually by exogenous sources. In contrast, fat was stored in large amounts and contributed significantly to egg production and body maintenance. Male Canvasbacks lost fat steadily-but not protein or calcium-as the breeding season progressed.

Direct targeting of MEK1/2 and RSK2 by silybin induces cell cycle arrest and inhibits melanoma cell growth

PubMed Central

Lee, Mee-Hyun; Huang, Zunnan; Kim, Dong Joon; Kim, Sung-Hyun; Kim, Myoung Ok; Lee, Sung-Young; Xie, Hua; Park, Si Jun; Kim, Jae Young; Kundu, Joydeb Kumar; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

2013-01-01

Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of nuclear factor-kappaB, activator protein-1 and signal transducer and activator of transcription-3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways. PMID:23447564

Delivery of CdiA Nuclease Toxins into Target Cells during Contact-Dependent Growth Inhibition

PubMed Central

Webb, Julia S.; Nikolakakis, Kiel C.; Willett, Julia L. E.; Aoki, Stephanie K.

2013-01-01

Bacterial contact-dependent growth inhibition (CDI) is mediated by the CdiB/CdiA family of two-partner secretion proteins. CDI systems deploy a variety of distinct toxins, which are contained within the polymorphic C-terminal region (CdiA-CT) of CdiA proteins. Several CdiA-CTs are nucleases, suggesting that the toxins are transported into the target cell cytoplasm to interact with their substrates. To analyze CdiA transfer to target bacteria, we used the CDI system of uropathogenic Escherichia coli 536 (UPEC536) as a model. Antibodies recognizing the amino- and carboxyl-termini of CdiAUPEC536 were used to visualize transfer of CdiA from CDIUPEC536+ inhibitor cells to target cells using fluorescence microscopy. The results indicate that the entire CdiAUPEC536 protein is deposited onto the surface of target bacteria. CdiAUPEC536 transfer to bamA101 mutants is reduced, consistent with low expression of the CDI receptor BamA on these cells. Notably, our results indicate that the C-terminal CdiA-CT toxin region of CdiAUPEC536 is translocated into target cells, but the N-terminal region remains at the cell surface based on protease sensitivity. These results suggest that the CdiA-CT toxin domain is cleaved from CdiAUPEC536 prior to translocation. Delivery of a heterologous Dickeya dadantii CdiA-CT toxin, which has DNase activity, was also visualized. Following incubation with CDI+ inhibitor cells targets became anucleate, showing that the D.dadantii CdiA-CT was delivered intracellularly. Together, these results demonstrate that diverse CDI toxins are efficiently translocated across target cell envelopes. PMID:23469034

Improved neovascularization and wound repair by targeting human basic fibroblast growth factor (bFGF) to fibrin.

PubMed

Zhao, Wenxue; Han, Qianqian; Lin, Hang; Gao, Yuan; Sun, Wenjie; Zhao, Yannan; Wang, Bin; Chen, Bing; Xiao, Zhifeng; Dai, Jianwu

2008-10-01

Targeted therapy is a new generation of therapeutics, where two critical factors are involved. One is the particular molecular target, and the other is the specific target-binding drug. In this work, the fibrin, a main component of plasma clot at wound sites, was used as the target for human bFGF, aiming to improve therapeutic neovascularization and wound repair. To endow bFGF with fibrin-targeting ability, a fibrin-binding peptide Kringle1 (K1), derived from human plasminogen, was fused to human bFGF. The recombinant K1bFGF showed high fibrin and plasma-clot-binding ability. When applied to the wound sites with plasma clots, K1bFGF induced robust neovascularization and improved wound healing. To extend the application of K1bFGF to other cases where no plasma clots exist, we developed a fibrin-scaffold/K1bFGF system. This system could induce localized neovascularization by delivery of K1bFGF in a sustained and site-targeting manner, and provide a microenvironment promoting cell growth and tissue regeneration. In summary, we successfully used the pathologic environment fibrin clot as the target for bFGF, and based on which bFGF was designed into a targeting agent by introduction of a fibrin-binding peptide. This provides a potential approach to improve therapeutic neovascularization and wound repair.

A targeted boost-and-sort immunization strategy using Escherichia coli BamA identifies rare growth inhibitory antibodies.

PubMed

Vij, Rajesh; Lin, Zhonghua; Chiang, Nancy; Vernes, Jean-Michel; Storek, Kelly M; Park, Summer; Chan, Joyce; Meng, Y Gloria; Comps-Agrar, Laetitia; Luan, Peng; Lee, Sophia; Schneider, Kellen; Bevers, Jack; Zilberleyb, Inna; Tam, Christine; Koth, Christopher M; Xu, Min; Gill, Avinash; Auerbach, Marcy R; Smith, Peter A; Rutherford, Steven T; Nakamura, Gerald; Seshasayee, Dhaya; Payandeh, Jian; Koerber, James T

2018-05-08

Outer membrane proteins (OMPs) in Gram-negative bacteria are essential for a number of cellular functions including nutrient transport and drug efflux. Escherichia coli BamA is an essential component of the OMP β-barrel assembly machinery and a potential novel antibacterial target that has been proposed to undergo large (~15 Å) conformational changes. Here, we explored methods to isolate anti-BamA monoclonal antibodies (mAbs) that might alter the function of this OMP and ultimately lead to bacterial growth inhibition. We first optimized traditional immunization approaches but failed to identify mAbs that altered cell growth after screening >3000 hybridomas. We then developed a "targeted boost-and-sort" strategy that combines bacterial cell immunizations, purified BamA protein boosts, and single hybridoma cell sorting using amphipol-reconstituted BamA antigen. This unique workflow improves the discovery efficiency of FACS + mAbs by >600-fold and enabled the identification of rare anti-BamA mAbs with bacterial growth inhibitory activity in the presence of a truncated lipopolysaccharide layer. These mAbs represent novel tools for dissecting the BamA-mediated mechanism of β-barrel folding and our workflow establishes a new template for the efficient discovery of novel mAbs against other highly dynamic membrane proteins.

Long-term effect of carbohydrate reserves on growth and reproduction of Prosopis denudans (Fabaceae): implications for conservation of woody perennials

PubMed Central

Vilela, Alejandra E.; Agüero, Paola R.; Ravetta, Damián; González-Paleo, Luciana

2016-01-01

Prosopis denudans, an extreme xerophyte shrub, is consumed by ungulates and threatened by firewood gathering, because it is one of the preferred species used by Mapuche indigenous people of Patagonia. In a scenario of uncontrolled use of vegetation, it is very difficult to develop a conservation plan that jointly protects natural resources and its users. We performed a field experiment to assess the impact of defoliation on growth, reproduction and stores of a wild population of P. denudans. We imposed four levels of defoliation (removal of 100, 66, 33 and 0% of leaves) and evaluated the short- and long-term (3 years) effects of this disturbance. Seasonal changes in shoot carbohydrates suggested that they support leaf-flush and blooming. Severely defoliated individuals also used root reserves to support growth and leaf-flush after clipping. Vegetative growth was not affected by defoliation history. Leaf mass area increased after the initial clipping, suggesting the development of structural defenses. The depletion of root reserves at the end of the first year affected inflorescence production the following spring. We conclude that P. denudans shrubs could lose up to one-third of their green tissues without affecting growth or inflorescence production. The removal of a higher proportion of leaves will diminish stores, which in turn, will reduce or completely prevent blooming and, therefore, fruit production the following seasons. Very few studies integrate conservation and plant physiology, and we are not aware, so far, of any work dealing with long-term plant carbon economy of a long-lived perennial shrub as an applied tool in conservation. These results might help the development of management strategies that consider both the use and the conservation of wild populations of P. denudans. PMID:27293747

Celastrol suppresses tumor cell growth through targeting an AR-ERG-NF-κB pathway in TMPRSS2/ERG fusion gene expressing prostate cancer.

PubMed

Shao, Longjiang; Zhou, Zhansong; Cai, Yi; Castro, Patricia; Dakhov, Olga; Shi, Ping; Bai, Yaoxia; Ji, Huixiang; Shen, Wenhao; Wang, Jianghua

2013-01-01

The TMPRSS2/ERG (T/E) fusion gene is present in the majority of all prostate cancers (PCa). We have shown previously that NF-kB signaling is highly activated in these T/E fusion expressing cells via phosphorylation of NF-kB p65 Ser536 (p536). We therefore hypothesize that targeting NF-kB signaling may be an efficacious approach for the subgroup of PCas that carry T/E fusions. Celastrol is a well known NF-kB inhibitor, and thus may inhibit T/E fusion expressing PCa cell growth. We therefore evaluated Celastrol's effects in vitro and in vivo in VCaP cells, which express the T/E fusion gene. VCaP cells were treated with different concentrations of Celastrol and growth inhibition and target expression were evaluated. To test its ability to inhibit growth in vivo, 0.5 mg/kg Celastrol was used to treat mice bearing subcutaneous VCaP xenograft tumors. Our results show Celastrol can significantly inhibit the growth of T/E fusion expressing PCa cells both in vitro and in vivo through targeting three critical signaling pathways: AR, ERG and NF-kB in these cells. When mice received 0.5 mg/kg Celastrol for 4 times/week, significant growth inhibition was seen with no obvious toxicity or significant weight loss. Therefore, Celastrol is a promising candidate drug for T/E fusion expressing PCa. Our findings provide a novel strategy for the targeted therapy which may benefit the more than half of PCa patients who have T/E fusion expressing PCas.

miRNA and Degradome Sequencing Reveal miRNA and Their Target Genes That May Mediate Shoot Growth in Spur Type Mutant “Yanfu 6”

PubMed Central

Song, Chunhui; Zhang, Dong; Zheng, Liwei; Zhang, Jie; Zhang, Baojuan; Luo, Wenwen; Li, Youmei; Li, Guangfang; Ma, Juanjuan; Han, Mingyu

2017-01-01

The spur-type growth habit in apple trees is characterized by short internodes, increased number of fruiting spurs, and compact growth that promotes flowering and facilitates management practices, such as pruning. The molecular mechanisms responsible for regulating spur-type growth have not been elucidated. In the present study, miRNAs and the expression of their potential target genes were evaluated in shoot tips of “Nagafu 2” (CF) and spur-type bud mutation “Yanfu 6” (YF). A total of 700 mature miRNAs were identified, including 202 known apple miRNAs and 498 potential novel miRNA candidates. A comparison of miRNA expression in CF and YF revealed 135 differentially expressed genes, most of which were downregulated in YF. YF also had lower levels of GA, ZR, IAA, and ABA hormones, relative to CF. Exogenous applications of GA promoted YF shoot growth. Based on the obtained results, a regulatory network involving plant hormones, miRNA, and their potential target genes is proposed for the molecular mechanism regulating the growth of YF. miRNA164, miRNA166, miRNA171, and their potential targets, and associated plant hormones, appear to regulate shoot apical meristem (SAM) growth. miRNA159, miRNA167, miRNA396, and their potential targets, and associated plant hormones appear to regulate cell division and internode length. This study provides a foundation for further studies designed to elucidate the mechanism underlying spur-type apple architecture. PMID:28424721

Hepatoma-derived growth factor: A survival-related protein in prostate oncogenesis and a potential target for vitamin K2.

PubMed

Shetty, Aditya; Dasari, Subramanyam; Banerjee, Souresh; Gheewala, Taher; Zheng, Guoxing; Chen, Aoshuang; Kajdacsy-Balla, Andre; Bosland, Maarten C; Munirathinam, Gnanasekar

2016-11-01

Hepatoma-derived growth factor (HDGF) is a heparin-binding growth factor, which has previously been shown to be expressed in a variety of cancers. HDGF overexpression has also previously been correlated with a poor prognosis in several cancers. The significance of HDGF in prostate cancer, however, has not been investigated. Here, we show that HDGF is overexpressed in both androgen-sensitive LNCaP cells and androgen-insensitive DU145, 22RV1, and PC-3 cells. Forced overexpression enhanced cell viability of RWPE-1 cells, whereas HDGF knockdown reduced cell proliferation in human prostate cancer cells. We also show that HDGF may serve as a survival-related protein as ectopic overexpression of HDGF in RWPE cells up-regulated the expression of antiapoptosis proteins cyclin E and BCL-2, whereas simultaneously down-regulating proapoptotic protein BAX. Western blot analysis also showed that HDGF overexpression modulated the activity of phospho-AKT as well as NF-kB, and these results correlated with in vitro migration and invasion assays. We next assessed the therapeutic potential of HDGF inhibition with a HDGF monoclonal antibody and vitamin k 2 , showing reduced cell proliferation as well as inhibition of NF-kB expression in HDGF overexpressed RWPE cells treated with a HDGF monoclonal antibody and vitamin K 2 . Collectively, our results suggest that HDGF is a relevant protein in prostate oncogenesis and may serve as a potential therapeutic target in prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells.

PubMed

Ferrari-Toninelli, Giulia; Bonini, Sara Anna; Uberti, Daniela; Buizza, Laura; Bettinsoli, Paola; Poliani, Pietro Luigi; Facchetti, Fabio; Memo, Maurizio

2010-12-01

High-risk neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Understanding the molecular mechanisms involved in tumor development and progression is strategic for the improvement of pharmacological therapies. Notch was recently proposed as a pharmacological target for the therapy of several cancers and is emerging as a new neuroblastoma-related molecular pathway. However, the precise role played by Notch in this cancer remains to be studied extensively. Here, we show that Notch activation by the Jagged1 ligand enhances the proliferation of neuroblastoma cells, and we propose the possible use of Notch-blocking γ-secretase inhibitors (GSIs) in neuroblastoma therapy. Two different GSIs, Compound E and DAPT, were tested alone or in combination with 13-cis retinoic acid (RA) on neuroblastoma cell lines. SH-SY5Y and IMR-32 cells were chosen as paradigms of lower and higher malignancy, respectively. Used alone, GSIs induced complete cell growth arrest, promoted neuronal differentiation, and significantly reduced cell motility. The combination of GSIs and 13-cis RA resulted in the enhanced growth inhibition, differentiation, and migration of neuroblastoma cells. In summary, our data suggest that a combination of GSIs with 13-cis RA offers a therapeutic advantage over a single agent, indicating a potential novel therapy for neuroblastoma.

New multi-targeting strategy in hair growth promotion: in vitro and in vivo studies.

PubMed

Marzani, Barbara; Pinto, Daniela; Sorbellini, Elisabetta; Rinaldi, Fabio

2018-06-01

Considering the importance of hair in our modern society and the impact of hair loss, the efforts of researchers are addressed to better understand the mechanisms behind the hair cycle regulation and dysregulation. Because hair loss is multifactorial, differenced and new approaches are required. In particular we addressed our attention to two recently identified targets in hair cycling and growth control: olfactory receptor and autophagy. The aim of the study was to evaluate: the possible pro-autophagic effect of N1-methylspermidine (a spermidine analogue) in vitro and, in a double blind clinical trial, the safety and efficacy of topical daily application of a lotion containing N1-methylspermidine and Sandalore®. Autophagic modulation by N1-methylspermidine was monitored in vitro by LC3 and p62 fluorescent signal cell line. Topical daily application of the lotion was tested in 60 male and female subjects with chronic telogen effluvium by means of non-invasive objective evaluation. The results obtained by in vitro tests showed the capacity of N1-methylspermidine to increase autophagic process while the clinical trials performed confirmed the safety and anti hair loss efficacy of the lotion reporting a reduction of hair loss (modified wash test) and hair growth stimulation as evaluated by hair density, hair shaft diameter, % of anagen hair and Hair Mass Index increase after 3 months of treatment. The lotion efficacy remained statistically significant for the above-mentioned parameters, with the exception of hair lost during wash, also 3 months after the end of treatment. Based on the obtained results, the daily use of the N1-methylspermidine and Sandalore®-based lotion is efficient to counteract hair loss and increase hair growth by a multifunctional targeting approach.

Tree Nonstructural Carbohydrate Reserves Across Eastern US Temperate Forests

NASA Astrophysics Data System (ADS)

Mantooth, J.; Dietze, M.

2015-12-01

Understanding the roles, importance, and dynamics of tree non-structural carbohydrates (NSCs) is currently an active area of research. The question of how the relationships between NSCs, growth, and mortality can be used to develop more accurate projections of forest dynamics is central to this research. To begin to address this question, we have asked an even more fundamental question: How much are trees allocating carbon to storage, in the form of NSCs, versus new growth? Ecological theory predicts that there should be trade-offs between different plant life history strategies provided that there are the carbon mass-balance constraints to enforce these trade-offs. Current data on tree NSCs lack the spatial and taxonomic extent required to properly address this question. Therefore, we established a network of forest inventory plots at ten sites across the eastern US and measured growth in adult trees using increment cores and repeat measures of diameter at breast height (DBH). Increment cores were also used to measure sapwood NSCs. We hypothesized that across the eastern US, shade tolerant species, e.g. Sugar Maple (Acer saccharum) have the largest NSC reserves and that shade intolerant species have the lowest reserves. We also hypothesized that NSC reserves increase with temperature and precipitation, as with growth, and that within species NSC reserves increase with growth rate. Initial analyses of tree NSCs indicates that trees of intermediate shade tolerance, e.g. Red Oak (Quercus rubra) have the highest concentrations of sapwood NSCs, and among the highest growth rates. Across the entire study region, NSC concentrations are positively correlated with tree size and growth rate. Within species, NSC concentrations are also positively correlated with growth rate. Across functional groups healthy individuals have significantly higher sapwood NSC concentrations than visibly stressed individuals. There are also significantly lower NSC concentrations in sapwood of

75 FR 18146 - Wetlands Reserve Enhancement Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-09

... DEPARTMENT OF AGRICULTURE Commodity Credit Corporation Wetlands Reserve Enhancement Program AGENCY... assistance will be made available in fiscal year (FY) 2010 for the Wetlands Reserve Enhancement Program (WREP... partners to help enhance conservation outcomes on wetlands and adjacent lands. WREP targets and leverages...

Identification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors.

PubMed Central

Xiao, J H; Feng, X; Di, W; Peng, Z H; Li, L A; Chambon, P; Voorhees, J J

1999-01-01

The role of retinoic acid receptors (RARs) in intercellular regulation of cell growth was assessed by targeting a dominant-negative RARalpha mutant (dnRARalpha) to differentiated suprabasal cells of mouse epidermis. dnRARalpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRARalpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA). dnRARalpha formed heterodimers with endogenous retinoid X receptor-alpha (RXRalpha) over RA response elements in competition with remaining endogenous RARgamma-RXRalpha heterodimers, and dose-dependently impaired retinoid-dependent gene transcription. To identify genes regulated by retinoid receptors and involved in cell growth control, we analyzed the retinoid effects on expression of the epidermal growth factor (EGF) receptor, EGF, transforming growth factor-alpha, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin genes. In normal epidermis, tRA rapidly and selectively induced expression of HB-EGF but not the others. This induction occurred exclusively in suprabasal cells. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell hyperproliferation. Together, our observations suggest that retinoid receptor heterodimers located in differentiated suprabasal cells mediate retinoid induction of HB-EGF, which in turn stimulates basal cell growth via intercellular signaling. These events may underlie retinoid action in epidermal regeneration during wound healing. PMID:10075925

Tyrosine kinase inhibitor induced growth factor receptor upregulation enhances the efficacy of near-infrared targeted photodynamic therapy in esophageal adenocarcinoma cell lines.

PubMed

Hartmans, Elmire; Linssen, Matthijs D; Sikkens, Claire; Levens, Afra; Witjes, Max J H; van Dam, Gooitzen M; Nagengast, Wouter B

2017-05-02

Esophageal carcinoma (EC) is a global health problem, with disappointing 5-year survival rates of only 15-25%. Near-infrared targeted photodynamic therapy (NIR-tPDT) is a novel strategy in which cancer-targeted phototoxicity is able to selectively treat malignant cells. In this in vitro report we demonstrate the applicability of antibody-based NIR-tPDT in esophageal adenocarcinoma (EAC), using the phototoxic compounds cetuximab-IRDye700DX and trastuzumab-IRDye700DX, targeting respectively epidermal growth factor receptor 1 (EGFR) and 2 (HER2). Furthermore, we demonstrate that NIR-tPDT can be made more effective by tyrosine kinase inhibitor (TKI) induced growth receptor upregulation. Together, these results unveil a novel strategy for non-invasive EAC treatment, and by pretreatment-induced receptor upregulation its future clinical application may be optimized.

Managing for old-growth forests: a moving target

Treesearch

Thomas A. Spies; Robert J. Pabst

2013-01-01

Presentation Abstract Old-growth Douglas-fi r (Pseudotsuga menziesii) forests are a goal for conservation and restoration across millions of acres of federal forest lands in western Oregon and Washington. Where old growth currently exists, management is typically focused on protecting stands and watersheds from logging and high-severity wildfi re. Where old growth was...

Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice

PubMed Central

2012-01-01

Background Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. Methods First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. Results Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. Conclusions We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics. PMID:22857000

Is fibroblast growth factor receptor 4 a suitable target of cancer therapy?

PubMed

Heinzle, Christine; Erdem, Zeynep; Paur, Jakob; Grasl-Kraupp, Bettina; Holzmann, Klaus; Grusch, Michael; Berger, Walter; Marian, Brigitte

2014-01-01

Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy.

Is Fibroblast Growth Factor Receptor 4 a Suitable Target of Cancer Therapy?

PubMed Central

Heinzle, Christine; Erdem, Zeynep; Paur, Jakob; Grasl-Kraupp, Bettina; Holzmann, Klaus; Grusch, Michael; Berger, Walter; Marian, Brigitte

2017-01-01

Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy. PMID:23944363

Alanine rich peptide from Populus trichocarpa inhibit growth of Staphylococcus aureus via targetting its extracellular domain of Sensor Histidine Kinase YycGex protein.

PubMed

Al Akeel, Raid; Mateen, Ayesha; Syed, Rabbani; Alqahtani, Mohammed S; Alqahtani, Ali S

2018-05-22

Due to growing concern towards microbial resistance, ongoing search for developing novel bioactive compounds such as peptides is on rise. The aim of this study was to evaluate antimicrobial effect of Populus trichocarpa extract, chemically identify the active peptide fraction and finds its target in Staphylococcus aureus. In this study the active fraction of P. trichocarpa crude extract was purified and characterized using MS/MS. This peptide PT13 antimicrobial activity was confirmed by in-vitro agar based disk diffusion and in-vivo infection model of G. mellonella. The proteomic expression analysis of S. aureus under influence of PT13 was studied using LTQ-Orbitrap-MS in-solution digestion and identity of target protein was acquired with their quantified expression using label-free approach of Progenesis QI software. Docking study was performed with peptide PT13 and its target YycG protein using CABS-dock. The active fraction PT13 sequence was identified as KVPVAAAAAAAAAVVASSMVVAAAK, with 25 amino acid including 13 alanine having M/Z 2194.2469. PT13 was uniformly inhibited growth S. aureus SA91 and MIC was determined 16 μg/mL for SA91 S. aureus strain. Sensor histidine kinase (YycG) was most significant target found differentially expressed under influence of PT13. G. mellonella larvae were killed rapidly due to S aureus infection, whereas death in protected group was insignificant in compare to control. The docking models showed ten docking models with RMSD value 1.89 for cluster 1 and RMSD value 3.95 for cluster 2 which is predicted to be high quality model. Alanine rich peptide could be useful in constructing as antimicrobial peptide for targeting extracellular Domain of Sensor Histidine Kinase YycG from S. aureus used in the study. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect of planning for connectivity on linear reserve networks.

PubMed

Lentini, Pia E; Gibbons, Philip; Carwardine, Josie; Fischer, Joern; Drielsma, Michael; Martin, Tara G

2013-08-01

Although the concept of connectivity is decades old, it remains poorly understood and defined, and some argue that habitat quality and area should take precedence in conservation planning instead. However, fragmented landscapes are often characterized by linear features that are inherently connected, such as streams and hedgerows. For these, both representation and connectivity targets may be met with little effect on the cost, area, or quality of the reserve network. We assessed how connectivity approaches affect planning outcomes for linear habitat networks by using the stock-route network of Australia as a case study. With the objective of representing vegetation communities across the network at a minimal cost, we ran scenarios with a range of representation targets (10%, 30%, 50%, and 70%) and used 3 approaches to account for connectivity (boundary length modifier, Euclidean distance, and landscape-value [LV]). We found that decisions regarding the target and connectivity approach used affected the spatial allocation of reserve systems. At targets ≥50%, networks designed with the Euclidean distance and LV approaches consisted of a greater number of small reserves. Hence, by maximizing both representation and connectivity, these networks compromised on larger contiguous areas. However, targets this high are rarely used in real-world conservation planning. Approaches for incorporating connectivity into the planning of linear reserve networks that account for both the spatial arrangement of reserves and the characteristics of the intervening matrix highlight important sections that link the landscape and that may otherwise be overlooked. © 2013 Society for Conservation Biology.

Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets.

PubMed

Tenhagen, M; van Diest, P J; Ivanova, I A; van der Wall, E; van der Groep, P

2012-08-01

Cancer treatments are increasingly focusing on the molecular mechanisms underlying the oncogenic processes present in tumors of individual patients. Fibroblast growth factor receptors (FGFRs) are among the many molecules that are involved in oncogenesis and are currently under investigation for their potential as drug targets in breast cancer patients. These receptor tyrosine kinases play a role in several processes including proliferation, angiogenesis, and migration. Alterations in these basal processes can contribute to the development and progression of tumors. Among breast cancer patients, several subgroups have been shown to harbor genetic aberrations in FGFRs, including amplifications of FGFR1, FGFR2, and FGFR4 and mutations in FGFR2 and FGFR4. Here, we review in vitro and in vivo models that have partly elucidated the molecular implications of these different genetic aberrations, the resulting tumor characteristics, and the potential of FGFRs as therapeutic targets for breast cancer treatment.

Targeted cancer therapy--are the days of systemic chemotherapy numbered?

PubMed

Joo, Won Duk; Visintin, Irene; Mor, Gil

2013-12-01

Targeted therapy or molecular targeted therapy has been defined as a type of treatment that blocks the growth of cancer cells by interfering with specific cell molecules required for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells as with traditional chemotherapy. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the growing relevance of this therapeutic approach. Targeted cancer therapies, also referred to as "Personalized Medicine", are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The objective of personalized medicine is the identification of patients that would benefit from a specific treatment based on the expression of molecular markers. Examples of this approach include bevacizumab and olaparib, which have been designated as promising targeted therapies for ovarian cancer. Combinations of trastuzumab with pertuzumab, or T-DM1 and mTOR inhibitors added to an aromatase inhibitor are new therapeutic strategies for breast cancer. Although this approach has been seen as a major step in the expansion of personalized medicine, it has substantial limitations including its high cost and the presence of serious adverse effects. The Cancer Genome Atlas is a useful resource to identify novel and more effective targets, which may help to overcome the present limitations. In this review we will discuss the clinical outcome of some of these new therapies with a focus on ovarian and breast cancer. We will also discuss novel concepts in targeted therapy, the target of cancer stem cells. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Inhibition of intracerebral glioblastoma growth by targeting the insulin-like growth factor 1 receptor involves different context-dependent mechanisms

PubMed Central

Zamykal, Martin; Martens, Tobias; Matschke, Jakob; Günther, Hauke S.; Kathagen, Annegret; Schulte, Alexander; Peters, Regina; Westphal, Manfred; Lamszus, Katrin

2015-01-01

Background Signaling by insulin-like growth factor 1 receptor (IGF-1R) can contribute to the formation and progression of many diverse tumor types, including glioblastoma. We investigated the effect of the IGF-1R blocking antibody IMC-A12 on glioblastoma growth in different in vivo models. Methods U87 cells were chosen to establish rapidly growing, angiogenesis-dependent tumors in the brains of nude mice, and the GS-12 cell line was used to generate highly invasive tumors. IMC-A12 was administered using convection-enhanced local delivery. Tumor parameters were quantified histologically, and the functional relevance of IGF-1R activation was analyzed in vitro. Results IMC-A12 treatment inhibited the growth of U87 and GS-12 tumors by 75% and 50%, respectively. In GS-12 tumors, the invasive tumor extension and proliferation rate were significantly reduced by IMC-A12 treatment, while apoptosis was increased. In IMC-A12–treated U87 tumors, intratumoral vascularization was markedly decreased, and tumor cell proliferation was moderately reduced. Flow cytometry showed that <2% of U87 cells but >85% of GS-12 cells expressed IGF-1R. Activation of IGF-1R by IGF-1 and IGF-2 in GS-12 cells was blocked by IMC-A12. Both ligands stimulated GS-12 cell proliferation, and IGF-2 also stimulated migration. IMC-A12 inhibited these stimulatory effects and increased apoptosis. In U87 cells, stimulation with either ligand had no functional effect. Conclusions IGF-1R blockade can inhibit glioblastoma growth by different mechanisms, including direct effects on the tumor cells as well as indirect anti-angiogenic effects. Hence, blocking IGF-1R may be useful to target both the highly proliferative, angiogenesis-dependent glioblastoma core component as well as the infiltrative periphery. PMID:25543125

Syndecan promotes axon regeneration by stabilizing growth cone migration.

PubMed

Edwards, Tyson J; Hammarlund, Marc

2014-07-10

Growth cones facilitate the repair of nervous system damage by providing the driving force for axon regeneration. Using single-neuron laser axotomy and in vivo time-lapse imaging, we show that syndecan, a heparan sulfate (HS) proteoglycan, is required for growth cone function during axon regeneration in C. elegans. In the absence of syndecan, regenerating growth cones form but are unstable and collapse, decreasing the effective growth rate and impeding regrowth to target cells. We provide evidence that syndecan has two distinct functions during axon regeneration: (1) a canonical function in axon guidance that requires expression outside the nervous system and depends on HS chains and (2) an intrinsic function in growth cone stabilization that is mediated by the syndecan core protein, independently of HS. Thus, syndecan is a regulator of a critical choke point in nervous system repair. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth.

PubMed

Desai, Janish; Wang, Yang; Wang, Ke; Malwal, Satish R; Oldfield, Eric

2016-10-06

We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdrawing aryl-alkyl side chains which inhibited the growth of Gram-negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ∼1-4 μg mL -1 levels. They were found to be potent inhibitors of FPPS; cell growth was partially "rescued" by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (∼2-6 μg mL -1 ) against Gram-positive but not Gram-negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ∼1-2 μg mL -1 . © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth.

PubMed

Lu, Hongbo; Kojima, Kensuke; Battula, Venkata Lokesh; Korchin, Borys; Shi, Yuexi; Chen, Ye; Spong, Suzanne; Thomas, Deborah A; Kantarjian, Hagop; Lock, Richard B; Andreeff, Michael; Konopleva, Marina

2014-03-01

Connective tissue growth factor (CTGF/CCN2) is involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in precursor B-acute lymphoblastic leukemia (ALL) and that increased expression of CTGF is associated with inferior outcome in B-ALL. In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knockdown CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA. Silencing of CTGF resulted in significant suppression of leukemia cell growth compared to control vector, which was associated with AKT/mTOR inactivation and increased levels of cyclin-dependent kinase inhibitor p27. CTGF knockdown sensitized ALL cells to vincristine and methotrexate. Treatment with an anti-CTGF monoclonal antibody, FG-3019, significantly prolonged survival of mice injected with primary xenograft B-ALL cells when co-treated with conventional chemotherapy (vincristine, L-asparaginase and dexamethasone). Data suggest that CTGF represents a targetable molecular aberration in B-ALL, and blocking CTGF signaling in conjunction with administration of chemotherapy may represent a novel therapeutic approach for ALL patients.

Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

PubMed

Ma, Shao; Yin, Ning; Qi, Xiaomei; Pfister, Sandra L; Zhang, Mei-Jie; Ma, Rong; Chen, Guan

2015-05-30

Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.

Tumor-targeting CTL expressing a single-chain Fv specific for VEGFR2.

PubMed

Kanagawa, Naoko; Yanagawa, Tatsuya; Mukai, Yohei; Yoshioka, Yasuo; Okada, Naoki; Nakagawa, Shinsaku

2010-03-26

Cytotoxic T lymphocytes (CTL) are critical effector cells in tumor immunity. Adoptive transfer therapy with in vitro-expanded tumor-specific CTL is a promising approach for preventing cancer metastasis and recurrence. Transferred CTL are not effective in clinical trials, however, due to inadequate tumor-infiltration. Therefore, the development of functionally modified CTL, such as tumor-targeting CTL, is widely desired. Here, we designed the tumor-targeting CTL expressing a single-chain antibody fragment (scFv-CTL) specific for vascular endothelial growth factor receptor 2 (VEGFR2/flk1) by transducing the CTL with a retroviral vector. The scFv-CTL bound to VEGFR2/flk1-expressing cells and retained their cytotoxic activity against tumor cells. In addition, adoptive transfer of scFv-CTL into tumor-bearing mice effectively suppressed tumor growth due to the augmented accumulation of the transferred CTL in the tumor tissue. These findings indicate that the creation of CTL capable of targeting tumor vascular endothelial cells by scFv-expression technique is considerably promising for improvement of efficacy in adoptive immunotherapy. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Ultrasound Targeted Microbubble Destruction-Mediated Delivery of a Transcription Factor Decoy Inhibits STAT3 Signaling and Tumor Growth

PubMed Central

Kopechek, Jonathan A.; Carson, Andrew R.; McTiernan, Charles F.; Chen, Xucai; Hasjim, Bima; Lavery, Linda; Sen, Malabika; Grandis, Jennifer R.; Villanueva, Flordeliza S.

