MicroRNA and receptor mediated signaling pathways as potential therapeutic targets in heart failure.

PubMed

Tuttolomondo, Antonino; Simonetta, Irene; Pinto, Antonio

2016-11-01

Cardiac remodelling is a complex pathogenetic pathway involving genome expression, molecular, cellular, and interstitial changes that cause changes in size, shape and function of the heart after cardiac injury. Areas covered: We will review recent advances in understanding the role of several receptor-mediated signaling pathways and micro-RNAs, in addition to their potential as candidate target pathways in the pathogenesis of heart failure. The myocyte is the main target cell involved in the remodelling process via ischemia, cell necrosis and apoptosis (by means of various receptor pathways), and other mechanisms mediated by micro-RNAs. We will analyze the role of some receptor mediated signaling pathways such as natriuretic peptides, mediators of glycogen synthase kinase 3 and ERK1/2 pathways, beta-adrenergic receptor subtypes and relaxin receptor signaling mechanisms, TNF/TNF receptor family and TWEAK/Fn14 axis, and some micro-RNAs as candidate target pathways in pathogenesis of heart failure. These mediators of receptor-mediated pathways and micro-RNA are the most addressed targets of emerging therapies in modern heart failure treatment strategies. Expert opinion: Future treatment strategies should address mediators involved in multiple steps within heart failure pathogenetic pathways.

Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting.

PubMed

Zilbermintz, Leeor; Leonardi, William; Jeong, Sun-Young; Sjodt, Megan; McComb, Ryan; Ho, Chi-Lee C; Retterer, Cary; Gharaibeh, Dima; Zamani, Rouzbeh; Soloveva, Veronica; Bavari, Sina; Levitin, Anastasia; West, Joel; Bradley, Kenneth A; Clubb, Robert T; Cohen, Stanley N; Gupta, Vivek; Martchenko, Mikhail

2015-08-27

A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.

About miRNAs, miRNA seeds, target genes and target pathways.

PubMed

Kehl, Tim; Backes, Christina; Kern, Fabian; Fehlmann, Tobias; Ludwig, Nicole; Meese, Eckart; Lenhof, Hans-Peter; Keller, Andreas

2017-12-05

miRNAs are typically repressing gene expression by binding to the 3' UTR, leading to degradation of the mRNA. This process is dominated by the eight-base seed region of the miRNA. Further, miRNAs are known not only to target genes but also to target significant parts of pathways. A logical line of thoughts is: miRNAs with similar (seed) sequence target similar sets of genes and thus similar sets of pathways. By calculating similarity scores for all 3.25 million pairs of 2,550 human miRNAs, we found that this pattern frequently holds, while we also observed exceptions. Respective results were obtained for both, predicted target genes as well as experimentally validated targets. We note that miRNAs target gene set similarity follows a bimodal distribution, pointing at a set of 282 miRNAs that seems to target genes with very high specificity. Further, we discuss miRNAs with different (seed) sequences that nonetheless regulate similar gene sets or pathways. Most intriguingly, we found miRNA pairs that regulate different gene sets but similar pathways such as miR-6886-5p and miR-3529-5p. These are jointly targeting different parts of the MAPK signaling cascade. The main goal of this study is to provide a general overview on the results, to highlight a selection of relevant results on miRNAs, miRNA seeds, target genes and target pathways and to raise awareness for artifacts in respective comparisons. The full set of information that allows to infer detailed results on each miRNA has been included in miRPathDB, the miRNA target pathway database (https://mpd.bioinf.uni-sb.de).

Facilitated Protein Association via Engineered Target Search Pathways Visualized by Paramagnetic NMR Spectroscopy.

PubMed

An, So Young; Kim, Eun-Hee; Suh, Jeong-Yong

2018-06-05

Proteins assemble to form functional complexes via the progressive evolution of nonspecific complexes formed by transient encounters. This target search process generally involves multiple routes that lead the initial encounters to the final complex. In this study, we have employed NMR paramagnetic relaxation enhancement to visualize the encounter complexes between histidine-containing phosphocarrier protein and the N-terminal domain of enzyme I and demonstrate that protein association can be significantly enhanced by engineering on-pathways. Specifically, mutations in surface charges away from the binding interface can elicit new on-pathway encounter complexes, increasing their binding affinity by an order of magnitude. The structure of these encounter complexes indicates that such on-pathways extend the built-in target search process of the native protein complex. Furthermore, blocking on-pathways by countering mutations reverts their binding affinity. Our study thus illustrates that protein interactions can be engineered by rewiring the target search process. Copyright © 2018 Elsevier Ltd. All rights reserved.

Multiple pathways from three types of sugar receptor sites to metabotropic transduction pathways of the blowfly: study by the whole cell-clamp experiments.

PubMed

Kan, Hideko; Kataoka-Shirasugi, Naoko; Amakawa, Taisaku

2011-09-01

Multiple pathways from three types of multiple receptor sites to three types of metabotropic signal transduction pathways were investigated in the whole cell-clamp experiments using isolated labellar sugar receptor neurons (cells) of the adult blowfly, Phormia regina. First, the concentration-response curves of three types of sweet taste components specialized to multiple receptor sites were obtained: sucrose for the pyranose sites (P-sites), fructose for the furanose sites (F-sites), and l-valine for the alkyl sites (R-sites). Next, the effects of inhibitors such as 2', 5'-dideoxyadenosine on adenylyl cyclase in the cAMP pathway, LY 83583 on guanylyl cyclase in the cGMP pathway, and U-73122 on phospholipase C in the IP₃ pathway were examined. The results showed that all of the inhibitors affected each specific target in the second-messenger transduction pathways. The obtained results verified that the P-site corresponded to the cAMP, the F-site to the cGMP, and the R-site to the IP₃ transduction pathway, and that these three signal pathways did not have crossing points. Copyright © 2011 Elsevier Inc. All rights reserved.

Overexpression of hypoxia-inducible factor and metabolic pathways: possible targets of cancer.

PubMed

Singh, Davinder; Arora, Rohit; Kaur, Pardeep; Singh, Balbir; Mannan, Rahul; Arora, Saroj

2017-01-01

Cancer, the main cause of human deaths in the modern world is a group of diseases. Anticancer drug discovery is a challenge for scientists because of involvement of multiple survival pathways of cancer cells. An extensive study on the regulation of each step of these pathways may help find a potential cancer target. Up-regulated HIF-1 expression and altered metabolic pathways are two classical characteristics of cancer. Oxygen-dependent (through pVHL, PHDs, calcium-mediated) and independent (through growth factor signaling pathway, mdm2 pathway, HSP90) regulation of HIF-1α leads to angiogenesis, metastasis, and cell survival. The two subunits of HIF-1 regulates in the same fashion through different mechanisms. HIF-1α translation upregulates via mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways, whereas HIF-1β through calmodulin kinase. Further, the stabilized interactions of these two subunits are important for proper functioning. Also, metabolic pathways crucial for the formation of building blocks (pentose phosphate pathway) and energy generation (glycolysis, TCA cycle and catabolism of glutamine) are altered in cancer cells to protect them from oxidative stress and to meet the reduced oxygen and nutrient supply. Up-regulated anaerobic metabolism occurs through enhanced expression of hexokinase, phosphofructokinase, triosephosphate isomerase, glucose 6-phosphate dehydrogenase and down-regulation of aerobic metabolism via pyruvate dehydrogenase kinase and lactate dehydrogenase which compensate energy requirements along with high glucose intake. Controlled expression of these two pathways through their common intermediate may serve as potent cancer target in future.

Targeting the Notch signaling pathway in autoimmune diseases.

PubMed

Ma, Daoxin; Zhu, Yuanchao; Ji, Chunyan; Hou, Ming

2010-05-01

The Notch signaling pathway regulates a variety of processes and has been linked to diverse effects. Aberrant Notch function is important in several disorders. Pre-clinical studies have suggested that inhibition of Notch is an attractive approach to treat hematologic and solid malignancies. Many patients with refractory autoimmune diseases respond poorly to therapy and have significant morbidity and the treatment is highly toxic, so more effective therapies for autoimmune diseases are being examined. The role of the Notch pathway and therapeutic strategies targeting it in many illnesses, especially autoimmune diseases. The Notch pathway has unique and attractive advantages for targeting. Targeting it has already been trialed in many experiments, which may show better efficacy and fewer side effects compared with classical drugs for the treatment. Targeting Notch might provide etiological rather than symptomatic treatment. Various methods targeting the Notch pathway have been under investigation. Rational targeting of the Notch signaling pathway in cancer and some autoimmune diseases has proven to be successful. Classical drugs for the treatment of autoimmune diseases are inefficient and toxic to some extent, and targeting the Notch pathway is a promising therapeutic concept. However, there are still many questions about targeting Notch in autoimmune diseases, and further investigation will be needed.

Targeted therapy of multiple myeloma.

PubMed

Dolloff, Nathan G; Talamo, Giampaolo

2013-01-01

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

Multiple shell fusion targets

DOEpatents

Lindl, J.D.; Bangerter, R.O.

1975-10-31

Multiple shell fusion targets for use with electron beam and ion beam implosion systems are described. The multiple shell targets are of the low-power type and use a separate relatively low Z, low density ablator at large radius for the outer shell, which reduces the focusing and power requirements of the implosion system while maintaining reasonable aspect ratios. The targets use a high Z, high density pusher shell placed at a much smaller radius in order to obtain an aspect ratio small enough to protect against fluid instability. Velocity multiplication between these shells further lowers the power requirements. Careful tuning of the power profile and intershell density results in a low entropy implosion which allows breakeven at low powers. For example, with ion beams as a power source, breakeven at 10-20 Terrawatts with 10 MeV alpha particles for imploding a multiple shell target can be accomplished.