2015-01-01

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers where it acts to promote tumor progression. A STAT3-specific transcription factor decoy has been developed to suppress STAT3 downstream signaling, but a delivery strategy is needed to improve clinical translation. Ultrasound-targeted microbubble destruction (UTMD) has been shown to enhance image-guided local delivery of molecular therapeutics to a target site. The objective of this study was to deliver STAT3 decoy to squamous cell carcinoma (SCC) tumors using UTMD to disrupt STAT3 signaling and inhibit tumor growth. Studies performed demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles inhibited STAT3 signaling in SCC cells in vitro. Studies performed in vivo demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles induced significant tumor growth inhibition (31-51% reduced tumor volume vs. controls, p < 0.05) in mice bearing SCC tumors. Furthermore, expression of STAT3 downstream target genes (Bcl-xL and cyclin D1) was significantly reduced (34-39%, p < 0.05) in tumors receiving UTMD treatment with STAT3 decoy-loaded microbubbles compared to controls. In addition, the quantity of radiolabeled STAT3 decoy detected in tumors eight hours after treatment was significantly higher with UTMD treatment compared to controls (70-150%, p < 0.05). This study demonstrates that UTMD can increase delivery of a transcription factor decoy to tumors in vivo and that the decoy can inhibit STAT3 signaling and tumor growth. These results suggest that UTMD treatment holds potential for clinical use to increase the concentration of a transcription factor signaling inhibitor in the tumor. PMID:26681983

An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth

PubMed Central

Tanno, Toshihiko; Zhang, Peng; Lazarski, Christopher A.; Liu, Yang

2017-01-01

The efficacy of traditional chemotherapy is limited by its toxicity, especially with regard to hematopoiesis. Here we show that miR-26a plays a critical role in protecting mice against chemotherapy-induced myeloid suppression by targeting a proapoptotic protein (Bak1) in hematopoietic stem/progenitor cells (HSPCs). Because c-Kit is expressed at high levels in HSPCs, we designed a microRNA-aptamer chimera that contains miR-26a mimic and c-Kit–targeting aptamer and successfully delivered miR-26a into HSPCs to attenuate toxicity of 5′ fluorouracil (5-FU) and carboplatin. Meanwhile, our in silico analysis revealed widespread and prognosis-associated downregulation of miR-26a in advanced breast cancer and also showed that KIT is overexpressed among basal-like breast cancer cells and that such expression is associated with poor prognosis. Importantly, the miR-26a aptamer effectively repressed tumor growth in vivo and synergized with 5-FU or carboplatin in cancer therapy in the mouse breast cancer models. Thus, targeted delivery of miR-26a suppresses tumor growth while protecting the host against myelosuppression by chemotherapy. PMID:29296753

Allelic Interactions among Pto-MIR475b and Its Four Target Genes Potentially Affect Growth and Wood Properties in Populus

PubMed Central

Xiao, Liang; Quan, Mingyang; Du, Qingzhang; Chen, Jinhui; Xie, Jianbo; Zhang, Deqiang

2017-01-01

MicroRNAs (miRNAs) play crucial roles in plant growth and development, but few studies have illuminated the allelic interactions among miRNAs and their targets in perennial plants. Here, we combined analysis of expression patterns and single-nucleotide polymorphism (SNP)-based association studies to explore the interactions between Pto-MIR475b and its four target genes (Pto-PPR1, Pto-PPR2, Pto-PPR3, and Pto-PPR4) in 435 unrelated individuals of Populus tomentosa. Expression patterns showed a significant negative correlation (r = -0.447 to -0.411, P < 0.01) between Pto-MIR475b and its four targets in eight tissues of P. tomentosa, suggesting that Pto-miR475b may negatively regulate the four targets. Single SNP-based association studies identified 93 significant associations (P < 0.01, Q < 0.1) representing associations of 80 unique SNPs in Pto-MIR475b and its four targets with nine traits, revealing their potential roles in tree growth and wood formation. Moreover, one common SNP in the precursor region significantly altered the secondary structure of the pre-Pto-miR475b and changed the expression level of Pto-MIR475b. Analysis of epistatic interactions identified 115 significant SNP–SNP associations (P < 0.01) representing 45 unique SNPs from Pto-MIR475b and its four targets for 10 traits, revealing that genetic interactions between Pto-MIR475b and its targets influence quantitative traits of perennial plants. Our study provided a feasible strategy to study population genetics in forest trees and enhanced our understanding of miRNAs by dissecting the allelic interactions between this miRNA and its targets in P. tomentosa. PMID:28680433

Growth cone travel in space and time: the cellular ensemble of cytoskeleton, adhesion, and membrane.

PubMed

Vitriol, Eric A; Zheng, James Q

2012-03-22

Growth cones, found at the tip of axonal projections, are the sensory and motile organelles of developing neurons that enable axon pathfinding and target recognition for precise wiring of the neural circuitry. To date, many families of conserved guidance molecules and their corresponding receptors have been identified that work in space and time to ensure billions of axons to reach their targets. Research in the past two decades has also gained significant insight into the ways in which growth cones translate extracellular signals into directional migration. This review aims to examine new progress toward understanding the cellular mechanisms underlying directional motility of the growth cone and to discuss questions that remain to be addressed. Specifically, we will focus on the cellular ensemble of cytoskeleton, adhesion, and membrane and examine how the intricate interplay between these processes orchestrates the directed movement of growth cones. Copyright © 2012 Elsevier Inc. All rights reserved.

Targeted Repression of Essential Genes To Arrest Growth and Increase Carbon Partitioning and Biofuel Titers in Cyanobacteria.

PubMed

Shabestary, Kiyan; Anfelt, Josefine; Ljungqvist, Emil; Jahn, Michael; Yao, Lun; Hudson, Elton P

2018-06-08

Photoautotrophic production of fuels and chemicals by cyanobacteria typically gives lower volumetric productivities and titers than heterotrophic production. Cyanobacteria cultures become light limited above an optimal cell density, so that this substrate is not supplied to all cells sufficiently. Here, we investigate genetic strategies for a two-phase cultivation, where biofuel-producing Synechocystis cultures are limited to an optimal cell density through inducible CRISPR interference (CRISPRi) repression of cell growth. Fixed CO 2 is diverted to ethanol or n-butanol. Among the most successful strategies was partial repression of citrate synthase gltA. Strong repression (>90%) of gltA at low culture densities increased carbon partitioning to n-butanol 5-fold relative to a nonrepression strain, but sacrificed volumetric productivity due to severe growth restriction. CO 2 fixation continued for at least 3 days after growth was arrested. By targeting sgRNAs to different regions of the gltA gene, we could modulate GltA expression and carbon partitioning between growth and product to increase both specific and volumetric productivity. These growth arrest strategies can be useful for improving performance of other photoautotrophic processes.

A role of placental growth factor in hair growth.

PubMed

Yoon, Sun-Young; Yoon, Ji-Seon; Jo, Seong Jin; Shin, Chang Yup; Shin, Jong-Yeon; Kim, Jong-Il; Kwon, Ohsang; Kim, Kyu Han

2014-05-01

The dermal papilla (DP) comprises specialized mesenchymal cells at the bottom of the hair follicle and plays a pivotal role in hair formation, anagen induction and the hair cycle. In this study, DPs were isolated from human hair follicles and serially subcultured. From each subculture at passages 1, 3, and 5 (n=4), we compared gene expression profiles using mRNA sequencing. Among the growth factors that were down-regulated in later passages of human DP cells (hDPCs), placental growth factor (PlGF) was selected. To elucidate the effect of PlGF on hair growth. We evaluated the effect of PlGF on hDPCs and on ex vivo hair organ culture. We investigated the effect of PlGF on an in vivo model of depilation-induced hair regeneration. We confirmed that the mRNA and protein expression levels of PlGF significantly decreased following subculture of the cells. It was shown that PlGF enhanced hair shaft elongation in ex vivo hair organ culture. Furthermore, PlGF significantly accelerated hair follicle growth and markedly prolonged anagen hair growth in an in vivo model of depilation-induced hair regeneration. PlGF prevented cell death by increasing the levels of phosphorylated extracellular signal-regulated kinase (ERK) and cyclin D1 and promoted survival by up-regulation of phosphorylated Akt and Bcl2, as determined by Western blotting. Our results suggest that PlGF plays a role in the promotion of hair growth and therefore may serve as an additional therapeutic target for the treatment of alopecia. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells.

PubMed

Srivastava, Sanjeev K; Bhardwaj, Arun; Singh, Seema; Arora, Sumit; Wang, Bin; Grizzle, William E; Singh, Ajay P

2011-12-01

Pancreatic cancer (PC) has the worst prognosis among all cancers due to its late diagnosis and lack of effective therapies. Therefore, identification of novel gene targets, which are differentially expressed in PC and functionally involved in malignant phenotypes, is critical to achieve early diagnosis and development of effective therapeutic strategies. We have shown previously that MUC4, an aberrantly overexpressed transmembrane mucin, promotes growth, invasion and metastasis of PC cells, thus underscoring its potential as a clinical target. Here, we report a novel microRNA (miRNA)-mediated mechanism underlying aberrant expression of MUC4 in PC. We demonstrate that the 3' untranslated region of MUC4 contains a highly conserved miRNA-150 (miR-150) binding motif and its direct interaction with miR-150 downregulates endogenous MUC4 protein levels. We also show that miR-150-mediated MUC4 downregulation is associated with a concomitant decrease in human epidermal growth factor receptor 2 and its phosphorylated form, leading to reduced activation of downstream signaling. Furthermore, our findings demonstrate that miR-150 overexpression inhibits growth, clonogenicity, migration and invasion and enhances intercellular adhesion in PC cells. Finally, our data reveal a downregulated expression of miR-150 in malignant pancreatic tissues, which is inversely associated with MUC4 protein levels. Altogether, these findings establish miR-150 as a novel regulator of MUC4 and a tumor suppressor miRNA in PC.

MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells

PubMed Central

Srivastava, Sanjeev K.; Bhardwaj, Arun; Singh, Seema; Arora, Sumit; Wang, Bin; Grizzle, William E.; Singh, Ajay P.

2011-01-01

Pancreatic cancer (PC) has the worst prognosis among all cancers due to its late diagnosis and lack of effective therapies. Therefore, identification of novel gene targets, which are differentially expressed in PC and functionally involved in malignant phenotypes, is critical to achieve early diagnosis and development of effective therapeutic strategies. We have shown previously that MUC4, an aberrantly overexpressed transmembrane mucin, promotes growth, invasion and metastasis of PC cells, thus underscoring its potential as a clinical target. Here, we report a novel microRNA (miRNA)-mediated mechanism underlying aberrant expression of MUC4 in PC. We demonstrate that the 3′ untranslated region of MUC4 contains a highly conserved miRNA-150 (miR-150) binding motif and its direct interaction with miR-150 downregulates endogenous MUC4 protein levels. We also show that miR-150-mediated MUC4 downregulation is associated with a concomitant decrease in human epidermal growth factor receptor 2 and its phosphorylated form, leading to reduced activation of downstream signaling. Furthermore, our findings demonstrate that miR-150 overexpression inhibits growth, clonogenicity, migration and invasion and enhances intercellular adhesion in PC cells. Finally, our data reveal a downregulated expression of miR-150 in malignant pancreatic tissues, which is inversely associated with MUC4 protein levels. Altogether, these findings establish miR-150 as a novel regulator of MUC4 and a tumor suppressor miRNA in PC. PMID:21983127

Marine reserve effects on fishery profit

PubMed Central

White, Crow; Kendall, Bruce E; Gaines, Steven; Siegel, David A; Costello, Christopher

2008-01-01

Some studies suggest that fishery yields can be higher with reserves than under conventional management. However, the economic performance of fisheries depends on economic profit, not fish yield. The predictions of higher yields with reserves rely on intensive fishing pressures between reserves; the exorbitant costs of harvesting low-density populations erode profits. We incorporated this effect into a bioeconomic model to evaluate the economic performance of reserve-based management. Our results indicate that reserves can still benefit fisheries, even those targeting species that are expensive to harvest. However, in contrast to studies focused on yield, only a moderate proportion of the coast in reserves (with moderate harvest pressures outside reserves) is required to maximize profit. Furthermore, reserve area and harvest intensity can be traded off with little impact on profits, allowing for management flexibility while still providing higher profit than attainable under conventional management. Ecology Letters (2008) 11: 370–379 PMID:18205836

Restoration of Degraded Soil in the Nanmangalam Reserve Forest with Native Tree Species: Effect of Indigenous Plant Growth-Promoting Bacteria

PubMed Central

Ramachandran, Andimuthu; Radhapriya, Parthasarathy

2016-01-01

Restoration of a highly degraded forest, which had lost its natural capacity for regeneration, was attempted in the Nanmangalam Reserve Forest in Eastern Ghats of India. In field experiment, 12 native tree species were planted. The restoration included inoculation with a consortium of 5 native plant growth-promoting bacteria (PGPB), with the addition of small amounts of compost and a chemical fertilizer (NPK). The experimental fields were maintained for 1080 days. The growth and biomass varied depending on the plant species. All native plants responded well to the supplementation with the native PGPB. The plants such as Pongamia pinnata, Tamarindus indica, Gmelina arborea, Wrightia tinctoria, Syzygium cumini, Albizia lebbeck, Terminalia bellirica, and Azadirachta indica performed well in the native soil. This study demonstrated, by using native trees and PGPB, a possibility to restore the degraded forest. PMID:27195310

Restoration of Degraded Soil in the Nanmangalam Reserve Forest with Native Tree Species: Effect of Indigenous Plant Growth-Promoting Bacteria.

PubMed

Ramachandran, Andimuthu; Radhapriya, Parthasarathy

Restoration of a highly degraded forest, which had lost its natural capacity for regeneration, was attempted in the Nanmangalam Reserve Forest in Eastern Ghats of India. In field experiment, 12 native tree species were planted. The restoration included inoculation with a consortium of 5 native plant growth-promoting bacteria (PGPB), with the addition of small amounts of compost and a chemical fertilizer (NPK). The experimental fields were maintained for 1080 days. The growth and biomass varied depending on the plant species. All native plants responded well to the supplementation with the native PGPB. The plants such as Pongamia pinnata, Tamarindus indica, Gmelina arborea, Wrightia tinctoria, Syzygium cumini, Albizia lebbeck, Terminalia bellirica, and Azadirachta indica performed well in the native soil. This study demonstrated, by using native trees and PGPB, a possibility to restore the degraded forest.

Prolonged-acting, Multi-targeting Gallium Nanoparticles Potently Inhibit Growth of Both HIV and Mycobacteria in Co-Infected Human Macrophages

PubMed Central

Narayanasamy, Prabagaran; Switzer, Barbara L.; Britigan, Bradley E.

2015-01-01

Human immunodeficiency virus (HIV) infection and Mycobacterium tuberculosis (TB) are responsible for two of the major global human infectious diseases that result in significant morbidity, mortality and socioeconomic impact. Furthermore, severity and disease prevention of both infections is enhanced by co-infection. Parallel limitations also exist in access to effective drug therapy and the emergence of resistance. Furthermore, drug-drug interactions have proven problematic during treatment of co-incident HIV and TB infections. Thus, improvements in drug access and simplified treatment regimens are needed immediately. One of the key host cells infected by both HIV and TB is the mononuclear phagocyte (MP; monocyte, macrophage and dendritic cell). Therefore, we hypothesized that one way this can be achieved is through drug-targeting by a nanoformulated drug that ideally would be active against both HIV and TB. Accordingly, we validated macrophage targeted long acting (sustained drug release) gallium (Ga) nanoformulation against HIV-mycobacterium co-infection. The multi-targeted Ga nanoparticle agent inhibited growth of both HIV and TB in the macrophage. The Ga nanoparticles reduced the growth of mycobacterium and HIV for up to 15 days following single drug loading. These results provide a potential new approach to treat HIV-TB co-infection that could eventually lead to improved clinical outcomes. PMID:25744727

Corruption of phage display libraries by target-unrelated clones: diagnosis and countermeasures.

PubMed

Thomas, William D; Golomb, Miriam; Smith, George P

2010-12-15

Phage display is used to discover peptides or proteins with a desired target property-most often, affinity for a target selector molecule. Libraries of phage clones displaying diverse surface peptides are subject to a selection process designed to enrich for the target behavior and subsequently propagated to restore phage numbers. A recurrent problem is enrichment of clones, called target-unrelated phages or peptides (TUPs), that lack the target behavior. Many TUPs are propagation related; they have mutations conferring a growth advantage and are enriched during the propagations accompanying selection. Unlike other filamentous phage libraries, fd-tet-based libraries are relatively resistant to propagation-related TUP corruption. Their minus-strand origin is disrupted by a large cassette that simultaneously confers resistance to tetracycline and imposes a rate-limiting growth defect that cannot be bypassed with simple mutations. Nonetheless, a new type of propagation-related TUP emerged in the output of in vivo selections from an fd-tet library. The founding clone had a complex rearrangement that restored the minus-strand origin while retaining tetracycline resistance. The rearrangement involved two recombination events, one with a contaminant having a wild-type minus-strand origin. The founder's infectivity advantage spread by simple recombination to clones displaying different peptides. We propose measures for minimizing TUP corruption. Copyright © 2010 Elsevier Inc. All rights reserved.

Increasing Reservation Attendance: Ganado's Approach.

ERIC Educational Resources Information Center

Foster, Carl; And Others

Based on recommendations of a District Attendance Task Force, in 1980 the Ganado School District (a Navajo Reservation District) formulated an Attendance Improvement Plan which decreased the primary school's absentee rate 37% over previous years and which dramatically increased Friday attendance. The primary school targeted "high risk"…

Therapeutic Innovations for Targeting Hepatoblastoma.

PubMed

Garnier, Agnès; Ilmer, Matthias; Kappler, Roland; Berger, Michael

2016-11-01

Hepatoblastoma is the most common pediatric liver tumor. Despite recent advances in treatment with surgery and chemotherapy, the prognosis in advanced stages remains poor. The neurokinin-1 receptor (NK1R) has recently been described to be pivotal in the development of cancer. Furthermore, overwhelming evidence now exists showing that pharmacological manipulation of NK1R can cause a robust anticancer effect. Consequently, NK1R antagonists, such as the clinical drug aprepitant, are under current investigation as future innovative anticancer agents. In that sense, new evidence suggests that NK1R is highly expressed in human hepatoblastoma and can be targeted to create a robust inhibiton of tumor growth in vivo and in vitro. The mechanisms behind this effect are only now being investigated but already reveal an arsenal of therapeutic possibilities. Our article describes the most recent developments in the field of therapeutic NK1R inhibition in cancer and focuses particularly on the newly discovered molecular mechanisms involved when targeting NK1R in hepatoblastoma. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons.

PubMed

Pittman, Sherry K; Gracias, Neilia G; Fehrenbacher, Jill C

2016-05-01

Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivity was assessed using the stimulated release of calcitonin gene-related peptide (CGRP), whereas morphology of established neurites was evaluated using a high content screening system. Dorsal root ganglion cultures, maintained in the absence or presence of NGF, were treated from day 7 to day 12 in culture with paclitaxel (300nM) or EpoB (30nM). Following treatment, the release of CGRP was stimulated using capsaicin or high extracellular potassium. In the presence of NGF, EpoB mimicked the effects of paclitaxel: capsaicin-stimulated release was attenuated, potassium-stimulated release was slightly enhanced and the total peptide content was unchanged. In the absence of NGF, both paclitaxel and EpoB decreased capsaicin- and potassium-stimulated release and the total peptide content, suggesting that NGF may reverse MTA-induced hyposensitivity. Paclitaxel and EpoB both decreased neurite length and branching, and this attenuation was unaffected by NGF in the growth media. These differential effects of NGF on neuronal sensitivity and morphology suggest that neurite retraction is not a causative factor to alter neuronal sensitivity. Copyright © 2016 Elsevier Inc. All rights reserved.

Deep sequencing of small RNA libraries from human prostate epithelial and stromal cells reveal distinct pattern of microRNAs primarily predicted to target growth factors.

PubMed

Singh, Savita; Zheng, Yun; Jagadeeswaran, Guru; Ebron, Jey Sabith; Sikand, Kavleen; Gupta, Sanjay; Sunker, Ramanjulu; Shukla, Girish C

2016-02-28

Complex epithelial and stromal cell interactions are required during the development and progression of prostate cancer. Regulatory small non-coding microRNAs (miRNAs) participate in the spatiotemporal regulation of messenger RNA (mRNA) and regulation of translation affecting a large number of genes involved in prostate carcinogenesis. In this study, through deep-sequencing of size fractionated small RNA libraries we profiled the miRNAs of prostate epithelial (PrEC) and stromal (PrSC) cells. Over 50 million reads were obtained for PrEC in which 860,468 were unique sequences. Similarly, nearly 76 million reads for PrSC were obtained in which over 1 million were unique reads. Expression of many miRNAs of broadly conserved and poorly conserved miRNA families were identified. Sixteen highly expressed miRNAs with significant change in expression in PrSC than PrEC were further analyzed in silico. ConsensusPathDB showed the target genes of these miRNAs were significantly involved in adherence junction, cell adhesion, EGRF, TGF-β and androgen signaling. Let-7 family of tumor-suppressor miRNAs expression was highly pervasive in both, PrEC and PrSC cells. In addition, we have also identified several miRNAs that are unique to PrEC or PrSC cells and their predicted putative targets are a group of transcription factors. This study provides perspective on the miRNA expression in PrEC and PrSC, and reveals a global trend in miRNA interactome. We conclude that the most abundant miRNAs are potential regulators of development and differentiation of the prostate gland by targeting a set of growth factors. Additionally, high level expression of the most members of let-7 family miRNAs suggests their role in the fine tuning of the growth and proliferation of prostate epithelial and stromal cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth

PubMed Central

Vittorio, Orazio; Brandl, Miriam; Cirillo, Giuseppe; Kimpton, Kathleen; Hinde, Elizabeth; Gaus, Katharina; Yee, Eugene; Kumar, Naresh; Duong, Hien; Fleming, Claudia; Haber, Michelle; Norris, Murray; Boyer, Cyrille; Kavallaris, Maria

2016-01-01

Neuroblastoma is frequently diagnosed at advanced stage disease and treatment includes high dose chemotherapy and surgery. Despite the use of aggressive therapy survival rates are poor and children that survive their disease experience long term side effects from their treatment, highlighting the need for effective and less toxic therapies. Catechin is a natural polyphenol with anti-cancer properties and limited side effects, however its mechanism of action is unknown. Here we report that Dextran-Catechin, a conjugated form of catechin that increases serum stability, is preferentially and markedly active against neuroblastoma cells having high levels of intracellular copper, without affecting non-malignant cells. Copper transporter 1 (CTR1) is the main transporter of copper in mammalian cells and it is upregulated in neuroblastoma. Functional studies showed that depletion of CTR1 expression reduced intracellular copper levels and led to a decrease in neuroblastoma cell sensitivity to Dextran-Catechin, implicating copper in the activity of this compound. Mechanistically, Dextran-Catechin was found to react with copper, inducing oxidative stress and decreasing glutathione levels, an intracellular antioxidant and regulator of copper homeostasis. In vivo, Dextran-Catechin significantly attenuated tumour growth in human xenograft and syngeneic models of neuroblastoma. Thus, Dextran-Catechin targets copper, inhibits tumour growth, and may be valuable in the treatment of aggressive neuroblastoma and other cancers dependent on copper for their growth. PMID:27374085

miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis.

PubMed

Sun, Xiaojuan; Charbonneau, Cherie; Wei, Lei; Chen, Qian; Terek, Richard M

2015-09-01

Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16. Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma. ©2015 American Association for Cancer Research.

miR-187 inhibits the growth of cervical cancer cells by targeting FGF9.

PubMed

Liang, Hua; Luo, Ruoyu; Chen, Xiaoqi; Zhao, Yuzi; Tan, Aili

2017-10-01

MicroRNAs (miRNAs) are a cluster of short non-coding RNAs playing critical roles in human cancers. miR-187 was recently found to be a novel cancer-related microRNA. However, the expression and function of miR-187 in cervical cancer have not been investigated. In this study, we found that miR-187 level was decreased in cervical cancer tissues and cell lines. Patients with low level of miR-187 had significantly decreased rate of overall survival (OS) and progression-free survival (DFS). miR-187 overexpression inhibited proliferation and promoted apoptosis of cervical cancer cells, whereas miR-187 knockdown promoted proliferation and inhibited apoptosis of cervical cancer cells. Forced expression of miR-187 inhibited the subcutaneous growth of cervical cancer cells in nude mice. Furthermore, FGF9 was found to be the downstream target of miR-187 in cervical cancer cells. Importantly, targeting FGF9 was required for miR-187 exerting its tumor suppressive roles in cervical cancer cells.

LED Systems Target Plant Growth

NASA Technical Reports Server (NTRS)

2010-01-01

To help develop technologies for growing edible biomass (food crops) in space, Kennedy Space Center partnered with Orbital Technologies Corporation (ORBITEC), of Madison, Wisconsin, through the Small Business Innovation Research (SBIR) program. One result of this research was the High Efficiency Lighting with Integrated Adaptive Control (HELIAC) system, components of which have been incorporated into a variety of agricultural greenhouse and consumer aquarium lighting features. The new lighting systems can be adapted to a specific plant species during a specific growth stage, allowing maximum efficiency in light absorption by all available photosynthetic tissues.

Renal toxicity of anticancer agents targeting vascular endothelial growth factor (VEGF) and its receptors (VEGFRs).

PubMed

Cosmai, Laura; Gallieni, Maurizio; Liguigli, Wanda; Porta, Camillo

2017-04-01

Since angiogenesis plays a key role in tumor growth, progression and metastasization, anti-vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) agents have been developed over the years as anticancer agents, and have changed, for the better, the natural history of a number of cancer types. In the present review, the renal safety profile of presently available agents targeting either VEGF or VEGFRs will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, renal toxicity (especially, but not exclusively, hypertension and proteinuria) are quite commonly observed with these agents, and may be increased by the concomitant use of cytoxic chemotherapeutics. Despite all the above, kidney impairment or dialysis must not be regarded di per se as reasons not to administer or to stop an active anticancer treatment, especially considering the possibility of a significant survival improvement in many cancer patients treated with these agents.

Co-Optima Targets Maximum Transportation Sector Efficiency, Energy

Science.gov Websites

Independence and Industry Growth | News | NREL Co-Optima Targets Maximum Transportation Sector Efficiency, Energy Independence and Industry Growth Co-Optima Targets Maximum Transportation Sector Efficiency, Energy Independence and Industry Growth February 6, 2017 Report cover on Co-Optima Year in Review

Reference curve for the first-year growth response to growth hormone treatment in prepubertal children with idiopathic growth hormone deficiency: validation of the KIGS first-year growth response curve using the Belgian Register for the Study of Growth and Puberty Problems.

PubMed

Straetemans, Saartje; Roelants, Mathieu; Thomas, Muriel; Rooman, Raoul; De Schepper, Jean

2014-01-01

Comparing observed and expected growth after first-year growth hormone (GH) therapy is useful for identifying a poor growth response to GH. To generate a first-year, age-specific growth response reference curve for prepubertal Belgian children with idiopathic growth hormone deficiency (iGHD) treated with a standard weight-adjusted GH dose and to compare this national reference with the response references derived from KIGS. First-year height data of 357 prepubertal children (240 males) with iGHD were analyzed. Smooth reference curves of first-year height velocity (HV) in relation to age were created. Differences with the KIGS targets were evaluated after z-score transformation. The observed first-year HVs were log-normal distributed by age and decreased significantly with age (p<0.001). No GH dose or gender effect was observed (p=0.5). Distance to target height, severity of GHD and occurrence of multiple pituitary hormone deficiencies had a positive effect (p<0.01) on the calculated HV SDS. When applying the KIGS targets for severe iGHD, mean HV SDS was close to zero (-0.09±0.84). The developed age-specific growth response curves enable rapid identification of poor response to first-year GH treatment in prepubertal iGHD children. Our results validate the published growth targets derived from the KIGS database. © 2014 S. Karger AG, Basel.

Targeting Sphingosine Kinase Isoforms Effectively Reduces Growth and Survival of Neoplastic Mast Cells With D816V-KIT

PubMed Central

Bandara, Geethani; Muñoz-Cano, Rosa; Tobío, Araceli; Yin, Yuzhi; Komarow, Hirsh D.; Desai, Avanti; Metcalfe, Dean D.; Olivera, Ana

2018-01-01

Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth. While SPHK2 inhibition prevented entry into the cell cycle in normal and neoplastic human MCs with minimal effect on cell survival, SPHK1 inhibition caused cell cycle arrest in G2/M and apoptosis, particularly in D816V-KIT MCs. This was mediated via activation of the DNA damage response (DDR) cascade, including phosphorylation of the checkpoint kinase 2 (CHK2), CHK2-mediated M-phase inducer phosphatase 3 depletion, and p53 activation. Combination treatment of SPHK inhibitors with KIT inhibitors showed greater growth inhibition of D816V-KIT MCs than either inhibitor alone. Furthermore, inhibition of SPHK isoforms reduced the number of malignant bone marrow MCs from patients with mastocytosis and the growth of D816V-KIT MCs in a xenograft mouse model. Our results reveal a role for SPHK isoforms in the regulation of growth and survival in normal and neoplastic MCs and suggest a regulatory function for SPHK1 in the DDR in MCs with KIT mutations. The findings also suggest that targeting the SPHK/S1P axis may provide an alternative to tyrosine kinase inhibitors, alone or in combination, for the treatment of aggressive mastocytosis and other hematological malignancies associated with the D816V-KIT mutation. PMID:29643855

Targeting Sphingosine Kinase Isoforms Effectively Reduces Growth and Survival of Neoplastic Mast Cells With D816V-KIT.

PubMed

Bandara, Geethani; Muñoz-Cano, Rosa; Tobío, Araceli; Yin, Yuzhi; Komarow, Hirsh D; Desai, Avanti; Metcalfe, Dean D; Olivera, Ana

2018-01-01

Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth. While SPHK2 inhibition prevented entry into the cell cycle in normal and neoplastic human MCs with minimal effect on cell survival, SPHK1 inhibition caused cell cycle arrest in G2/M and apoptosis, particularly in D816V-KIT MCs. This was mediated via activation of the DNA damage response (DDR) cascade, including phosphorylation of the checkpoint kinase 2 (CHK2), CHK2-mediated M-phase inducer phosphatase 3 depletion, and p53 activation. Combination treatment of SPHK inhibitors with KIT inhibitors showed greater growth inhibition of D816V-KIT MCs than either inhibitor alone. Furthermore, inhibition of SPHK isoforms reduced the number of malignant bone marrow MCs from patients with mastocytosis and the growth of D816V-KIT MCs in a xenograft mouse model. Our results reveal a role for SPHK isoforms in the regulation of growth and survival in normal and neoplastic MCs and suggest a regulatory function for SPHK1 in the DDR in MCs with KIT mutations. The findings also suggest that targeting the SPHK/S1P axis may provide an alternative to tyrosine kinase inhibitors, alone or in combination, for the treatment of aggressive mastocytosis and other hematological malignancies associated with the D816V-KIT mutation.

Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1.

PubMed

Guo, Yue; Shu, Limin; Zhang, Chengyue; Su, Zheng-Yuan; Kong, Ah-Ng Tony

2015-03-15

Colorectal cancer remains the most prevalent malignancy in humans. The impact of epigenetic alterations on the development of this complex disease is now being recognized. The dynamic and reversible nature of epigenetic modifications makes them a promising target in colorectal cancer chemoprevention and treatment. Curcumin (CUR), the major component in Curcuma longa, has been shown as a potent chemopreventive phytochemical that modulates various signaling pathways. Deleted in lung and esophageal cancer 1 (DLEC1) is a tumor suppressor gene with reduced transcriptional activity and promoter hypermethylation in various cancers, including colorectal cancer. In the present study, we aimed to investigate the inhibitory role of DLEC1 in anchorage-independent growth of the human colorectal adenocarcinoma HT29 cells and epigenetic regulation by CUR. Specifically, we found that CUR treatment inhibited colony formation of HT29 cells, whereas stable knockdown of DLEC1 using lentiviral short hairpin RNA vector increased cell proliferation and colony formation. Knockdown of DLEC1 in HT29 cells attenuated the ability of CUR to inhibit anchorage-independent growth. Methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and methylated DNA immunoprecipitation revealed that CUR decreased CpG methylation of the DLEC1 promoter in HT29 cells after 5 days of treatment, corresponding to increased mRNA expression of DLEC1. Furthermore, CUR decreased the protein expression of DNA methyltransferases and subtypes of histone deacetylases (HDAC4, 5, 6, and 8). Taken together, our results suggest that the inhibitory effect of CUR on anchorage-independent growth of HT29 cells could, at least in part, involve the epigenetic demethylation and up-regulation of DLEC1. Copyright © 2015 Elsevier Inc. All rights reserved.

Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice.

PubMed

Mackenzie, Gerardo G; Huang, Liqun; Alston, Ninche; Ouyang, Nengtai; Vrankova, Kvetoslava; Mattheolabakis, George; Constantinides, Panayiotis P; Rigas, Basil

2013-01-01

New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.

miRNA-27b Targets Vascular Endothelial Growth Factor C to Inhibit Tumor Progression and Angiogenesis in Colorectal Cancer

PubMed Central

Wu, Dang; Wu, Pin; Ni, Chao; Zhang, Zhigang; Chen, Zhigang; Qiu, Fuming; Xu, Jinghong; Huang, Jian

2013-01-01

Colorectal cancer (CRC) is one of the most prevalent cancers globally and is one of the leading causes of cancer-related deaths due to therapy resistance and metastasis. Understanding the mechanism underlying colorectal carcinogenesis is essential for the diagnosis and treatment of CRC. microRNAs (miRNAs) can act as either oncogenes or tumor suppressors in many cancers. A tumor suppressor role for miR-27b has recently been reported in neuroblastoma, while no information about miR-27b in CRC is available. In this study, we demonstrated that miR-27b expression is decreased in most CRC tissues and determined that overexpression of miR-27b represses CRC cell proliferation, colony formation and tumor growth in vitro and in vivo. We identified vascular endothelial growth factor C (VEGFC) as a novel target gene of miR-27b and determined that miR-27b functioned as an inhibitor of tumor progression and angiogenesis through targeting VEGFC in CRC. We further determined that DNA hypermethylation of miR-27b CpG islands decreases miR-27b expression. In summary, an anti-tumor role for miR-27b and its novel target VEGFC in vivo could lead to tumor necrosis and provide a rationale for developing miR-27b as a therapeutic agent. PMID:23593282

Enhanced antitumor efficacy of folate targeted nanoparticles co-loaded with docetaxel and curcumin.

PubMed

Hu, Liandong; Pang, Saixi; Hu, Qiaofeng; Gu, Deliang; Kong, Dongqian; Xiong, Xiaoyun; Su, Jianying

2015-10-01

The current study aimed to investigate whether the novel folate (FT) modified nanoparticles (NPs) co-loaded with docetaxel (DT) and curcumin (CU) (named as FT-NPs) could enhance the delivery efficiency to tumor compared with the NPs without FT (non-targeted NPs). FT-NPs were successfully formulated in this article. In vitro cytotoxic activity against A549 cells and in vivo antitumor activity of FT-NPs in S180 cell bearing mice were conducted. Cellular uptake test was used to evaluate uptake efficiency of FT-NPs. Histological observation was used to determine the lung security. Besides, the physical chemical properties such as stability, particle size, zeta potential, drug encapsulation efficiency, transmission electron microscopy (TEM) were also conducted. FT-NPs exhibited stronger growth inhibition effects on A549 cells compared with non-targeted NPs, moreover, the novel FT-NPs indicated more effective antitumor efficacy in inhibiting tumor growth. Confocal laser scanning microscopy indicated that the uptake of FT-NPs was facilitated and effective. Histological observation meant that FT-NPs were biocompatible and appropriate for pulmonary administration. These results confirmed that FT-NPs with relatively high drug loading capacity could effectively inhibit tumor growth and reduce toxicity. The novel FT-NPs could produce as an outstanding nanocarrier for the targeted treatment of cancers. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting.

PubMed

Jonckheere, Nicolas; Vasseur, Romain; Van Seuningen, Isabelle

2017-03-01

RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of potential additions to conventional oil and gas resources of the world (outside the United States) from reserve growth, 2012

USGS Publications Warehouse

Klett, Timothy R.; Cook, Troy A.; Charpentier, Ronald R.; Tennyson, Marilyn E.; Attanasi, E.D.; Freeman, Phil A.; Ryder, Robert T.; Gautier, Donald L.; Verma, Mahendra K.; Le, Phuong A.; Schenk, Christopher J.