Targeting the GPI biosynthetic pathway.

PubMed

Yadav, Usha; Khan, Mohd Ashraf

2018-02-27

The GPI (Glycosylphosphatidylinositol) biosynthetic pathway is a multistep conserved pathway in eukaryotes that culminates in the generation of GPI glycolipid which in turn anchors many proteins (GPI-APs) to the cell surface. In spite of the overall conservation of the pathway, there still exist subtle differences in the GPI pathway of mammals and other eukaryotes which holds a great promise so far as the development of drugs/inhibitors against specific targets in the GPI pathway of pathogens is concerned. Many of the GPI structures and their anchored proteins in pathogenic protozoans and fungi act as pathogenicity factors. Notable examples include GPI-anchored variant surface glycoprotein (VSG) in Trypanosoma brucei, GPI-anchored merozoite surface protein 1 (MSP1) and MSP2 in Plasmodium falciparum, protein-free GPI related molecules like lipophosphoglycans (LPGs) and glycoinositolphospholipids (GIPLs) in Leishmania spp., GPI-anchored Gal/GalNAc lectin and proteophosphoglycans in Entamoeba histolytica or the GPI-anchored mannoproteins in pathogenic fungi like Candida albicans. Research in this active area has already yielded encouraging results in Trypanosoma brucei by the development of parasite-specific inhibitors of GlcNCONH 2 -β-PI, GlcNCONH 2 -(2-O-octyl)-PI and salicylic hydroxamic acid (SHAM) targeting trypanosomal GlcNAc-PI de-N-acetylase as well as the development of antifungal inhibitors like BIQ/E1210/gepinacin/G365/G884 and YW3548/M743/M720 targeting the GPI specific fungal inositol acyltransferase (Gwt1) and the phosphoethanolamine transferase-I (Mcd4), respectively. These confirm the fact that the GPI pathway continues to be the focus of researchers, given its implications for the betterment of human life.

Targeting arachidonic acid pathway by natural products for cancer prevention and therapy.

PubMed

Yarla, Nagendra Sastry; Bishayee, Anupam; Sethi, Gautam; Reddanna, Pallu; Kalle, Arunasree M; Dhananjaya, Bhadrapura Lakkappa; Dowluru, Kaladhar S V G K; Chintala, Ramakrishna; Duddukuri, Govinda Rao

2016-10-01

Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A 2 s (PLA 2 s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA 2 s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

NAViGaTing the Micronome – Using Multiple MicroRNA Prediction Databases to Identify Signalling Pathway-Associated MicroRNAs

PubMed Central

Shirdel, Elize A.; Xie, Wing; Mak, Tak W.; Jurisica, Igor

2011-01-01

Background MicroRNAs are a class of small RNAs known to regulate gene expression at the transcript level, the protein level, or both. Since microRNA binding is sequence-based but possibly structure-specific, work in this area has resulted in multiple databases storing predicted microRNA:target relationships computed using diverse algorithms. We integrate prediction databases, compare predictions to in vitro data, and use cross-database predictions to model the microRNA:transcript interactome – referred to as the micronome – to study microRNA involvement in well-known signalling pathways as well as associations with disease. We make this data freely available with a flexible user interface as our microRNA Data Integration Portal — mirDIP (http://ophid.utoronto.ca/mirDIP). Results mirDIP integrates prediction databases to elucidate accurate microRNA:target relationships. Using NAViGaTOR to produce interaction networks implicating microRNAs in literature-based, KEGG-based and Reactome-based pathways, we find these signalling pathway networks have significantly more microRNA involvement compared to chance (p<0.05), suggesting microRNAs co-target many genes in a given pathway. Further examination of the micronome shows two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets (p<0.0001), to be more studied (p<0.0002), and to have higher degree in the KEGG cancer pathway (p<0.0001), compared to intra-pathway microRNAs. Conclusions Our pathway-based analysis of mirDIP data suggests microRNAs are involved in intra-pathway signalling. We identify two distinct classes of microRNAs, suggesting a hierarchical organization of microRNAs co-targeting genes both within and between pathways, and implying differential involvement of universe and intra-pathway microRNAs at the disease level. PMID

The therapeutic potential of cell cycle targeting in multiple myeloma.

PubMed

Maes, Anke; Menu, Eline; Veirman, Kim De; Maes, Ken; Vand Erkerken, Karin; De Bruyne, Elke

2017-10-27

Proper cell cycle progression through the interphase and mitosis is regulated by coordinated activation of important cell cycle proteins (including cyclin-dependent kinases and mitotic kinases) and several checkpoint pathways. Aberrant activity of these cell cycle proteins and checkpoint pathways results in deregulation of cell cycle progression, which is one of the key hallmarks of cancer. Consequently, intensive research on targeting these cell cycle regulatory proteins identified several candidate small molecule inhibitors that are able to induce cell cycle arrest and even apoptosis in cancer cells. Importantly, several of these cell cycle regulatory proteins have also been proposed as therapeutic targets in the plasma cell malignancy multiple myeloma (MM). Despite the enormous progress in the treatment of MM the past 5 years, MM still remains most often incurable due to the development of drug resistance. Deregulated expression of the cyclins D is observed in virtually all myeloma patients, emphasizing the potential therapeutic interest of cyclin-dependent kinase inhibitors in MM. Furthermore, other targets have also been identified in MM, such as microtubules, kinesin motor proteins, aurora kinases, polo-like kinases and the anaphase promoting complex/cyclosome. This review will provide an overview of the cell cycle proteins and checkpoint pathways deregulated in MM and discuss the therapeutic potential of targeting proteins or protein complexes involved in cell cycle control in MM.

Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma.

PubMed

Sekido, Yoshitaka

2018-03-22

Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities and is highly refractory to conventional therapies. Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF , NF2 , and BAP1 tumor-suppressor genes. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM. The NF2 gene encodes merlin, a protein that regulates multiple cell-signaling cascades including the Hippo pathway. MMs also exhibit inactivation of Hippo pathway components including LATS1/2, strongly suggesting that merlin-Hippo pathway dysregulation plays a key role in the development and progression of MM. Furthermore, Hippo pathway inactivation has been shown to result in constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells. Critical YAP1/TAZ target genes, including prooncogenic CCDN1 and CTGF , have also been shown to enhance the malignant phenotypes of MM cells. Together, these data indicate the Hippo pathway as a therapeutic target for the treatment of MM, and support the development of new strategies to effectively target the activation status of YAP1/TAZ as a promising therapeutic modality for this formidable disease.

Multiple oxygen entry pathways in globin proteins revealed by intrinsic pathway identification method

NASA Astrophysics Data System (ADS)

Takayanagi, Masayoshi; Kurisaki, Ikuo; Nagaoka, Masataka

2015-12-01

Each subunit of human hemoglobin (HbA) stores an oxygen molecule (O2) in the binding site (BS) cavity near the heme group. The BS is buried in the interior of the subunit so that there is a debate over the O2 entry pathways from solvent to the BS; histidine gate or multiple pathways. To elucidate the O2 entry pathways, we executed ensemble molecular dynamics (MD) simulations of T-state tetramer HbA in high concentration O2 solvent to simulate spontaneous O2 entry from solvent into the BS. By analyzing 128 independent 8 ns MD trajectories by intrinsic pathway identification by clustering (IPIC) method, we found 141 and 425 O2 entry events into the BS of the α and β subunits, respectively. In both subunits, we found that multiple O2 entry pathways through inside cavities play a significant role for O2 entry process of HbA. The rate constants of O2 entry estimated from the MD trajectories correspond to the experimentally observed values. In addition, by analyzing monomer myoglobin, we verified that the high O2 concentration condition can reproduce the ratios of each multiple pathway in the one-tenth lower O2 concentration condition. These indicate the validity of the multiple pathways obtained in our MD simulations.

Integrated QSAR study for inhibitors of hedgehog signal pathway against multiple cell lines:a collaborative filtering method

PubMed Central

2012-01-01

Background The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. Results In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have

Integrated QSAR study for inhibitors of Hedgehog Signal Pathway against multiple cell lines:a collaborative filtering method.

PubMed

Gao, Jun; Che, Dongsheng; Zheng, Vincent W; Zhu, Ruixin; Liu, Qi

2012-07-31

The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have proposed several

Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways

PubMed Central

Cai, H L; Jiang, P; Tan, Q Y; Dang, R L; Tang, M M; Xue, Y; Deng, Y; Zhang, B K; Fang, P F; Xu, P; Xiang, D X; Li, H D; Yao, J K

2017-01-01

Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic–pituitary–adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography–mass spectrometry (UPLC–MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine–phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment. PMID:28509906

Pharmacophore based design of some multi-targeted compounds targeted against pathways of diabetic complications.

PubMed

Chadha, Navriti; Silakari, Om

2017-09-01

Diabetic complications is a complex metabolic disorder developed primarily due to prolonged hyperglycemia in the body. The complexity of the disease state as well as the unifying pathophysiology discussed in the literature reports exhibited that the use of multi-targeted agents with multiple complementary biological activities may offer promising therapy for the intervention of the disease over the single-target drugs. In the present study, novel thiazolidine-2,4-dione analogues were designed as multi-targeted agents implicated against the molecular pathways involved in diabetic complications using knowledge based as well as in-silico approaches such as pharmacophore mapping, molecular docking etc. The hit molecules were duly synthesized and biochemical estimation of these molecules against aldose reductase (ALR2), protein kinase Cβ (PKCβ) and poly (ADP-ribose) polymerase 1 (PARP-1) led to identification of compound 2 that showed good potency against PARP-1 and ALR2 enzymes. These positive results support the progress of a low cost multi-targeted agent with putative roles in diabetic complications. Copyright © 2017 Elsevier Inc. All rights reserved.

A multicolor panel of TALE-KRAB based transcriptional repressor vectors enabling knockdown of multiple gene targets

PubMed Central

Zhang, Zhonghui; Wu, Elise; Qian, Zhijian; Wu, Wen-Shu

2014-01-01

Stable and efficient knockdown of multiple gene targets is highly desirable for dissection of molecular pathways. Because it allows sequence-specific DNA binding, transcription activator-like effector (TALE) offers a new genetic perturbation technique that allows for gene-specific repression. Here, we constructed a multicolor lentiviral TALE-Kruppel-associated box (KRAB) expression vector platform that enables knockdown of multiple gene targets. This platform is fully compatible with the Golden Gate TALEN and TAL Effector Kit 2.0, a widely used and efficient method for TALE assembly. We showed that this multicolor TALE-KRAB vector system when combined together with bone marrow transplantation could quickly knock down c-kit and PU.1 genes in hematopoietic stem and progenitor cells of recipient mice. Furthermore, our data demonstrated that this platform simultaneously knocked down both c-Kit and PU.1 genes in the same primary cell populations. Together, our results suggest that this multicolor TALE-KRAB vector platform is a promising and versatile tool for knockdown of multiple gene targets and could greatly facilitate dissection of molecular pathways. PMID:25475013

A multicolor panel of TALE-KRAB based transcriptional repressor vectors enabling knockdown of multiple gene targets.

PubMed

Zhang, Zhonghui; Wu, Elise; Qian, Zhijian; Wu, Wen-Shu

2014-12-05

Stable and efficient knockdown of multiple gene targets is highly desirable for dissection of molecular pathways. Because it allows sequence-specific DNA binding, transcription activator-like effector (TALE) offers a new genetic perturbation technique that allows for gene-specific repression. Here, we constructed a multicolor lentiviral TALE-Kruppel-associated box (KRAB) expression vector platform that enables knockdown of multiple gene targets. This platform is fully compatible with the Golden Gate TALEN and TAL Effector Kit 2.0, a widely used and efficient method for TALE assembly. We showed that this multicolor TALE-KRAB vector system when combined together with bone marrow transplantation could quickly knock down c-kit and PU.1 genes in hematopoietic stem and progenitor cells of recipient mice. Furthermore, our data demonstrated that this platform simultaneously knocked down both c-Kit and PU.1 genes in the same primary cell populations. Together, our results suggest that this multicolor TALE-KRAB vector platform is a promising and versatile tool for knockdown of multiple gene targets and could greatly facilitate dissection of molecular pathways.

Is the canonical RAF-MEK-ERK signaling pathway a therapeutic target in SCLC?

PubMed Central

Cristea, Sandra; Sage, Julien

2017-01-01

The activity of the RAF-MEK-ERK signaling pathway is critical for the proliferation of normal and cancerous cells. Oncogenic mutations driving the development of lung adenocarcinoma often activate this signaling pathway. In contrast, pathway activity levels and their biological roles are not well established in small cell lung cancer (SCLC), a fast-growing neuroendocrine lung cancer subtype. Here we discuss the function of the RAF-MEK-ERK kinase pathway and the mechanisms leading to its activation in SCLC cells. In particular, we argue that activation of this pathway may be beneficial to the survival, proliferation and spread of SCLC cells in response to multiple stimuli. We also consider evidence that high levels of RAF-MEK-ERK pathway activity may be detrimental to SCLC tumors, including in part by interfering with their neuroendocrine fate. Based on these observations, we examine when small molecules targeting kinases in the RAF-MEK-ERK pathway may be useful therapeutically in SCLC patients, including in combination with other therapeutic agents. PMID:27133774

Target of Rapamycin Complex 2 Regulates Actin Polarization and Endocytosis via Multiple Pathways*

PubMed Central

Rispal, Delphine; Eltschinger, Sandra; Stahl, Michael; Vaga, Stefania; Bodenmiller, Bernd; Abraham, Yann; Filipuzzi, Ireos; Movva, N. Rao; Aebersold, Ruedi; Helliwell, Stephen B.; Loewith, Robbie

2015-01-01

Target of rapamycin is a Ser/Thr kinase that operates in two conserved multiprotein complexes, TORC1 and TORC2. Unlike TORC1, TORC2 is insensitive to rapamycin, and its functional characterization is less advanced. Previous genetic studies demonstrated that TORC2 depletion leads to loss of actin polarization and loss of endocytosis. To determine how TORC2 regulates these readouts, we engineered a yeast strain in which TORC2 can be specifically and acutely inhibited by the imidazoquinoline NVP-BHS345. Kinetic analyses following inhibition of TORC2, supported with quantitative phosphoproteomics, revealed that TORC2 regulates these readouts via distinct pathways as follows: rapidly through direct protein phosphorylation cascades and slowly through indirect changes in the tensile properties of the plasma membrane. The rapid signaling events are mediated in large part through the phospholipid flippase kinases Fpk1 and Fpk2, whereas the slow signaling pathway involves increased plasma membrane tension resulting from a gradual depletion of sphingolipids. Additional hits in our phosphoproteomic screens highlight the intricate control TORC2 exerts over diverse aspects of eukaryote cell physiology. PMID:25882841

Polymeric RNAi Microsponge Delivery Simultaneously Targeting Multiple Genes for Novel Pathway Inhibition of Ovarian Cancer

DTIC Science & Technology

2016-10-01

October 2016 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION...MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012...the treatment of ovarian cancer. 4 KEYWORDS: Ovarian cancer, RNAi, targeting, pathways, novel therapeutics Research Accomplishments Major Task 1

Therapeutic Efficacy of Suppressing the JAK/STAT Pathway in Multiple Models of EAE1

PubMed Central

Liu, Yudong; Holdbrooks, Andrew T.; De Sarno, Patrizia; Rowse, Amber L.; Yanagisawa, Lora L.; McFarland, Braden C.; Harrington, Laurie E.; Raman, Chander; Sabbaj, Steffanie; Benveniste, Etty N.; Qin, Hongwei

2014-01-01

Pathogenic T helper cells and myeloid cells are involved in the pathogenesis of Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. The JAK/STAT pathway is utilized by numerous cytokines for signaling, and is critical for development, regulation and termination of immune responses. Dysregulation of the JAK/STAT pathway has pathological implications in autoimmune and neuroinflammatory diseases. Many of the cytokines involved in MS/EAE, including IL-6, IL-12, IL-23, IFN-γ and GM-CSF, use the JAK/STAT pathway to induce biological responses. Thus, targeting JAKs has implications for treating autoimmune inflammation of the brain. We have utilized AZD1480, a JAK1/2 inhibitor, to investigate the therapeutic potential of inhibiting the JAK/STAT pathway in models of EAE. AZD1480 treatment inhibits disease severity in MOG-induced classical and atypical EAE models by preventing entry of immune cells into the brain, suppressing differentiation of Th1 and Th17 cells, deactivating myeloid cells, inhibiting STAT activation in the brain, and reducing expression of pro-inflammatory cytokines and chemokines. Treatment of SJL/J mice with AZD1480 delays disease onset of PLP-induced relapsing-remitting disease, reduces relapses and diminishes clinical severity. AZD1480 treatment was also effective in reducing ongoing paralysis induced by adoptive transfer of either pathogenic Th1 or Th17 cells. In vivo AZD1480 treatment impairs both the priming and expansion of T-cells, and attenuates antigen-presentation functions of myeloid cells. Inhibition of the JAK/STAT pathway has clinical efficacy in multiple pre-clinical models of MS, suggesting the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases. PMID:24323580

Trehalose pathway as an antifungal target.

PubMed

Perfect, John R; Tenor, Jennifer L; Miao, Yi; Brennan, Richard G

2017-02-17

With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.

Targeting survival pathways in chronic myeloid leukaemia stem cells

PubMed Central

Sinclair, A; Latif, A L; Holyoake, T L

2013-01-01

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23517124

Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways.