2012-01-01

The U.S. Geological Survey estimated volumes of technically recoverable, conventional petroleum resources resulting from reserve growth for discovered fields outside the United States that have reported in-place oil and gas volumes of 500 million barrels of oil equivalent or greater. The mean volumes were estimated at 665 billion barrels of crude oil, 1,429 trillion cubic feet of natural gas, and 16 billion barrels of natural gas liquids. These volumes constitute a significant portion of the world's oil and gas resources.

Therapeutics Targeting FGF Signaling Network in Human Diseases.

PubMed

Katoh, Masaru

2016-12-01

Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis. FGF traps, anti-FGF/FGFR monoclonal antibodies (mAbs), and small-molecule FGFR inhibitors are anti-FGF signaling therapeutics under development for the treatment of cancer, chondrodysplasia, and rickets. Here, I discuss the benefit-risk and cost-effectiveness issues of precision medicine targeting FGFRs, ALK, EGFR, and FLT3. FGFR-targeted therapy should be optimized for cancer treatment, focusing on genomic tests and recurrence. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibition of prostate cancer growth using doxorubicin assisted by ultrasound-targeted nanobubble destruction

PubMed Central

Fan, Xiaozhou; Wang, Luofu; Guo, Yanli; Xiong, Xingyu; Zhu, Lianhua; Fang, Kejing

2016-01-01

Ultrasound (US)-targeted microbubble destruction has been widely used as an effective drug-delivery system. However, nanobubbles (NBs) have better stability and stronger penetration than microbubbles, and drug delivery assisted by US-targeted NB destruction (UTND) still needs to be investigated. Our aim was to investigate the effect of doxorubicin (DOX) on the inhibition of prostate cancer growth under UTND. Contrast-enhanced US imaging of transplanted PC3 prostate cancer in mice showed that under a combination of 1 W/cm2 US power and a 100 Hz intermittent pulse with a “5 seconds on, 5 seconds off” mode, NBs with an average size of (485.7±33) nm were effectively destroyed within 15 minutes in the tumor location. PC3 cells and 20 tumor-bearing mice were divided into four groups: a DOX group, a DOX + NB group, a DOX + US group, and a DOX + NB + US group. The cell growth-inhibition rate and DOX concentration of xenografts in the DOX + NB + US group were highest. Based on another control group and these four groups, another 25 tumor-bearing mice were used to observe the treatment effect of nine DOX injections under UTND. The xenografts in the DOX + NB + US group decreased more obviously and had more cellular apoptosis than other groups. Finally, electron microscopy was used to estimate the cavitation effect of NBs under US irradiation in the control group, NB group, US group, and NB + US group. The results of scanning electron microscopy showed that PC3 cells in the DOX + NB + US group had more holes and significantly increased cell-surface folds. Meanwhile, transmission electric microscopy confirmed that more lanthanum nitrate particles entered the parenchymal cells in xenografts in the NB + US group compared with the other groups. This study suggested that UTND technology could be an effective method to promote drugs to function in US-irradiated sites, and the underlying mechanism may be associated with a cavitation effect. PMID:27536100

New targeted therapies in pancreatic cancer.

PubMed

Seicean, Andrada; Petrusel, Livia; Seicean, Radu

2015-05-28

Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways.

Capital Growth Paths of the Neoclassical Growth Model

PubMed Central

Takahashi, Taro

2012-01-01

This paper derives the first-order approximated paths of both types of capital in the two-capital neoclassical growth model. The derived capital growth paths reveal that the short-run growth effect of capital injection differs considerably depending on which type of capital is enhanced. This result demonstrates the importance of well-targeted capital enhancement programs such as public sector projects and foreign aid. PMID:23185344

Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging.

PubMed

Liu, Heng; Chen, Xiao; Xue, Wei; Chu, Chengchao; Liu, Yu; Tong, Haipeng; Du, Xuesong; Xie, Tian; Liu, Gang; Zhang, Weiguo

The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

MicroRNA-365 inhibits growth, invasion and metastasis of malignant melanoma by targeting NRP1 expression.

PubMed

Bai, Juanjuan; Zhang, Zhongling; Li, Xing; Liu, Huifan

2015-01-01

The role of miR-365 in cancer cells seemed controversial in previous studies. We thereby in this article aimed to define the role of miR-365 in malignant melanoma (MM) pathogenesis. We detected miR-365 expression in malignant melanoma cell lines and then investigated the effects of miR-365 on the metastasis and malignancy of melanoma cells. The correlation between miR-365 level and NRP1 (neuropilin1) was further investigated in clinical malignant melanoma specimens. MiR-365 was strongly down-regulated in malignant melanoma (MM) tissues and cell lines, and its expression levels were associated with lymph node metastasis and clinical stage, as well as overall survival and replase-free survival of MM. We also found that ectopic expression of miR-365 inhibited MM cell proliferation and MM metastasis in vitro and in vivo. We further identified a novel mechanism of miR-365 to suppress MM growth and metastasis. NRP1 was proved to be a direct target of miR-365, using luciferase assay and western blot. NRP1 over-expression in miR-365 expressing cells could rescue invasion and growth defects of miR-365. In addition, miR-365 expression inversely correlated with NRP1 protein levels in MM. Our data suggest that miR-365 functions as a tumor suppressor in MM development and progression, and holds promise as a prognostic biomarker and potential therapeutic target for MM.

Embryo growth, testa permeability, and endosperm weakening are major targets for the environmentally regulated inhibition of Lepidium sativum seed germination by myrigalone A

PubMed Central

2012-01-01

Myrigalone A (MyA) is a rare flavonoid in fruit leachates of Myrica gale, a deciduous shrub adapted to flood-prone habitats. As a putative allelochemical it inhibits seed germination and seedling growth. Using Lepidium sativum as a model target species, experiments were conducted to investigate how environmental cues modulate MyA’s interference with key processes of seed germination. Time course analyses of L. sativum testa and endosperm rupture under different light conditions and water potentials were combined with quantifying testa permeability, endosperm weakening, tissue-specific gibberellin (GA) and abscisic acid (ABA) contents, as well as embryo growth and apoplastic superoxide production important for cell expansion growth. Lepidium sativum testa permeability and early water uptake by imbibition is enhanced by MyA. During late germination, MyA inhibits endosperm weakening and embryo growth, both processes required for endosperm rupture. Inhibition of embryo cell expansion by MyA depends on environmental cues, which is evident from the light-modulated severity of the MyA-mediated inhibition of apoplastic superoxide accumulation. Several important key weakening and growth processes during early and late germination are targets for MyA. These effects are modulated by light conditions and ambient water potential. It is speculated that MyA is a soil seed bank-destroying allelochemical that secures the persistence of M. gale in its flood-prone environment. PMID:22821938

Fibroblast Growth Factor Receptors: From the Oncogenic Pathway to Targeted Therapy.

PubMed

Saichaemchan, S; Ariyawutyakorn, W; Varella-Garcia, M

2016-01-01

The family of fibroblast growth factor (FGFs) and their receptors (FGFRs) regulates vital roles in many biological processes affecting cell proliferation, migration, differentiation and survival. Deregulation of the FGF/FGFR signaling pathway in cancers has been better understood and the main molecular mechanisms responsible for the activation of this pathway are gene mutations, gene fusions and gene amplification. DNA and RNA-based technologies have been used to detect these abnormalities, especially in FGFR1, FGFR2 and FGFR3 and tests have been developed for their detection, but no assay has been proved ideal for molecular diagnosis. Interestingly, the increase in the molecular biology knowledge has supported and assisted the development of therapeutic drugs targeting the most important components of this pathway. Multi- and selective tyrosine kinase inhibitors (TKIs) as well as monoclonal antibodies anti-FGFR are under investigation in preclinical and clinical trials. In this article, we reviewed those aspects with special emphasis on the pathway genomic alterations related to solid tumors, and the molecular diagnostic assays potentially able to stratify patients for the treatment with FGFR TKIs.

Individual growth of Heleobia piscium in natural populations (Gastropoda: Cochliopidae) from the multiple use natural Reserve Isla Martin Garcia, Buenos Aires, Argentina.

PubMed

Martin, S M

2008-08-01

The present work analyses the individual growth of Heleobia piscium in natural conditions in coastal drainage channels of the Multiple Use Natural Reserve Isla Martín García, Buenos Aires, Argentina. Isla Martín García is located in the Upper Río de la Plata, to the south of the mouth of the Uruguay river (34 degrees 11' 25" S and 58 degrees 15' 38" W). Monthly collections were made from July 2005 to July 2006 in the eastern part of the island (Arena Beach). The population of H. piscium showed a complex and dynamic structure of sizes during a long period of the annual cycle. Two cohorts could be detected. The Bertalanffy growth equation was: Lt = 6 (1-e -1.85 (t+0.38)) and Lt = 3.9 (1-e -0.19 (t+4.84)) for cohorts 1 and 2, respectively. The pattern of population growth displayed a staggered model, where the greatest growth is observed during the summer. The reproductive period occurred during six months, from the beginning of summer to middle of fall. Based on only one reproductive effort, this pattern is not similar to that of other cogeneric species already studied.

Cytokine-targeting biologics for allergic diseases.

PubMed

Lawrence, Monica G; Steinke, John W; Borish, Larry

2018-04-01

Asthma and allergic diseases continue to increase in prevalence, creating a financial burden on the health care system and affecting the quality of life for those who have these diseases. Many intrinsic and extrinsic factors are involved in the initiation and maintenance of the allergic response. Cytokines are proteins with growth, differentiation, and activation functions that regulate and direct the nature of immune responses. clinicaltrials.gov and PubMed. Relevant clinical trials and recent basic science studies were chosen for discussion. Many cytokines have been implicated in the development and perpetuation of the allergic response. Biologics have been and are continuing to be developed that target these molecules for use in patients with asthma and atopic dermatitis where standard treatment options fail. The current state of cytokine-targeting therapies is discussed. This review focused on cytokines involved in the allergic response with an emphasis on those for which therapies are being or have been developed. Copyright © 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Small cell lung cancer growth is inhibited by miR-342 through its effect of the target gene IA-2.

PubMed

Xu, Huanyu; Cai, Tao; Carmona, Gilberto N; Abuhatzira, Liron; Notkins, Abner L

2016-09-26

Small cell lung cancers (SCLC) are tumors of neuroendocrine origin. Previous in vitro studies from our laboratory showed that SCLC expresses high levels of the transmembrane dense core vesicle protein IA-2 (islet cell antigen-2) as compared to normal lung cells. IA-2, through its effect on dense core vesicles (DCVs), is known to be involved in the secretion of hormones and neurotransmitters. It is believed that the dysregulated release of the neurotransmitter Acetylcholine (ACh) by DCVs has an autocrine effect on SCLC cell growth. Recently, we found that IA-2 is a target of the microRNA miR-342 and that miR-342 mimics suppress the expression of IA-2. The present experiments were initiated to see whether IA-2 and/or miR-342 affect the growth of SCLC. SCLC cell growth was evaluated following the knockdown of endogenous IA-2 with RNAi or by overexpressing miR-342 with a mimic. The secretion and content of ACh in SCLC cells was analyzed using a human acetylcholine ELISA (enzyme-linked immunosorbent assay) kit. The knockdown of endogenous IA-2 by RNAi reduced SCLC cell growth within 4 days by 40 % or more. Similar results were obtained when these cell lines were transfected with a miR-342 mimic. The knockdown of IA-2 by RNAi or miR-342 with a mimic also resulted in a significant decrease in the secretion of ACh, one of the autocrine hormones secreted by SCLC. Further studies revealed that the growth of SCLC cell lines that had been treated with the miR-342 mimic was restored to nearly normal levels by treatment with ACh. Our studies show for the first time that both miR-342 and its target gene IA-2 are involved in the growth process of SCLC cells and act by their effect on autocrine secretion. These findings point to possible new therapeutic approaches for the treatment of autocrine-induced tumor proliferation.

Growth hormone regulation of follicular growth.

PubMed

Lucy, Matthew C

2011-01-01

The somatotropic axis-consisting of growth hormone (GH), the insulin-like growth factors 1 and 2 (IGF1 and IGF2), GH binding protein (GHBP), IGF binding proteins (IGFBPs) 1 to 6, and the cell-surface receptors for GH and the IGFs-has major effects on growth, lactation and reproduction. The primary target tissues for GH are involved in growth and metabolism. The functionality of the somatotropic axis depends in part on the expression of liver GH receptor (GHR), which determines the amount of IGF1 released from the liver in response to GH. The IGF1 acts as a pleiotropic growth factor and also serves as the endocrine negative feedback signal controlling pituitary GH secretion. Growth hormone and IGF1 undergo dynamic changes throughout the life cycle, particularly when animals are either growing, early post partum or lactating. Cells within the reproductive tract can respond directly to GH but to a lesser degree than the primary target tissues. The major impact that GH has on reproduction, therefore, may be secondary to its systemic effects on metabolism (including insulin sensitivity) or secondary to the capacity for GH to control IGF1 secretion. Insulin-like growth factor 1 and IGFBP are also synthesised within the ovary and this local synthesis is a component of the collective IGF1 action on the follicle. Future studies of GH should focus on its direct effects on the follicle as well as its indirect effects mediated by shifts in nutrient metabolism, insulin sensitivity, IGF1 and IGFBP.

Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products.

PubMed

Grossman, Elizabeth A; Ward, Carl C; Spradlin, Jessica N; Bateman, Leslie A; Huffman, Tucker R; Miyamoto, David K; Kleinman, Jordan I; Nomura, Daniel K

2017-11-16

Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation. We developed a more synthetically tractable cysteine-reactive covalent ligand, JNS 1-40, that selectively targets C377 of PPP2R1A to impair breast cancer signaling, proliferation, and in vivo tumor growth. Our study highlights the utility of using chemoproteomics to map druggable hotspots targeted by complex natural products and subsequently interrogating these sites with more synthetically tractable covalent ligands for cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.

PubMed

Lou, Yuanmei; McDonald, Paul C; Oloumi, Arusha; Chia, Stephen; Ostlund, Christina; Ahmadi, Ardalan; Kyle, Alastair; Auf dem Keller, Ulrich; Leung, Samuel; Huntsman, David; Clarke, Blaise; Sutherland, Brent W; Waterhouse, Dawn; Bally, Marcel; Roskelley, Calvin; Overall, Christopher M; Minchinton, Andrew; Pacchiano, Fabio; Carta, Fabrizio; Scozzafava, Andrea; Touisni, Nadia; Winum, Jean-Yves; Supuran, Claudiu T; Dedhar, Shoukat

2011-05-01

Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis.

EGFR-targeted gelatin nanoparticles for systemic administration of gemcitabine in an orthotopic pancreatic cancer model.

PubMed

Singh, Amit; Xu, Jing; Mattheolabakis, George; Amiji, Mansoor

2016-04-01

In this study, we have formulated redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a targeted vector for systemic delivery of gemcitabine therapy in pancreatic cancer. The gelatin nanoparticles were formed by ethanol-induced desolvation process to encapsulate the bound drug. The surface of the nanoparticles was decorated either with poly(ethylene glycol) (PEG) chains to impart enhanced circulation time or with EGFR targeting peptide to confer target specificity. Our in vitro studies in Panc-1 human pancreatic ductal adenocarcinoma cells confirm that gemcitabine encapsulated in EGFR-targeted gelatin nanoparticles, released through disulfide bond cleavage, had a significantly improved cytotoxic profile. Further, the in vivo anticancer activity was evaluated in an orthotopic pancreatic adenocarcinoma tumor bearing SCID beige mice, which confirmed that EGFR-targeted gelatin nanoparticles could efficiently deliver gemcitabine to the tumor leading to higher therapeutic benefit as compared to the drug in solution. The treatment of pancreatic cancer remains unsatisfactory, with an average 5-year survival of less than 5%. New treatment modalities are thus urgently needed. In this study, the authors presented their formulation of redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a carrier for gemcitabine. In-vitro and in-vivo experiments showed encouraging results. It is hoped that the findings would provide a novel and alternative drug delivery platform for the future. Copyright © 2015 Elsevier Inc. All rights reserved.

Catch, bycatch and discards of the Galapagos Marine Reserve small-scale handline fishery.

PubMed

Zimmerhackel, Johanna S; Schuhbauer, Anna C; Usseglio, Paolo; Heel, Lena C; Salinas-de-León, Pelayo

2015-01-01

Fisheries bycatch is a significant marine conservation issue as valuable fish are wasted and protected species harmed with potential negative ecological and socio-economic consequences. Even though there are indications that the small-scale handline fishery of the Galapagos Marine Reserve has a low selectivity, information on its bycatch has never been published. We used onboard monitoring and interview data to assess the bycatch of the Galapagos handline fishery by estimating the bycatch ratio, determining species compositions of landings and bycatch, identifying fishers' reasons for discarding certain individuals, and revealing historical trends in the bycatch ratio. The estimated bycatch ratio as a function of biomass of 0.40 and a diverse species composition of target catch and bycatch confirmed the low selectivity of this fishery. Most individuals were not landed for economic motivations, either because species (77.4%) or sizes (17.7%) are unmarketable or for regulatory reasons (5.9%). We found that bycatch contributes to growth overfishing of some target species because they are discarded or used as bait before reaching their first maturity. Moreover, over half of interviewees perceived a historical decrease in bycatch ratios that was explained by a diversification of the target catch due to the reduction in abundance of the traditionally most important target species. As some target species show signs of overfishing and to date there are no specific regulations for the finfish fishery species in place, we recommend the implementation of a series of management measures to protect critical life stages of overexploited species and to improve the selectivity of the Galapagos handline fishery.

Catch, bycatch and discards of the Galapagos Marine Reserve small-scale handline fishery

PubMed Central

Schuhbauer, Anna C.; Usseglio, Paolo; Heel, Lena C.; Salinas-de-León, Pelayo

2015-01-01

Fisheries bycatch is a significant marine conservation issue as valuable fish are wasted and protected species harmed with potential negative ecological and socio-economic consequences. Even though there are indications that the small-scale handline fishery of the Galapagos Marine Reserve has a low selectivity, information on its bycatch has never been published. We used onboard monitoring and interview data to assess the bycatch of the Galapagos handline fishery by estimating the bycatch ratio, determining species compositions of landings and bycatch, identifying fishers’ reasons for discarding certain individuals, and revealing historical trends in the bycatch ratio. The estimated bycatch ratio as a function of biomass of 0.40 and a diverse species composition of target catch and bycatch confirmed the low selectivity of this fishery. Most individuals were not landed for economic motivations, either because species (77.4%) or sizes (17.7%) are unmarketable or for regulatory reasons (5.9%). We found that bycatch contributes to growth overfishing of some target species because they are discarded or used as bait before reaching their first maturity. Moreover, over half of interviewees perceived a historical decrease in bycatch ratios that was explained by a diversification of the target catch due to the reduction in abundance of the traditionally most important target species. As some target species show signs of overfishing and to date there are no specific regulations for the finfish fishery species in place, we recommend the implementation of a series of management measures to protect critical life stages of overexploited species and to improve the selectivity of the Galapagos handline fishery. PMID:26082874

Competitive Growth Enhances Conditional Growth Mutant Sensitivity to Antibiotics and Exposes a Two-Component System as an Emerging Antibacterial Target in Burkholderia cenocepacia.

PubMed

Gislason, April S; Choy, Matthew; Bloodworth, Ruhi A M; Qu, Wubin; Stietz, Maria S; Li, Xuan; Zhang, Chenggang; Cardona, Silvia T

2017-01-01

Chemogenetic approaches to profile an antibiotic mode of action are based on detecting differential sensitivities of engineered bacterial strains in which the antibacterial target (usually encoded by an essential gene) or an associated process is regulated. We previously developed an essential-gene knockdown mutant library in the multidrug-resistant Burkholderia cenocepacia by transposon delivery of a rhamnose-inducible promoter. In this work, we used Illumina sequencing of multiplex-PCR-amplified transposon junctions to track individual mutants during pooled growth in the presence of antibiotics. We found that competition from nontarget mutants magnified the hypersensitivity of a clone underexpressing gyrB to novobiocin by 8-fold compared with hypersensitivity measured during clonal growth. Additional profiling of various antibiotics against a pilot library representing most categories of essential genes revealed a two-component system with unknown function, which, upon depletion of the response regulator, sensitized B. cenocepacia to novobiocin, ciprofloxacin, tetracycline, chloramphenicol, kanamycin, meropenem, and carbonyl cyanide 3-chlorophenylhydrazone, but not to colistin, hydrogen peroxide, and dimethyl sulfoxide. We named the gene cluster esaSR for enhanced sensitivity to antibiotics sensor and response regulator. Mutational analysis and efflux activity assays revealed that while esaS is not essential and is involved in antibiotic-induced efflux, esaR is an essential gene and regulates efflux independently of antibiotic-mediated induction. Furthermore, microscopic analysis of cells stained with propidium iodide provided evidence that depletion of EsaR has a profound effect on the integrity of cell membranes. In summary, we unraveled a previously uncharacterized two-component system that can be targeted to reduce antibiotic resistance in B. cenocepacia. Copyright © 2016 American Society for Microbiology.

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

PubMed

Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

2015-12-29

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

PubMed Central

Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

2015-01-01

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

Colorimetric Detection of Small Molecules in Complex Matrixes via Target-Mediated Growth of Aptamer-Functionalized Gold Nanoparticles.

PubMed

Soh, Jun Hui; Lin, Yiyang; Rana, Subinoy; Ying, Jackie Y; Stevens, Molly M

2015-08-04

A versatile and sensitive colorimetric assay that allows the rapid detection of small-molecule targets using the naked eye is demonstrated. The working principle of the assay integrates aptamer-target recognition and the aptamer-controlled growth of gold nanoparticles (Au NPs). Aptamer-target interactions modulate the amount of aptamer strands adsorbed on the surface of aptamer-functionalized Au NPs via desorption of the aptamer strands when target molecules bind with the aptamer. Depending on the resulting aptamer coverage, Au NPs grow into morphologically varied nanostructures, which give rise to different colored solutions. Au NPs with low aptamer coverage grow into spherical NPs, which produce red-colored solutions, whereas Au NPs with high aptamer coverage grow into branched NPs, which produce blue-colored solutions. We achieved visible colorimetric response and nanomolar detection limits for the detection of ochratoxin A (1 nM) in red wine samples, as well as cocaine (1 nM) and 17β-estradiol (0.2 nM) in spiked synthetic urine and saliva, respectively. The detection limits were well within clinically and physiologically relevant ranges, and below the maximum food safety limits. The assay is highly sensitive, specific, and able to detect an array of analytes rapidly without requiring sophisticated equipment, making it relevant for many applications, such as high-throughput drug and clinical screening, food sampling, and diagnostics. Furthermore, the assay is easily adapted as a chip-based platform for rapid and portable target detection.

Therapeutic effect of photodynamic therapy combined with targeted delivery of silencing vascular endothelial growth factor (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hsu, Yih-Chih

2016-03-01

Photodynamic therapy is a novel therapeutic modality to treat cancer by using a photosensitizer which is activated by a light source to produce reactive oxygen species and mediates tumours oxygen-independent hypoxic conditions. Vascular endothelial growth factor (VEGF) is one of the primary factors that affect tumor angiogenesis. Another emerging treatment to cure cancer is the use of interference RNA to silence a specific mRNA sequence. Such treatment requires a delivery system such as liposomes. The nanoparticle size measured was about 30 nm. Cellular uptake study was performed to verify that the nanoparticles have a sigma receptor mediated pathway. Non-targeted LCP NPs did not show significant difference with or without haloperidol but has a lower intensity as than targeted LCP NPs. These results confirm that LCP NPs have a receptor mediated pathway. Cell viability was found to decrease at 25 nM of transfected VEGF siRNA. Combined therapy of PDT and VEGF siRNA showed significant response as compared with PDT and gene therapy alone. In vivo toxicity assay with mice treated with targeted LCP NPs containing control siRNA or VEGF siRNA and non-targeted LCP NPs containing VEGF siRNA did not show any significant difference with the PBS injected group which suggests that there is no toxicity with the dose. It suggests that PDT combined with targeted gene therapy has a potential mean to achieve better therapeutic outcome.

Knockdown of Oncogenic KRAS in Non-Small Cell Lung Cancers Suppresses Tumor Growth and Sensitizes Tumor Cells to Targeted Therapy

PubMed Central

Sunaga, Noriaki; Shames, David S.; Girard, Luc; Peyton, Michael; Larsen, Jill E.; Imai, Hisao; Soh, Junichi; Sato, Mitsuo; Yanagitani, Noriko; Kaira, Kyoichi; Xie, Yang; Gazdar, Adi F.; Mori, Masatomo; Minna, John D.

2011-01-01

Oncogenic KRAS is found in >25% of lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we performed microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines (HBECs) with and without oncogenic KRAS. We found that while the MAPK pathway is significantly down-regulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho-EGFR, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment but may offer possibilities of combining anti-KRAS strategies with other targeted drugs. PMID:21306997

Cyclophilin J Is a Novel Peptidyl-Prolyl Isomerase and Target for Repressing the Growth of Hepatocellular Carcinoma

PubMed Central

Chen, Jian; Chen, Shuai; Wang, Jiahui; Zhang, Mingjun; Gong, Zhaohua; Wei, Youheng; Li, Li; Zhang, Yuanyuan; Zhao, Xuemei; Jiang, Songmin; Yu, Long

2015-01-01

Cyclophilin J (CYPJ) is a new member of the peptidyl-prolyl cis/trans-isomerase (PPIase) identified with upregulated expression in human glioma. However, the biological function of CYPJ remained unclear. We aimed to study the role of CYPJ in hepatocellular carcinoma (HCC) carcinogenesis and its therapeutic potential. We determined the expression of CYPJ in HCC/adjacent normal tissues using Western blot, Northern blot and semi-quantitative RT-PCR, analyzed the biochemical characteristics of CYPJ, and resolved the 3D-structure of CYPJ/Cyclosporin A (CsA) complex. We also studied the roles of CYPJ in cell cycle, cyclin D1 regulation, in vitro and in vivo tumor growth. We found that CYPJ expression was upregulated in over 60% HCC tissues. The PPIase activity of CYPJ could be inhibited by the widely used immunosuppressive drug CsA. CYPJ was found expressed in the whole cell of HCC with preferential location at the cell nucleus. CYPJ promoted the transition of cells from G1 phase to S phase in a PPIase-dependent manner by activating cyclin D1 promoter. CYPJ overexpression accelerated liver cell growth in vitro (cell growth assay, colony formation) and in vivo (xenograft tumor formation). Inhibition of CYPJ by its inhibitor CsA or CYPJ-specific RNAi diminished the growth of liver cancer cells in vitro and in vivo. In conclusion, CYPJ could facilitate HCC growth by promoting cell cycle transition from G1 to S phase through the upregulation of cyclin D1. Suppression of CYPJ could repress the growth of HCC, which makes CYPJ a potential target for the development of new strategies to treat this malignancy. PMID:26020957

Targeting oncogenic KRAS in non-small cell lung cancer cells by phenformin inhibits growth and angiogenesis.

PubMed

Wang, Zhi Dong; Wei, Sheng Quan; Wang, Qin Yi

2015-01-01

Tumors require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors. Many potential oncogenic mutations have been identified in tumor angiogenesis. Somatic mutations in the small GTPase KRAS are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated anti-tumor activity both in vitro and in vivo. The extracellular regulated protein kinases (ERK) signaling is known to be a major cellular target of biguanides. Based on KRAS activates several down-stream effectors leading to the stimulation of the RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAF/MEK/ERK) and phosphatidylinositol-3-kinase (PI3K) pathways, we investigated the anti-tumor effects of biguanides on the proliferation of KRAS-mutated tumor cells in vitro and on KRAS-driven tumor growth in vivo. In cancer cells harboring oncogenic KRAS, phenformin switches off the ERK pathway and inhibit the expression of pro-angiogenic molecules. In tumor xenografts harboring the KRAS mutation, phenformin extensively modifies the tumor growth causing abrogation of angiogenesis. These results strongly suggest that significant therapeutic advantage may be achieved by phenformin anti-angiogenesis for the treatment of tumor.

Impact of marine reserve on maximum sustainable yield in a traditional prey-predator system

NASA Astrophysics Data System (ADS)

Paul, Prosenjit; Kar, T. K.; Ghorai, Abhijit

2018-01-01

Multispecies fisheries management requires managers to consider the impact of fishing activities on several species as fishing impacts both targeted and non-targeted species directly or indirectly in several ways. The intended goal of traditional fisheries management is to achieve maximum sustainable yield (MSY) from the targeted species, which on many occasions affect the targeted species as well as the entire ecosystem. Marine reserves are often acclaimed as the marine ecosystem management tool. Few attempts have been made to generalize the ecological effects of marine reserve on MSY policy. We examine here how MSY and population level in a prey-predator system are affected by the low, medium and high reserve size under different possible scenarios. Our simulation works shows that low reserve area, the value of MSY for prey exploitation is maximum when both prey and predator species have fast movement rate. For medium reserve size, our analysis revealed that the maximum value of MSY for prey exploitation is obtained when prey population has fast movement rate and predator population has slow movement rate. For high reserve area, the maximum value of MSY for prey's exploitation is very low compared to the maximum value of MSY for prey's exploitation in case of low and medium reserve. On the other hand, for low and medium reserve area, MSY for predator exploitation is maximum when both the species have fast movement rate.

miR-24 and miR-122 Negatively Regulate the Transforming Growth Factor-β/Smad Signaling Pathway in Skeletal Muscle Fibrosis.

PubMed

Sun, Yaying; Wang, Hui; Li, Yan; Liu, Shaohua; Chen, Jiwu; Ying, Hao

2018-06-01

Fibrosis is common after skeletal muscle injury, undermining tissue regeneration and function. The mechanism underlying skeletal muscle fibrosis remains unveiled. Transforming growth factor-β/Smad signaling pathway is supposed to play a pivotal role. However, how microRNAs interact with transforming growth factor-β/Smad-related muscle fibrosis remains unclear. We showed that microRNA (miR)-24-3p and miR-122-5p declined in skeletal muscle fibrosis, which was a consequence of transforming growth factor-β. Upregulating Smad4 suppressed two microRNAs, whereas inhibiting Smad4 elevated microRNAs. Luciferase reporter assay and chromatin immunoprecipitation confirmed that Smad4 directly inhibited two microRNAs. On the other hand, overexpression of these two miRs retarded fibrotic process. We further identified that Smad2 was a direct target of miR-24-3p, whereas miR-122-5p targeted transforming growth factor-β receptor-II. Both targets were important participants in transforming growth factor-β/Smad signaling. Taken together, a positive feedback loop in transforming growth factor-β/Smad4 signaling pathway in skeletal muscle fibrosis was identified. Transforming growth factor-β/Smad axis could be downregulated by microRNAs. This effect, however, was suppressed by Smad4, the downstream of transforming growth factor-β. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

The role of marine reserves in achieving sustainable fisheries

PubMed Central

Roberts, Callum M.; Hawkins, Julie P.; Gell, Fiona R.

2005-01-01

Many fishery management tools currently in use have conservation value. They are designed to maintain stocks of commercially important species above target levels. However, their limitations are evident from continuing declines in fish stocks throughout the world. We make the case that to reverse fishery declines, safeguard marine life and sustain ecosystem processes, extensive marine reserves that are off limits to fishing must become part of the management strategy. Marine reserves should be incorporated into modern fishery management because they can achieve many things that conventional tools cannot. Only complete and permanent protection from fishing can protect the most sensitive habitats and vulnerable species. Only reserves will allow the development of natural, extended age structures of target species, maintain their genetic variability and prevent deleterious evolutionary change from the effects of fishing. Species with natural age structures will sustain higher rates of reproduction and will be more resilient to environmental variability. Higher stock levels maintained by reserves will provide insurance against management failure, including risk-prone quota setting, provided the broader conservation role of reserves is firmly established and legislatively protected. Fishery management measures outside protected areas are necessary to complement the protection offered by marine reserves, but cannot substitute for it. PMID:15713592

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

PubMed Central

Amin, A.R.M. Ruhul; Karpowicz, Phillip A.; Carey, Thomas E.; Arbiser, Jack; Nahta, Rita; Chen, Zhuo G.; Dong, Jin-Tang; Kucuk, Omer; Khan, Gazala N.; Huang, Gloria S.; Mi, Shijun; Lee, Ho-Young; Reichrath, Joerg; Honoki, Kanya; Georgakilas, Alexandros G.; Amedei, Amedeo; Amin, Amr; Helferich, Bill; Boosani, Chandra S.; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I.; Azmi, Asfar S.; Keith, W Nicol; Bhakta, Dipita; Halicka, Dorota; Niccolai, Elena; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S. Salman; Nowsheen, Somaira; Yang, Xujuan; Bilsland, Alan; Shin, Dong M.

2015-01-01

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting. PMID:25749195

Vasodilator-stimulated phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-dependent plasma membrane targeting of transforming growth factor beta receptors.

PubMed

Tu, Kangsheng; Li, Jiachu; Verma, Vikas K; Liu, Chunsheng; Billadeau, Daniel D; Lamprecht, Georg; Xiang, Xiaoyu; Guo, Luyang; Dhanasekaran, Renumathy; Roberts, Lewis R; Shah, Vijay H; Kang, Ningling

2015-01-01

Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF-β) stimulation, hepatic stellate cells (HSCs), which are liver-specific pericytes, transdifferentiate into tumor-associated myofibroblasts that promote tumor implantation (TI) and growth in the liver. However, the regulation of this HSC activation process remains poorly understood. In this study, we tested whether vasodilator-stimulated phosphoprotein (VASP) of HSCs regulated the TGF-β-mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced up-regulation of VASP and alpha-smooth muscle actin (α-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF-β-mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF-β receptor II (TβRII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11-dependent targeting of TβRII to the plasma membrane, thereby desensitizing HSCs to TGF-β1 stimulation. Our study demonstrates a requirement of VASP for TGF-β-mediated HSC activation in the tumor microenvironment by regulating Rab11-dependent recycling of TβRII to the plasma membrane. VASP and its effector, Rab11, in the tumor microenvironment thus present therapeutic targets for reducing TI and metastatic growth in the liver. © 2014 by the American Association for the Study of Liver Diseases.