PubMed

Lian, Xiaolan; Lin, Yu-Min; Kozono, Shingo; Herbert, Megan K; Li, Xin; Yuan, Xiaohong; Guo, Jiangrui; Guo, Yafei; Tang, Min; Lin, Jia; Huang, Yiping; Wang, Bixin; Qiu, Chenxi; Tsai, Cheng-Yu; Xie, Jane; Cao, Ziang Jeff; Wu, Yong; Liu, Hekun; Zhou, Xiaozhen; Lu, Kunping; Chen, Yuanzhong

2018-05-30

The increasing genomic complexity of acute myeloid leukemia (AML), the most common form of acute leukemia, poses a major challenge to its therapy. To identify potent therapeutic targets with the ability to block multiple cancer-driving pathways is thus imperative. The unique peptidyl-prolyl cis-trans isomerase Pin1 has been reported to promote tumorigenesis through upregulation of numerous cancer-driving pathways. Although Pin1 is a key drug target for treating acute promyelocytic leukemia (APL) caused by a fusion oncogene, much less is known about the role of Pin1 in other heterogeneous leukemia. The mRNA and protein levels of Pin1 were detected in samples from de novo leukemia patients and healthy controls using real-time quantitative RT-PCR (qRT-PCR) and western blot. The establishment of the lentiviral stable-expressed short hairpin RNA (shRNA) system and the tetracycline-inducible shRNA system for targeting Pin1 were used to analyze the biological function of Pin1 in AML cells. The expression of cancer-related Pin1 downstream oncoproteins in shPin1 (Pin1 knockdown) and Pin1 inhibitor all-trans retinoic acid (ATRA) treated leukemia cells were examined by western blot, followed by evaluating the effects of genetic and chemical inhibition of Pin1 in leukemia cells on transformed phenotype, including cell proliferation and colony formation ability, using trypan blue, cell counting assay, and colony formation assay in vitro, as well as the tumorigenesis ability using in vivo xenograft mouse models. First, we found that the expression of Pin1 mRNA and protein was significantly increased in both de novo leukemia clinical samples and multiple leukemia cell lines, compared with healthy controls. Furthermore, genetic or chemical inhibition of Pin1 in human multiple leukemia cell lines potently inhibited multiple Pin1 substrate oncoproteins and effectively suppressed leukemia cell proliferation and colony formation ability in cell culture models in vitro. Moreover

miRPathDB: a new dictionary on microRNAs and target pathways.

PubMed

Backes, Christina; Kehl, Tim; Stöckel, Daniel; Fehlmann, Tobias; Schneider, Lara; Meese, Eckart; Lenhof, Hans-Peter; Keller, Andreas

2017-01-04

In the last decade, miRNAs and their regulatory mechanisms have been intensively studied and many tools for the analysis of miRNAs and their targets have been developed. We previously presented a dictionary on single miRNAs and their putative target pathways. Since then, the number of miRNAs has tripled and the knowledge on miRNAs and targets has grown substantially. This, along with changes in pathway resources such as KEGG, leads to an improved understanding of miRNAs, their target genes and related pathways. Here, we introduce the miRNA Pathway Dictionary Database (miRPathDB), freely accessible at https://mpd.bioinf.uni-sb.de/ With the database we aim to complement available target pathway web-servers by providing researchers easy access to the information which pathways are regulated by a miRNA, which miRNAs target a pathway and how specific these regulations are. The database contains a large number of miRNAs (2595 human miRNAs), different miRNA target sets (14 773 experimentally validated target genes as well as 19 281 predicted targets genes) and a broad selection of functional biochemical categories (KEGG-, WikiPathways-, BioCarta-, SMPDB-, PID-, Reactome pathways, functional categories from gene ontology (GO), protein families from Pfam and chromosomal locations totaling 12 875 categories). In addition to Homo sapiens, also Mus musculus data are stored and can be compared to human target pathways. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism

PubMed Central

van Dongen, Stijn; Haluck-Kangas, Ashley; Sarshad, Aishe A; Bartom, Elizabeth T; Kim, Kwang-Youn A; Scholtens, Denise M; Hafner, Markus; Zhao, Jonathan C; Murmann, Andrea E

2017-01-01

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3’UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells. PMID:29063830

Multiple Pathways for All Students

ERIC Educational Resources Information Center

Stirling, Lee Anna

2012-01-01

Maine has been focusing on the importance of postsecondary training. Maine's Skowhegan Area High School (SAHS) and Somerset Career and Technical Center (SCTC) have partnered in a Multiple Pathways initiative (funded by the Nellie Mae Education Foundation) to increase students' high school completion rate and to increase enrollment in postsecondary…

Proteomics of buccal squamous cell carcinoma: the involvement of multiple pathways in tumorigenesis.

PubMed

Chen, Jia; He, Qing-Yu; Yuen, Anthony Po-Wing; Chiu, Jeng-Fu

2004-08-01

Squamous cell carcinoma (SCC) of the buccal mucosa is an aggressive oral cancer. It mainly occurs in Central and Southeast Asia, and is closely related to the practice of tobacco smoking and betel squid chewing. The high recurrence and low survival rates of buccal SCC require our continued efforts to understand the pathogenesis of the disease for designing better therapeutic strategies. We used proteomic technology to analyze buccal SCC tissues aiming at identifying tumor-associated proteins for the utilization as biomarkers or molecular targets. With the exception of alpha B-crystallin being substantially reduced, a number of proteins were found to be significantly over-expressed in cancer tissues. These increased proteins included glycolytic enzymes, heat-shock proteins, tumor antigens, cytoskeleton proteins, enzymes involved in detoxification and anti-oxidation systems, and proteins involved in mitochondrial and intracellular signaling pathways. These extensive protein variations indicate that multiple cellular pathways were involved in the process of tumorigenesis, and suggest that multiple protein molecules should be simultaneously targeted as an effective strategy to counter the disease. At least, SCC antigen, G protein, glutathione S-transferase, manganese superoxide dismutase, annexins, voltage-dependent anion channel, cyclophilin A, stratifin and galectin 7 are candidates for targeted proteins. The present findings also demonstrated that rich protein information can be produced by means of proteomic analysis for a better understanding of the oncogenesis and pathogenesis in a global way, which in turn is a basis for the rational designs of diagnostic and therapeutic methods.

Finding off-targets, biological pathways, and target diseases for chymase inhibitors via structure-based systems biology approach.

PubMed

Arooj, Mahreen; Sakkiah, Sugunadevi; Cao, Guang Ping; Kim, Songmi; Arulalapperumal, Venkatesh; Lee, Keun Woo

2015-07-01

Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off-targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off-targets. These off-targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors. © 2014 Wiley Periodicals, Inc.

miR-150 exerts antileukemia activity in vitro and in vivo through regulating genes in multiple pathways

PubMed Central

Fang, Zhi Hong; Wang, Si Li; Zhao, Jin Tao; Lin, Zhi Juan; Chen, Lin Yan; Su, Rui; Xie, Si Ting; Carter, Bing Z; Xu, Bing

2016-01-01

MicroRNAs, a class of small noncoding RNAs, have been implicated to regulate gene expression in virtually all important biological processes. Although accumulating evidence demonstrates that miR-150, an important regulator in hematopoiesis, is deregulated in various types of hematopoietic malignancies, the precise mechanisms of miR-150 action are largely unknown. In this study, we found that miR-150 is downregulated in samples from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia, and normalized after patients achieved complete remission. Restoration of miR-150 markedly inhibited growth and induced apoptosis of leukemia cells, and reduced tumorigenicity in a xenograft leukemia murine model. Microarray analysis identified multiple novel targets of miR-150, which were validated by quantitative real-time PCR and luciferase reporter assay. Gene ontology and pathway analysis illustrated potential roles of these targets in small-molecule metabolism, transcriptional regulation, RNA metabolism, proteoglycan synthesis in cancer, mTOR signaling pathway, or Wnt signaling pathway. Interestingly, knockdown one of four miR-150 targets (EIF4B, FOXO4B, PRKCA, and TET3) showed an antileukemia activity similar to that of miR-150 restoration. Collectively, our study demonstrates that miR-150 functions as a tumor suppressor through multiple mechanisms in human leukemia and provides a rationale for utilizing miR-150 as a novel therapeutic agent for leukemia treatment. PMID:27899822

Controversies in cancer stem cells: targeting embryonic signaling pathways.

PubMed

Takebe, Naoko; Ivy, S Percy

2010-06-15

Selectively targeting cancer stem cells (CSC) or tumor-initiating cells (TIC; from this point onward referred to as CSCs) with novel agents is a rapidly emerging field of oncology. Our knowledge of CSCs and their niche microenvironments remains a nascent field. CSC's critical dependence upon self-renewal makes these regulatory signaling pathways ripe for the development of experimental therapeutic agents. Investigational agents targeting the Notch, Hedgehog, and Wnt pathways are currently in late preclinical development stages, with some early phase 1-2 testing in human subjects. This series of articles will provide an overview and summary of the current state of knowledge of CSCs, their interactive microenvironment, and how they may serve as important targets for antitumor therapies. We also examine the scope and stage of development of early experimental agents that specifically target these highly conserved embryonic signaling pathways. (c) 2010 AACR.

Shared elements of host-targeting pathways among apicomplexan parasites of differing lifestyles.

PubMed

Pellé, Karell G; Jiang, Rays H Y; Mantel, Pierre-Yves; Xiao, Yu-Ping; Hjelmqvist, Daisy; Gallego-Lopez, Gina M; O T Lau, Audrey; Kang, Byung-Ho; Allred, David R; Marti, Matthias

2015-11-01

Apicomplexans are a diverse group of obligate parasites occupying different intracellular niches that require modification to meet the needs of the parasite. To efficiently manipulate their environment, apicomplexans translocate numerous parasite proteins into the host cell. Whereas some parasites remain contained within a parasitophorous vacuole membrane (PVM) throughout their developmental cycle, others do not, a difference that affects the machinery needed for protein export. A signal-mediated pathway for protein export into the host cell has been characterized in Plasmodium parasites, which maintain the PVM. Here, we functionally demonstrate an analogous host-targeting pathway involving organellar staging prior to secretion in the related bovine parasite, Babesia bovis, a parasite that destroys the PVM shortly after invasion. Taking into account recent identification of a similar signal-mediated pathway in the coccidian parasite Toxoplasma gondii, we suggest a model in which this conserved pathway has evolved in multiple steps from signal-mediated trafficking to specific secretory organelles for controlled secretion to a complex protein translocation process across the PVM. © 2015 John Wiley & Sons Ltd.

Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy

PubMed Central

Lohr, Jens G.; Stojanov, Petar; Carter, Scott L.; Cruz-Gordillo, Peter; Lawrence, Michael S.; Auclair, Daniel; Sougnez, Carrie; Knoechel, Birgit; Gould, Joshua; Saksena, Gordon; Cibulskis, Kristian; McKenna, Aaron; Chapman, Michael A.; Straussman, Ravid; Levy, Joan; Perkins, Louise M.; Keats, Jonathan J.; Schumacher, Steven E.; Rosenberg, Mara; Getz, Gad

2014-01-01

SUMMARY We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations, and discovered putative tumor suppressor genes by determining homozygous deletions and loss-of-heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53 and DIS3 (particularly in non-hyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g. KRAS, NRAS and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of non-mutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions. PMID:24434212

Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.

PubMed

Lohr, Jens G; Stojanov, Petar; Carter, Scott L; Cruz-Gordillo, Peter; Lawrence, Michael S; Auclair, Daniel; Sougnez, Carrie; Knoechel, Birgit; Gould, Joshua; Saksena, Gordon; Cibulskis, Kristian; McKenna, Aaron; Chapman, Michael A; Straussman, Ravid; Levy, Joan; Perkins, Louise M; Keats, Jonathan J; Schumacher, Steven E; Rosenberg, Mara; Getz, Gad; Golub, Todd R

2014-01-13

We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions. Copyright © 2014 Elsevier Inc. All rights reserved.

Th17 Cells Pathways in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders: Pathophysiological and Therapeutic Implications

PubMed Central

Passos, Giordani Rodrigues Dos; Sato, Douglas Kazutoshi; Becker, Jefferson; Fujihara, Kazuo

2016-01-01

Several animal and human studies have implicated CD4+ T helper 17 (Th17) cells and their downstream pathways in the pathogenesis of central nervous system (CNS) autoimmunity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), challenging the traditional Th1-Th2 paradigm. Th17 cells can efficiently cross the blood-brain barrier using alternate ways from Th1 cells, promote its disruption, and induce the activation of other inflammatory cells in the CNS. A number of environmental factors modulate the activity of Th17 pathways, so changes in the diet, exposure to infections, and other environmental factors can potentially change the risk of development of autoimmunity. Currently, new drugs targeting specific points of the Th17 pathways are already being tested in clinical trials and provide basis for the development of biomarkers to monitor disease activity. Herein, we review the key findings supporting the relevance of the Th17 pathways in the pathogenesis of MS and NMOSD, as well as their potential role as therapeutic targets in the treatment of immune-mediated CNS disorders. PMID:26941483

Beyond Tracking: Multiple Pathways to College, Career, and Civic Participation

ERIC Educational Resources Information Center

Oakes, Jeannie, Ed.; Saunders, Marisa, Ed.

2008-01-01

"Beyond Tracking" responds to the a sobering assessment of American high schools by delineating and promoting an innovative and well-defined notion of multiple pathways. The book's authors clearly distinguish their use of the term "multiple pathways" from any updated version of the tracking system that marked so many American high schools during…

Inhibitors targeting on cell wall biosynthesis pathway of MRSA.

PubMed

Hao, Haihong; Cheng, Guyue; Dai, Menghong; Wu, Qinghua; Yuan, Zonghui

2012-11-01

Methicillin resistant Staphylococcus aureus (MRSA), widely known as a type of new superbug, has aroused world-wide concern. Cell wall biosynthesis pathway is an old but good target for the development of antibacterial agents. Peptidoglycan and wall teichoic acids (WTAs) biosynthesis are two main processes of the cell wall biosynthesis pathway (CWBP). Other than penicillin-binding proteins (PBPs), some key factors (Mur enzymes, lipid I or II precursor, etc.) in CWBP are becoming attractive molecule targets for the discovery of anti-MRSA compounds. A number of new compounds, with higher affinity for PBPs or with inhibitory activity on such molecule targets in CWBP of MRSA, have been in the pipeline recently. This review concludes recent research achievements and provides a complete picture of CWBP of MRSA, including the peptidoglycan and wall teichoic acids synthesis pathway. The potential inhibitors targeting on CWBP are subsequently presented to improve development of novel therapeutic strategies for MRSA.

Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma

PubMed Central

Cruickshanks, Nichola; Zhang, Ying; Yuan, Fang; Pahuski, Mary; Gibert, Myron; Abounader, Roger

2017-01-01

Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has focused on inhibiting RTKs as a novel and effective therapy for GBM. Overexpression of RTK mesenchymal epithelial transition (MET), and its ligand, hepatocyte growth factor (HGF), in GBM highlights a promising new therapeutic target. This review will discuss the role of MET in cell cycle regulation, cell proliferation, evasion of apoptosis, cell migration and invasion, angiogenesis and therapeutic resistance in GBM. It will also discuss the modes of deregulation of HGF/MET and their regulation by microRNAs. As the HGF/MET pathway is a vital regulator of multiple pro-survival pathways, efforts and strategies for its exploitation for GBM therapy are also described. PMID:28696366

Targeting Notch signalling pathway of cancer stem cells.

PubMed

Venkatesh, Vandana; Nataraj, Raghu; Thangaraj, Gopenath S; Karthikeyan, Murugesan; Gnanasekaran, Ashok; Kaginelli, Shanmukhappa B; Kuppanna, Gobianand; Kallappa, Chandrashekrappa Gowdru; Basalingappa, Kanthesh M

2018-01-01

Cancer stem cells (CSCs) have been defined as cells within tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. CSCs have been increasingly identified in blood cancer, prostate, ovarian, lung, melanoma, pancreatic, colon, brain and many more malignancies. CSCs have slow growth rate and are resistant to chemotherapy and radiotherapy that lead to the failure of traditional current therapy. Eradicating the CSCs and recurrence, is promising aspect for the cure of cancer. The CSCs like any other stem cells activate the signal transduction pathways that involve the development and tissue homeostasis, which include Notch signaling pathway. The new treatment targets these pathway that control stem-cell replication, survival and differentiation that are under development. Notch inhibitors either single or in combination with chemotherapy drugs have been developed to treat cancer and its recurrence. This approach of targeting signaling pathway of CSCs represents a promising future direction for the therapeutic strategy to cure cancer.

[Analysis on "component-target-pathway" of Paeonia lactiflora in treating cardiac diseases based on data mining].

PubMed

Liu, Yang; Zhang, Fang-Bo; Tang, Shi-Huan; Wang, Ping; Li, Sen; Su, Jin; Zhou, Rong-Rong; Zhang, Jia-Qi; Sun, Hui-Feng

2018-04-01

Based on the literature review and modern application of Paeonia lactiflora in heart diseases, this article would predict the target of drug and disease by intergrative pharmacology platform of traditional Chinese medicine (TCMIP, http://www.tcmip.cn), and then explore the molecular mechanism of P. lactiflora in treatment of heart disease, providing theoretical basis and method for further studies on P. lactiflora. According to the ancient books, P. lactiflora with functions of "removing the vascular obstruction, removing the lumps, relieving pain, diuretic, nutrient qi" and other effects, have been used for many times to treat heart disease. Some prescriptions are also favored by the modern physicians nowadays. With the development of science, the chemical components that play a role in heart disease and the interrelation between these components and the body become the research hotspot. In order to further reveal the pharmacological substance base and molecular mechanism of P. lactiflora for the treatment of such diseases, TCM-IP was used to obtain multiple molecular targets and signaling pathways in treatment of heart disease. ATP1A1, a common target of drug and disease, was related to energy, and HDAC2 mainly regulated cardiomyocyte hypertrophy gene and cardiomyocyte expression. Other main drug targets such as GCK, CHUK and PRKAA2 indirectly regulated heart disease through many pathways; multiple disease-associated signaling pathways interfered with various heart diseases including coronary heart disease, myocardial ischemia and myocardial hypertrophy through influencing energy metabolism, enzyme activity and gene expression. In conclusion, P. lactiflora plays a role in protecting heart function by regulating the gene expression of cardiomyocytes directly. Meanwhile, it can indirectly intervene in other pathways of heart function, and thus participate in the treatment of heart disease. In this paper, the molecular mechanism of P. lactiflora for treatment of

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

PubMed Central

Haley, Shannon L.; Tzvetkov, Evgeni P.; Meuwissen, Samantha; Plummer, Joseph R.