The RNA-binding protein PCBP2 facilitates gastric carcinoma growth by targeting miR-34a

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Cheng-En; Liu, Yong-Chao; Zhang, Hui-Dong

Highlights: • PCBP2 is overexpressed in human gastric cancer. • PCBP2 high expression predicts poor survival. • PCBP2 regulates gastric cancer growth in vitro and in vivo. • PCBP2 regulates gastric cancer apoptosis by targeting miR-34a. - Abstract: Gastric carcinoma is the fourth most common cancer worldwide, with a high rate of death and low 5-year survival rate. However, the mechanism underling gastric cancer is still not fully understood. Here in the present study, we identify the RNA-binding protein PCBP2 as an oncogenic protein in human gastric carcinoma. Our results show that PCBP2 is up-regulated in human gastric cancer tissuesmore » compared to adjacent normal tissues, and that high level of PCBP2 predicts poor overall and disease-free survival. Knockdown of PCBP2 in gastric cancer cells inhibits cell proliferation and colony formation in vitro, whereas opposing results are obtained when PCBP2 is overexpressed. Our in vivo subcutaneous xenograft results also show that PCBP2 can critically regulate gastric cancer cell growth. In addition, we find that PCBP2-depletion induces apoptosis in gastric cancer cells via up-regulating expression of pro-apoptotic proteins and down-regulating anti-apoptotic proteins. Mechanically, we identify that miR-34a as a target of PCBP2, and that miR-34a is critically essential for the function of PCBP2. In summary, PCBP2 promotes gastric carcinoma development by regulating the level of miR-34a.« less

CONNECTIVE TISSUE GROWTH FACTOR IS A TARGET OF NOTCH SIGNALING IN CELLS OF THE OSTEOBLASTIC LINEAGE

PubMed Central

Canalis, Ernesto; Zanotti, Stefano; Smerdel-Ramoya, Anna

2014-01-01

Connective tissue growth factor (Ctgf) or CCN2 is a protein synthesized by osteoblasts necessary for skeletal homeostasis, although its overexpression inhibits osteogenic signals and bone formation. Ctgf is induced by bone morphogenetic proteins, transforming growth factor β and Wnt; and in the present studies, we explored whether Notch regulated Ctgf expression in osteoblasts. We employed RosaNotch mice, where the Notch intracellular domain (NICD) is expressed following the excision of a STOP cassette, placed between the Rosa26 promoter and NICD. Notch was activated by transduction of adenoviral vectors expressing Cre recombinase (Ad-CMV-Cre). Notch induced Ctgf mRNA levels in a time dependent manner and increased Ctgf heterogeneous nuclear RNA. Notch also destabilized Ctgf mRNA shortening its half-life from 13 h to 3 h. The effect of Notch on Ctgf expression was lost following Rbpjκ downregulation, demonstrating that it was mediated by Notch canonical signaling. However, downregulation of the classic Notch target genes Hes1, Hey1 and Hey2 did not modify the effect of Notch on Ctgf expression. Wild type osteoblasts exposed to immobilized Delta-like 1 displayed enhanced Notch signaling and increased Ctgf expression. In addition to the effects of Notch in vitro, Notch induced Ctgf in vivo, and calvariae and femurs from RosaNotch mice mated with transgenics expressing the Cre recombinase in cells of the osteoblastic lineage exhibited increased expression of Ctgf. In conclusion, Ctgf is a target of Notch canonical signaling in osteoblasts, and may act in concert with Notch to regulate skeletal homeostasis. PMID:24792956

U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo

PubMed Central

Goraczniak, Rafal; Wall, Brian A; Behlke, Mark A; Lennox, Kim A; Ho, Eric S; Zaphiros, Nikolas H; Jakubowski, Christopher; Patel, Neil R; Zhao, Steven; Magaway, Carlo; Subbie, Stacey A; Jenny Yu, Lumeng; LaCava, Stephanie; Reuhl, Kenneth R; Chen, Suzie; Gunderson, Samuel I

2013-01-01

U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2) and metabotropic glutamate receptor 1 (GRM1), in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv) administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6) indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups) validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases. PMID:23673539

Epidermal growth factor expression in esophageal adenocarcinoma: a clinically relevant target?

PubMed

Harper, Nicholas; Li, Yan; Farmer, Russell; Martin, Robert C G

2012-05-01

There has been recent widespread enthusiasm in epidermal growth factor (EGFR) as a molecularly active target in esophageal adenocarcinoma (EAC). However, there is limited data on the extent of EGFR expression in EAC. Thus, the aim of this study was to evaluated EGFR, pErk1/2, and total Erk1/2 expression in malignant and benign specimens. Baseline expression of EGFR in the human normal squamous, Barrett's, and EAC cell lines were determined as well as after bile acid treatment and curcumin pretreatment. In addition, EGFR expression was also evaluated in 60 matched normal and malignant EAC resected specimens. The in vitro studies in the Het-1a, BarT, and OE19 cell lines failed to show any measurable expression of EGFR via Western blot technique. The marker serving as the positive control for the study, MnSOD, showed expression in each cell line for all three treatment regimens at approximately 24 kDa EGFR, showing moderate staining in the malignant tumor specimens and low staining in the benign tissue specimens. pErk1/2 showed low staining in the malignant tumor specimens and no staining in the benign tissue specimens. Total Erk1/2 showed high staining in both the malignant tumor specimens and benign tissue specimens. The differences in the mean staining scores for the malignant versus benign tissue specimens for pErk1/2 and total Erk1/2 are not statistically significant (p = 0.0726 and p = 0.7054, respectively). Thus, in conclusion, EGFR expression has been confirmed to be limited to non-existent in EAC and thus its use as a clinically active target is limited at best. Prior to the use of these expensive anti-EGFR therapies, confirmation of overexpression should be verified.

Inhalable magnetic nanoparticles for targeted hyperthermia in lung cancer therapy.

PubMed

Sadhukha, Tanmoy; Wiedmann, Timothy S; Panyam, Jayanth

2013-07-01

Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need for developing an effective means to treat NSCLC. Magnetic hyperthermia is a non-invasive approach for tumor ablation, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance while non-targeted delivery of these particles to the healthy tissues can result in toxicity. In our studies, we evaluated the effectiveness of tumor-targeted SPIO nanoparticles for magnetic hyperthermia of lung cancer. EGFR-targeted, inhalable SPIO nanoparticles were synthesized and characterized for targeting lung tumor cells as well as for magnetic hyperthermia-mediated antitumor efficacy in a mouse orthotopic model of NSCLC. Our results show that EGFR targeting enhances tumor retention of SPIO nanoparticles. Further, magnetic hyperthermia treatment using targeted SPIO nanoparticles resulted in significant inhibition of in vivo lung tumor growth. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC based on targeted magnetic hyperthermia. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function.

PubMed

Hennig, Maria; Fiedler, Saskia; Jux, Christian; Thierfelder, Ludwig; Drenckhahn, Jörg-Detlef

2017-08-04

Fetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of mTORC1 in intrauterine growth restriction and prenatal heart growth. We inhibited mTORC1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces mTORC1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin-treated neonates exhibit a 16% reduction in body weight compared with vehicle-treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin- versus vehicle-treated mice at birth. Although proliferation rates in neonatal rapamycin-treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle-treated neonates. Rapamycin-treated mice exhibit postnatal catch-up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal mTORC1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling. Prenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of mTORC1 in perinatal cardiac growth. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC) in a KRas/p53 transgenic mouse model.

PubMed

Deneka, Alexander Y; Haber, Leora; Kopp, Meghan C; Gaponova, Anna V; Nikonova, Anna S; Golemis, Erica A

2017-01-01

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Potential strategies to address NSCLC mortality include improvements in early detection and prevention, and development of new therapies suitable for use in patients with early and late stage diagnoses. Controlling the growth of early stage tumors could yield significant clinical benefits for patients with comorbidities that make them poor candidates for surgery: however, many drugs that limit cancer growth are not useful in the setting of long-term use or in comorbid patients, because of associated toxicities. In this study, we explored the use of a recently described small molecule agent, STA-8666, as a potential agent for controlling early stage tumor growth. STA-8666 uses a cleavable linker to merge a tumor-targeting moiety that binds heat shock protein 90 (HSP90) with the cytotoxic chemical SN38, and has been shown to have high efficacy and low toxicity, associated with efficient tumor targeting, in preclinical studies using patient-derived and other xenograft models for pancreatic, bladder, and small cell lung cancer. Using a genetically engineered model of NSCLC arising from induced mutation of KRas and knockout of Trp53, we continuously dosed mice with STA-8666 from immediately after tumor induction for 15 weeks. STA-8666 significantly slowed the rate of tumor growth, and was well tolerated over this extended dosing period. STA-8666 induced DNA damage and apoptosis, and reduced proliferation and phosphorylation of the proliferation-associated protein ERK1/2, selectively in tumor tissue. In contrast, STA-8666 did not affect tumor features, such as degree of vimentin staining, associated with epithelial-mesenchymal transition (EMT), or downregulate tumor expression of HSP90. These data suggest STA-8666 and other similar targeted compounds may be useful additions to control the growth of early stage NSCLC in patient populations.

Overlapping activities of TGF-β and Hedgehog signaling in cancer: therapeutic targets for cancer treatment.

PubMed

Perrot, Carole Y; Javelaud, Delphine; Mauviel, Alain

2013-02-01

Recent advances in the field of cancer therapeutics come from the development of drugs that specifically recognize validated oncogenic or pro-metastatic targets. The latter may be mutated proteins with altered function, such as kinases that become constitutively active, or critical components of growth factor signaling pathways, whose deregulation leads to aberrant malignant cell proliferation and dissemination to metastatic sites. We herein focus on the description of the overlapping activities of two important developmental pathways often exacerbated in cancer, namely Transforming Growth Factor-β (TGF-β) and Hedgehog (HH) signaling, with a special emphasis on the unifying oncogenic role played by GLI1/2 transcription factors. The latter are the main effectors of the canonical HH pathway, yet are direct target genes of TGF-β/SMAD signal transduction. While tumor-suppressor in healthy and pre-malignant tissues, TGF-β is often expressed at high levels in tumors and contributes to tumor growth, escape from immune surveillance, invasion and metastasis. HH signaling regulates cell proliferation, differentiation and apoptosis, and aberrant HH signaling is found in a variety of cancers. We discuss the current knowledge on HH and TGF-β implication in cancer including cancer stem cell biology, as well as the current state, both successes and failures, of targeted therapeutics aimed at blocking either of these pathways in the pre-clinical and clinical settings. Copyright © 2012 Elsevier Inc. All rights reserved.

MicroRNA-9 suppresses the growth, migration, and invasion of malignant melanoma cells via targeting NRP1.

PubMed

Xu, Dan; Chen, Xiaofeng; He, Quanyong; Luo, Chengqun

2016-01-01

MicroRNAs (miRs) are a class of small noncoding RNAs that negatively regulate the gene expression by directly binding to the 3' untranslated region of their target mRNA, thus resulting in mRNA degradation or translational repression. miR-9 has recently been demonstrated to play a role in the development and progression of malignant melanoma (MM), but the regulatory mechanism of miR-9 in the malignant phenotypes of MM still remains largely unknown. In this study, a total of 73 pairs of MM tissues and adjacent normal tissues were collected. Real-time reverse transcription polymerase chain reaction and Western blot were used to detect the mRNA and protein expression of miR-9. MTT assay, wound healing assay, and transwell assay were conducted to determine the cell proliferation, migration, and invasion. Luciferase reporter assay was used to determine the targeting relationship between miR-9 and NRP1. Our data demonstrated that miR-9 expression was significantly downregulated in MM tissues compared with that in adjacent normal tissues. The decreased miR-9 level was significantly associated with the tumor stage and metastasis of MM. We also found that the expression level of miR-9 was decreased in MM cell lines (G361, B16, A375, and HME1) compared with normal skin HACAT cells. Ectopic expression of miR-9 led to a significant decrease in the ability of proliferation, migration, and invasion in A375 cells. NRP1 was further identified as a direct target gene of miR-9, and the protein expression of NRP1 was negatively regulated by miR-9 in A375 cells. Furthermore, overexpression of NRP1 reversed the suppressive effects of miR-9 on the malignant phenotypes of A375 cells. In vivo study revealed that miR-9 overexpression decreased the tumor growth, while overexpression of NRP1 increased MM growth. In summary, our findings suggest that the miR-9/NRP1 axis may serve as a potential target for the treatment of MM.

West nile virus-induced activation of mammalian target of rapamycin complex 1 supports viral growth and viral protein expression.

PubMed

Shives, Katherine D; Beatman, Erica L; Chamanian, Mastooreh; O'Brien, Caitlin; Hobson-Peters, Jody; Beckham, J David

2014-08-01

Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states of the United States and is now the leading cause of epidemic encephalitis in North America. As a member of the family Flaviviridae, WNV is part of a group of clinically important human pathogens, including dengue virus and Japanese encephalitis virus. The members of this family of positive-sense, single-stranded RNA viruses have limited coding capacity and are therefore obligated to co-opt a significant amount of cellular factors to translate their genomes effectively. Our previous work has shown that WNV growth was independent of macroautophagy activation, but the role of the evolutionarily conserved mammalian target of rapamycin (mTOR) pathway during WNV infection was not well understood. mTOR is a serine/threonine kinase that acts as a central cellular censor of nutrient status and exercises control of vital anabolic and catabolic cellular responses such as protein synthesis and autophagy, respectively. We now show that WNV activates mTOR and cognate downstream activators of cap-dependent protein synthesis at early time points postinfection and that pharmacologic inhibition of mTOR (KU0063794) significantly reduced WNV growth. We used an inducible Raptor and Rictor knockout mouse embryonic fibroblast (MEF) system to further define the role of mTOR complexes 1 and 2 in WNV growth and viral protein synthesis. Following inducible genetic knockout of the major mTOR cofactors raptor (TOR complex 1 [TORC1]) and rictor (TORC2), we now show that TORC1 supports flavivirus protein synthesis via cap-dependent protein synthesis pathways and supports subsequent WNV growth. Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states in the United States and is now the leading cause of epidemic encephalitis in North America. Currently, the mechanism by which flaviviruses such as WNV translate their genomes in

Reserve Design under Climate Change: From Land Facets Back to Ecosystem Representation

PubMed Central

Schneider, Richard R.; Bayne, Erin M.

2015-01-01

Ecosystem distributions are expected to shift as a result of global warming, raising concerns about the long-term utility of reserve systems based on coarse-filter ecosystem representation. We tested the extent to which proportional ecosystem representation targets would be maintained under a changing climate by projecting the distribution of the major ecosystems of Alberta, Canada, into the future using bioclimatic envelope models and then calculating the composition of reserves in successive periods. We used the Marxan conservation planning software to generate the suite of reserve systems for our test, varying the representation target and degree of reserve clumping. Our climate envelope projections for the 2080s indicate that virtually all reserves will, in time, be comprised of different ecosystem types than today. Nevertheless, our proportional targets for ecosystem representation were maintained across all time periods, with only minor exceptions. We hypothesize that this stability in representation arises because ecosystems may be serving as proxies for land facets, the stable abiotic landscape features that delineate major arenas of biological activity. The implication is that accommodating climate change may not require abandoning the conventional ecosystem-based approach to reserve design in favour of a strictly abiotic approach, since the two approaches may be largely synonymous. PMID:25978759

Targeted expression of miR-34a using the T-VISA system suppresses breast cancer cell growth and invasion.

PubMed

Li, Laisheng; Xie, Xinhua; Luo, Jinmei; Liu, Min; Xi, Shaoyan; Guo, Jiaoli; Kong, Yanan; Wu, Minqing; Gao, Jie; Xie, Zeming; Tang, Jun; Wang, Xi; Wei, Weidong; Yang, Mingtian; Hung, Mien-Chie; Xie, Xiaoming

2012-12-01

Recurrence and metastasis result in a poor prognosis for breast cancer patients. Recent studies have demonstrated that microRNAs (miRNAs) play vital roles in the development and metastasis of breast cancer. In this study, we investigated the therapeutic potential of miR-34a in breast cancer. We found that miR-34a is downregulated in breast cancer cell lines and tissues, compared with normal cell lines and the adjacent nontumor tissues, respectively. To explore the therapeutic potential of miR-34a, we designed a targeted miR-34a expression plasmid (T-VISA-miR-34a) using the T-VISA system, and evaluated its antitumor effects, efficacy, mechanism of action, and systemic toxicity. T-VISA-miR-34a induced robust, persistent expression of miR-34a, and dramatically suppressed breast cancer cell growth, migration, and invasion in vitro by downregulating the protein expression levels of the miR-34a target genes E2F3, CD44, and SIRT1. In an orthotopic mouse model of breast cancer, intravenous injection of T-VISA-miR-34a:liposomal complex nanoparticles significantly inhibited tumor growth, prolonged survival, and did not induce systemic toxicity. In conclusion, T-VISA-miR-34a lead to robust, specific overexpression of miR-34a in breast cancer cells and induced potent antitumor effects in vitro and in vivo. T-VISA-miR-34a may provide a potentially useful, specific, and safe-targeted therapeutic approach for breast cancer.

Targeted Expression of miR-34a Using the T-VISA System Suppresses Breast Cancer Cell Growth and Invasion

PubMed Central

Li, Laisheng; Xie, Xinhua; Luo, Jinmei; Liu, Min; Xi, Shaoyan; Guo, Jiaoli; Kong, Yanan; Wu, Minqing; Gao, Jie; Xie, Zeming; Tang, Jun; Wang, Xi; Wei, Weidong; Yang, Mingtian; Hung, Mien-Chie; Xie, Xiaoming

2012-01-01

Recurrence and metastasis result in a poor prognosis for breast cancer patients. Recent studies have demonstrated that microRNAs (miRNAs) play vital roles in the development and metastasis of breast cancer. In this study, we investigated the therapeutic potential of miR-34a in breast cancer. We found that miR-34a is downregulated in breast cancer cell lines and tissues, compared with normal cell lines and the adjacent nontumor tissues, respectively. To explore the therapeutic potential of miR-34a, we designed a targeted miR-34a expression plasmid (T-VISA-miR-34a) using the T-VISA system, and evaluated its antitumor effects, efficacy, mechanism of action, and systemic toxicity. T-VISA-miR-34a induced robust, persistent expression of miR-34a, and dramatically suppressed breast cancer cell growth, migration, and invasion in vitro by downregulating the protein expression levels of the miR-34a target genes E2F3, CD44, and SIRT1. In an orthotopic mouse model of breast cancer, intravenous injection of T-VISA-miR-34a:liposomal complex nanoparticles significantly inhibited tumor growth, prolonged survival, and did not induce systemic toxicity. In conclusion, T-VISA-miR-34a lead to robust, specific overexpression of miR-34a in breast cancer cells and induced potent antitumor effects in vitro and in vivo. T-VISA-miR-34a may provide a potentially useful, specific, and safe-targeted therapeutic approach for breast cancer. PMID:23032974

Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice.

PubMed

Chinnasamy, Dhanalakshmi; Yu, Zhiya; Theoret, Marc R; Zhao, Yangbing; Shrimali, Rajeev K; Morgan, Richard A; Feldman, Steven A; Restifo, Nicholas P; Rosenberg, Steven A

2010-11-01

Immunotherapies based on adoptive cell transfer are highly effective in the treatment of metastatic melanoma, but the use of this approach in other cancer histologies has been hampered by the identification of appropriate target molecules. Immunologic approaches targeting tumor vasculature provide a means for the therapy of multiple solid tumor types. We developed a method to target tumor vasculature, using genetically redirected syngeneic or autologous T cells. Mouse and human T cells were engineered to express a chimeric antigen receptor (CAR) targeted against VEGFR-2, which is overexpressed in tumor vasculature and is responsible for VEGF-mediated tumor progression and metastasis. Mouse and human T cells expressing the relevant VEGFR-2 CARs mediated specific immune responses against VEGFR-2 protein as well as VEGFR-2-expressing cells in vitro. A single dose of VEGFR-2 CAR-engineered mouse T cells plus exogenous IL-2 significantly inhibited the growth of 5 different types of established, vascularized syngeneic tumors in 2 different strains of mice and prolonged the survival of mice. T cells transduced with VEGFR-2 CAR showed durable and increased tumor infiltration, correlating with their antitumor effect. This approach provides a potential method for the gene therapy of a variety of human cancers.

Is insulin-like growth factor 1 (IGF-1) system an attractive target inflammatory bowel diseases? Benefits and limitation of potential therapy.

PubMed

Zatorski, Hubert; Marynowski, Mateusz; Fichna, Jakub

2016-08-01

Inflammatory bowel diseases (IBD) are chronic gastrointestinal disorders with unknown etiology, whose incidence dramatically increased over the past 50 years. Currently available strategies for IBD treatment, such as biological therapies, corticosteroids, and immunosuppressive agents are effective, but their side effects and economic costs cannot be ignored. Better understanding of IBD etiology and new therapeutics are thus needed. The aim of this paper is to briefly discuss IGF-1 dependent functions, with particular focus on IGF-1 use in IBD therapy. Data collection was based on records found in medical literature. Data analysis included records published between 1984 and 2014. The IGF-1 system is involved in major physiological functions, such as cell proliferation and metabolism, and growth promotion. Most importantly IGF-1 has anti-inflammatory properties and its use in IBD treatment can be recommended. However, potential IGF-1 therapy has some limitations, which include aggravation of fibrosis in Crohn's patients and facilitated transformation to malignancy. Taken into consideration their possible side effects, IGF-1 analogs and recombinants are nonetheless a promising target for IBD therapy for a specific group of patients. Further studies, at the clinical level are thus recommended. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Effects of mistletoe removal on growth, N and C reserves, and carbon and oxygen isotope composition in Scots pine hosts.

PubMed

Yan, Cai-Feng; Gessler, Arthur; Rigling, Andreas; Dobbertin, Matthias; Han, Xing-Guo; Li, Mai-He

2016-05-01

Most mistletoes are xylem-tapping hemiparasites, which derive their resources from the host's xylem solution. Thus, they affect the host's water relations and resource balance. To understand the physiological mechanisms underlying the mistletoe-host relationship, we experimentally removed Viscum album ssp. austriacum (Wiesb.) Vollmann from adult Pinus sylvestris L. host trees growing in a Swiss dry valley. We analyzed the effects of mistletoe removal over time on host tree growth and on concentrations of nonstructural carbohydrates (NSC) and nitrogen (N) in needles, fine roots and sapwood. In addition, we assessed the δ(13)C and δ(18)O in host tree rings. After mistletoe removal, δ(13)C did not change in newly produced tree rings compared with tree rings in control trees (still infected with mistletoe), but δ(18)O values increased. This pattern might be interpreted as a decrease in assimilation (A) and stomatal conductance (gs), but in our study, it most likely points to an inadequacy of the dual isotope approach. Instead, we interpret the unchanged δ(13)C in tree rings upon mistletoe removal as a balanced increase in A and gs that resulted in a constant intrinsic water use efficiency (defined as A/gs). Needle area-based concentrations of N, soluble sugars and NSC, as well as needle length, single needle area, tree ring width and shoot growth, were significantly higher in trees from which mistletoe was removed than in control trees. This finding suggests that mistletoe removal results in increased N availability and carbon gain, which in turn leads to increased growth rates of the hosts. Hence, in areas where mistletoe is common and the population is large, mistletoe management (e.g., removal) may be needed to improve the host vigor, growth rate and productivity, especially for relatively small trees and crop trees in xeric growth conditions. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth.

PubMed

Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M; Yang, Jun; Starbuck, Michael W; Ravoori, Murali K; Kundra, Vikas; Vazquez, Elba; Navone, Nora M

2012-03-01

Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth

Use of Stored Carbon Reserves in Growth of Temperate Tree Roots and Leaf Buds: Analyses Using Radiocarbon Measurements and Modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaudinski, Julia B.; Torn, Margaret S.; Riley, W. J.

2009-01-01

Characterizing the use of C reserves in trees is important for understanding stress responses, impacts of asynchrony between photosynthesis and growth demand, and isotopic exchanges in plant dynamic studies. Using an inadvertent, whole ecosystem radiocarbon (14C) exposure in a temperate deciduous oak forest and numerical modeling, we calculated that the mean age of stored C used to grow leaf buds and new fine root tissue is 0.5-1.0 y. The mean age of stored C used to grow new roots was about 0.7 y across a range of realistic values of 14C inputs to the system. The amount of stored Cmore » used on an annual basis to grow fine roots was between 15 and 55% of total root growth, with the range defined by the assumed 14C input profile. We estimate the annually-averaged mean age of C in new root tissues is 1-5 months. Therefore, accounting for storage C use in isotope root models may be unnecessary in all but the fastest cycling root populations (i.e., mean age <1 y). Consistent with the whole ecosystem labeling results, we found, using "bomb-14C," that the mean C age of new root tissues in three additional forest sites (one deciduous, two coniferous) was less than 2 years. We conclude that in many ecosystem types, growth from stored C is insufficient to impact bomb-14C based estimates of long root lifetimes.« less

Neuroendocrine tumors: insights into innovative therapeutic options and rational development of targeted therapies.

PubMed

Barbieri, Federica; Albertelli, Manuela; Grillo, Federica; Mohamed, Amira; Saveanu, Alexandru; Barlier, Anne; Ferone, Diego; Florio, Tullio

2014-04-01

Neuroendocrine tumors (NETs) are heterogeneous neoplasms with respect to molecular characteristics and clinical outcome. Although slow-growing, NETs are often late diagnosed, already showing invasion of adjacent tissues and metastases. Precise knowledge of NET biological and molecular features has opened the door to the identification of novel pharmacological targets. Therapeutic options include somatostatin analogs, alone or in combination with interferon-α, multi-targeted tyrosine kinase inhibitors (e.g. sunitinib) or mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus). Antiangiogenic approaches and anti insulin-like growth factor receptor (IGFR) compounds have been also proposed as combination therapies with the aforementioned compounds. This review will focus on recent studies that have improved therapeutic strategies in NETs, discussing management challenges such as drug resistance development as well as focusing on the need for predictive biomarkers to design distinct drug combinations and optimize pharmacological control. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRalpha.

PubMed

Baumgartner, Christian; Gleixner, Karoline V; Peter, Barbara; Ferenc, Veronika; Gruze, Alexander; Remsing Rix, Lily L; Bennett, Keiryn L; Samorapoompichit, Puchit; Lee, Francis Y; Pickl, Winfried F; Esterbauer, Harald; Sillaber, Christian; Superti-Furga, Giulio; Valent, Peter

2008-10-01

Chronic eosinophilic leukemia (CEL) is a myeloproliferative disorder characterized by molecular and/or cytogenetic evidence of clonality of eosinophils, marked eosinophilia, and organ damage. In many patients, the transforming mutation FIP1L1-PDGFRalpha and the related CHIC2 deletion are found. The respective oncoprotein, FIP1L1-PDGFRalpha, is considered to play a major role in malignant cell growth in CEL. The tyrosine kinase (TK) inhibitor imatinib (STI571) has been described to counteract the TK activity of FIP1L1-PDGFRalpha in most patients. However, not all patients with CEL show a response to imatinib. Therefore, several attempts have been made to identify other TK inhibitors that counteract growth of neoplastic eosinophils. We provide evidence that dasatinib, a multi-targeted kinase inhibitor, blocks the growth and survival of EOL-1, an eosinophil leukemia cell line carrying FIP1L1-PDGFRalpha. The effects of dasatinib on proliferation of EOL-1 cells were dose-dependent, with an IC50 of 0.5 to 1 nM, which was found to be in the same range when compared to IC50 values produced with imatinib. Dasatinib was also found to induce apoptosis in EOL-1 cells in a dose-dependent manner (IC50: 1-10 nM). The apoptosis-inducing effects of dasatinib on EOL-1 cells were demonstrable by light microscopy, flow cytometry, and in a TUNEL assay. In Western blot experiments, dasatinib completely blocked the phosphorylation of FIP1L1-PDGFRalpha in EOL-1 cells. Dasatinib inhibits the growth of leukemic eosinophils through targeting of the disease-related oncoprotein FIP1L1-PDGFRalpha. Based on this observation, dasatinib may be considered as a new interesting treatment option for patients with CEL.

Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth.

PubMed

Kock, Anna; Larsson, Karin; Bergqvist, Filip; Eissler, Nina; Elfman, Lotta H M; Raouf, Joan; Korotkova, Marina; Johnsen, John Inge; Jakobsson, Per-Johan; Kogner, Per

2018-06-01

Despite recent progress in diagnosis and treatment, survival for children with high-risk metastatic neuroblastoma is still poor. Prostaglandin E 2 (PGE 2 )-driven inflammation promotes tumor growth, immune suppression, angiogenesis and resistance to established cancer therapies. In neuroblastoma, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment are the primary source of PGE 2 . However, clinical targeting of PGE 2 with current non-steroidal anti-inflammatory drugs or cyclooxygenase inhibitors has been limited due to risk of adverse side effects. By specifically targeting microsomal prostaglandin E synthase-1 (mPGES-1) activity with a small molecule inhibitor we could block CAF-derived PGE 2 production leading to reduced tumor growth, impaired angiogenesis, inhibited CAF migration and infiltration, reduced tumor cell proliferation and a favorable shift in the M1/M2 macrophage ratio. In this study, we provide proof-of-principle of the benefits of targeting mPGES-1 in neuroblastoma, applicable to a wide variety of tumors. This non-toxic single drug treatment targeting infiltrating stromal cells opens up for combination treatment options with established cancer therapies. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Targeted delivery of let-7a microRNA encapsulated ephrin-A1 conjugated liposomal nanoparticles inhibit tumor growth in lung cancer

PubMed Central

Lee, Hung-Yen; Mohammed, Kamal A; Kaye, Fredric; Sharma, Parvesh; Moudgil, Brij M; Clapp, William L; Nasreen, Najmunnisa

2013-01-01

MicroRNAs (miRs) are small noncoding RNA sequences that negatively regulate the expression of target genes by posttranscriptional repression. miRs are dysregulated in various diseases, including cancer. let-7a miR, an antioncogenic miR, is downregulated in lung cancers. Our earlier studies demonstrated that let-7a miR inhibits tumor growth in malignant pleural mesothelioma (MPM) and could be a potential therapeutic against lung cancer. EphA2 (ephrin type-A receptor 2) tyrosine kinase is overexpressed in most cancer cells, including MPM and non-small-cell lung cancer (NSCLC) cells. Ephrin-A1, a specific ligand of the EphA2 receptor, inhibits cell proliferation and migration. In this study, to enhance the delivery of miR, the miRs were encapsulated in the DOTAP (N-[1-(2.3-dioleoyloxy)propyl]-N,N,N-trimethyl ammonium)/Cholesterol/DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[cyanur(polyethylene glycol)-2000])-PEG (polyethylene glycol)-cyanur liposomal nanoparticles (LNP) and ephrin-A1 was conjugated on the surface of LNP to target receptor EphA2 on lung cancer cells. The LNP with an average diameter of 100 nm showed high stability, low cytotoxicity, and high loading efficiency of precursor let-7a miR and ephrin-A1. The ephrin-A1 conjugated LNP (ephrin-A1–LNP) and let-7a miR encapsulated LNP (miR–LNP) showed improved transfection efficiency against MPM and NSCLC. The effectiveness of targeted delivery of let-7a miR encapsulated ephrin-A1 conjugated LNP (miR–ephrin-A1–LNP) was determined on MPM and NSCLC tumor growth in vitro. miR–ephrin-A1–LNP significantly increased the delivery of let-7a miR in lung cancer cells when compared with free let-7a miR. In addition, the expression of target gene Ras was significantly repressed following miR–ephrin-A1–LNP treatment. Furthermore, the miR–ephrin-A1–LNP complex significantly inhibited MPM and NSCLC proliferation, migration, and tumor growth. Our results demonstrate that the engineered mi

Prevalence-Based Targets Underestimate Home Dialysis Program Activity and Requirements for Growth.

PubMed

Bevilacqua, Micheli U; Er, Lee; Copland, Michael A; Singh, R Suneet; Jamal, Abeed; Dunne, Órla Marie; Brumby, Catherine; Levin, Adeera

2018-01-01

Many renal programs have targets to increase home dialysis prevalence. Data from a large Canadian home dialysis program were analyzed to determine if home dialysis prevalence accurately reflects program activity and whether prevalence-based assessments adequately reflect the work required for program growth. Data from home dialysis programs in British Columbia, Canada, were analyzed from 2005 to 2015. Prevalence data were compared to dialysis activity data including intakes and exits to describe program turnover. Using current attrition rates, recruitment rates needed to increase home dialysis prevalence proportions were identified. We analyzed 7,746 patient-years of peritoneal dialysis (PD) and 1,362 patient-years of home hemodialysis (HHD). The proportion of patients on home dialysis increased by 3.34% over the ten years examined, while the number of prevalent home dialysis patients increased 2.65% per year and the number of patients receiving home dialysis at any time in the year increased 4.04% per year. For every 1 patient net home dialysis growth, 13.6 new patients were recruited. Patient turnover included higher rates of transplantation in home dialysis than facility-based HD. Overall, the proportion dialyzing at home increased from 29.3 to 32.6%. There is high patient turnover in home dialysis such that program prevalence is an incomplete marker of total program activity. This turnover includes high rates of transplantation, which is a desirable interaction that affects home dialysis prevalence. The shortcomings of this commonly used metric are important for renal programs to consider, and better understanding of the activities that support home dialysis and the complex trajectories that home dialysis patients follow is needed. Copyright © 2018 International Society for Peritoneal Dialysis.

Targeted gene expression profiling in European sea bass (Dicentrarchus labrax, L.) follicles from primary growth to late vitellogenesis.

PubMed

García-López, Angel; Sánchez-Amaya, María Isabel; Prat, Francisco

2011-11-01

A real-time PCR-based gene expression survey was performed on isolated European sea bass follicles from primary growth to late vitellogenesis. Expression levels of 18 transcripts with demonstrated relevance during oogenesis, encoding gonadotropin, thyrotropin, estrogen, androgen, and vitellogenin receptors, steroidogenesis-related as well as growth and transcription factors were measured. Primary oocytes showed high mRNA levels of insulin-like growth factors 1 and 2, bone morphogenetic protein 4, estrogen receptor 2b, androgen receptor b, and SRY-box containing gene 17 together with low transcript amounts of gonadotropin receptors. Follicles at the lipid vesicles stage (i.e., the beginning of the secondary growth phase) showed elevated mRNA amounts of follicle stimulating hormone receptor (fshr) and anti-Mullerian hormone. Early-to-mid vitellogenic follicles showed high mRNA levels of fshr and cytochrome P450, family 19, subfamily A, polypeptide 1a while mid-to-late vitellogenic follicles expressed increasing transcript amounts of luteinizing hormone/choriogonadotropin receptor, steroidogenic acute regulatory protein, and estrogen receptors 1 and 2a. The molecular data presented here may serve as a solid base for future studies focused on unraveling the specific mechanisms orchestrating follicular development in teleost fish. Copyright © 2011 Elsevier Inc. All rights reserved.

Targeting delivery of etoposide to inhibit the growth of human glioblastoma multiforme using lactoferrin- and folic acid-grafted poly(lactide-co-glycolide) nanoparticles.