2017-01-01

requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality. PMID:28148792

Molecular pathways and therapeutic targets in lung cancer

PubMed Central

Shtivelman, Emma; Hensing, Thomas; Simon, George R.; Dennis, Phillip A.; Otterson, Gregory A.; Bueno, Raphael; Salgia, Ravi

2014-01-01

Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review. PMID:24722523

mir-30d Regulates multiple genes in the autophagy pathway and impairs autophagy process in human cancer cells

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

Yang, Xiaojun; Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 710000; Zhong, Xiaomin

2013-02-15

Highlights: ► Gene set enrichment analysis indicated mir-30d might regulate the autophagy pathway. ► mir-30d represses the expression of BECN1, BNIP3L, ATG12, ATG5 and ATG2. ► BECN1, BNIP3L, ATG12, ATG5 and ATG2 are direct targets of mir-30d. ► mir-30d inhibits autophagosome formation and LC3B-I conversion to LC3B-II. ► mir-30d regulates the autophagy process. -- Abstract: In human epithelial cancers, the microRNA (miRNA) mir-30d is amplified with high frequency and serves as a critical oncomir by regulating metastasis, apoptosis, proliferation, and differentiation. Autophagy, a degradation pathway for long-lived protein and organelles, regulates the survival and death of many cell types. Increasingmore » evidence suggests that autophagy plays an important function in epithelial tumor initiation and progression. Using a combined bioinformatics approach, gene set enrichment analysis, and miRNA target prediction, we found that mir-30d might regulate multiple genes in the autophagy pathway including BECN1, BNIP3L, ATG12, ATG5, and ATG2. Our further functional experiments demonstrated that the expression of these core proteins in the autophagy pathway was directly suppressed by mir-30d in cancer cells. Finally, we showed that mir-30d regulated the autophagy process by inhibiting autophagosome formation and LC3B-I conversion to LC3B-II. Taken together, our results provide evidence that the oncomir mir-30d impairs the autophagy process by targeting multiple genes in the autophagy pathway. This result will contribute to understanding the molecular mechanism of mir-30d in tumorigenesis and developing novel cancer therapy strategy.« less

Targeting Developmental Pathways: The Achilles Heel of Cancer?

PubMed

Dempke, Wolfram C M; Fenchel, Klaus; Uciechowski, Peter; Chevassut, Timothy

2017-01-01

Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways. © 2017 S. Karger AG, Basel.

Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway.

PubMed

Pollard, Patrick J; Spencer-Dene, Bradley; Shukla, Deepa; Howarth, Kimberley; Nye, Emma; El-Bahrawy, Mona; Deheragoda, Maesha; Joannou, Maria; McDonald, Stuart; Martin, Alison; Igarashi, Peter; Varsani-Brown, Sunita; Rosewell, Ian; Poulsom, Richard; Maxwell, Patrick; Stamp, Gordon W; Tomlinson, Ian P M

2007-04-01

Germline mutations in the fumarate hydratase (FH) tumor suppressor gene predispose to leiomyomatosis, renal cysts, and renal cell cancer (HLRCC). HLRCC tumors overexpress HIF1alpha and hypoxia pathway genes. We conditionally inactivated mouse Fh1 in the kidney. Fh1 mutants developed multiple clonal renal cysts that overexpressed Hif1alpha and Hif2alpha. Hif targets, such as Glut1 and Vegf, were upregulated. We found that Fh1-deficient murine embryonic stem cells and renal carcinomas from HLRCC showed similar overexpression of HIF and hypoxia pathway components to the mouse cysts. Our data have shown in vivo that pseudohypoxic drive, resulting from HIF1alpha (and HIF2alpha) overexpression, is a direct consequence of Fh1 inactivation. Our mouse may be useful for testing therapeutic interventions that target angiogenesis and HIF-prolyl hydroxylation.

Redox Pathways as Drug Targets in Microaerophilic Parasites.

PubMed

Leitsch, David; Williams, Catrin F; Hrdý, Ivan

2018-05-25

The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia jointly cause hundreds of millions of infections in humans every year. Other microaerophilic parasites such as Tritrichomonas foetus and Spironucleus spp. pose a relevant health problem in veterinary medicine. Unfortunately, vaccines against these pathogens are unavailable, but their microaerophilic lifestyle opens opportunities for specifically developed chemotherapeutics. In particular, their high sensitivity towards oxygen can be exploited by targeting redox enzymes. This review focusses on the redox pathways of microaerophilic parasites and on drugs, either already in use or currently in the state of development, which target these pathways. Copyright © 2018 Elsevier Ltd. All rights reserved.

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis.

PubMed

Haley, Shannon L; Tzvetkov, Evgeni P; Meuwissen, Samantha; Plummer, Joseph R; McGettigan, James P

2017-04-15

rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality. Copyright © 2017 American Society for Microbiology.

Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development.

PubMed

Tsukamoto, Sachiko; Yokosawa, Hideyoshi

2006-01-01

The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitin-proteasome proteolytic pathway.

Transition model for ricin-aptamer interactions with multiple pathways and energy barriers

NASA Astrophysics Data System (ADS)

Wang, Bin; Xu, Bingqian

2014-02-01

We develop a transition model to interpret single-molecule ricin-aptamer interactions with multiple unbinding pathways and energy barriers measured by atomic force microscopy dynamic force spectroscopy. Molecular simulations establish the relationship between binding conformations and the corresponding unbinding pathways. Each unbinding pathway follows a Bell-Evans multiple-barrier model. Markov-type transition matrices are developed to analyze the redistribution of unbinding events among the pathways under different loading rates. Our study provides detailed information about complex behaviors in ricin-aptamer unbinding events.

Multiple target laser ablation system

DOEpatents

Mashburn, D.N.

1996-01-09

A laser ablation apparatus and method are provided in which multiple targets consisting of material to be ablated are mounted on a movable support. The material transfer rate is determined for each target material, and these rates are stored in a controller. A position detector determines which target material is in a position to be ablated, and then the controller controls the beam trigger timing and energy level to achieve a desired proportion of each constituent material in the resulting film. 3 figs.

Multiple target laser ablation system

DOEpatents

Mashburn, Douglas N.

1996-01-01

A laser ablation apparatus and method are provided in which multiple targets consisting of material to be ablated are mounted on a movable support. The material transfer rate is determined for each target material, and these rates are stored in a controller. A position detector determines which target material is in a position to be ablated, and then the controller controls the beam trigger timing and energy level to achieve a desired proportion of each constituent material in the resulting film.

Mapping the pathways of resistance to targeted therapies

PubMed Central

Wood, Kris C.

2015-01-01

Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacological approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients. PMID:26392071

BCL-2 Antagonism to Target the Intrinsic Mitochondrial Pathway of Apoptosis

PubMed Central

Gibson, Christopher J.; Davids, Matthew S.

2015-01-01

Despite significant improvements in treatment, cure rates for many cancers remain suboptimal. The rise of cytotoxic chemotherapy has led to curative therapy for a subset of cancers, though intrinsic treatment resistance is difficult to predict for individual patients. The recent wave of molecularly targeted therapies has focused on druggable activating mutations, and is thus limited to specific subsets of patients. The lessons learned from these two disparate approaches suggest the need for therapies that borrow aspects of both, targeting biological properties of cancer that are at once distinct from normal cells and yet common enough to make the drugs widely applicable across a range of cancer subtypes. The intrinsic mitochondrial pathway of apoptosis represents one such promising target for new therapies, and successfully targeting this pathway has the potential to alter the therapeutic landscape of therapy for a variety of cancers. Here, we discuss the biology of the intrinsic pathway of apoptosis, an assay known as BH3 profiling that can interrogate this pathway, early attempts to target BCL-2 clinically, and the recent promising results with the BCL-2 antagonist venetoclax (ABT-199) in clinical trials in hematologic malignancies. PMID:26567361

Aliskiren targets multiple systems to alleviate cancer cachexia.

PubMed

Wang, Chaoyi; Guo, Dunwei; Wang, Qiang; You, Song; Qiao, Zhongpeng; Liu, Yong; Dai, Hang; Tang, Hua

2016-11-01

To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).

THE PATHOPHYSIOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION AND THE COMPLEMENT PATHWAY AS A THERAPEUTIC TARGET

PubMed Central

Schmidt-Erfurth, Ursula; van Lookeren Campagne, Menno; Henry, Erin C.; Brittain, Christopher

2017-01-01

Purpose: Geographic atrophy (GA) is an advanced, vision-threatening form of age-related macular degeneration (AMD) affecting approximately five million individuals worldwide. To date, there are no approved therapeutics for GA treatment; however, several are in clinical trials. This review focuses on the pathophysiology of GA, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade. Methods: Primary literature search on PubMed for GA, complement cascade in age-related macular degeneration. ClinicalTrials.gov was searched for natural history studies in GA and clinical trials of drugs targeting the complement cascade for GA. Results: Cumulative damage to the retina by aging, environmental stress, and other factors triggers inflammation via multiple pathways, including the complement cascade. When regulatory components in these pathways are compromised, as with several GA-linked genetic risk factors in the complement cascade, chronic inflammation can ultimately lead to the retinal cell death characteristic of GA. Complement inhibition has been identified as a key candidate for therapeutic intervention, and drugs targeting the complement pathway are currently in clinical trials. Conclusion: The complement cascade is a strategic target for GA therapy. Further research, including on natural history and genetics, is crucial to expand the understanding of GA pathophysiology and identify effective therapeutic targets. PMID:27902638

Hybrid foraging search: Searching for multiple instances of multiple types of target.

PubMed

Wolfe, Jeremy M; Aizenman, Avigael M; Boettcher, Sage E P; Cain, Matthew S

2016-02-01

This paper introduces the "hybrid foraging" paradigm. In typical visual search tasks, observers search for one instance of one target among distractors. In hybrid search, observers search through visual displays for one instance of any of several types of target held in memory. In foraging search, observers collect multiple instances of a single target type from visual displays. Combining these paradigms, in hybrid foraging tasks observers search visual displays for multiple instances of any of several types of target (as might be the case in searching the kitchen for dinner ingredients or an X-ray for different pathologies). In the present experiment, observers held 8-64 target objects in memory. They viewed displays of 60-105 randomly moving photographs of objects and used the computer mouse to collect multiple targets before choosing to move to the next display. Rather than selecting at random among available targets, observers tended to collect items in runs of one target type. Reaction time (RT) data indicate searching again for the same item is more efficient than searching for any other targets, held in memory. Observers were trying to maximize collection rate. As a result, and consistent with optimal foraging theory, they tended to leave 25-33% of targets uncollected when moving to the next screen/patch. The pattern of RTs shows that while observers were collecting a target item, they had already begun searching memory and the visual display for additional targets, making the hybrid foraging task a useful way to investigate the interaction of visual and memory search. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hybrid foraging search: Searching for multiple instances of multiple types of target

PubMed Central

Wolfe, Jeremy M.; Aizenman, Avigael M.; Boettcher, Sage E.P.; Cain, Matthew S.

2016-01-01

This paper introduces the “hybrid foraging” paradigm. In typical visual search tasks, observers search for one instance of one target among distractors. In hybrid search, observers search through visual displays for one instance of any of several types of target held in memory. In foraging search, observers collect multiple instances of a single target type from visual displays. Combining these paradigms, in hybrid foraging tasks observers search visual displays for multiple instances of any of several types of target (as might be the case in searching the kitchen for dinner ingredients or an X-ray for different pathologies). In the present experiment, observers held 8–64 targets objects in memory. They viewed displays of 60–105 randomly moving photographs of objects and used the computer mouse to collect multiple targets before choosing to move to the next display. Rather than selecting at random among available targets, observers tended to collect items in runs of one target type. Reaction time (RT) data indicate searching again for the same item is more efficient than searching for any other targets, held in memory. Observers were trying to maximize collection rate. As a result, and consistent with optimal foraging theory, they tended to leave 25–33% of targets uncollected when moving to the next screen/patch. The pattern of RTs shows that while observers were collecting a target item, they had already begun searching memory and the visual display for additional targets, making the hybrid foraging task a useful way to investigate the interaction of visual and memory search. PMID:26731644

Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

PubMed

Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

2017-08-01

Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Adverse effects of anticancer agents that target the VEGF pathway.

PubMed

Chen, Helen X; Cleck, Jessica N

2009-08-01

Antiangiogenesis agents that target the VEGF/VEGF receptor pathway have become an important part of standard therapy in multiple cancer indications. With expanded clinical experience with this class of agents has come the increasing recognition of the diverse adverse effects related to disturbance of VEGF-dependent physiological functions and homeostasis in the cardiovascular and renal systems, as well as wound healing and tissue repair. Although most adverse effects of VEGF inhibitors are modest and manageable, some are associated with serious and life-threatening consequences, particularly in high-risk patients and in certain clinical settings. This Review examines the toxicity profiles of anti-VEGF antibodies and small-molecule inhibitors. The potential mechanisms of the adverse effects, risk factors, and the implications for selection of patients and management are discussed.

Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors.

PubMed

Andersen, Jannik N; Sathyanarayanan, Sriram; Di Bacco, Alessandra; Chi, An; Zhang, Theresa; Chen, Albert H; Dolinski, Brian; Kraus, Manfred; Roberts, Brian; Arthur, William; Klinghoffer, Rich A; Gargano, Diana; Li, Lixia; Feldman, Igor; Lynch, Bethany; Rush, John; Hendrickson, Ronald C; Blume-Jensen, Peter; Paweletz, Cloud P

2010-08-04

Although we have made great progress in understanding the complex genetic alterations that underlie human cancer, it has proven difficult to identify which molecularly targeted therapeutics will benefit which patients. Drug-specific modulation of oncogenic signaling pathways in specific patient subpopulations can predict responsiveness to targeted therapy. Here, we report a pathway-based phosphoprofiling approach to identify and quantify clinically relevant, drug-specific biomarkers for phosphatidylinositol 3-kinase (PI3K) pathway inhibitors that target AKT, phosphoinositide-dependent kinase 1 (PDK1), and PI3K-mammalian target of rapamycin (mTOR). We quantified 375 nonredundant PI3K pathway-relevant phosphopeptides, all containing AKT, PDK1, or mitogen-activated protein kinase substrate recognition motifs. Of these phosphopeptides, 71 were drug-regulated, 11 of them by all three inhibitors. Drug-modulated phosphoproteins were enriched for involvement in cytoskeletal reorganization (filamin, stathmin, dynamin, PAK4, and PTPN14), vesicle transport (LARP1, VPS13D, and SLC20A1), and protein translation (S6RP and PRAS40). We then generated phosphospecific antibodies against selected, drug-regulated phosphorylation sites that would be suitable as biomarker tools for PI3K pathway inhibitors. As proof of concept, we show clinical translation feasibility for an antibody against phospho-PRAS40(Thr246). Evaluation of binding of this antibody in human cancer cell lines, a PTEN (phosphatase and tensin homolog deleted from chromosome 10)-deficient mouse prostate tumor model, and triple-negative breast tumor tissues showed that phospho-PRAS40(Thr246) positively correlates with PI3K pathway activation and predicts AKT inhibitor sensitivity. In contrast to phosphorylation of AKT(Thr308), the phospho-PRAS40(Thr246) epitope is highly stable in tissue samples and thus is ideal for immunohistochemistry. In summary, our study illustrates a rational approach for discovery of drug

Multi-target drugs to address multiple checkpoints in complex inflammatory pathologies: evolutionary cues for novel "first-in-class" anti-inflammatory drug candidates: a reviewer's perspective.

PubMed

Mathew, Geetha; Unnikrishnan, M K

2015-10-01

Inflammation is a complex, metabolically expensive process involving multiple signaling pathways and regulatory mechanisms which have evolved over evolutionary timescale. Addressing multiple targets of inflammation holistically, in moderation, is probably a more evolutionarily viable strategy, as compared to current therapy which addresses drug targets in isolation. Polypharmacology, addressing multiple targets, is commonly used in complex ailments, suggesting the superior safety and efficacy profile of multi-target (MT) drugs. Phenotypic drug discovery, which generated successful MT and first-in-class drugs in the past, is now re-emerging. A multi-pronged approach, which modulates the evolutionarily conserved, robust and pervasive cellular mechanisms of tissue repair, with AMPK at the helm, regulating the complex metabolic/immune/redox pathways underlying inflammation, is perhaps a more viable strategy than addressing single targets in isolation. Molecules that modulate multiple molecular mechanisms of inflammation in moderation (modulating TH cells toward the anti-inflammatory phenotype, activating AMPK, stimulating Nrf2 and inhibiting NFκB) might serve as a model for a novel Darwinian "first-in-class" therapeutic category that holistically addresses immune, redox and metabolic processes associated with inflammatory repair. Such a multimodal biological activity is supported by the fact that several non-calorific pleiotropic natural products with anti-inflammatory action have been incorporated into diet (chiefly guided by the adaptive development of olfacto-gustatory preferences over evolutionary timescales) rendering such molecules, endowed with evolutionarily privileged molecular scaffolds, naturally oriented toward multiple targets.

Clearance Pathways and Tumor Targeting of Imaging Nanoparticles

PubMed Central

Yu, Mengxiao; Zheng, Jie

2016-01-01

A basic understanding of how imaging nanoparticles are removed from the normal organs/tissues but retained in the tumors is important for their future clinical applications in early cancer diagnosis and therapy. In this review, we discuss current understandings of clearance pathways and tumor targeting of small-molecule- and inorganic-nanoparticle-based imaging probes with an emphasis on molecular nanoprobes, a class of inorganic nanoprobes that can escape reticuloendothelial system (RES) uptake and be rapidly eliminated from the normal tissues/organs via kidneys but can still passively target the tumor with high efficiency through the enhanced permeability permeability and retention (EPR) effect. The impact of nanoparticle design (size, shape, and surface chemistry) on their excretion, pharmacokinetics, and passive tumor targeting were quantitatively discussed. Synergetic integration of effective renal clearance and EPR effect offers a promising pathway to design low-toxicity and high-contrast-enhancement imaging nanoparticles that could meet with the clinical translational requirements of regulatory agencies. PMID:26149184

Sensor Compromise Detection in Multiple-Target Tracking Systems

PubMed Central

Doucette, Emily A.; Curtis, Jess W.

2018-01-01

Tracking multiple targets using a single estimator is a problem that is commonly approached within a trusted framework. There are many weaknesses that an adversary can exploit if it gains control over the sensors. Because the number of targets that the estimator has to track is not known with anticipation, an adversary could cause a loss of information or a degradation in the tracking precision. Other concerns include the introduction of false targets, which would result in a waste of computational and material resources, depending on the application. In this work, we study the problem of detecting compromised or faulty sensors in a multiple-target tracker, starting with the single-sensor case and then considering the multiple-sensor scenario. We propose an algorithm to detect a variety of attacks in the multiple-sensor case, via the application of finite set statistics (FISST), one-class classifiers and hypothesis testing using nonparametric techniques. PMID:29466314

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

PubMed Central

Allman, Erik L.; Painter, Heather J.; Samra, Jasmeet; Carrasquilla, Manuela

2016-01-01

The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated the in vitro metabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field. PMID:27572391

Curcumin Induces Apoptosis of Upper Aerodigestive Tract Cancer Cells by Targeting Multiple Pathways

PubMed Central

Amin, A. R. M. Ruhul; Haque, Abedul; Rahman, Mohammad Aminur; Chen, Zhuo Georgia; Khuri, Fadlo Raja; Shin, Dong Moon

2015-01-01

Curcumin, a natural compound isolated from the Indian spice "Haldi" or "curry powder", has been used for centuries as a traditional remedy for many ailments. Recently, the potential use of curcumin in cancer prevention and therapy urges studies to uncover the molecular mechanisms associated with its anti-tumor effects. In the current manuscript, we investigated the mechanism of curcumin-induced apoptosis in upper aerodigestive tract cancer cell lines and showed that curcumin-induced apoptosis is mediated by the modulation of multiple pathways such as induction of p73, and inhibition of p-AKT and Bcl-2. Treatment of cells with curcumin induced both p53 and the related protein p73 in head and neck and lung cancer cell lines. Inactivation of p73 by dominant negative p73 significantly protected cells from curcumin-induced apoptosis, whereas ablation of p53 by shRNA had no effect. Curcumin treatment also strongly inhibited p-AKT and Bcl-2 and overexpression of constitutively active AKT or Bcl-2 significantly inhibited curcumin-induced apoptosis. Taken together, our findings suggest that curcumin-induced apoptosis is mediated via activating tumor suppressor p73 and inhibiting p-AKT and Bcl-2. PMID:25910231

A mathematical analysis of multiple-target SELEX.