PubMed

Kuo, Yung-Chih; Chen, Yu-Chun

2015-02-01

Lactoferrin (Lf) and folic acid (FA) were crosslinked on poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for transporting etoposide across the blood-brain barrier (BBB) and treating human brain malignant glioblastoma. Lf- and FA-grafted PLGA NPs (Lf/FA/PLGA NPs) were employed to permeate the monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes and to inhibit the multiplication of U87MG cells. Lf/FA/PLGA NPs showed a satisfactory entrapment efficiency of etoposide and characteristics of sustained drug release. When compared with PLGA NPs, the permeability coefficient for etoposide across the BBB using Lf/FA/PLGA NPs increased about twofold. The antiproliferative efficacy against the growth of U87MG cells was in the following order: Lf/FA/PLGA NPs>FA/PLGA NPs>PLGA NPs>free etoposide solution. In addition, the targeting ability of Lf/FA/PLGA NPs was evidenced by immunostaining of Lf receptor on HBMECs and folate receptor on U87MG cells during endocytosis. Lf/FA/PLGA NPs with loaded etoposide can be a promising anticancer pharmacotherapy to enhance the delivery of etoposide to malignant brain tumors for preclinical trials. Copyright © 2014 Elsevier B.V. All rights reserved.

Accelerating bacterial growth detection and antimicrobial susceptibility assessment in integrated picoliter droplet platform.

PubMed

Kaushik, Aniruddha M; Hsieh, Kuangwen; Chen, Liben; Shin, Dong Jin; Liao, Joseph C; Wang, Tza-Huei

2017-11-15

There remains an urgent need for rapid diagnostic methods that can evaluate antibiotic resistance for pathogenic bacteria in order to deliver targeted antibiotic treatments. Toward this end, we present a rapid and integrated single-cell biosensing platform, termed dropFAST, for bacterial growth detection and antimicrobial susceptibility assessment. DropFAST utilizes a rapid resazurin-based fluorescent growth assay coupled with stochastic confinement of bacteria in 20 pL droplets to detect signal from growing bacteria after 1h incubation, equivalent to 2-3 bacterial replications. Full integration of droplet generation, incubation, and detection into a single, uninterrupted stream also renders this platform uniquely suitable for in-line bacterial phenotypic growth assessment. To illustrate the concept of rapid digital antimicrobial susceptibility assessment, we employ the dropFAST platform to evaluate the antibacterial effect of gentamicin on E. coli growth. Copyright © 2017 Elsevier B.V. All rights reserved.

Randomized controlled trial of SecondStory, an intervention targeting posttraumatic growth, with bereaved adults.

PubMed

Roepke, Ann Marie; Tsukayama, Eli; Forgeard, Marie; Blackie, Laura; Jayawickreme, Eranda

2018-06-01

People often report positive psychological changes after adversity, a phenomenon known as posttraumatic growth (PTG). Few PTG-focused interventions have been rigorously tested, and measurement strategies have had significant limitations. This study evaluated the effects of a new group-format psychosocial intervention, SecondStory, aimed at facilitating PTG by helping participants make meaning of the past and plan a purposeful future. In a randomized controlled trial, adults (N = 112, 64% women) bereaved within 5 years were randomly assigned to SecondStory or an active control, expressive writing. The primary outcome, PTG, was measured using two contrasting methods: the Posttraumatic Growth Inventory, which asks participants retrospectively how much they believe they have changed due to struggling with adversity, and the Current-Standing Posttraumatic Growth Inventory, which tracks quantifiable change in participants' standing in PTG domains over time. Secondary outcomes included depression symptoms, posttraumatic stress symptoms, and life satisfaction. Outcomes were measured at 2-week intervals: pretest, posttest, and three follow-up occasions. Hierarchical linear modeling was used to assess whether SecondStory participants experienced greater gains in primary and/or secondary outcomes over the 8-week trial. Results indicated that SecondStory participants did not show significantly greater improvements than control participants on measures of PTG, posttraumatic stress, or life satisfaction, but they did show greater decreases in depression symptoms by the first follow-up. These findings suggest that SecondStory may not facilitate PTG more effectively than existing interventions but may be promising for addressing depression. Positive interventions may productively be refined to support people experiencing trauma and loss. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Fruit development, growth, and stored reserves in macauba palm (Acrocomia aculeata), an alternative bioenergy crop.

PubMed

Montoya, Sebastián Giraldo; Motoike, Sérgio Yoshimitsu; Kuki, Kacilda Naomi; Couto, Adriano Donato

2016-10-01

Main conclusion Macauba palm fruiting is supra-annual, and the fruit growth follows a double sigmoidal trend. The prevailing compound in the mesocarp differs as the fruit ages, oil being the major storage compound. Acrocomia aculeata, macauba palm, is a conspicuous species in the tropical Americas. Because the species is highly productive in oil-rich fruits, it is the subject of domestication as an alternative vegetable oil crop, especially as a bioenergy feedstock. This detailed study first presents the macauba fruit growth and development patterns, morphological changes and accumulation of organic compounds. Fruits were monitored weekly in a natural population. The fruiting was supra-annual, and the fruit growth curve followed a double sigmoidal trend with four stages (S): SI-slow growth and negligible differentiation of the fruit inner parts; SII-first growth spurt and visible, but not complete, differentiation of the inner parts; SIII-growth slowed down and all structures attained differentiation; and SIV-second growth spurt and fruit maturation. In SII, the exocarp and endocarp were the main contributors to fruit growth, whereas the mesocarp and endosperm were responsible for most of the weight gain during SIV. In comparison with starch and oil, soluble sugars did not accumulate in the mesocarp. However, starch was transitory and fueled the oil synthesis. The protective layers, the exocarp and endocarp, fulfilling their ecological roles, were the first to reach maturity, followed by the storage tissues, the mesocarp, and endosperm. The amount and nature of organic compounds in the mesocarp varied with the fruit development and growth stages, and oil was the main and final storage material. The description of macauba fruit's transformations and their temporal order may be of importance for future ecological and agronomical references.

MiR-34a Regulates Axonal Growth of Dorsal Root Ganglia Neurons by Targeting FOXP2 and VAT1 in Postnatal and Adult Mouse.

PubMed

Jia, Longfei; Chopp, Michael; Wang, Lei; Lu, Xuerong; Zhang, Yi; Szalad, Alexandra; Zhang, Zheng Gang

2018-04-10

Hyperglycemia impairs nerve fibers of dorsal root ganglia (DRG) neurons, leading to diabetic peripheral neuropathy (DPN). However, the molecular mechanisms underlying DPN are not fully understood. Using a mouse model of type II diabetes (db/db mouse), we found that microRNA-34a (miR-34a) was over-expressed in DRG, sciatic nerve, and foot pad tissues of db/db mice. In vitro, high glucose significantly upregulated miR-34a in postnatal and adult DRG neurons, which was associated with inhibition of axonal growth. Overexpression and attenuation of miR-34a in postnatal and adult DRG neurons suppressed and promoted, respectively, axonal growth. Bioinformatic analysis suggested that miR-34a putatively targets forkhead box protein P2 (FOXP2) and vesicle amine transport 1 (VAT1), which were decreased in diabetic tissues and in cultured DRG neurons under high glucose conditions. Dual-luciferase assay showed that miR-34a downregulated FOXP2 and VAT1 expression by targeting their 3' UTR. Gain-of- and loss-of-function analysis showed an inverse relation between augmentation of miR-34a and reduction of FOXP2 and VAT1 proteins in postnatal and adult DRG neurons. Knockdown of FOXP2 and VAT1 reduced axonal growth. Together, these findings suggest that miR-34a and its target genes of FOXP2 and VAT1 are involved in DRG neuron damage under hyperglycemia.

Targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin squamous cell carcinoma cell growth in vitro and in vivo.

PubMed

Zou, Ying; Ge, Minggai; Wang, Xuemin

2017-08-19

Abnormal activation of PI3K-AKT-mTOR signaling is detected in human skin squamous cell carcinoma (SCC). LY3023414 is a novel, potent, and orally bio-available PI3K-AKT-mTOR inhibitor. Its activity against human skin SCC cells was tested. We demonstrated that LY3023414 was cytotoxic when added to established (A431 line) and primary (patient-derived) human skin SCC cells. LY3023414 induced G0/1-S arrest and inhibited proliferation of skin SCC cells. Moreover, LY3023414 induced activation of caspase-3/-9 and apoptosis in skin SCC cells. Intriguingly, LY3023414 was yet non-cytotoxic nor pro-apoptotic to normal human skin cells (melanocytes, keratinocytes and fibroblasts). At the molecular level, LY3023414 blocked PI3K-AKT-mTOR activation in skin SCC cells, as it dephosphorylated PI3K-AKT-mTOR substrates: P85, AKT and S6K1. In vivo studies showed that oral administration of LY3023414 at well-tolerated doses inhibited A431 xenograft tumor growth in severe combined immunodeficiency (SCID) mice. AKT-mTOR activation in LY3023414-treated tumors was also largely inhibited. Together, these results suggest that targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin SCC cell growth in vitro and in vivo, establishing the rationale for further clinical testing. Copyright © 2017 Elsevier Inc. All rights reserved.

miR-491-5p suppresses cell growth and invasion by targeting Notch3 in nasopharyngeal carcinoma.

PubMed

Zhang, Qi; Li, Qiang; Xu, Tao; Jiang, Hui; Xu, Lin-Gen

2016-06-01

MicroRNAs (miRNAs) have critical roles in the progression of nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer that is widely prevalent in Southern China. miR-491-5p has been implicated in multiple types of cancer; however, its biological role and underlying mechanism in NPC have not been fully explored. In the present study, we found that miR-491-5p was downregulated in NPC tissues and cell lines compared with the corresponding normal counterparts. Overexpression of miR-491-5p significantly inhibited cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Using miRNA target prediction algorithms and reporter assays, we showed that miR-491-5p suppressed Notch3 expression both at the mRNA and protein level through directly targeting the 3' untranslated region (3'-UTR) of Notch3 mRNA. Overexpression of Notch3 significantly reversed the tumor-suppressive effects of miR‑491-5p. Taken together, the present study reveals a mechanistic link between miR-491-5p and Notch3 in the pathogenesis of NPC and that miR-491-5p has potential as a therapeutic target for NPC.

Modelling a stochastic HIV model with logistic target cell growth and nonlinear immune response function

NASA Astrophysics Data System (ADS)

Wang, Yan; Jiang, Daqing; Alsaedi, Ahmed; Hayat, Tasawar

2018-07-01

A stochastic HIV viral model with both logistic target cell growth and nonlinear immune response function is formulated to investigate the effect of white noise on each population. The existence of the global solution is verified. By employing a novel combination of Lyapunov functions, we obtain the existence of the unique stationary distribution for small white noises. We also derive the extinction of the virus for large white noises. Numerical simulations are performed to highlight the effect of white noises on model dynamic behaviour under the realistic parameters. It is found that the small intensities of white noises can keep the irregular blips of HIV virus and CTL immune response, while the larger ones force the virus infection and immune response to lose efficacy.

Future Targets for Female Sexual Dysfunction.

PubMed

Farmer, Melissa; Yoon, Hana; Goldstein, Irwin

2016-08-01

Female sexual function reflects a dynamic interplay of central and peripheral nervous, vascular, and endocrine systems. The primary challenge in the development of novel treatments for female sexual dysfunction is the identification and targeted modulation of excitatory sexual circuits using pharmacologic treatments that facilitate the synthesis, release, and/or receptor binding of neurochemicals, peptides, and hormones that promote female sexual function. To develop an evidence-based state-of-the-art consensus report that critically integrates current knowledge of the therapeutic potential for known molecular and cellular targets to facilitate the physiologic processes underlying female sexual function. State-of-the-art review representing the opinions of international experts developed in a consensus process during a 1-year period. Expert opinion was established by grading the evidence-based medical literature, intensive internal committee discussion, public presentation, and debate. Scientific investigation is urgently needed to expand knowledge and foster development of future treatments that maintain genital tissue integrity, enhance genital physiologic responsiveness, and optimize positive subjective appraisal of internal and external sexual cues. This article critically condenses the current knowledge of therapeutic manipulation of molecular and cellular targets within biological systems responsible for female sexual physiologic function. Future treatment targets include pharmacologic modulation of emotional learning circuits, restoration of normal tactile sensation, growth factor therapy, gene therapy, stem cell-based therapies, and regenerative medicine. Concurrent use of centrally and peripherally acting therapies could optimize treatment response. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Nanomedicine Strategies to Target Tumor-Associated Macrophages

PubMed Central

Binnemars-Postma, Karin; Storm, Gert; Prakash, Jai

2017-01-01

In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail. PMID:28471401

A Designed Peptide Targets Two Types of Modifications of p53 with Anti-cancer Activity.

PubMed

Liang, Lunxi; Wang, Huanbin; Shi, Hubing; Li, Zhaoli; Yao, Han; Bu, Zhigao; Song, Ningning; Li, Chushu; Xiang, Dabin; Zhang, Yao; Wang, Jilin; Hu, Ye; Xu, Qi; Ma, Yanlei; Cheng, Zhongyi; Wang, Yingchao; Zhao, Shuliang; Qian, Jin; Chen, Yingxuan; Fang, Jing-Yuan; Xu, Jie

2018-06-21

Many cancer-related proteins are controlled by composite post-translational modifications (PTMs), but prevalent strategies only target one type of modification. Here we describe a designed peptide that controls two types of modifications of the p53 tumor suppressor, based on the discovery of a protein complex that suppresses p53 (suppresome). We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53. The molecular functions of Morn3 were validated through in vivo assays and chemico-biological intervention. A rationally designed Morn3-targeting peptide (Morncide) successfully activated p53 and suppressed tumor growth. These findings shed light on the regulation of protein PTMs and present a strategy for targeting two modifications with one molecule. Copyright © 2018 Elsevier Ltd. All rights reserved.

The role of nutrient reserves for clutch formation by Northern Pintails in Alaska

USGS Publications Warehouse

Esler, Daniel N.; Grand, James B.

1994-01-01

We analyzed carcass composition of female Northern Pintails (Anas acuta) in Alaska to assess the importance of nutrient reserves for formation of first clutches (n = 85) and renests (n = 39). Habitat (tundra vs. boreal forest), hen age (yearling vs. adult), and year (1990 vs. 1991) did not affect nutrient reserve use. During formation of first clutches, Northern Pintail hens relied on lipid reserves more than any other duck species that has been studied. For much of the nesting season, lipid reserves were used to meet costs beyond those incurred by clutch formation. Date of initiation of rapid follicle growth was related to lipid reserve dynamics; lipid reserves at initiation and the rate of lipid use both declined through the season. Protein reserves declined slightly with commitment of protein to the clutch and with date of initiation of rapid follicle growth. Use of mineral reserves for first nests was negligible. Renesting females did not use nutrient reserves. Lipid reserve levels were positively related to the amount of lipid reserves needed to complete the clutch and clutch sizes predicted from a lipid dynamics model were consistent with known clutch sizes. Similar relationships did not exist for protein. We suggest that lipid reserve levels affect timing of nesting and proximately limit clutch size of Northern Pintails.

Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor.

PubMed

Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun; Feng, Jian-Quan; Kobayashi, Tatsuya; Merregaert, Joseph; Liu, Chuan-Ju

2016-08-01

Chondrogenesis and endochondral ossification are precisely controlled by cellular interactions with surrounding matrix proteins and growth factors that mediate cellular signaling pathways. Here, we report that extracellular matrix protein 1 (ECM1) is a previously unrecognized regulator of chondrogenesis. ECM1 is induced in the course of chondrogenesis and its expression in chondrocytes strictly depends on parathyroid hormone-related peptide (PTHrP) signaling pathway. Overexpression of ECM1 suppresses, whereas suppression of ECM1 enhances, chondrocyte differentiation and hypertrophy in vitro and ex vivo In addition, target transgene of ECM1 in chondrocytes or osteoblasts in mice leads to striking defects in cartilage development and endochondral bone formation. Of importance, ECM1 seems to be critical for PTHrP action in chondrogenesis, as blockage of ECM1 nearly abolishes PTHrP regulation of chondrocyte hypertrophy, and overexpression of ECM1 rescues disorganized growth plates of PTHrP-null mice. Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an interaction network and act in concert in the regulation of chondrogenesis.-Kong, L., Zhao, Y.-P., Tian, Q.-Y., Feng, J.-Q., Kobayashi, T., Merregaert, J., Liu, C.-J. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. © FASEB.

Galangin inhibits human osteosarcoma cells growth by inducing transforming growth factor-β1-dependent osteogenic differentiation.

PubMed

Liu, Chunhong; Ma, Mingming; Zhang, Junde; Gui, Shaoliu; Zhang, Xiaohai; Xue, Shuangtao

2017-05-01

Osteosarcoma is the most common primary malignancy of the musculoskeletal system, and is associated with excessive proliferation and poor differentiation of osteoblasts. Currently, despite the use of traditional chemotherapy and radiotherapy, no satisfactory and effective agent has been developed to treat the disease. Herein, we found that a flavonoid natural product, galangin, could significantly attenuate human osteosarcoma cells proliferation, without causing obvious cell apoptosis. Moreover, galangin enhanced the expression of osteoblast differentiation markers (collagen type I, alkaline phosphatase, osteocalcin and osteopontin) remarkably and elevated the alkaline phosphatase activity in human osteosarcoma cells. And galangin could also attenuated osteosarcoma growth in vivo. These bioactivities of galangin resulted from its selective activation of the transforming growth factor (TGF)-β1/Smad2/3 signaling pathway, which was demonstrated by pathway blocking experiments. These findings suggested that galangin could be a promising agent to treat osteosarcoma. In addition, targeting TGF-β1 to induce osteogenic differentiation might represent a novel therapeutic strategy to treat osteosarcoma with minimal side effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Janus "nano-bullets" for magnetic targeting liver cancer chemotherapy.

PubMed

Shao, Dan; Li, Jing; Zheng, Xiao; Pan, Yue; Wang, Zheng; Zhang, Ming; Chen, Qi-Xian; Dong, Wen-Fei; Chen, Li

2016-09-01

Tumor-targeted delivery of anti-cancer drugs with controlled drug release function has been recognized as a promising strategy for pursuit of increased chemotherapeutic efficacy and reduced adverse effects. Development of magnetic nanoparticulates as delivery carriers to accommodate cytotoxic drugs for liver cancer treatment has evoked immense interest with respect to their convenience in biomedical application. Herein, we engineered multifunctional Janus nanocomposites, characterized by a head of magnetic Fe3O4 and a body of mesoporous SiO2 containing doxorubicin (DOX) as "nano-bullets" (M-MSNs-DOX). This nanodrug formulation possessed nanosize with controlled aspect-ratio, defined abundance in pore structures, and superior magnetic properties. M-MSN-DOX was determined to induce selective growth inhibition to the cancer cell under magnetic field rather than human normal cells due to its preferable endocytosis by the tumor cells and pH-promoted DOX release in the interior of cancer cells. Ultimately, both subcutaneous and orthotropic liver tumor models in mice have demonstrated that the proposed Janus nano-bullets imposed remarkable suppression of the tumor growth and significantly reduced systematic toxicity. Taken together, this study demonstrates an intriguing targeting strategy for liver cancer treatment based on a novel Janus nano-bullet, aiming for utilization of nanotechnology to obtain safe and efficient treatment of liver cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Two-Layer Gene Circuit for Decoupling Cell Growth from Metabolite Production.

PubMed

Lo, Tat-Ming; Chng, Si Hui; Teo, Wei Suong; Cho, Han-Saem; Chang, Matthew Wook

2016-08-01

We present a synthetic gene circuit for decoupling cell growth from metabolite production through autonomous regulation of enzymatic pathways by integrated modules that sense nutrient and substrate. The two-layer circuit allows Escherichia coli to selectively utilize target substrates in a mixed pool; channel metabolic resources to growth by delaying enzymatic conversion until nutrient depletion; and activate, terminate, and re-activate conversion upon substrate availability. We developed two versions of controller, both of which have glucose nutrient sensors but differ in their substrate-sensing modules. One controller is specific for hydroxycinnamic acid and the other for oleic acid. Our hydroxycinnamic acid controller lowered metabolic stress 2-fold and increased the growth rate 2-fold and productivity 5-fold, whereas our oleic acid controller lowered metabolic stress 2-fold and increased the growth rate 1.3-fold and productivity 2.4-fold. These results demonstrate the potential for engineering strategies that decouple growth and production to make bio-based production more economical and sustainable. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The antimalarial drug primaquine targets Fe-S cluster proteins and yeast respiratory growth.

PubMed

Lalève, Anaïs; Vallières, Cindy; Golinelli-Cohen, Marie-Pierre; Bouton, Cécile; Song, Zehua; Pawlik, Grzegorz; Tindall, Sarah M; Avery, Simon V; Clain, Jérôme; Meunier, Brigitte

2016-04-01

Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood. In this study, we used the yeast Saccharomyces cerevisiae model to help uncover the mode of action of primaquine. We found that the growth inhibitory effect of primaquine was restricted to cells that relied on respiratory function to proliferate and that deletion of SOD2 encoding the mitochondrial superoxide dismutase severely increased its effect, which can be countered by the overexpression of AIM32 and MCR1 encoding mitochondrial enzymes involved in the response to oxidative stress. This indicated that ROS produced by respiratory activity had a key role in primaquine-induced growth defect. We observed that Δsod2 cells treated with primaquine displayed a severely decreased activity of aconitase that contains a Fe-S cluster notoriously sensitive to oxidative damage. We also showed that in vitro exposure to primaquine impaired the activity of purified aconitase and accelerated the turnover of the Fe-S cluster of the essential protein Rli1. It is suggested that ROS-labile Fe-S groups are the primary targets of primaquine. Aconitase activity is known to be essential at certain life-cycle stages of the malaria parasite. Thus primaquine-induced damage of its labile Fe-S cluster - and of other ROS-sensitive enzymes - could inhibit parasite development. Copyright © 2015. Published by Elsevier B.V.

Understanding and Targeting Cell Growth Networks in Breast Cancer

DTIC Science & Technology

2011-04-01

nucleolus .     NPM   normally   responds   to   growth   factors   and,   due   to   its   nucleolar...entirety  of   this   growth   phenotype   is   dependent   on  NPM   and   p68DDX5   expression   in   the   nucleolus ...the   nucleolus  of  breast  epithelial  cells  and  how  they  impact   both  ribosome  biogenesis  and

Enhanced Antitumor Effects of Epidermal Growth Factor Receptor Targetable Cetuximab-Conjugated Polymeric Micelles for Photodynamic Therapy.

PubMed

Chang, Ming-Hsiang; Pai, Chin-Ling; Chen, Ying-Chen; Yu, Hsiu-Ping; Hsu, Chia-Yen; Lai, Ping-Shan

2018-02-22

Nanocarrier-based delivery systems are promising strategies for enhanced therapeutic efficacy and safety of toxic drugs. Photodynamic therapy (PDT)-a light-triggered chemical reaction that generates localized tissue damage for disease treatments-usually has side effects, and thus patients receiving photosensitizers should be kept away from direct light to avoid skin phototoxicity. In this study, a clinically therapeutic antibody cetuximab (C225) was conjugated to the surface of methoxy poly(ethylene glycol)- b -poly(lactide) (mPEG- b -PLA) micelles via thiol-maleimide coupling to allow tumor-targetable chlorin e6 (Ce6) delivery. Our results demonstrate that more C225-conjugated Ce6-loaded polymeric micelles (C225-Ce6/PM) were selectively taken up than Ce6/PM or IgG conjugated Ce6/PM by epidermal growth factor receptor (EGFR)-overexpressing A431 cells observed by confocal laser scanning microscopy (CLSM), thereby decreasing the IC 50 value of Ce6-mediated PDT from 0.42 to 0.173 μM. No significant differences were observed in cellular uptake study or IC 50 value between C225-Ce6/PM and Ce6/PM groups in lower EGFR expression HT-29 cells. For antitumor study, the tumor volumes in the C225-Ce6/PM-PDT group (percentage of tumor growth inhibition, TGI% = 84.8) were significantly smaller than those in the Ce6-PDT (TGI% = 38.4) and Ce6/PM-PDT groups (TGI% = 53.3) ( p < 0.05) at day 21 through reduced cell proliferation in A431 xenografted mice. These results indicated that active EGFR targeting of photosensitizer-loaded micelles provides a possible way to resolve the dose-limiting toxicity of conventional photosensitizers and represents a potential delivery system for PDT in a clinical setting.

Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.

PubMed

Groeneweg, Jolijn W; Hernandez, Silvia F; Byron, Virginia F; DiGloria, Celeste M; Lopez, Hector; Scialabba, Vanessa; Kim, Minji; Zhang, Ling; Borger, Darrell R; Tambouret, Rosemary; Foster, Rosemary; Rueda, Bo R; Growdon, Whitfield B

2014-12-15

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts. Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation. Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation. ©2014 American Association for Cancer Research.

Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFα prevents radiation-induced fibrosis.

PubMed

Nawroth, Isabel; Alsner, Jan; Behlke, Mark A; Besenbacher, Flemming; Overgaard, Jens; Howard, Kenneth A; Kjems, Jørgen

2010-10-01

One of the most common and dose-limiting long-term adverse effects of radiation therapy is radiation-induced fibrosis (RIF), which is characterized by restricted tissue flexibility, reduced compliance or strictures, pain and in severe cases, ulceration and necrosis. Several strategies have been proposed to ameliorate RIF but presently no effective one is available. Recent studies have reported that tumor necrosis factor-α (TNFα) plays a role in fibrogenesis. Male CDF1 mice were radiated with a single dose of 45 Gy. Chitosan/DsiRNA nanoparticles targeting TNFα were intraperitoneal injected and late radiation-induced fibrosis (RIF) was assessed using a modification of the leg contracture model. Additionally, the effect of these nanoparticles on tumor growth and tumor control probability in the absence of radiation was examined in a C3H mammary carcinoma model. We show in this work, that targeting TNFα in macrophages by intraperitoneal administration of chitosan/DsiRNA nanoparticles completely prevented radiation-induced fibrosis in CDF1 mice without revealing any cytotoxic side-effects after a long-term administration. Furthermore, such TNFα targeting was selective without any significant influence on tumor growth or irradiation-related tumor control probability. This nanoparticle-based RNAi approach represents a novel approach to prevent RIF with potential application to improve clinical radiation therapeutic strategies. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Decadal trends in marine reserves reveal differential rates of change in direct and indirect effects

USGS Publications Warehouse

Babcock, R.C.; Shears, N.T.; Alcala, A.C.; Barrett, N.S.; Edgar, G.J.; Lafferty, K.D.; McClanahan, T.R.; Russ, G.R.

2010-01-01

Decadal-scale observations of marine reserves suggest that indirect effects on taxa that occur through cascading trophic interactions take longer to develop than direct effects on target species. Combining and analyzing a unique set of long-term time series of ecologic data in and out of fisheries closures from disparate regions, we found that the time to initial detection of direct effects on target species (+ or -SE) was 5.13 + or - 1.9 years, whereas initial detection of indirect effects on other taxa, which were often trait mediated, took significantly longer (13.1 + or - 2.0 years). Most target species showed initial direct effects, but their trajectories over time were highly variable. Many target species continued to increase, some leveled off, and others decreased. Decreases were due to natural fluctuations, fishing impacts from outside reserves, or indirect effects from target species at higher trophic levels. The average duration of stable periods for direct effects was 6.2 + or - 1.2 years, even in studies of more than 15 years. For indirect effects, stable periods averaged 9.1 + or - 1.6 years, although this was not significantly different from direct effects. Populations of directly targeted species were more stable in reserves than in fished areas, suggesting increased ecologic resilience. This is an important benefit of marine reserves with respect to their function as a tool for conservation and restoration.

Decadal trends in marine reserves reveal differential rates of change in direct and indirect effects.

PubMed

Babcock, R C; Shears, N T; Alcala, A C; Barrett, N S; Edgar, G J; Lafferty, K D; McClanahan, T R; Russ, G R

2010-10-26

Decadal-scale observations of marine reserves suggest that indirect effects on taxa that occur through cascading trophic interactions take longer to develop than direct effects on target species. Combining and analyzing a unique set of long-term time series of ecologic data in and out of fisheries closures from disparate regions, we found that the time to initial detection of direct effects on target species (±SE) was 5.13 ± 1.9 years, whereas initial detection of indirect effects on other taxa, which were often trait mediated, took significantly longer (13.1 ± 2.0 years). Most target species showed initial direct effects, but their trajectories over time were highly variable. Many target species continued to increase, some leveled off, and others decreased. Decreases were due to natural fluctuations, fishing impacts from outside reserves, or indirect effects from target species at higher trophic levels. The average duration of stable periods for direct effects was 6.2 ± 1.2 years, even in studies of more than 15 years. For indirect effects, stable periods averaged 9.1 ± 1.6 years, although this was not significantly different from direct effects. Populations of directly targeted species were more stable in reserves than in fished areas, suggesting increased ecologic resilience. This is an important benefit of marine reserves with respect to their function as a tool for conservation and restoration.

Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of Bromelain in Ehrlich's Ascites Carcinoma.

PubMed

Bhatnagar, Priyanka; Pant, Aditya Bhushan; Shukla, Yogeshwer; Panda, Amulya; Gupta, Kailash Chand

2016-08-01

Rapidly increasing malignant neoplastic disease demands immediate attention. Several dietary compounds have recently emerged as strong anti-cancerous agents. Among, Bromelain (BL), a protease from pineapple plant, was used to enhance its anti-cancerous efficacy using nanotechnology. In lieu of this, hyaluronic acid (HA) grafted PLGA copolymer, having tumor targeting ability, was developed. BL was encapsulated in copolymer to obtain BL-copolymer nanoparticles (NPs) that ranged between 140 to 281nm in size. NPs exhibited higher cellular uptake and cytotoxicity in cells with high CD44 expression as compared with non-targeted NPs. In vivo results on tumor bearing mice showed that NPs were efficient in suppressing the tumor growth. Hence, the formulation could be used as a self-targeting drug delivery cargo for the remission of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

MiR-615 inhibits cell proliferation, migration and invasion by targeting EGFR in human glioblastoma.

PubMed

Ji, Yanwei; Sun, Qingshan; Zhang, Jianbin; Hu, Haoran

2018-05-15

MiR-615 and epidermal growth factor receptor (EGFR) are associated with a number of disease processes and pathogenesis. However, little is known about the mechanisms of miR-615 and EGFR in human glioblastoma multiforme (GBM). Here, we found that down-regulation of miR-615 expression occurred in GBM tissues and cells, and was inversely correlated with overall survival, relapse-free survival, WHO grade as well as EGFR expression. We further determined that miR-615 functions as a tumor suppressor by inhibiting GBM cell proliferation, cell cycle, migration and invasion, and promoting cell apoptosis. In-vivo assay validated the inhibition effect of miR-615 on tumor growth and EGFR expression. Luciferase reporter assays demonstrated that miR-615 targeted the 3'-untranslated region (3'-UTR) of EGFR. Besides, over-expression of EGFR reversed the inhibition effects of miR-615, while silencing of EGFR aggravated these inhibition effects. In conclusions, we identified that miR-615 plays a tumor suppressor role in GBM cell proliferation, migration and invasion by targeting EGFR expression, and miR-615 may act as a novel biomarker for early diagnosis or therapeutic targets of GBM. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification of Keratinocyte Growth Factor as a Target of microRNA-155 in Lung Fibroblasts: Implication in Epithelial-Mesenchymal Interactions

PubMed Central

Chevalier, Benoit; Puisségur, Marie-Pierre; Lebrigand, Kevin; Robbe-Sermesant, Karine; Bertero, Thomas; Lino Cardenas, Christian L.; Courcot, Elisabeth; Rios, Géraldine; Fourre, Sandra; Lo-Guidice, Jean-Marc; Marcet, Brice; Cardinaud, Bruno; Barbry, Pascal; Mari, Bernard

2009-01-01

Background Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-α, IL-1β and TGF-β. Methodology/Principal Findings MiR-155 was significantly induced by inflammatory cytokines TNF-α and IL-1β while it was down-regulated by TGF-β. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to “cell to cell signalling”, “cell morphology” and “cellular movement”. This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3′-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3′-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3′-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. Conclusions/Significance Our results strongly suggest a physiological function of miR-155 in

Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase

PubMed Central

Sun, Huimin; Xiao, Juanjuan; Lu, Tao; Huang, Guangqian; Chen, Pianpian; Zhang, Jianmin; Zhu, Feng; Li, Hua; Duan, Qiuhong

2016-01-01

T-cell-originated protein kinase (TOPK) is highly expressed in several cancer cells and promotes tumorigenesis and progression, and therefore, it is an important target for drug treatment of tumor. Pantoprazole (PPZ) was identified to be a TOPK inhibitor from FDA-approved drug database by structure based virtual ligand screening. Herein, the data indicated that pantoprazole inhibited TOPK activities by directly binding with TOPK in vitro and in vivo. Ex vivo studies showed that pantoprazole inhibited TOPK activities in JB6 Cl41 cells and HCT 116 colorectal cancer cells. Moreover, knockdown of TOPK in HCT 116 cells decreased their sensitivities to pantoprazole. Results of an in vivo study demonstrated that i.p. injection of pantoprazole in HCT 116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after pantoprazole treatment. In short, pantoprazole can suppress growth of colorectal cancer cells as a TOPK inhibitor both in vitro and in vivo. PMID:26967058

Altered decorin leads to disrupted endothelial cell function: a possible mechanism in the pathogenesis of fetal growth restriction?

PubMed

Chui, A; Murthi, P; Gunatillake, T; Brennecke, S P; Ignjatovic, V; Monagle, P T; Whitelock, J M; Said, J M

2014-08-01

Fetal growth restriction (FGR) is a key cause of adverse pregnancy outcome where maternal and fetal factors are identified as contributing to this condition. Idiopathic FGR is associated with altered vascular endothelial cell functions. Decorin (DCN) has important roles in the regulation of endothelial cell functions in vascular environments. DCN expression is reduced in FGR. The objectives were to determine the functional consequences of reduced DCN in a human microvascular endothelial cell line model (HMVEC), and to determine downstream targets of DCN and their expression in primary placental microvascular endothelial cells (PLECs) from control and FGR-affected placentae. Short-interference RNA was used to reduce DCN expression in HMVECs and the effect on proliferation, angiogenesis and thrombin generation was determined. A Growth Factor PCR Array was used to identify downstream targets of DCN. The expression of target genes in control and FGR PLECs was performed. DCN reduction decreased proliferation and angiogenesis but increased thrombin generation with no effect on apoptosis. The array identified three targets of DCN: FGF17, IL18 and MSTN. Validation of target genes confirmed decreased expression of VEGFA, MMP9, EGFR1, IGFR1 and PLGF in HMVECs and PLECs from control and FGR pregnancies. Reduction of DCN in vascular endothelial cells leads to disrupted cell functions. The targets of DCN include genes that play important roles in angiogenesis and cellular growth. Therefore, differential expression of these may contribute to the pathogenesis of FGR and disease states in other microvascular circulations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Targets of curcumin

PubMed Central

Zhou, Hongyu; Beevers, Christopher S.; Huang, Shile

2010-01-01

Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here. PMID:20955148

TARGET Research Goals

Cancer.gov

TARGET researchers use various sequencing and array-based methods to examine the genomes, transcriptomes, and for some diseases epigenomes of select childhood cancers. This “multi-omic” approach generates a comprehensive profile of molecular alterations for each cancer type. Alterations are changes in DNA or RNA, such as rearrangements in chromosome structure or variations in gene expression, respectively. Through computational analyses and assays to validate biological function, TARGET researchers predict which alterations disrupt the function of a gene or pathway and promote cancer growth, progression, and/or survival. Researchers identify candidate therapeutic targets and/or prognostic markers from the cancer-associated alterations.

Targeting acid sphingomyelinase with anti-angiogenic chemotherapy.

PubMed

Jacobi, Jeanna; García-Barros, Mónica; Rao, Shyam; Rotolo, Jimmy A; Thompson, Chris; Mizrachi, Aviram; Feldman, Regina; Manova, Katia; Bielawska, Alicja; Bielawska, Jacek; Fuks, Zvi; Kolesnick, Richard; Haimovitz-Friedman, Adriana

2017-01-01

Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase +/+ , but not in asmase -/- , hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1-2h before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

The combi-targeting concept: synthesis of stable nitrosoureas designed to inhibit the epidermal growth factor receptor (EGFR).

PubMed

Domarkas, Juozas; Dudouit, Fabienne; Williams, Christopher; Qiyu, Qiu; Banerjee, Ranjita; Brahimi, Fouad; Jean-Claude, Bertrand Jacques

2006-06-15

According to the "combi-targeting" concept, the EGFR tyrosine kinase (TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds (3'-Cl and Br series) with small angles (0.5-3 degrees ) were generally stronger EGFR TK inhibitors than those with large angles (18-21 degrees ). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC(50) values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line (Pearson r = 0.8). On the basis of stability (t(1/2)), EGFR TK inhibitory potency (IC(50)), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.

Targeted sequencing for high-resolution evolutionary analyses following genome duplication in salmonid fish: Proof of concept for key components of the insulin-like growth factor axis.

PubMed

Lappin, Fiona M; Shaw, Rebecca L; Macqueen, Daniel J

2016-12-01

High-throughput sequencing has revolutionised comparative and evolutionary genome biology. It has now become relatively commonplace to generate multiple genomes and/or transcriptomes to characterize the evolution of large taxonomic groups of interest. Nevertheless, such efforts may be unsuited to some research questions or remain beyond the scope of some research groups. Here we show that targeted high-throughput sequencing offers a viable alternative to study genome evolution across a vertebrate family of great scientific interest. Specifically, we exploited sequence capture and Illumina sequencing to characterize the evolution of key components from the insulin-like growth (IGF) signalling axis of salmonid fish at unprecedented phylogenetic resolution. The IGF axis represents a central governor of vertebrate growth and its core components were expanded by whole genome duplication in the salmonid ancestor ~95Ma. Using RNA baits synthesised to genes encoding the complete family of IGF binding proteins (IGFBP) and an IGF hormone (IGF2), we captured, sequenced and assembled orthologous and paralogous exons from species representing all ten salmonid genera. This approach generated 299 novel sequences, most as complete or near-complete protein-coding sequences. Phylogenetic analyses confirmed congruent evolutionary histories for all nineteen recognized salmonid IGFBP family members and identified novel salmonid-specific IGF2 paralogues. Moreover, we reconstructed the evolution of duplicated IGF axis paralogues across a replete salmonid phylogeny, revealing complex historic selection regimes - both ancestral to salmonids and lineage-restricted - that frequently involved asymmetric paralogue divergence under positive and/or relaxed purifying selection. Our findings add to an emerging literature highlighting diverse applications for targeted sequencing in comparative-evolutionary genomics. We also set out a viable approach to obtain large sets of nuclear genes for any

Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma.

PubMed

Johnson, Jennifer; Ascierto, Maria Libera; Mittal, Sandeep; Newsome, David; Kang, Liang; Briggs, Michael; Tanner, Kirk; Marincola, Francesco M; Berens, Michael E; Vande Woude, George F; Xie, Qian

2015-09-17

Constitutive MET signaling promotes invasiveness in most primary and recurrent GBM. However, deployment of available MET-targeting agents is confounded by lack of effective biomarkers for selecting suitable patients for treatment. Because endogenous HGF overexpression often causes autocrine MET activation, and also indicates sensitivity to MET inhibitors, we investigated whether it drives the expression of distinct genes which could serve as a signature indicating vulnerability to MET-targeted therapy in GBM. Interrogation of genomic data from TCGA GBM (Student's t test, GBM patients with high and low HGF expression, p ≤ 0.00001) referenced against patient-derived xenograft (PDX) models (Student's t test, sensitive vs. insensitive models, p ≤ 0.005) was used to identify the HGF-dependent signature. Genomic analysis of GBM xenograft models using both human and mouse gene expression microarrays (Student's t test, treated vs. vehicle tumors, p ≤ 0.01) were performed to elucidate the tumor and microenvironment cross talk. A PDX model with EGFR(amp) was tested for MET activation as a mechanism of erlotinib resistance. We identified a group of 20 genes highly associated with HGF overexpression in GBM and were up- or down-regulated only in tumors sensitive to MET inhibitor. The MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall impede tumor growth by inhibiting cell cycle progression. EGFR (amp) tumors undergo erlotinib resistance responded to a combination of MET and EGFR inhibitors. Combining TCGA primary tumor datasets (human) and xenograft tumor model datasets (human tumor grown in mice) using therapeutic efficacy as an endpoint may serve as a useful approach to discover and develop molecular signatures as therapeutic biomarkers for targeted therapy. The HGF dependent signature may serve as a candidate predictive signature for patient enrollment in clinical trials using MET inhibitors

Platelet-camouflaged nanococktail: Simultaneous inhibition of drug-resistant tumor growth and metastasis via a cancer cells and tumor vasculature dual-targeting strategy.

PubMed

Jing, Lijia; Qu, Haijing; Wu, Dongqi; Zhu, Chaojian; Yang, Yongbo; Jin, Xing; Zheng, Jian; Shi, Xiangsheng; Yan, Xiufeng; Wang, Yang

2018-01-01

Multidrug resistance (MDR) poses a great challenge to cancer therapy. It is difficult to inhibit the growth of MDR cancer due to its chemoresistance. Furthermore, MDR cancers are more likely to metastasize, causing a high mortality among cancer patients. In this study, a nanomedicine RGD-NPVs@MNPs/DOX was developed by encapsulating melanin nanoparticles (MNPs) and doxorubicin (DOX) inside RGD peptide (c(RGDyC))-modified nanoscale platelet vesicles (RGD-NPVs) to efficiently inhibit the growth and metastasis of drug-resistant tumors via a cancer cells and tumor vasculature dual-targeting strategy. Methods: The in vitro immune evasion potential and the targeting performance of RGD-NPVs@MNPs/DOX were examined using RAW264.7, HUVECs, MDA-MB-231 and MDA-MB-231/ADR cells lines. We also evaluated the pharmacokinetic behavior and the in vivo therapeutic performance of RGD-NPVs@MNPs/DOX using a MDA-MB-231/ADR tumor-bearing nude mouse model. Results: By taking advantage of the self-recognizing property of the platelet membrane and the conjugated RGD peptides, RGD-NPVs@MNPs/DOX was found to evade immune clearance and target the αvβ3 integrin on tumor vasculature and resistant breast tumor cells. Under irradiation with a NIR laser, RGD-NPVs@MNPs/DOX produced a multipronged effect, including reversal of cancer MDR, efficient killing of resistant cells by chemo-photothermal therapy, elimination of tumor vasculature for blocking metastasis, and long-lasting inhibition of the expressions of VEGF, MMP2 and MMP9 within the tumor. Conclusion: This versatile nanomedicine of RGD-NPVs@MNPs/DOX integrating unique biomimetic properties, excellent targeting performance, and comprehensive therapeutic strategies in one formulation might bring opportunities to MDR cancer therapy.

Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

PubMed

Bianchi, Enrica; Taurone, Samanta; Bardella, Lia; Signore, Alberto; Pompili, Elena; Sessa, Vincenzo; Chiappetta, Caterina; Fumagalli, Lorenzo; Di Gioia, Cira; Pastore, Francesco S; Scarpa, Susanna; Artico, Marco

2015-10-01

Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD). © 2015 Authors; published by Portland Press Limited.

Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

PubMed

Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

2010-05-14

Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

Molecular genetics and targeted therapeutics in biliary tract carcinoma

PubMed Central

Marks, Eric I; Yee, Nelson S

2016-01-01

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract. PMID:26819503

Molecular genetics and targeted therapeutics in biliary tract carcinoma.

PubMed

Marks, Eric I; Yee, Nelson S

2016-01-28

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)

PubMed Central

Zhou, Yihua; Xu, Bixiong C.; Maheshwari, Hiralal G.; He, Li; Reed, Michael; Lozykowski, Maria; Okada, Shigeru; Cataldo, Lori; Coschigamo, Karen; Wagner, Thomas E.; Baumann, Gerhard; Kopchick, John J.

1997-01-01

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans. PMID:9371826

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse).

PubMed

Zhou, Y; Xu, B C; Maheshwari, H G; He, L; Reed, M; Lozykowski, M; Okada, S; Cataldo, L; Coschigamo, K; Wagner, T E; Baumann, G; Kopchick, J J

1997-11-25

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.

Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor

PubMed Central

Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun; Feng, Jian-Quan; Kobayashi, Tatsuya; Merregaert, Joseph; Liu, Chuan-Ju

2016-01-01

Chondrogenesis and endochondral ossification are precisely controlled by cellular interactions with surrounding matrix proteins and growth factors that mediate cellular signaling pathways. Here, we report that extracellular matrix protein 1 (ECM1) is a previously unrecognized regulator of chondrogenesis. ECM1 is induced in the course of chondrogenesis and its expression in chondrocytes strictly depends on parathyroid hormone–related peptide (PTHrP) signaling pathway. Overexpression of ECM1 suppresses, whereas suppression of ECM1 enhances, chondrocyte differentiation and hypertrophy in vitro and ex vivo. In addition, target transgene of ECM1 in chondrocytes or osteoblasts in mice leads to striking defects in cartilage development and endochondral bone formation. Of importance, ECM1 seems to be critical for PTHrP action in chondrogenesis, as blockage of ECM1 nearly abolishes PTHrP regulation of chondrocyte hypertrophy, and overexpression of ECM1 rescues disorganized growth plates of PTHrP-null mice. Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an interaction network and act in concert in the regulation of chondrogenesis.—Kong, L., Zhao, Y.-P., Tian, Q.-Y., Feng, J.-Q., Kobayashi, T., Merregaert, J., Liu, C.-J. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. PMID:27075243

Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites.

PubMed

Cestari, Igor; Haas, Paige; Moretti, Nilmar Silvio; Schenkman, Sergio; Stuart, Ken

2016-05-19

Kinetoplastids cause Chagas disease, human African trypanosomiasis, and leishmaniases. Current treatments for these diseases are toxic and inefficient, and our limited knowledge of drug targets and inhibitors has dramatically hindered the development of new drugs. Here we used a chemogenetic approach to identify new kinetoplastid drug targets and inhibitors. We conditionally knocked down Trypanosoma brucei inositol phosphate (IP) pathway genes and showed that almost every pathway step is essential for parasite growth and infection. Using a genetic and chemical screen, we identified inhibitors that target IP pathway enzymes and are selective against T. brucei. Two series of these inhibitors acted on T. brucei inositol polyphosphate multikinase (IPMK) preventing Ins(1,4,5)P3 and Ins(1,3,4,5)P4 phosphorylation. We show that IPMK is functionally conserved among kinetoplastids and that its inhibition is also lethal for Trypanosoma cruzi. Hence, IP enzymes are viable drug targets in kinetoplastids, and IPMK inhibitors may aid the development of new drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

A novel stilbene-like compound that inhibits melanoma growth by regulating melanocyte differentiation and proliferation.

PubMed

Stueven, Noah A; Schlaeger, Nicholas M; Monte, Aaron P; Hwang, Sheng-Ping L; Huang, Cheng-Chen

2017-12-15

Melanoma is the most aggressive form of skin cancer. Current challenges to melanoma therapy include the adverse effects from immunobiologics, resistance to drugs targeting the MAPK pathway, intricate interaction of many signal pathways, and cancer heterogeneity. Thus combinational therapy with drugs targeting multiple signaling pathways becomes a new promising therapy. Here, we report a family of stilbene-like compounds called A11 that can inhibit melanoma growth in both melanoma-forming zebrafish embryos and mouse melanoma cells. The growth inhibition by A11 is a result of mitosis reduction but not apoptosis enhancement. Meanwhile, A11 activates both MAPK and Akt signaling pathways. Many A11-treated mouse melanoma cells exhibit morphological changes and resemble normal melanocytes. Furthermore, we found that A11 causes down-regulation of melanocyte differentiation genes, including Pax3 and MITF. Together, our results suggest that A11 could be a new melanoma therapeutic agent by inhibiting melanocyte differentiation and proliferation. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds.

PubMed

Crowther, Gregory J; Napuli, Alberto J; Gilligan, James H; Gagaring, Kerstin; Borboa, Rachel; Francek, Carolyn; Chen, Zhong; Dagostino, Eleanor F; Stockmyer, Justin B; Wang, Yu; Rodenbough, Philip P; Castaneda, Lisa J; Leibly, David J; Bhandari, Janhavi; Gelb, Michael H; Brinker, Achim; Engels, Ingo H; Taylor, Jennifer; Chatterjee, Arnab K; Fantauzzi, Pascal; Glynne, Richard J; Van Voorhis, Wesley C; Kuhen, Kelli L

2011-01-01

The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC(50) values below 1.25μM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology. Copyright © 2010 Elsevier B.V. All rights reserved.

Role of nature reserves in giant panda protection.

PubMed

Kang, Dongwei; Li, Junqing

2018-02-01

Giant panda (Ailuropoda melanoleuca) is a flagship species in nature conservation of the world; to protect this species, 67 nature reserves have been established in China. To evaluate the protection effect of giant panda nature reserves, we analyzed the variation of giant panda number and habitat area of 23 giant panda nature reserves of Sichuan province based on the national survey data released by State Forestry Administration and Sichuan Forestry Department. Results showed that from the third national survey to the fourth, giant panda number and habitat area of 23 giant panda nature reserves of Sichuan province failed to realize the significant increase. Furthermore, we found that the total population growth rate of 23 nature reserves in the last 12 years was lower than those of the province total of Sichuan and the national total of China, and the total habitat area of the 23 nature reserves was decreasing in the last 12 years, but the province total and national total were all increasing. We propose that giant panda protection should pay more attention to how to improve the protective effects of nature reserves.

Apatinib as targeted therapy for sarcoma

PubMed Central

Li, Feng; Liao, Zhichao; Zhang, Chao; Zhao, Jun; Xing, Ruwei; Teng, Sheng; Zhang, Jin; Yang, Yun; Yang, Jilong

2018-01-01

Sarcomas are a group of malignant tumors originating from mesenchymal tissue with a variety of cell subtypes. Despite several major treatment breakthroughs, standard treatment using surgery, radiation, and chemotherapy has failed to improve overall survival. Therefore, there is an urgent need to explore new strategies and innovative therapies to further improve the survival rates of patients with sarcomas. Pathological angiogenesis has an important role in the growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFRs) play a central role in tumor angiogenesis and represent potential targets for anticancer therapy. As a novel targeted therapy, especially with regard to angiogenesis, apatinib is a new type of small molecule tyrosine kinase inhibitor that selectively targets VEGFR-2 and has shown encouraging anticancer activity in a wide range of malignancies, including gastric cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma, and sarcomas. In this review, we summarize the preclinical and clinical data for apatinib, focusing primarily on its use in the treatment of sarcomas. PMID:29849960

Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics.

PubMed

Christopoulos, Panagiotis F; Corthay, Alexandre; Koutsilieris, Michael

2018-02-01

Despite the major discoveries occurred in oncology the recent years, breast malignancies remain one of the most common causes of cancer-related deaths for women in developed countries. Development of HER2-targeting drugs has been considered a breakthrough in anti-cancer approaches and alluded to the potential of targeting growth factors in breast cancer (BrCa) therapeutics. More than twenty-five years have passed since the Insulin-like Growth Factor-1 (IGF-1) system was initially recognized as a potential target candidate in BrCa therapy. To date, a growing body of studies have implicated the IGF-1 signaling with the BrCa biology. Despite the promising experimental evidence, the impression from clinical trials is rather disappointing. Several reasons may account for this and the last word regarding the efficacy of this system as a target candidate in BrCa therapeutics is probably not written yet. Herein, we provide the theoretical basis, as well as, a comprehensive overview of the current literature, regarding the different strategies targeting the various components of the IGF-1/IGF-1R axis in several pathophysiological aspects of BrCa, including the tumor micro-environment and cancer stemness. In addition, we review the rationale for targeting the IGF-1 system in the different BrCa molecular subtypes and in treatment resistant breast tumors with a focus on both the molecular mechanisms and on the clinical perspectives of such approaches in specific population subgroups. We also discuss the future challenges, as well as, the development of novel molecules and strategies targeting the system and suggest potential improvements in the field. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fibroblast growth factor receptors in breast cancer.

PubMed

Wang, Shuwei; Ding, Zhongyang

2017-05-01

Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.

Targeted therapies in gastric cancer and future perspectives.

PubMed

Yazici, Ozan; Sendur, M Ali Nahit; Ozdemir, Nuriye; Aksoy, Sercan

2016-01-14

Advanced gastric cancer (AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after first-line platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase I-II trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER (2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.

Macronutrient intake in preschoolers with cystic fibrosis and the relationship between macronutrients and growth.

PubMed

Filigno, Stephanie S; Robson, Shannon M; Szczesniak, Rhonda D; Chamberlin, Leigh A; Baker, Meredith A; Sullivan, Stephanie M; Kroner, John; Powers, Scott W

2017-07-01

Adequate nutrition is essential for growth in children with cystic fibrosis (CF). The new CF Foundation Clinical Practice Guidelines bring attention to monitoring macronutrient intake as well as total energy. Dietary intake of 75 preschool children with CF and pancreatic insufficiency was examined and compared to the Clinical Practice Guidelines. Regression analyses examined relationships between macronutrient intake and growth. Approximately 45% of children met the 110% minimum recommended dietary allowance (RDA) recommendation. Children consumed 35.3% (6.1) of total daily energy intake from fat, 12.7% (1.7) from protein, and 52.0% (6.1) from carbohydrates. Percent energy from protein was associated with height growth. Many preschoolers with CF are not meeting nutrition benchmarks for total energy and fat. To optimize nutrition early, dietary monitoring with frequent individualized feedback is needed. Optimizing intake of macronutrients that promote growth, especially fat and protein, should be a primary clinical target. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Weina, E-mail: liweina228@163.com; He, Fei, E-mail: hesili1027@163.com

2014-07-18

Highlights: • Expression of MMD is increased in lung cancer tissues. • Knockdown of MMD inhibits growth of A549 and LLC cells in vitro and in vivo. • MMD is a direct functional target of miR-140-5p. • MiR-140-5p/MMD axis regulates Erk1/2 signaling. - Abstract: Monocyte to macrophage differentiation-associated (MMD) is identified in macrophages as a gene associated with the differentiation from monocytes to macrophages. Recent microarray analysis for non-small cell lung cancer (NSCLC) suggests that MMD is an important signature associated with relapse and survival among patients with NSCLC. Therefore, we speculate that MMD likely plays a role in lungmore » cancer. In this study, we found that the protein level of MMD was increased in lung cancer compared to benign lung tissues, and knockdown of MMD inhibited the growth of A549 and Lewis lung cancer cells (LLC) in vitro and in vivo. Integrated analysis demonstrated that MMD was a direct functional target of miR-140-5p. Furthermore, we found that miR-140-5p/MMD axis could affect the cell proliferation of lung cancer cells by regulating Erk signaling. Together, our results highlight the significance of miR-140-5p/MMD axis in lung cancer, and miR-140-5p/MMD axis could serve as new molecular targets for the therapy against lung cancer.« less

Anthropogenic disturbances jeopardize biodiversity conservation within tropical rainforest reserves.

PubMed

Martínez-Ramos, Miguel; Ortiz-Rodríguez, Iván A; Piñero, Daniel; Dirzo, Rodolfo; Sarukhán, José

2016-05-10

Anthropogenic disturbances affecting tropical forest reserves have been documented, but their ecological long-term cumulative effects are poorly understood. Habitat fragmentation and defaunation are two major anthropogenic threats to the integrity of tropical reserves. Based on a long-term (four decades) study, we document how these disturbances synergistically disrupt ecological processes and imperil biodiversity conservation and ecosystem functioning at Los Tuxtlas, the northernmost tropical rainforest reserve in the Americas. Deforestation around this reserve has reduced the reserve to a medium-sized fragment (640 ha), leading to an increased frequency of canopy-gap formation. In addition, hunting and habitat loss have caused the decline or local extinction of medium and large herbivores. Combining empirical, experimental, and modeling approaches, we support the hypothesis that such disturbances produced a demographic explosion of the long-lived (≈120 y old, maximum height of 7 m) understory palm Astrocaryum mexicanum, whose population has increased from 1,243-4,058 adult individuals per hectare in only 39 y (annual growth rate of ca 3%). Faster gap formation increased understory light availability, enhancing seed production and the growth of immature palms, whereas release from mammalian herbivory and trampling increased survival of seedlings and juveniles. In turn, the palm's demographic explosion was followed by a reduction of tree species diversity, changing forest composition, altering the relative contribution of trees to forest biomass, and disrupting litterfall dynamics. We highlight how indirect anthropogenic disturbances (e.g., palm proliferation) on otherwise protected areas threaten tropical conservation, a phenomenon that is currently eroding the planet's richest repositories of biodiversity.

Anthropogenic disturbances jeopardize biodiversity conservation within tropical rainforest reserves

PubMed Central

Martínez-Ramos, Miguel; Ortiz-Rodríguez, Iván A.; Piñero, Daniel; Dirzo, Rodolfo; Sarukhán, José

2016-01-01

Anthropogenic disturbances affecting tropical forest reserves have been documented, but their ecological long-term cumulative effects are poorly understood. Habitat fragmentation and defaunation are two major anthropogenic threats to the integrity of tropical reserves. Based on a long-term (four decades) study, we document how these disturbances synergistically disrupt ecological processes and imperil biodiversity conservation and ecosystem functioning at Los Tuxtlas, the northernmost tropical rainforest reserve in the Americas. Deforestation around this reserve has reduced the reserve to a medium-sized fragment (640 ha), leading to an increased frequency of canopy-gap formation. In addition, hunting and habitat loss have caused the decline or local extinction of medium and large herbivores. Combining empirical, experimental, and modeling approaches, we support the hypothesis that such disturbances produced a demographic explosion of the long-lived (≈120 y old, maximum height of 7 m) understory palm Astrocaryum mexicanum, whose population has increased from 1,243–4,058 adult individuals per hectare in only 39 y (annual growth rate of ca. 3%). Faster gap formation increased understory light availability, enhancing seed production and the growth of immature palms, whereas release from mammalian herbivory and trampling increased survival of seedlings and juveniles. In turn, the palm’s demographic explosion was followed by a reduction of tree species diversity, changing forest composition, altering the relative contribution of trees to forest biomass, and disrupting litterfall dynamics. We highlight how indirect anthropogenic disturbances (e.g., palm proliferation) on otherwise protected areas threaten tropical conservation, a phenomenon that is currently eroding the planet’s richest repositories of biodiversity. PMID:27071122

MYD88 Inhibitor ST2825 Suppresses the Growth of Lymphoma and Leukaemia Cells.

PubMed

Shiratori, Erika; Itoh, Mai; Tohda, Shuji

2017-11-01

Myeloid differentiation primary response gene 88 (MYD88), which activates the nuclear factor kappa B (NF-κB) pathway, is important for the growth of lymphoma and leukaemia cells. In this study, we investigated the effects of ST2825, a synthetic peptidomimetic compound which inhibits MYD88 homodimerization, on their growth. Seven lymphoma and leukaemia cell lines including TMD8, a B-cell lymphoma line with MYD88-activating mutation, were treated with ST2825 and analysed for cell proliferation and expression of NF-κB signalling-related molecules. ST2825 suppressed the growth of all cell lines by inducing apoptosis and down-regulating phosphorylation of NF-κB pathway components inhibitor of nuclear factor kappa B kinase (IκB) and reticuloendotheliosis oncogene A (RelA), as well as of MYD88 activator Bruton tyrosine kinase (BTK), suggesting that MYD88 may affect BTK activity. ST2825 effects were specific as MYD88-targeting siRNA also suppressed phosphorylation of NF-κB signalling proteins and BTK in TMD8 cells. ST2825 may be a novel drug targeting not only B-lymphoid malignancies with MYD88 mutations, but also lymphoma and leukaemia with wild-type MYD88. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Targeting long non-coding RNA-TUG1 inhibits tumor growth and angiogenesis in hepatoblastoma

PubMed Central

Dong, R; Liu, G-B; Liu, B-H; Chen, G; Li, K; Zheng, S; Dong, K-R

2016-01-01

Hepatoblastoma is the most common liver tumor of early childhood, which is usually characterized by unusual hypervascularity. Recently, long non-coding RNAs (lncRNA) have emerged as gene regulators and prognostic markers in several cancers, including hepatoblastoma. We previously reveal that lnRNA-TUG1 is upregulated in hepatoblastoma specimens by microarray analysis. In this study, we aim to elucidate the biological and clinical significance of TUG1 upregulation in hepatoblastoma. We show that TUG1 is significantly upregulated in human hepatoblastoma specimens and metastatic hepatoblastoma cell lines. TUG1 knockdown inhibits tumor growth and angiogenesis in vivo, and decreases hepatoblastoma cell viability, proliferation, migration, and invasion in vitro. TUG1, miR-34a-5p, and VEGFA constitutes to a regulatory network, and participates in regulating hepatoblastoma cell function, tumor progression, and tumor angiogenesis. Overall, our findings indicate that TUG1 upregulation contributes to unusual hypervascularity of hepatoblastoma. TUG1 is a promising therapeutic target for aggressive, recurrent, or metastatic hepatoblastoma. PMID:27362796

Targeting long non-coding RNA-TUG1 inhibits tumor growth and angiogenesis in hepatoblastoma.

PubMed

Dong, R; Liu, G-B; Liu, B-H; Chen, G; Li, K; Zheng, S; Dong, K-R

2016-06-30

Hepatoblastoma is the most common liver tumor of early childhood, which is usually characterized by unusual hypervascularity. Recently, long non-coding RNAs (lncRNA) have emerged as gene regulators and prognostic markers in several cancers, including hepatoblastoma. We previously reveal that lnRNA-TUG1 is upregulated in hepatoblastoma specimens by microarray analysis. In this study, we aim to elucidate the biological and clinical significance of TUG1 upregulation in hepatoblastoma. We show that TUG1 is significantly upregulated in human hepatoblastoma specimens and metastatic hepatoblastoma cell lines. TUG1 knockdown inhibits tumor growth and angiogenesis in vivo, and decreases hepatoblastoma cell viability, proliferation, migration, and invasion in vitro. TUG1, miR-34a-5p, and VEGFA constitutes to a regulatory network, and participates in regulating hepatoblastoma cell function, tumor progression, and tumor angiogenesis. Overall, our findings indicate that TUG1 upregulation contributes to unusual hypervascularity of hepatoblastoma. TUG1 is a promising therapeutic target for aggressive, recurrent, or metastatic hepatoblastoma.

Thermophilic growth and enzymatic thermostability are polyphyletic traits within Chaetomiaceae.

PubMed

van den Brink, Joost; Facun, Kryss; de Vries, Michel; Stielow, J Benjamin

2015-12-01

Thermophilic fungi have the potential to produce industrial-relevant thermostable enzymes, in particular for the degradation of plant biomass. Sordariales is one of the few fungal orders containing several thermophilic taxa, of which many have been associated with the production of thermostable enzymes. The evolutionary affiliation of Sordariales fungi, especially between thermophiles and non-thermophilic relatives, is however poorly understood. Phylogenetic analysis within the current study was based on sequence data, derived from a traditional Sanger and highly multiplexed targeted next generation sequencing approach of 45 isolates. The inferred phylogeny and detailed growth analysis rendered the trait 'thermophily' as polyphyletic within Chaetomiaceae (Sordariales, Sordariomycetes), and characteristic to: Myceliophthora spp., Thielavia terrestris, Chaetomium thermophilum, and Mycothermus thermophilus. Compared to mesophiles, the isolates within thermophilic taxa produced enzyme mixtures with the highest thermostability of known cellulase activities. Temperature profiles of the enzyme activities correlated strongly with the optimal growth temperatures of the isolates but not with their phylogenetic relationships. This strong correlation between growth and enzyme characteristics indicated that detailed analysis of growth does give predictive information on enzyme physiology. The variation in growth and enzyme characteristics reveals these fungi as an excellent platform to better understand fungal thermophily and enzyme thermostability. Copyright © 2015 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.

PubMed

Pérez-Pérez, María-Jesús; Priego, Eva-María; Bueno, Oskía; Martins, Maria Solange; Canela, María-Dolores; Liekens, Sandra

2016-10-13

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

Regeneration of cervical reserve cell-like cells from human induced pluripotent stem cells (iPSCs): A new approach to finding targets for cervical cancer stem cell treatment.

PubMed

Sato, Masakazu; Kawana, Kei; Adachi, Katsuyuki; Fujimoto, Asaha; Yoshida, Mitsuyo; Nakamura, Hiroe; Nishida, Haruka; Inoue, Tomoko; Taguchi, Ayumi; Ogishima, Juri; Eguchi, Satoko; Yamashita, Aki; Tomio, Kensuke; Wada-Hiraike, Osamu; Oda, Katsutoshi; Nagamatsu, Takeshi; Osuga, Yutaka; Fujii, Tomoyuki

2017-06-20

Cervical reserve cells are epithelial progenitor cells that are pathologically evident as the origin of cervical cancer. Thus, investigating the characteristics of cervical reserve cells could yield insight into the features of cervical cancer stem cells (CSCs). In this study, we established a method for the regeneration of cervical reserve cell-like properties from human induced pluripotent stem cells (iPSCs) and named these cells induced reserve cell-like cells (iRCs). Approximately 70% of iRCs were positive for the reserve cell markers p63, CK5 and CK8. iRCs also expressed the SC junction markers CK7, AGR2, CD63, MMP7 and GDA. While iRCs expressed neither ERα nor ERβ, they expressed CA125. These data indicated that iRCs possessed characteristics of cervical epithelial progenitor cells. iRCs secreted higher levels of several inflammatory cytokines such as macrophage migration inhibitory factor (MIF), soluble intercellular adhesion molecule 1 (sICAM-1) and C-X-C motif ligand 10 (CXCL-10) compared with normal cervical epithelial cells. iRCs also expressed human leukocyte antigen-G (HLA-G), which is an important cell-surface antigen for immune tolerance and carcinogenesis. Together with the fact that cervical CSCs can originate from reserve cells, our data suggested that iRCs were potent immune modulators that might favor cervical cancer cell survival. In conclusion, by generating reserve cell-like properties from iPSCs, we provide a new approach that may yield new insight into cervical cancer stem cells and help find new oncogenic targets.

Di-Ethylhexylphthalate (DEHP) Modulates Cell Invasion, Migration and Anchorage Independent Growth through Targeting S100P in LN-229 Glioblastoma Cells

PubMed Central

Sims, Jennifer Nicole; Graham, Barbara; Pacurari, Maricica; Leggett, Sophia S.; Tchounwou, Paul B.; Ndebele, Kenneth

2014-01-01

Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a median survival of 1–2 years. The treatment of GBM includes surgical resection, radiation and chemotherapy, which minimally extends survival. This poor prognosis necessitates the identification of novel molecular targets associated with glioblastoma. S100P is associated with drug resistance, metastasis, and poor clinical outcomes in many malignancies. The functional role of S100P in glioblastoma has not been fully investigated. In this study, we examined the role of S100P mediating the effects of the environmental contaminant, DEHP, in glioblastoma cells (LN-229) by assessing cell proliferation, apoptosis, anchorage independent growth, cell migration and invasion following DEHP exposure. Silencing S100P and DEHP treatment inhibited LN-229 glioblastoma cell proliferation and induced apoptosis. Anchorage independent growth study revealed significantly decreased colony formation in shS100P cells. We also observed reduced cell migration in cells treated with DEHP following S100P knockdown. Similar results were observed in spheroid formation and expansion. This study is the first to demonstrate the effects of DEHP on glioblastoma cells, and implicates S100P as a potential therapeutic target that may be useful as a drug response biomarker. PMID:24821384

Engineering a growth sensor to select intracellular antibodies in the cytosol of mammalian cells.

PubMed

Nguyen, Thuy Duong; Takasuka, Hitoshi; Kaku, Yoshihiro; Inoue, Satoshi; Nagamune, Teruyuki; Kawahara, Masahiro

2017-07-01

Intracellular antibodies (intrabodies) are expected to function as therapeutics as well as tools for elucidating in vivo function of proteins. In this study, we propose a novel intrabody selection method in the cytosol of mammalian cells by utilizing a growth signal, induced by the interaction of the target antigen and an scFv-c-kit growth sensor. Here, we challenge this method to select specific intrabodies against rabies virus nucleoprotein (RV-N) for the first time. As a result, we successfully select antigen-specific intrabodies from a naïve synthetic library using phage panning followed by our growth sensor-based intracellular selection method, demonstrating the feasibility of the method. Additionally, we succeed in improving the response of the growth sensor by re-engineering the linker region of its construction. Collectively, the described selection method utilizing a growth sensor may become a highly efficient platform for selection of functional intrabodies in the future. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice.

PubMed

Steinmetz, Adam B; Stern, Sarah A; Kohtz, Amy S; Descalzi, Giannina; Alberini, Cristina M

2018-01-24

Autism spectrum disorder (ASD) is a developmental disability characterized by impairments in social interaction and repetitive behavior, and is also associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASD symptomatology; thus, identifying novel therapies is urgently needed. We used male BTBR T + Itpr3 tf /J (BTBR) mice, a model that reproduces most of the core behavioral phenotypes of ASD, to test the effects of systemic administration of insulin-like growth factor II (IGF-II), a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-II treatments reverse the typical defects in social interaction, cognitive/executive functions, and repetitive behaviors reflective of ASD-like phenotypes. In BTBR mice, IGF-II, via IGF-II receptor, but not via IGF-I receptor, reverses the abnormal levels of the AMPK-mTOR-S6K pathway and of active translation at synapses. Thus, IGF-II may represent a novel potential therapy for ASD. SIGNIFICANCE STATEMENT Currently, there is no effective treatment for autism spectrum disorder (ASD), a developmental disability affecting a high number of children. Using a mouse model that expresses most of the key core as well as associated behavioral deficits of ASD, that are, social, cognitive, and repetitive behaviors, we report that a systemic administration of the polypeptide insulin-like growth factor II (IGF-II) reverses all these deficits. The effects of IGF-II occur via IGF-II receptors, and not IGF-I receptors, and target both basal and learning-dependent molecular abnormalities found in several ASD mice models, including those of identified genetic mutations. We suggest that IGF-II represents a potential novel therapeutic target for ASD. Copyright © 2018 the authors 0270-6474/18/371015-15$15.00/0.

Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS

PubMed Central

Rocca, Maria A.; Leavitt, Victoria M.; Dackovic, Jelena; Mesaros, Sarlota; Drulovic, Jelena; DeLuca, John; Filippi, Massimo

2014-01-01

Objective: Based on the theories of brain reserve and cognitive reserve, we investigated whether larger maximal lifetime brain growth (MLBG) and/or greater lifetime intellectual enrichment protect against cognitive decline over time. Methods: Forty patients with multiple sclerosis (MS) underwent baseline and 4.5-year follow-up evaluations of cognitive efficiency (Symbol Digit Modalities Test, Paced Auditory Serial Addition Task) and memory (Selective Reminding Test, Spatial Recall Test). Baseline and follow-up MRIs quantified disease progression: percentage brain volume change (cerebral atrophy), percentage change in T2 lesion volume. MLBG (brain reserve) was estimated with intracranial volume; intellectual enrichment (cognitive reserve) was estimated with vocabulary. We performed repeated-measures analyses of covariance to investigate whether larger MLBG and/or greater intellectual enrichment moderate/attenuate cognitive decline over time, controlling for disease progression. Results: Patients with MS declined in cognitive efficiency and memory (p < 0.001). MLBG moderated decline in cognitive efficiency (p = 0.031, ηp2 = 0.122), with larger MLBG protecting against decline. MLBG did not moderate memory decline (p = 0.234, ηp2 = 0.039). Intellectual enrichment moderated decline in cognitive efficiency (p = 0.031, ηp2 = 0.126) and memory (p = 0.037, ηp2 = 0.115), with greater intellectual enrichment protecting against decline. MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower vs higher MLBG and intellectual enrichment. Conclusion: We provide longitudinal support for theories of brain reserve and cognitive reserve in MS. Larger MLBG protects against decline in cognitive efficiency, and greater intellectual enrichment protects against decline in cognitive efficiency and memory. Consideration of these protective factors should improve prediction of future cognitive decline in patients with

Growth and metabolic characteristics of oleaginous microalgal isolates from Nilgiri biosphere Reserve of India.

PubMed

Thangavel, Kalaiselvi; Radha Krishnan, Preethi; Nagaiah, Srimeena; Kuppusamy, Senthil; Chinnasamy, Senthil; Rajadorai, Jude Sudhagar; Nellaiappan Olaganathan, Gopal; Dananjeyan, Balachandar

2018-01-03

Renewable energy for sustainable development is a subject of a worldwide debate since continuous utilization of non-renewable energy sources has a drastic impact on the environment and economy; a search for alternative energy resources is indispensable. Microalgae are promising and potential alternate energy resources for biodiesel production. Thus, our efforts were focused on surveying the natural diversity of microalgae for the production of biodiesel. The present study aimed at identification, isolation, and characterization of oleaginous microalgae from shola forests of Nilgiri Biosphere Reserve (NBR), the biodiversity hot spot of India, where the microalgal diversity has not yet been systematically investigated. Overall the higher biomass yield, higher lipid accumulation and thermotolerance observed in the isolated microalgal strains have been found to be the desirable traits for the efficient biodiesel production. Species composition and diversity analysis yielded ten potential microalgal isolates belonging to Chlorophyceae and Cyanophyceae classes. The chlorophytes exhibited higher growth rate, maximum biomass yield, and higher lipid accumulation than Cyanophyceae. Among the chlorophytes, the best performing strains were identified and represented by Acutodesmus dissociatus (TGA1), Chlorella sp. (TGA2), Chlamydomonadales sp. (TGA3) and Hindakia tetrachotoma (PGA1). The Chlamydomonadales sp. recorded with the highest growth rate, lipid accumulation and biomass yield of 0.28 ± 0.03 day -1 (μ exp ), 29.7 ± 0.69% and 134.17 ± 16.87 mg L -1  day -1 , respectively. It was also found to grow well at various temperatures, viz., 25 °C, 35 °C, and 45 °C, indicating its suitability for open pond cultivation. The fatty acid methyl ester (FAME) analysis of stationary phase cultures of selected four algal strains by tandem mass spectrograph showed C16:0, C18:1 and C18:3 as dominant fatty acids suitable for biodiesel production. All the three

R7 Photoreceptor Axon Growth Is Temporally Controlled by the Transcription Factor Ttk69, Which Inhibits Growth in Part by Promoting Transforming Growth Factor-β/Activin Signaling

PubMed Central

Kniss, Jonathan S.; Holbrook, Scott

2013-01-01

Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF-β/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-β/Activin-independent mechanism. PMID:23345225

Can we protect the gut in critical illness? The role of growth factors and other novel approaches.

PubMed

Dominguez, Jessica A; Coopersmith, Craig M

2010-07-01

The intestine plays a central role in the pathophysiology of critical illness and is frequently called the "motor" of the systemic inflammatory response. Perturbations to the intestinal barrier can lead to distant organ damage and multiple organ failure. Therefore, identifying ways to preserve intestinal integrity may be of paramount importance. Growth factors and other peptides have emerged as potential tools for modulation of intestinal inflammation and repair due to their roles in cellular proliferation, differentiation, migration, and survival. This review examines the involvement of growth factors and other peptides in intestinal epithelial repair during critical illness and their potential use as therapeutic targets. Copyright 2010 Elsevier Inc. All rights reserved.

A33 antibody-functionalized exosomes for targeted delivery of doxorubicin against colorectal Cancer.

PubMed

Li, Yan; Gao, Yuan; Gong, Chunai; Wang, Zhuo; Xia, Qingming; Gu, Fenfen; Hu, Chuling; Zhang, Lijuan; Guo, Huiling; Gao, Shen

2018-06-20

Exosomes have emerged as a promising drug carrier with low immunogenicity, high biocompatibility and delivery efficiency. Here in, we isolated exosomes from A33-positive LIM1215 cells (A33-Exo) and loaded them with doxorubicin (Dox). Furthermore, we coated surface-carboxyl superparamagnetic iron oxide nanoparticles (US) with A33 antibodies (A33Ab-US), expecting that these A33 antibodies on the surface of the nanoparticles could bind to A33-positive exosomes and form a complex (A33Ab-US-Exo/Dox) to target A33-positive colon cancer cells. The results showed that A33Ab-US-Exo/Dox had good binding affinity and antiproliferative effect in LIM1215 cells, as shown by increased uptake of the complex. In vivo study showed that A33Ab-US-Exo/Dox had an excellent tumor targeting ability, and was able to inhibit tumor growth and prolong the survival of the mice with reduced cardiotoxicity. In summary, exosomes functionalized by targeting ligands through coating with high-density antibodies may prove to be a novel delivery system for targeted drugs against human cancers. Copyright © 2018 Elsevier Inc. All rights reserved.

Antibacterial application of engineered bacteriophage nanomedicines: antibody-targeted, chloramphenicol prodrug loaded bacteriophages for inhibiting the growth of Staphylococcus aureus bacteria.

PubMed

Vaks, Lilach; Benhar, Itai

2011-01-01

The increasing development of bacterial resistance to traditional antibiotics has reached alarming levels, thus there is an urgent need to develop new antimicrobial agents. To be effective, these new antimicrobials should possess novel modes of action and/or different cellular targets compared with existing antibiotics. Bacteriophages (phages) have been used for over a century as tools for the treatment of bacterial infections, for nearly half a century as tools in genetic research, for about two decades as tools for the discovery of specific target-binding proteins and peptides, and for almost a decade as tools for vaccine development. We describe a new application in the area of antibacterial nanomedicines where filamentous phages can be formulated as targeted drug-delivery vehicles of nanometric dimensions (phage nanomedicines) and used for therapeutic purposes. This protocol involves both genetic and chemical engineering of these phages. The genetic engineering of the phage coat, which results in the display of a target-specificity-conferring peptide or protein on the phage coat, can be used to design the drug-release mechanism and is not described herein. However, the methods used to chemically conjugate cytotoxic drugs at high density on the phage coat are described. Further, assays to measure the drug load on the surface of the phage and the potency of the system in the inhibition of growth of target cells as well as assessment of the therapeutic potential of the phages in a mouse disease model are discussed.

Optimal design of compact and connected nature reserves for multiple species.

PubMed

Wang, Yicheng; Önal, Hayri

2016-04-01

When designing a conservation reserve system for multiple species, spatial attributes of the reserves must be taken into account at species level. The existing optimal reserve design literature considers either one spatial attribute or when multiple attributes are considered the analysis is restricted only to one species. We built a linear integer programing model that incorporates compactness and connectivity of the landscape reserved for multiple species. The model identifies multiple reserves that each serve a subset of target species with a specified coverage probability threshold to ensure the species' long-term survival in the reserve, and each target species is covered (protected) with another probability threshold at the reserve system level. We modeled compactness by minimizing the total distance between selected sites and central sites, and we modeled connectivity of a selected site to its designated central site by selecting at least one of its adjacent sites that has a nearer distance to the central site. We considered structural distance and functional distances that incorporated site quality between sites. We tested the model using randomly generated data on 2 species, one ground species that required structural connectivity and the other an avian species that required functional connectivity. We applied the model to 10 bird species listed as endangered by the state of Illinois (U.S.A.). Spatial coherence and selection cost of the reserves differed substantially depending on the weights assigned to these 2 criteria. The model can be used to design a reserve system for multiple species, especially species whose habitats are far apart in which case multiple disjunct but compact and connected reserves are advantageous. The model can be modified to increase or decrease the distance between reserves to reduce or promote population connectivity. © 2015 Society for Conservation Biology.

Targeting of PHOX2B expression allows the identification of drugs effective in counteracting neuroblastoma cell growth

PubMed Central

Zanni, Eleonora Di; Bianchi, Giovanna; Ravazzolo, Roberto; Raffaghello, Lizzia; Ceccherini, Isabella; Bachetti, Tiziana

2017-01-01

The pathogenic role of the PHOX2B gene in neuroblastoma is indicated by heterozygous mutations in neuroblastoma patients and by gene overexpression in both neuroblastoma cell lines and tumor samples. PHOX2B encodes a transcription factor which is crucial for the correct development and differentiation of sympathetic neurons. PHOX2B overexpression is considered a prognostic marker for neuroblastoma and it is also used by clinicians to monitor minimal residual disease. Furthermore, it has been observed that neuronal differentiation in neuroblastoma is dependent on down-regulation of PHOX2B expression, which confirms that PHOX2B expression may be considered a target in neuroblastoma. Here, PHOX2B promoter or 3′ untranslated region were used as molecular targets in an in vitro high-throughput approach that led to the identification of molecules able to decrease PHOX2B expression at transcriptional and likely even at post-transcriptional levels. Further functional investigations carried out on PHOX2B mRNA levels and biological consequences, such as neuroblastoma cell apoptosis and growth, showed that chloroquine and mycophenolate mofetil are most promising agents for neuroblastoma therapy based on down-regulation of PHOX2B expression. Finally, a strong correlation between the effect of drugs in terms of down-regulation of PHOX2B expression and of biological consequences in neuroblastoma cells confirms the role of PHOX2B as a potential molecular target in neuroblastoma. PMID:29069774

Comparing different methods of human breast milk fortification using measured v. assumed macronutrient composition to target reference growth: a randomised controlled trial.

PubMed

McLeod, Gemma; Sherriff, Jill; Hartmann, Peter E; Nathan, Elizabeth; Geddes, Donna; Simmer, Karen

2016-02-14

The variable content of human breast milk suggests that its routine fortification may result in sub-optimal nutritional intakes and growth. In a pragmatic trial, we randomised infants born below 30 weeks of gestation to either the intervention (Igp) of fortifying milk on measured composition according to birth weight criteria and postmenstrual age (PMA) or our routine practice (RPgp) of fortifying on assumed milk composition to target 3·8-4·4 g protein/kg per d and 545-629 kJ/kg per d. Milk composition was measured using the MIRIS® Human Milk Analyser. Percentage fat mass (%FM) was measured using PEA POD (COSMED). The effects of macronutrient intakes and clinical variables on growth were assessed using mixed model analysis. Mean measured protein content (1·6 g/100 ml) was higher than the assumed value (1·4 g/100 ml), often leading to lower amounts of fortifier added to the milk of intervention infants. At discharge (Igp v. RPgp), total protein (3·2 (SD 0·3) v. 3·4 (SD 0·4) g; P=0·067) and energy (456 (SD 39) v. 481 (SD 48) kJ; P=0·079) intakes from all nutrition sources, weight gain velocity (11·4 (SD 1·4) v. 12·1 (SD 1·6) g/kg per d; P=0·135) and %FM (13·7 (SD 3·6) v.13·6 (SD 3·5) %; P=0·984) did not significantly differ between groups. A protein intake >3·4 g/kg per d reduced %FM by 2%. Nutrition and growth was not improved by targeting milk fortification according to birth weight criteria and PMA using measured milk composition, compared with routine practice. Targeting fortification on measured composition is labour intensive, requiring frequent milk sampling and precision measuring equipment, perhaps reasons for its limited practice. Guidance around safe upper levels of milk fortification is needed.

Wind offering in energy and reserve markets

NASA Astrophysics Data System (ADS)

Soares, T.; Pinson, P.; Morais, H.

2016-09-01

The increasing penetration of wind generation in power systems to fulfil the ambitious European targets will make wind power producers to play an even more important role in the future power system. Wind power producers are being incentivized to participate in reserve markets to increase their revenue, since currently wind turbine/farm technologies allow them to provide ancillary services. Thus, wind power producers are to develop offering strategies for participation in both energy and reserve markets, accounting for market rules, while ensuring optimal revenue. We consider a proportional offering strategy to optimally decide upon participation in both markets by maximizing expected revenue from day-ahead decisions while accounting for estimated regulation costs for failing to provide the services. An evaluation of considering the same proportional splitting of energy and reserve in both day- ahead and balancing market is performed. A set of numerical examples illustrate the behavior of such strategy. An important conclusion is that the optimal split of the available wind power between energy and reserve strongly depends upon prices and penalties on both market trading floors.

Thermal treatment of galactose-branched polyelectrolyte microcapsules to improve drug delivery with reserved targetability.

PubMed

Zhang, Fu; Wu, Qi; Liu, Li-Jun; Chen, Zhi-Chun; Lin, Xian-Fu

2008-06-05

A novel multilayered drug delivery system by LbL assembly of galactosylated polyelectrolyte, which is possible to have the potential in hepatic targeting by the presence of galactose residues at the microcapsule's surface, is designed. Thermal treatment was performed on the capsules and a dramatic thermal shrinkage up to 60% decrease of capsule diameter above 50 degrees C was observed. This thermal behavior was then used to manipulate drug loading capacity and release rate. Heating after drug loading could seal the capsule shell, enhancing the loading capacity and reducing the release rate significantly. Excellent affinity between galactose-binding lectin and heated galactose-containing microcapsules were observed, indicating a stable targeting potential even after high temperature elevating up to 90 degrees C.

Systematic transcriptome-wide analysis of mRNA-miRNA interactions reveals the involvement of miR-142-5p and its target (FOXO3) in skeletal muscle growth in chickens.

PubMed

Li, Zhenhui; Abdalla, Bahareldin Ali; Zheng, Ming; He, Xiaomei; Cai, Bolin; Han, Peigong; Ouyang, Hongjia; Chen, Biao; Nie, Qinghua; Zhang, Xiquan

2018-02-01

The goal of this study was to perform a systematic transcriptome-wide analysis of mRNA-miRNA interactions and to identify candidates involved in the interplay between miRNAs and mRNAs that regulate chicken muscle growth. We used our previously published mRNA (GSE72424) and miRNA (GSE62971) deep sequencing data from two-tailed samples [i.e., the highest (h) and lowest (l) body weights] of Recessive White Rock (WRR) and Xinghua (XH) chickens to conduct integrative analyses of the miRNA-mRNA interactions involved in chicken skeletal muscle growth. A total of 162, 15, 173, and 27 miRNA-mRNA pairs with negatively correlated expression patterns were identified in miRNA-mRNA networks constructed on the basis of the WRR h vs. XH h , WRR h vs. WRR l , WRR l vs. XH l , and XH h vs. XH l comparisons, respectively. Ingenuity Pathway Analysis revealed that gene networks identified for the WRR h vs. XH h contrast were associated with developmental disorders. Importantly, the WRR h vs. XH h contrast miRNA-mRNA network was enriched in IGF-1 signaling pathway genes, including FOXO3. A dual-luciferase reporter assay showed that FOXO3 was a target of miR-142-5p. Furthermore, miR-142-5p overexpression significantly decreased FOXO3 mRNA levels and promoted the expression of growth-related genes. These data demonstrated that miR-142-5p targets FOXO3 and promotes growth-related gene expression and regulates skeletal muscle growth in chicken. Comprehensive analysis facilitated the identification of miRNAs and target genes that might contribute to the regulation of skeletal muscle development. Our results provide new clues for understanding the molecular basis of chicken growth.

Targeting the androgen receptor in triple-negative breast cancer.

PubMed

Gucalp, Ayca; Traina, Tiffany A

Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast cancer-related deaths each year. Owing to the lack of estrogen, progesterone, and human epidermal growth factor receptor 2 expression, patients with triple-negative breast cancer do not benefit from generally well-tolerated and effective therapies targeting the estrogen and human epidermal growth factor receptor 2 signaling pathways and are faced with an increased risk of disease progression and poorer overall survival. The heterogeneity of triple-negative breast cancer has been increasingly recognized and this may lead to therapeutic opportunities because of newly defined oncogenic drivers and targets. A subset of triple-negative breast tumors expresses the androgen receptor (AR) and this may benefit from treatments that inhibit the AR-signaling pathway. The first proof-of-concept trial established activity of the AR antagonist, bicalutamide, in patients with advanced AR+ triple-negative breast cancer. Since that time, evidence further supports the activity of other next-generation AR-targeted agents such as enzalutamide. Not unlike in estrogen receptor-positive breast cancer, mechanisms of resistance are being investigated and rationale exists for thoughtful, well-designed combination regimens such as AR antagonism with CDK4/6 pathway inhibitors or PI3K inhibitors. Furthermore, novel agents developed for the treatment of prostate cancer, which reduce androgen production such as abiraterone acetate and seviteronel, are being tested as well. This review summarizes the underlying biology of AR signaling in breast cancer development and the available clinical trial data for the use of anti-androgen therapy in the treatment of AR+ triple-negative breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.

PubMed

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-07-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

Development, implementation, and impact of a collaborative junior faculty engagement and professional growth program: The Young Faculty Leadership Initiative.

PubMed

Pate, Adam; Smith, Jennifer; Caldwell, David; Horace, Alexis; Zagar, Michelle

2018-03-01

To develop, implement, and evaluate the effect of a faculty engagement and professional growth program targeted at junior faculty members. A faculty engagement and growth program based on adult learning theory was piloted in a clinical sciences department. Effect of the model was evaluated using a pre/post-survey evaluating faculty output and work engagement using the Utrecht Work Engagement Scale (UWES). Average number of publications/projects with cross-campus collaboration increased (0.58 versus 1.25, P = 0.03, 95%CI 0.059-1.264). Involvement in national/state organizations, number of accepted poster presentations, and grants submitted and/or funded all increased (p>0.05). Total UWES score increased (4.13 vs. 4.495 p = 0.21) with the greatest subscale increase in vigor (3.833 vs 4.347, P = 0.1). A faculty engagement and growth program targeting junior faculty members using adult learning theory as a framework may provide a novel and economic way for schools to support the development of these critical team members. Copyright © 2017 Elsevier Inc. All rights reserved.

Growth factor restriction impedes progression of wound healing following cataract surgery: identification of VEGF as a putative therapeutic target

PubMed Central

Eldred, Julie A.; McDonald, Matthew; Wilkes, Helen S.; Spalton, David J.; Wormstone, I. Michael

2016-01-01

Secondary visual loss occurs in millions of patients due to a wound-healing response, known as posterior capsule opacification (PCO), following cataract surgery. An intraocular lens (IOL) is implanted into residual lens tissue, known as the capsular bag, following cataract removal. Standard IOLs allow the anterior and posterior capsules to become physically connected. This places pressure on the IOL and improves contact with the underlying posterior capsule. New open bag IOL designs separate the anterior capsule and posterior capsules and further reduce PCO incidence. It is hypothesised that this results from reduced cytokine availability due to greater irrigation of the bag. We therefore explored the role of growth factor restriction on PCO using human lens cell and tissue culture models. We demonstrate that cytokine dilution, by increasing medium volume, significantly reduced cell coverage in both closed and open capsular bag models. This coincided with reduced cell density and myofibroblast formation. A screen of 27 cytokines identified nine candidates whose expression profile correlated with growth. In particular, VEGF was found to regulate cell survival, growth and myofibroblast formation. VEGF provides a therapeutic target to further manage PCO development and will yield best results when used in conjunction with open bag IOL designs. PMID:27076230

Prognostic Value of Coronary Flow Reserve Obtained on Dobutamine Stress Echocardiography and its Correlation with Target Heart Rate.

PubMed

Abreu, José Sebastião de; Rocha, Eduardo Arrais; Machado, Isadora Sucupira; Parahyba, Isabelle O; Rocha, Thais Brito; Paes, Fernando José Villar Nogueira; Diogenes, Tereza Cristina Pinheiro; Abreu, Marília Esther Benevides de; Farias, Ana Gardenia Liberato Ponte; Carneiro, Marcia Maria; Paes, José Nogueira

2017-05-01

Normal coronary flow velocity reserve (CFVR) (≥ 2) obtained in the left anterior descending coronary artery (LAD) from transthoracic echocardiography is associated with a good prognosis, but there is no study correlating CFVR with submaximal target heart rate (HR). To evaluate the prognostic value of CFVR obtained in the LAD of patients with preserved (>50%) left ventricular ejection fraction (LVEF) who completed a dobutamine stress echocardiography (DSE), considering target HR. Prospective study of patients with preserved LVEF and CFVR obtained in the LAD who completed DSE. In Group I (GI = 31), normal CFVR was obtained before achieving target HR, and, in Group II (GII = 28), after that. Group III (G III=24) reached target HR, but CFVR was abnormal. Death, acute coronary insufficiency, coronary intervention, coronary angiography without further intervention, and hospitalization were considered events. In 28 ± 4 months, there were 18 (21.6%) events: 6% (2/31) in GI, 18% (5/28) in GII, and 46% (11/24) in GIII. There were 4 (4.8%) deaths, 6 (7.2%) coronary interventions and 8 (9.6%) coronary angiographies without further intervention. In event-free survival by regression analysis, GIII had more events than GI (p < 0.001) and GII (p < 0.045), with no difference between GI and GII (p = 0.160). After adjustment, the only difference was between GIII and GI (p = 0.012). In patients with preserved LVEF and who completed their DSE, normal CFVR obtained before achieving target HR was associated with better prognosis. A reserva de velocidade de fluxo coronariano (RVFC) adequada (≥ 2) obtida na artéria descendente anterior (ADA) através do ecocardiograma transtorácico associa-se a bom prognóstico, mas não há estudo correlacionando-a com a frequência cardíaca (FC) alvo (submáxima). Avaliar o valor prognóstico da RVFC obtida na ADA de pacientes com fração de ejeção do ventrículo esquerdo (FEVE) preservada (>50%) e ecocardiograma sob estresse com dobutamina

Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs.

PubMed

Ortiz, Diana; Forquer, Isaac; Boitz, Jan; Soysa, Radika; Elya, Carolyn; Fulwiler, Audrey; Nilsen, Aaron; Polley, Tamsen; Riscoe, Michael K; Ullman, Buddy; Landfear, Scott M

2016-08-01

Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc1 from Plasmodium falciparum and Toxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain of Leishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes of Leishmania mexicana and L. donovani, with 50% inhibitory concentrations (IC50s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochrome bc1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Bone marrow adipocytes: a neglected target tissue for growth hormone.

PubMed

Gevers, Evelien F; Loveridge, Nigel; Robinson, Iain C A F

2002-10-01

Bone marrow (BM) contains numerous adipocytes. These share a common precursor with osteoblasts and chondrocytes, but their function is unknown. It is unclear what regulates the differentiation of these three different cell types, though their subsequent metabolic activity is under hormonal regulation. GH and estrogen stimulate bone growth and mineralization, by direct effects on chondrocytes and osteoblasts. GH also stimulates lipolysis in subcutaneous and visceral adipocytes. However, adipocytes in BM have largely been ignored as potential targets for GH or estrogen action. We have addressed this by measuring BM adipocyte number, perimeter and area as well as bone area and osteoblast activity in GH-deficient dwarf (dw/dw), normal, or ovariectomized (Ovx) rats, with or without GH, IGF-1, PTH, or estrogen treatment or high fat feeding. Marrow adipocyte numbers were increased 5-fold (P < 0.001) in dw/dw rats, and cell size was also increased by 20%. These values returned toward normal in dw/dw rats given GH but not when given IGF-1. Cancellous bone area and osteoblast number were significantly (P < 0.005) lower in dw/dw rats, though alkaline phosphatase (ALP) activity in individual osteoblasts was unchanged. GH treatment increased % osteoblast covered bone surface without affecting individual cell ALP activity. Ovariectomy in normal or dw/dw rats had no affect on marrow adipocyte number nor size, although estrogen treatment in ovariectomized (Ovx) normal rats did increase adipocyte number. Ovx decreased tibial cancellous bone area in normal rats (64%; P < 0.05) and decreased osteoblast ALP-activity (P < 0.01) but did not affect the percentage of osteoblast-covered bone surface. Estrogen replacement reversed these changes. While treatment with PTH by continuous sc infusion decreased cancellous bone (P < 0.05) and high fat feeding increased the size of BM adipocytes (P < 0.01), they did not affect BM adipocyte number. These results suggest that GH has a specific action

MicroRNA-361-5p Inhibits Cancer Cell Growth by Targeting CXCR6 in Hepatocellular Carcinoma.

PubMed

Sun, Jian-Jun; Chen, Guo-Yong; Xie, Zhan-Tao

2016-01-01

A growing body of evidence supports the notion that MicroRNAs (miRNAs) function as key regulators of tumorigenesis. In the present study, the expression and roles of miRNA-361-5p were explored in hepatocellular carcinoma (HCC). Quantitative real-time PCR was used to detect the expression miR-361-5p in HCC tissues and pair-matched adjacent normal tissues. MTT and BrdU assays were used to identify the role of miR-361-5p in the regulation of proliferation and invasion of HCC cells. Using bioinformatics analysis, luciferase reporter assays and Western blots were used to identify the molecular target of miR-361-5p. nude mice were used to detect the anti-tumor role of miR-361-5p in vivo. miR-361-5p was down-regulated in HCC tissues in comparison to adjacent normal tissues, due to hypermethylation at its promoter region. Overexpression of miR-361-5p suppressed proliferation and invasion of HCC cells. Chemokine (C-X-C Motif) receptor 6 (CXCR6) was identified as a target of miR-361-5p. Indeed, knockdown of CXCR6 photocopied, while overexpression of CXCR6 largely attenuated the anti-proliferative effect of miR-361-5p. More importantly, in vivo studies demonstrated that forced expression of miR-361-5p significantly inhibited tumor growth in the nude mice. Our results indicate that miR-361-5p acts as a tumor suppressor and might serve as a novel therapeutic target for the treatment of HCC patients. © 2016 The Author(s) Published by S. Karger AG, Basel.

Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity.

PubMed

Zhang, Jianglin; Lei, Zhou; Huang, Zunnan; Zhang, Xu; Zhou, Youyou; Luo, Zhongling; Zeng, Weiqi; Su, Juan; Peng, Cong; Chen, Xiang

2016-11-29

TRAF6 (TNF Receptor-Associated Factor 6) is an E3 ubiquitin ligase that contains a Ring domain, induces K63-linked polyubiquitination, and plays a critical role in signaling transduction. Our previous results demonstrated that TRAF6 is overexpressed in melanoma and that TRAF6 knockdown dramatically attenuates tumor cell growth and metastasis. In this study, we found that EGCG can directly bind to TRAF6, and a computational model of the interaction between EGCG and TRAF6 revealed that EGCG probably interacts with TRAF6 at the residues of Gln54, Gly55, Asp57 ILe72, Cys73 and Lys96. Among these amino acids, mutation of Gln54, Asp57, ILe72 in TRAF6 could destroy EGCG bound to TRAF6, furthermore, our results demonstrated that EGCG significantly attenuates interaction between TRAF6 and UBC13(E2) and suppresses TRAF6 E3 ubiquitin ligase activity in vivo and in vitro. Additionally, the phosphorylation of IκBα, p-TAK1 expression are decreased and the nuclear translocation of p65 and p50 is blocked by treatment with EGCG, leading to inactivation of the NF-κB pathway. Moreover, EGCG significantly inhibits cell growth as well as the migration and invasion of melanoma cells. Taken together, these findings show that EGCG is a novel E3 ubiquitin ligase inhibitor that could be used to target TRAF6 for chemotherapy or the prevention of melanoma.

Targeting Btk with ibrutinib inhibit gastric carcinoma cells growth.

PubMed

Wang, Jin Dao; Chen, Xiao Ying; Ji, Ke Wei; Tao, Feng

2016-01-01

Bruton's tyrosine kinase (Btk) is a member of the Tec-family non-receptor tyrosine kinases family. It has previously been reported to be expressed in B cells and has an important role in B-cell malignancies. While the roles of Btk in the pathogenesis of certain B-cell malignancies are well established, the functions of Btk in gastric carcinoma have never been investigated. Herein, we found that Btk is over-expressed in gastric carcinoma tissues and gastric cancer cells. Knockdown of Btk expression selectively inhibits the growth of gastric cancer cells, but not that of the normal gastric mucosa epithelial cell, which express very little Btk. Inhibition of Btk by its inhibitor ibrutinib has an additive inhibitory effect on gastric cancer cell growth. Treatment of gastric cancer cells, but not immortalized breast epithelial cells with ibrutinib results in effective cell killing, accompanied by the attenuation of Btk signals. Ibrutinib also induces apoptosis in gastric carcinoma cells as well as is a chemo-sensitizer for docetaxel (DTX), a standard of care for gastric carcinoma patients. Finally, ibrutinib markedly reduces tumor growth and increases tumor cell apoptosis in the tumors formed in mice inoculated with the gastric carcinoma cells. Given these promising preclinical results for ibrutinib in gastric carcinoma, a strategy combining Btk inhibitor warrants attention in gastric cancer.

Targeting Btk with ibrutinib inhibit gastric carcinoma cells growth

PubMed Central

Wang, Jin Dao; Chen, Xiao Ying; Ji, Ke Wei; Tao, Feng

2016-01-01

Bruton’s tyrosine kinase (Btk) is a member of the Tec-family non-receptor tyrosine kinases family. It has previously been reported to be expressed in B cells and has an important role in B-cell malignancies. While the roles of Btk in the pathogenesis of certain B-cell malignancies are well established, the functions of Btk in gastric carcinoma have never been investigated. Herein, we found that Btk is over-expressed in gastric carcinoma tissues and gastric cancer cells. Knockdown of Btk expression selectively inhibits the growth of gastric cancer cells, but not that of the normal gastric mucosa epithelial cell, which express very little Btk. Inhibition of Btk by its inhibitor ibrutinib has an additive inhibitory effect on gastric cancer cell growth. Treatment of gastric cancer cells, but not immortalized breast epithelial cells with ibrutinib results in effective cell killing, accompanied by the attenuation of Btk signals. Ibrutinib also induces apoptosis in gastric carcinoma cells as well as is a chemo-sensitizer for docetaxel (DTX), a standard of care for gastric carcinoma patients. Finally, ibrutinib markedly reduces tumor growth and increases tumor cell apoptosis in the tumors formed in mice inoculated with the gastric carcinoma cells. Given these promising preclinical results for ibrutinib in gastric carcinoma, a strategy combining Btk inhibitor warrants attention in gastric cancer. PMID:27508020

Target of rapamycin signaling regulates metabolism, growth, and lifespan in Arabidopsis

USDA-ARS?s Scientific Manuscript database

TOR is a major nutrition and energy sensor that regulates growth and lifespan in yeast and animals. In plants growth and lifespan are intertwined with not only nutrient acquisition but also nutrition generation and unique aspects of development and differentiation. How TOR functions in these process...

Matching marine reserve design to reserve objectives.

PubMed Central

Halpern, Benjamin S; Warner, Robert R

2003-01-01

Recent interest in using marine reserves for marine resource management and conservation has largely been driven by the hope that reserves might counteract declines in fish populations and protect the biodiversity of the seas. However, the creation of reserves has led to dissension from some interested groups, such as fishermen, who fear that reserves will do more harm than good. These perceived differences in the effect of marine reserves on various stakeholder interests has led to a contentious debate over their merit. We argue here that recent findings in marine ecology suggest that this debate is largely unnecessary, and that a single general design of a network of reserves of moderate size and variable spacing can meet the needs and goals of most stakeholders interested in marine resources. Given the high fecundity of most marine organisms and recent evidence for limited distance of larval dispersal, it is likely that reserves can both maintain their own biodiversity and service nearby non-reserve areas. In particular, spillover of larger organisms and dispersal of larvae to areas outside reserves can lead to reserves sustaining or even increasing local fisheries. Ultimately, the success of any reserve network requires attention to the uncertainty and variability in dispersal patterns of marine organisms, clear statements of goals by all stakeholder groups and proper evaluation of reserve performance. PMID:14561299

The targets of curcumin.

PubMed

Zhou, Hongyu; Beevers, Christopher S; Huang, Shile

2011-03-01

Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here.

The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis.

PubMed

Huang, Shifang; Chen, Linxi; Lu, Liqun; Li, Lanfang

2016-05-01

Apelin, an endogenous ligand of the G-protein-coupled receptor APJ, is expressed in a diverse number of organs. The apelin-APJ axis helps to control the processes of pathological and physiological fibrosis, including renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. However, the role of apelin-APJ in organ fibrosis remains controversial due to conflicting study results. The apelin-APJ axis is a detrimental mechanism which promotes liver fibrosis mainly via up-regulation the expression of collagen-II and platelet-derived growth factor receptor β (PDGFRβ). On the contrary, the apelin-APJ axis is beneficial for renal fibrosis, cardiac fibrosis and pulmonary fibrosis. The apelin-APJ axis alleviates renal fibrosis by restraining the expression of transforming growth factor-β1 (TGF-β1). In addition, the apelin-APJ axis attenuates cardiac fibrosis through multiple pathways. Furthermore, the apelin-APJ axis has beneficial effects on experimental bronchopulmonary dysplasia (BPD) and acute respiratory distress syndrome (ARDS) which suggest the apelin-APJ axis potentially alleviates pulmonary fibrosis. In this article, we review the controversies associated with apelin-APJ in organ fibrosis and introduce the drugs that target apelin-APJ. We conclude that future studies should place more emphasis on the relationship among apelin isoforms, APJ receptor subtypes and organ fibrosis. The apelin-APJ axis will be a potential therapeutic target and those drugs targeted for apelin-APJ may constitute a novel therapeutic strategy for renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Experimental study on ablative stabilization of Rayleigh-Taylor instability of laser-irradiated targets

NASA Astrophysics Data System (ADS)

Shigemori, Keisuke; Sakaiya, Tatsuhiko; Otani, Kazuto; Fujioka, Shinsuke; Nakai, Mitsuo; Azechi, Hiroshi; Shiraga, Hiroyuki; Tamari, Yohei; Okuno, Kazuki; Sunahara, Atsushi; Nagatomo, Hideo; Murakami, Masakatsu; Nishihara, Katsunobu; Izawa, Yasukazu

2004-09-01

Hydrodynamic instabilities are key issues of the physics of inertial confinement fusion (ICF) targets. Among the instabilities, Rayleigh-Taylor (RT) instability is the most important because it gives the largest growth factor in the ICF targets. Perturbations on the laser irradiated surface grow exponentially, but the growth rate is reduced by ablation flow. The growth rate γ is written as Takabe-Betti formula: γ = [kg/(1+kL)]1/2-βkm/pa, where k is wave number of the perturbation, g is acceleration, L is density scale-length, β is a coefficient, m is mass ablation rate per unit surface, and ρa is density at the ablation front. We experimentally measured all the parameters in the formula for polystyrene (CH) targets. Experiments were done on the HIPER laser facility at Institute of Laser Engineering, Osaka University. We found that the β value in the formula is ~ 1.7, which is in good agreements with the theoretical prediction, whereas the β for certain perturbation wavelengths are larger than the prediction. This disagreement between the experiment and the theory is mainly due to the deformation of the cutoff surface, which is created by non-uniform ablation flow from the ablation surface. We also found that high-Z doped plastic targets have multiablation structure, which can reduce the RT growth rate. When a low-Z target with high-Z dopant is irradiated by laser, radiation due to the high-Z dopant creates secondary ablation front deep inside the target. Since, the secondary ablation front is ablated by x-rays, the mass ablation rate is larger than the laser-irradiated ablation surface, that is, further reduction of the RT growth is expected. We measured the RT growth rate of Br-doped polystyrene targets. The experimental results indicate that of the CHBr targets show significantly small growth rate, which is very good news for the design of the ICF targets.

Reactive Power Compensation Method Considering Minimum Effective Reactive Power Reserve

NASA Astrophysics Data System (ADS)

Gong, Yiyu; Zhang, Kai; Pu, Zhang; Li, Xuenan; Zuo, Xianghong; Zhen, Jiao; Sudan, Teng

2017-05-01

According to the calculation model of minimum generator reactive power reserve of power system voltage stability under the premise of the guarantee, the reactive power management system with reactive power compensation combined generator, the formation of a multi-objective optimization problem, propose a reactive power reserve is considered the minimum generator reactive power compensation optimization method. This method through the improvement of the objective function and constraint conditions, when the system load growth, relying solely on reactive power generation system can not meet the requirement of safe operation, increase the reactive power reserve to solve the problem of minimum generator reactive power compensation in the case of load node.

Simultaneous Drug Targeting of the Promoter MYC G-Quadruplex and BCL2 i-Motif in Diffuse Large B-Cell Lymphoma Delays Tumor Growth.

PubMed

Kendrick, Samantha; Muranyi, Andrea; Gokhale, Vijay; Hurley, Laurence H; Rimsza, Lisa M

2017-08-10

Secondary DNA structures are uniquely poised as therapeutic targets due to their molecular switch function in turning gene expression on or off and scaffold-like properties for protein and small molecule interaction. Strategies to alter gene transcription through these structures thus far involve targeting single DNA conformations. Here we investigate the feasibility of simultaneously targeting different secondary DNA structures to modulate two key oncogenes, cellular-myelocytomatosis (MYC) and B-cell lymphoma gene-2 (BCL2), in diffuse large B-cell lymphoma (DLBCL). Cotreatment with previously identified ellipticine and pregnanol derivatives that recognize the MYC G-quadruplex and BCL2 i-motif promoter DNA structures lowered mRNA levels and subsequently enhanced sensitivity to a standard chemotherapy drug, cyclophosphamide, in DLBCL cell lines. In vivo repression of MYC and BCL2 in combination with cyclophosphamide also significantly slowed tumor growth in DLBCL xenograft mice. Our findings demonstrate concurrent targeting of different DNA secondary structures offers an effective, precise, medicine-based approach to directly impede transcription and overcome aberrant pathways in aggressive malignancies.

Role of plant growth regulators as chemical signals in plant-microbe interactions: a double edged sword.

PubMed

Spence, Carla; Bais, Harsh

2015-10-01

Growth regulators act not only as chemicals that modulate plant growth but they also act as signal molecules under various biotic and abiotic stresses. Of all growth regulators, abscisic acid (ABA) is long known for its role in modulating plants response against both biotic and abiotic stress. Although the genetic information for ABA biosynthesis in plants is well documented, the knowledge about ABA biosynthesis in other organisms is still in its infancy. It is known that various microbes including bacteria produce and secrete ABA, but the overall functional significance of why ABA is synthesized by microbes is not known. Here we discuss the functional involvement of ABA biosynthesis by a pathogenic fungus. Furthermore, we propose that ABA biosynthesis in plant pathogenic fungi could be targeted for novel fungicidal discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Targeted Therapies for Brain Metastases from Breast Cancer.

PubMed

Venur, Vyshak Alva; Leone, José Pablo

2016-09-13

The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%-30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways.

Anti-PDGF receptor β antibody-conjugated squarticles loaded with minoxidil for alopecia treatment by targeting hair follicles and dermal papilla cells.

PubMed

Aljuffali, Ibrahim A; Pan, Tai-Long; Sung, Calvin T; Chang, Shu-Hao; Fang, Jia-You

2015-08-01

This study developed lipid nanocarriers, called squarticles, conjugated with anti-platelet-derived growth factor (PDGF)-receptor β antibody to determine whether targeted Minoxidil (MXD) delivery to the follicles and dermal papilla cells (DPCs) could be achieved. Squalene and hexadecyl palmitate (HP) were used as the matrix of the squarticles. The PDGF-squarticles showed a mean diameter and zeta potential of 195 nm and -46 mV, respectively. Nanoparticle encapsulation enhanced MXD porcine skin deposition from 0.11 to 0.23 μg/mg. The antibody-conjugated nanoparticles ameliorated follicular uptake of MXD by 3-fold compared to that of the control solution in the in vivo mouse model. Both vertical and horizontal skin sections exhibited a wide distribution of nanoparticles in the follicles, epidermis, and deeper skin strata. The encapsulated MXD moderately elicited proliferation of DPCs and vascular endothelial growth factor (VEGF) expression. The active targeting of PDGF-squarticles may be advantageous to improving the limited success of alopecia therapy. Topical use of minoxidil is only one of the very few treatment options for alopecia. Nonetheless, the current delivery method is far from ideal. In this article, the authors developed lipid nanocarriers with anti-platelet-derived growth factor receptor ? antibody to target dermal papilla cells, and showed enhanced uptake of minoxidil. Copyright © 2015 Elsevier Inc. All rights reserved.

Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach

PubMed Central

Chen, Lian; Cui, Hengmin

2015-01-01

Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase. There are currently several drugs that target glutaminase under development or clinical trials. Also, glutamine metabolism restriction has been proved to be effective in inhibiting tumor growth both in vivo and vitro through inducing apoptosis, growth arrest and/or autophagy. Here, we review recent researches about glutamine metabolism in cancer, and cell death induced by targeting glutamine, and their potential roles in cancer therapy. PMID:26402672

Regulation of cellular growth by the Drosophila target of rapamycin dTOR

PubMed Central

Zhang, Hongbing; Stallock, James P.; Ng, Joyce C.; Reinhard, Christoph; Neufeld, Thomas P.

2000-01-01

The TOR protein kinases (TOR1 and TOR2 in yeast; mTOR/FRAP/RAFT1 in mammals) promote cellular proliferation in response to nutrients and growth factors, but their role in development is poorly understood. Here, we show that the Drosophila TOR homolog dTOR is required cell autonomously for normal growth and proliferation during larval development, and for increases in cellular growth caused by activation of the phosphoinositide 3-kinase (PI3K) signaling pathway. As in mammalian cells, the kinase activity of dTOR is required for growth factor-dependent phosphorylation of p70 S6 kinase (p70S6K) in vitro, and we demonstrate that overexpression of p70S6K in vivo can rescue dTOR mutant animals to viability. Loss of dTOR also results in cellular phenotypes characteristic of amino acid deprivation, including reduced nucleolar size, lipid vesicle aggregation in the larval fat body, and a cell type-specific pattern of cell cycle arrest that can be bypassed by overexpression of the S-phase regulator cyclin E. Our results suggest that dTOR regulates growth during animal development by coupling growth factor signaling to nutrient availability. PMID:11069888

Molecular targeted therapies for solid tumors: management of side effects.

PubMed

Grünwald, Viktor; Soltau, Jens; Ivanyi, Philipp; Rentschler, Jochen; Reuter, Christoph; Drevs, Joachim

2009-03-01

This review will provide physicians and oncologists with an overview of side effects related to targeted agents that inhibit vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and mammalian target of rapamycin (mTOR) signaling in the treatment of solid tumors. Such targeted agents can be divided into monoclonal antibodies, tyrosine kinase inhibitors, multitargeted tyrosine kinase inhibitors and serine/threonine kinase inhibitors. Molecular targeted therapies are generally well tolerated, but inhibitory effects on the biological function of the targets in healthy tissue can result in specific treatment-related side effects, particularly with multitargeted agents. We offer some guidance on how to manage adverse events in cancer patients based on the range of options currently available. Copyright 2009 S. Karger AG, Basel.

Modeling nonstructural carbohydrate reserve dynamics in forest trees

NASA Astrophysics Data System (ADS)

Richardson, A. D.; Keenan, T. F.; Carbone, M. S.; Czimczik, C. I.; Hollinger, D. Y.; Murakami, P.; Schaberg, P.; Xu, X.

2012-12-01

-year lag between carbon uptake and growth can be explained; (4) reconciles the apparent contradiction of a reserve pool that is both highly dynamic over time, and also a decade old on average; and (5) shows how younger reserves can be preferentially used to support growth and metabolism, but allows for the older reserves to be drawn on if the younger reserves are depleted. The improved performance and greater realism of our model is achieved without requiring a substantial increase in model complexity. From the perspective of modeling forest responses to climate change, we expect that models incorporating dynamic stored reserves should be better able to represent the lagged effects of climate extremes and disturbance on ecosystem C fluxes.

Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting.

PubMed

Wang, Hao; Mann, Paul A; Xiao, Li; Gill, Charles; Galgoci, Andrew M; Howe, John A; Villafania, Artjohn; Barbieri, Christopher M; Malinverni, Juliana C; Sher, Xinwei; Mayhood, Todd; McCurry, Megan D; Murgolo, Nicholas; Flattery, Amy; Mack, Matthias; Roemer, Terry

2017-05-18

Riboswitches are bacterial-specific, broadly conserved, non-coding RNA structural elements that control gene expression of numerous metabolic pathways and transport functions essential for cell growth. As such, riboswitch inhibitors represent a new class of potential antibacterial agents. Recently, we identified ribocil-C, a highly selective inhibitor of the flavin mononucleotide (FMN) riboswitch that controls expression of de novo riboflavin (RF, vitamin B2) biosynthesis in Escherichia coli. Here, we provide a mechanistic characterization of the antibacterial effects of ribocil-C as well as of roseoflavin (RoF), an antimetabolite analog of RF, among medically significant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis. We provide genetic, biophysical, computational, biochemical, and pharmacological evidence that ribocil-C and RoF specifically inhibit dual FMN riboswitches, separately controlling RF biosynthesis and uptake processes essential for MRSA growth and pathogenesis. Such a dual-targeting mechanism is specifically required to develop broad-spectrum Gram-positive antibacterial agents targeting RF metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR.

PubMed

Xu, Bin; Tao, Tao; Wang, Yiduo; Fang, Fang; Huang, Yeqing; Chen, Shuqiu; Zhu, Weidong; Chen, Ming

2016-10-01

Prostate cancer is one of the leading causes of death in men worldwide. Differentially expressed microRNAs (miRNAs) are associated with metastatic prostate cancer. However, their potential roles for affecting prostate cancer initiation and progression remain largely unknown. Here, we examined the aberrant expression profiles of miRNAs in human metastatic prostate cancer tissues. We further validated our miRNA expression data using two large, independent clinical prostate cancer datasets from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA). Our data support a model in which hsa-miR-135-1 acts as a potential tumor suppressor in metastatic prostate cancer. First, its downregulation was positively correlated with late TNM stage, high Gleason score, and adverse prognosis. Second, cell growth, cell cycle progression, cell migration and invasion, and xenograft tumor formation were dramatically inhibited by miR-135a overexpression. Third, in the microarray gene expression data analysis using Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, Ingenuity Pathway Analysis (IPA), and Oncomine concept analysis, we showed that miR-135a targets multiple oncogenic pathways including epidermal growth factor receptor (EGFR), which we verified using functional experimental assays. These results help advance our understanding of the function of miRNAs in metastatic prostate cancer and provide a basis for further clinical investigation.

Metformin targets multiple signaling pathways in cancer.

PubMed

Lei, Yong; Yi, Yanhua; Liu, Yang; Liu, Xia; Keller, Evan T; Qian, Chao-Nan; Zhang, Jian; Lu, Yi

2017-01-26

Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.

Nutritional catch-up growth.

PubMed

Gat-Yablonski, Galia; Pando, Rakefet; Phillip, Moshe

2013-01-01

Malnutrition, marked by variant nutrient deficiencies, is considered a leading cause of stunted growth worldwide. In developing countries, malnutrition is caused mainly by food shortage and infectious diseases. Malnutrition may also be found in the developed world, where it is due mostly to prematurity, chronic diseases, and anorexia nervosa. In most cases, when food consumption is corrected, spontaneous catch-up (CU) growth occurs. However, CU growth is not always complete, leading to growth deficits. Therefore, it is important to understand the mechanisms that govern this process. Using a rat model of food restriction followed by refeeding, we established a nutrition-induced CU growth model. Levels of leptin and insulin-like growth factor-1 were found to significantly decrease when food was restricted and to increase already 1 day after refeeding. Gene expression analysis of the growth plate revealed that food restriction specifically affects transcription factors such as the hypoxia inducible factor-1 and its downstream targets on the one hand, and global gene expression, indicating epigenetic regulation, on the other. Food restriction also reduced the level of several microRNAs, including the chondrocyte-specific miR-140, which led to an increase in its target, SIRT1, a class III histone deacetylase. These findings may explain the global changes in gene expression observed under nutritional manipulation. We suggest that multiple levels of regulation, including transcription factors, epigenetic mechanisms, and microRNAs respond to nutritional cues and offer a possible explanation for some of the effects of food restriction on epiphyseal growth plate growth. The means whereby these components sense changes in nutritional status are still unknown. Deciphering the role of epigenetic regulation in growth may pave the way for the development of new treatments for children with growth disorders. Copyright © 2013 S. Karger AG, Basel.

Cancer-linked targets modulated by curcumin

PubMed Central

Hasima, Noor; Aggarwal, Bharat B

2012-01-01

In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting. PMID:23301199

Glucose metabolism-targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor-induced drug-tolerant persisters.

PubMed

Kunimasa, Kei; Nagano, Tatsuya; Shimono, Yohei; Dokuni, Ryota; Kiriu, Tatsunori; Tokunaga, Shuntaro; Tamura, Daisuke; Yamamoto, Masatsugu; Tachihara, Motoko; Kobayashi, Kazuyuki; Satouchi, Miyako; Nishimura, Yoshihiro

2017-07-01

In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor-tyrosine kinase inhibitor-induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR-mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell-related markers by quantitative RT-PCR and the expression of the cellular senescence-associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem-like cell targeting drug, withaferin A. Drug-tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem-like cells (CSCs) and the other with the properties of therapy-induced senescent (TIS) cells. The CD133 high cell population had CSC properties and the CD133 low cell population had TIS properties. The CD133 low cell population containing TIS cells showed a senescence-associated secretory phenotype that supported the emergence of the CD133 high cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133 low cell population. Withaferin A effectively eliminated the CD133 high cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib-resistant tumor growth. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Effects of level of nutrient intake and age on mammalian target of rapamycin, insulin, and insulin-like growth factor-1 gene network expression in skeletal muscle of young Holstein calves.

PubMed

Wang, P; Drackley, J K; Stamey-Lanier, J A; Keisler, D; Loor, J J

2014-01-01

The molecular mechanisms by which level of nutrient intake enhances skeletal muscle growth in young ruminants are not fully understood. We examined mammalian target of rapamycin (mTOR), insulin, and insulin-like growth factor-1 (IGF-1) gene network expression in semitendinosus muscle tissue of young male Holstein calves fed a conventional milk replacer plus conventional starter (CON) or an enhanced milk replacer plus high-protein starter (ENH) for 5 wk followed by a conventional starter or a high-protein starter until 10 wk of age. Feeding ENH led to greater concentration of plasma IGF-1 and leptin and greater carcass protein and fat mass throughout the study. Despite the greater plasma IGF-1 and protein mass at wk 5, calves fed ENH had lower expression of IGF1R, INSR, and RPS6KB1 but greater expression of IRS1 and PDPK1 in muscle tissue. Except for IGF1R expression, which did not differ at wk 10, these differences persisted at wk 10, suggesting a long-term effect of greater nutrient intake on physiological and molecular mechanisms. Components of mTOR complex (mTORC)1 and mTORC2 (RICTOR and RPTOR) and FOXO1 expression decreased by wk 10 regardless of diet. Overall, the present data revealed that greater nutrient intake throughout the milk-fed and early postweaning phase alters body mass composition partly by altering hormonal and molecular profiles of genes associated with glucose and amino acid signaling. Those networks may play a crucial role in coordinating neonatal muscle growth and metabolism in response to level of nutrient intake. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Molecular targets for the therapy of cancer associated with metabolic syndrome (transcription and growth factors).

PubMed

Yunusova, Natalia V; Kondakova, Irina V; Kolomiets, Larisa A; Afanas'ev, Sergey G; Chernyshova, Alena L; Kudryavtsev, Igor V; Tsydenova, Anastasia A

2018-06-01

Metabolic syndrome (MS) is one of the leading risk factors for the development of cardiovascular diseases, type II diabetes mellitus and reproductive system diseases. Currently, not only cardiovascular disease and reproductive history risks related with MS are frequently discussed, but it has been also shown that MS is associated with increased risk of some common cancers (endometrial cancer, postmenopausal breast cancer, colorectal cancer, biliary tract cancers and liver cancer for men). Further studies are required to understand the mechanisms of the involvement of MS components in the pathogenesis of malignant neoplasms. Changes in the expression of transcription and growth factors in the peripheral tissues as well as in cancer tissues of patients with MS were revealed. Transcription factors (AMP-activated protein kinase-1, STAT3, sterol regulatory element-binding protein-1 and peroxisome proliferator-activated receptor-γ), leptin and adiponectin receptors seem to be the most promising molecular targets for the therapy of cancers associated with MS. © 2017 John Wiley & Sons Australia, Ltd.

Hemangiosarcoma and its cancer stem cell subpopulation are effectively killed by a toxin targeted through epidermal growth factor and urokinase receptors.

PubMed

Schappa, Jill T; Frantz, Aric M; Gorden, Brandi H; Dickerson, Erin B; Vallera, Daniel A; Modiano, Jaime F

2013-10-15

Targeted toxins have the potential to overcome intrinsic or acquired resistance of cancer cells to conventional cytotoxic agents. Here, we hypothesized that EGFuPA-toxin, a bispecific ligand-targeted toxin (BLT) consisting of a deimmunized Pseudomonas exotoxin (PE) conjugated to epidermal growth factor and urokinase, would efficiently target and kill cells derived from canine hemangiosarcoma (HSA), a highly chemotherapy resistant tumor, as well as cultured hemangiospheres, used as a surrogate for cancer stem cells (CSC). EGFuPA-toxin showed cytotoxicity in four HSA cell lines (Emma, Frog, DD-1 and SB) at a concentration of ≤100 nM, and the cytotoxicity was dependent on specific ligand-receptor interactions. Monospecific targeted toxins also killed these chemoresistant cells; in this case, a "threshold" level of EGFR expression appeared to be required to make cells sensitive to the monospecific EGF-toxin, but not to the monospecific uPA-toxin. The IC₅₀ of CSCs was higher by approximately two orders of magnitude as compared to non-CSCs, but these cells were still sensitive to EGFuPA-toxin at nanomolar (i.e., pharmacologically relevant) concentrations, and when targeted by EGFuPA-toxin, resulted in death of the entire cell population. Taken together, our results support the use of these toxins to treat chemoresistant tumors such as sarcomas, including those that conform to the CSC model. Our results also support the use of companion animals with cancer for further translational development of these cytotoxic molecules. Copyright © 2013 UICC.

Reserves as tools for alleviating impacts of marine disease

PubMed Central

Wenger, Amelia S.; Devlin, Michelle J.; Ceccarelli, Daniela M.; Williamson, David H.; Willis, Bette L.

2016-01-01

Marine protected areas can prevent over-exploitation, but their effect on marine diseases is less clear. We examined how marine reserves can reduce diseases affecting reef-building corals following acute and chronic disturbances. One year after a severe tropical cyclone, corals inside reserves had sevenfold lower levels of disease than those in non-reserves. Similarly, disease prevalence was threefold lower on reserve reefs following chronic exposure to terrestrial run-off from a degraded river catchment, when exposure duration was below the long-term site average. Examination of 35 predictor variables indicated that lower levels of derelict fishing line and injured corals inside reserves were correlated with lower levels of coral disease in both case studies, signifying that successful disease mitigation occurs when activities that damage reefs are restricted. Conversely, reserves were ineffective in moderating disease when sites were exposed to higher than average levels of run-off, demonstrating that reductions in water quality undermine resilience afforded by reserve protection. In addition to implementing protected areas, we highlight that disease management efforts should also target improving water quality and limiting anthropogenic activities that cause injury. PMID:26880842

Reserves as tools for alleviating impacts of marine disease.

PubMed

Lamb, Joleah B; Wenger, Amelia S; Devlin, Michelle J; Ceccarelli, Daniela M; Williamson, David H; Willis, Bette L

2016-03-05

Marine protected areas can prevent over-exploitation, but their effect on marine diseases is less clear. We examined how marine reserves can reduce diseases affecting reef-building corals following acute and chronic disturbances. One year after a severe tropical cyclone, corals inside reserves had sevenfold lower levels of disease than those in non-reserves. Similarly, disease prevalence was threefold lower on reserve reefs following chronic exposure to terrestrial run-off from a degraded river catchment, when exposure duration was below the long-term site average. Examination of 35 predictor variables indicated that lower levels of derelict fishing line and injured corals inside reserves were correlated with lower levels of coral disease in both case studies, signifying that successful disease mitigation occurs when activities that damage reefs are restricted. Conversely, reserves were ineffective in moderating disease when sites were exposed to higher than average levels of run-off, demonstrating that reductions in water quality undermine resilience afforded by reserve protection. In addition to implementing protected areas, we highlight that disease management efforts should also target improving water quality and limiting anthropogenic activities that cause injury. © 2016 The Author(s).

High purity tungsten targets

NASA Technical Reports Server (NTRS)

1975-01-01

High purity tungsten, which is used for targets in X-ray tubes was considered for space processing. The demand for X-ray tubes was calculated using the growth rates for dental and medical X-ray machines. It is concluded that the cost benefits are uncertain.

Design of ligand-targeted nanoparticles for enhanced cancer targeting

NASA Astrophysics Data System (ADS)

Stefanick, Jared F.

Ligand-targeted nanoparticles are increasingly used as drug delivery vehicles for cancer therapy, yet have not consistently produced successful clinical outcomes. Although these inconsistencies may arise from differences in disease models and target receptors, nanoparticle design parameters can significantly influence therapeutic efficacy. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, this work evaluates the roles of polyethylene glycol (PEG) coating, ethylene glycol (EG) peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size on tumor targeting in a systematic manner. These parameters were analyzed in multiple disease models by targeting human epidermal growth factor receptor 2 (HER2) in breast cancer and very late antigen-4 (VLA-4) in multiple myeloma to demonstrate the widespread applicability of this approach. By increasing the hydrophilicity of the targeting peptide sequence and simultaneously optimizing the EG peptide-linker length, the in vitro cellular uptake of targeted liposomes was significantly enhanced. Specifically, including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake ~80-fold using an EG6 peptide-linker compared to ~10-fold using an EG45 linker. In vivo, targeted liposomes prepared in a traditional manner lacking the oligolysine chain demonstrated similar biodistribution and tumor uptake to non-targeted liposomes. However, by including the oligolysine chain, targeted liposomes using an EG45 linker significantly improved tumor uptake ~8-fold over non-targeted liposomes, while the use of an EG6 linker decreased tumor accumulation and uptake, owing to differences in cellular uptake kinetics, clearance mechanisms, and binding site barrier effects. To further improve tumor targeting and enhance the selectivity of targeted

Memory for found targets interferes with subsequent performance in multiple-target visual search.

PubMed

Cain, Matthew S; Mitroff, Stephen R

2013-10-01

Multiple-target visual searches--when more than 1 target can appear in a given search display--are commonplace in radiology, airport security screening, and the military. Whereas 1 target is often found accurately, additional targets are more likely to be missed in multiple-target searches. To better understand this decrement in 2nd-target detection, here we examined 2 potential forms of interference that can arise from finding a 1st target: interference from the perceptual salience of the 1st target (a now highly relevant distractor in a known location) and interference from a newly created memory representation for the 1st target. Here, we found that removing found targets from the display or making them salient and easily segregated color singletons improved subsequent search accuracy. However, replacing found targets with random distractor items did not improve subsequent search accuracy. Removing and highlighting found targets likely reduced both a target's visual salience and its memory load, whereas replacing a target removed its visual salience but not its representation in memory. Collectively, the current experiments suggest that the working memory load of a found target has a larger effect on subsequent search accuracy than does its perceptual salience. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Growth Hormone

MedlinePlus

... for Targeted Cancer Therapy Glucose Tests Gonorrhea Testing Gram Stain Growth Hormone Haptoglobin hCG Pregnancy hCG Tumor Marker HDL Cholesterol Heavy Metals Helicobacter pylori ... is then given a standard glucose solution (usually 100 grams of glucose) to drink. Blood samples are drawn ...

Control of Oriented Tissue Growth through Repression of Organ Boundary Genes Promotes Stem Morphogenesis.

PubMed

Bencivenga, Stefano; Serrano-Mislata, Antonio; Bush, Max; Fox, Samantha; Sablowski, Robert

2016-10-24

The origin of the stem is a major but poorly understood aspect of plant development, partly because the stem initiates in a relatively inaccessible region of the shoot apical meristem called the rib zone (RZ). We developed quantitative 3D image analysis and clonal analysis tools, which revealed that the Arabidopsis homeodomain protein REPLUMLESS (RPL) establishes distinct patterns of oriented cell division and growth in the central and peripheral regions of the RZ. A genome-wide screen for target genes connected RPL directly to many of the key shoot development pathways, including the development of organ boundaries; accordingly, mutation of the organ boundary gene LIGHT-SENSITIVE HYPOCOTYL 4 restored RZ function and stem growth in the rpl mutant. Our work opens the way to study a developmental process of importance to crop improvement and highlights how apparently simple changes in 3D organ growth can reflect more complex internal changes in oriented cell activities. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

[Lentiviral vector-mediated short hairpin RNA targeting survivin inhibits abdominal growth of human endometrium xenograft in nude mice].

PubMed

Peng, Dongxian; He, Yuanli

2015-02-01

To investigate the inhibitory effect of lentiviral vector-mediated short hairpin RNA targeting survivin (LV-survivin shRNA) on the growth of human endometrium xenograft in the abdominal cavity of nude mice. The endometrium xenografts from 8 women with endometriosis were injected into the peritoneal cavities of 45 nude mice. The mice were then randomly assigned to receive intraperitoneal injection of LV-survivin shRNA, pGCL-NC-GFP (negative control) or PBS (blank control). Two weeks later, the number and morphometry of endometriotic lesions were quantified and the expression of survivin protein were detected by immunohistochemistry. The formation of endometriotic lesions was significantly suppressed in mice receiving LV-survivin shRNA injection as compared with those in the two control groups (P/0.001). The mice in LV-survivin-shRNA group showed significantly down-regulated expression levels of survivin protein compared with those in the negative and blank control groups, presenting also necrosis in the endometriosis-like lesions in microscopic observation. Lentiviral vector-mediated shRNA can effectively inhibit the expression of survivin in human endometrium xengrafts and suppress the formation and growth of endometriotic lesions in the abdominal cavities of nude mice.

Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer.

PubMed

Chung, Suyoun; Suzuki, Hanae; Miyamoto, Takashi; Takamatsu, Naofumi; Tatsuguchi, Ayako; Ueda, Koji; Kijima, Kyoko; Nakamura, Yusuke; Matsuo, Yo

2012-12-01

We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also reported to be highly upregulated in multiple types of human cancer. It was implied to play indispensable roles in cancer cell survival and indicated its involvement in the maintenance of tumor-initiating cells. We conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTSSP167 with IC₅₀ of 0.41 nM. OTSSP167 inhibited the phosphorylation of PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which we identified as novel MELK substrates and are important for stem-cell characteristics and invasiveness. The compound suppressed mammosphere formation of breast cancer cells and exhibited significant tumor growth suppression in xenograft studies using breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. This MELK inhibitor should be a promising compound possibly to suppress the growth of tumor-initiating cells and be applied for treatment of a wide range of human cancer.

EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor-β-mediated growth inhibition in hepatocellular carcinoma

PubMed Central

Yasui, Kohichiroh; Konishi, Chika; Gen, Yasuyuki; Endo, Mio; Dohi, Osamu; Tomie, Akira; Kitaichi, Tomoko; Yamada, Nobuhisa; Iwai, Naoto; Nishikawa, Taichiro; Yamaguchi, Kanji; Moriguchi, Michihisa; Sumida, Yoshio; Mitsuyoshi, Hironori; Tanaka, Shinji; Arii, Shigeki; Itoh, Yoshito

2015-01-01

EVI1 (ecotropic viral integration site 1) is one of the most aggressive oncogenes associated with myeloid leukemia. We investigated DNA copy number aberrations in human hepatocellular carcinoma (HCC) cell lines using a high-density oligonucleotide microarray. We found that a novel amplification at the chromosomal region 3q26 occurs in the HCC cell line JHH-1, and that MECOM (MDS1 and EVI1 complex locus), which lies within the 3q26 region, was amplified. Quantitative PCR analysis of the three transcripts transcribed from MECOM indicated that only EVI1, but not the fusion transcript MDS1–EVI1 or MDS1, was overexpressed in JHH-1 cells and was significantly upregulated in 22 (61%) of 36 primary HCC tumors when compared with their non-tumorous counterparts. A copy number gain of EVI1 was observed in 24 (36%) of 66 primary HCC tumors. High EVI1 expression was significantly associated with larger tumor size and higher level of des-γ-carboxy prothrombin, a tumor marker for HCC. Knockdown of EVI1 resulted in increased induction of the cyclin-dependent kinase inhibitor p15INK4B by transforming growth factor (TGF)-β and decreased expression of c-Myc, cyclin D1, and phosphorylated Rb in TGF-β-treated cells. Consequently, knockdown of EVI1 led to reduced DNA synthesis and cell viability. Collectively, our results suggest that EVI1 is a probable target gene that acts as a driving force for the amplification at 3q26 in HCC and that the oncoprotein EVI1 antagonizes TGF-β-mediated growth inhibition of HCC cells. PMID:25959919

Targeting the tumor blood vessel network to enhance the efficacy of radiation therapy.

PubMed

Siemann, Dietmar W; Shi, Wenyin

2003-01-01

It has been well established that the vascularization of solid tumors is a prerequisite if a clinically relevant size is to be reached. For progressive tumor growth, the vessel network must continuously expand to satisfy the neoplastic cells' nutritional needs and waste product removal requirements. This utter reliance of the tumor on its vasculature provides a logical target for new approaches to cancer therapy. Indeed, there currently exists a great deal of enthusiasm for the development of interventions that compromise the growth and/or function of the tumor neovasculature. Two primary directions are being pursued. Inhibitors of angiogenesis seek to interrupt the angiogenic process to prevent new vessel formation. Antivascular approaches aim to cause direct damage to the tumor endothelium and thus lead to extensive secondary neoplastic cell death. The application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies. Copyright 2003, Elsevier Science (USA). All rights reserved.

Anti-Cancer Activity of an Osthole Derivative, NBM-T-BMX-OS01: Targeting Vascular Endothelial Growth Factor Receptor Signaling and Angiogenesis

PubMed Central

Chiu, Pei-Ting; Ho, Shiau-Jing; Wang, Chi-Han; Chi, Chih-Chin; Huang, Yu-Han; Lee, Cheng-Feng; Li, Ying-Shiuan; Ou, George; Hsu, Ming-Jen

2013-01-01

Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer. PMID:24312323

Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity

PubMed Central

Wang, Liang-Chuan S; Lo, Albert; Scholler, John; Sun, Jing; Majumdar, Rajrupa S; Kapoor, Veena; Antzis, Michael; Cotner, Cody E.; Johnson, Laura A; Durham, Amy C; Solomides, Charalambos C.; June, Carl H; Puré, Ellen; Albelda, Steven M

2013-01-01

The majority of chimeric antigen receptor (CAR) T cell research has focused on attacking cancer cells. Here we show that targeting the tumor-promoting, non-transformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single chain Fv FAP (mAb 73.3) with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFNγ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8+ T cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective suggesting that further clinical development of anti-human FAP-CAR is warranted. PMID:24778279

Petroleum Development Oman gas exploration unlocks major new reserves

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, A.; Mozetic, A.

1995-08-01

Since 1985, Petroleum Development Oman (PDO) has been exploring for gas on behalf of the Government of Oman under a ten-year agreement signed in June 1984. The aim of the one-rig programme was to find additional non-associated gas reserves (3 TCF) to meet domestic energy requirements for a minimum of 40 years, for which the available reserves at that time (5.6 TCF) were insufficient. Initial results of the campaign, which principally targeted the Permian Khuff Formation, were disappointing, analogues to the major accumulations of the Arabian Gulf failing to materialise. During the second half of the programme, therefore, the strategymore » was revised to address the prospectivity of higher risk/higher reward plays recognised at greater depths. Well Saih Nihayda-24, drilled in 1989, found gas/condensate-bearing reservoirs in Cambro/Ordovician sandstones of the Andam Formation below 4000 metres. This discovery, in a seismically poorly defined anticline, sparked an intensive effort of 2D, and later 3D, long cable seismic acquisition. This led in 1991 to additional major gas/condensate finds in Saih Rawl and Barik, and a dedicated two-year two-rig appraisal campaign has since proven up sufficient reserves to support an LNG gas export scheme. The ten-year programme has more than tripled Oman`s non-associated gas expectation reserves to some 22 TCF, exceeding-the target more than five-fold. Significant potential for further gas discoveries identified in both North and South Oman provides encouragement for continued successful gas exploration in the future.« less