PubMed

Seo, Yeon-Jung; Chen, Shiliang; Nilsen-Hamilton, Marit; Levine, Howard A

2010-10-01

SELEX (Systematic Evolution of Ligands by Exponential Enrichment) is a procedure by which a mixture of nucleic acids can be fractionated with the goal of identifying those with specific biochemical activities. One combines the mixture with a specific target molecule and then separates the target-NA complex from the resulting reactions. The target-NA complex is separated from the unbound NA by mechanical means (such as by filtration), the NA is eluted from the complex, amplified by PCR (polymerase chain reaction), and the process repeated. After several rounds, one should be left with the nucleic acids that best bind to the target. The problem was first formulated mathematically in Irvine et al. (J. Mol. Biol. 222:739-761, 1991). In Levine and Nilsen-Hamilton (Comput. Biol. Chem. 31:11-25, 2007), a mathematical analysis of the process was given. In Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998), multiple target SELEX was considered. It was assumed that each target has a single nucleic acid binding site that permits occupation by no more than one nucleic acid. Here, we revisit Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998) using the same assumptions. The iteration scheme is shown to be convergent and a simplified algorithm is given. Our interest here is in the behavior of the multiple target SELEX process as a discrete "time" dynamical system. Our goal is to characterize the limiting states and their dependence on the initial distribution of nucleic acid and target fraction components. (In multiple target SELEX, we vary the target component fractions, but not their concentrations, as fixed and the initial pool of nucleic acids as a variable starting condition). Given N nucleic acids and a target consisting of M subtarget component species, there is an M × N matrix of affinities, the (i,j) entry corresponding to the affinity of the jth nucleic acid for the ith subtarget. We give a structure condition on this matrix that is equivalent to the following

Targeting the Hippo signalling pathway for cancer treatment.

PubMed

Nakatani, Keisuke; Maehama, Tomohiko; Nishio, Miki; Goto, Hiroki; Kato, Wakako; Omori, Hirofumi; Miyachi, Yosuke; Togashi, Hideru; Shimono, Yohei; Suzuki, Akira

2017-03-01

The Hippo signalling pathway monitors cell-cell contact and external factors that shape tissue structure. In mice, tumourigenesis and developmental abnormalities are common consequences of dysregulated Hippo signalling. Expression of Hippo pathway components is also frequently altered in human tumours and correlates with poor prognosis and reduced patient survival. Thus, the Hippo pathway is an attractive anti-cancer target. Here, we provide an overview of the function and regulation of Hippo signalling components and summarize progress to date on the development of agents able to regulate Hippo signalling for cancer therapy. © The Authors 2016. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

SuperTarget goes quantitative: update on drug–target interactions

PubMed Central

Hecker, Nikolai; Ahmed, Jessica; von Eichborn, Joachim; Dunkel, Mathias; Macha, Karel; Eckert, Andreas; Gilson, Michael K.; Bourne, Philip E.; Preissner, Robert

2012-01-01

There are at least two good reasons for the on-going interest in drug–target interactions: first, drug-effects can only be fully understood by considering a complex network of interactions to multiple targets (so-called off-target effects) including metabolic and signaling pathways; second, it is crucial to consider drug-target-pathway relations for the identification of novel targets for drug development. To address this on-going need, we have developed a web-based data warehouse named SuperTarget, which integrates drug-related information associated with medical indications, adverse drug effects, drug metabolism, pathways and Gene Ontology (GO) terms for target proteins. At present, the updated database contains >6000 target proteins, which are annotated with >330 000 relations to 196 000 compounds (including approved drugs); the vast majority of interactions include binding affinities and pointers to the respective literature sources. The user interface provides tools for drug screening and target similarity inclusion. A query interface enables the user to pose complex queries, for example, to find drugs that target a certain pathway, interacting drugs that are metabolized by the same cytochrome P450 or drugs that target proteins within a certain affinity range. SuperTarget is available at http://bioinformatics.charite.de/supertarget. PMID:22067455

Eliminating Cancer Stem Cells by Targeting Embryonic Signaling Pathways.

PubMed

Oren, Ohad; Smith, B Douglas

2017-02-01

Dramatic advances have been made in the understanding of cancer over the past decade. Prime among those are better appreciation of the biology of cancer and the development of targeted therapies. Despite these improvements, however, most tumors remain refractory to anti-cancer medications and frequently recur. Cancer Stem Cells (CSCs), which in some cases express markers of pluripotency (e.g., Oct-4), share many of the molecular features of normal stem cells. These cells have been hypothesised to play a role in tumor resistance and relapse. They exhibit dependence on many primitive regulatory pathways and may be best viewed in the context of embryonic signaling pathways. In this article, we review important embryonic signaling cascades and their differential expression in CSCs. We also discuss these pathways as actionable targets for novel therapies in hopes that eliminating cancer stem cells will lead to an improvement in overall survival for patients.

Signaling pathways targeted by curcumin in acute and chronic injury: burns and photo-damaged skin.

PubMed

Heng, Madalene C Y

2013-05-01

Phosphorylase kinase (PhK) is a unique enzyme in which the spatial arrangements of the specificity determinants can be manipulated to allow the enzyme to recognize substrates of different specificities. In this way, PhK is capable of transferring high energy phosphate bonds from ATP to serine/threonine and tyrosine moieties in serine/threonine kinases and tyrosine kinases, thus playing a key role in the activation of multiple signaling pathways. Phosphorylase kinase is released within five minutes following injury and is responsible for activating inflammatory pathways in injury-activated scarring following burns. In photo-damaged skin, PhK plays an important role in promoting photocarcinogenesis through activation of NF-kB-dependent signaling pathways with inhibition of apoptosis of photo-damaged cells, thus promoting the survival of precancerous cells and allowing for subsequent tumor transformation. Curcumin, the active ingredient in the spice, turmeric, is a selective and non-competitive PhK inhibitor. By inhibition of PhK, curcumin targets multiple PhK-dependent pathways, with salutary effects on a number of skin diseases induced by injury. In this paper, we show that curcumin gel produces rapid healing of burns, with little or no residual scarring. Curcumin gel is also beneficial in the repair of photo-damaged skin, including pigmentary changes, solar elastosis, thinning of the skin with telangiectasia (actinic poikiloderma), and premalignant lesions such as actinic keratoses, dysplastic nevi, and advanced solar lentigines, but the repair process takes many months. © 2012 The International Society of Dermatology.

HPV: Molecular pathways and targets.

PubMed

Gupta, Shilpi; Kumar, Prabhat; Das, Bhudev C

2018-04-05

Infection of high-risk human papillomaviruses (HPVs) is a prerequisite for the development of cervical carcinoma. HPV infections are also implicated in the development of other types of carcinomas. Chronic or persistent infection of HPV is essential but HPV alone is inadequate, additional endogenous or exogenous cues are needed along with HPV to induce cervical carcinogenesis. The strategies that high-risk HPVs have developed in differentiating epithelial cells to reach a DNA-synthesis competent state leading to tumorigenic transformation are basically due to overexpression of the E6 and E7 oncoproteins and the activation of diverse cellular regulatory or signaling pathways that are targeted by them. Moreover, the Wnt/β-catenin/Notch and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways are deregulated in various cancers, and have also been implicated in HPV-induced cancers. These are basically related to the "cancer hallmarks," and include sustaining proliferative signals, the evasion of growth suppression and immune destruction, replicative immortality, inflammation, invasion, metastasis and angiogenesis, as well as genome instability, resisting cell death, and deregulation of cellular energetics. These information could eventually aid in identifying or developing new diagnostic, prognostic biomarkers, and may contribute to design more effective targeted therapeutics and treatment strategies. Although surgery, chemotherapy and radiotherapy can cure more than 90% of women with early stage cervical cancer, the recurrent and metastatic disease remains a major cause of cancer mortality. Numerous efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent years, research on treatment strategies has proposed several options, including the role of HPV E5, E6, and E7 oncogenes, which are retained and overexpressed in most of the cervical cancers and whose respective oncoproteins are critical to the induction

The Application of the Weighted k-Partite Graph Problem to the Multiple Alignment for Metabolic Pathways.

PubMed

Chen, Wenbin; Hendrix, William; Samatova, Nagiza F

2017-12-01

The problem of aligning multiple metabolic pathways is one of very challenging problems in computational biology. A metabolic pathway consists of three types of entities: reactions, compounds, and enzymes. Based on similarities between enzymes, Tohsato et al. gave an algorithm for aligning multiple metabolic pathways. However, the algorithm given by Tohsato et al. neglects the similarities among reactions, compounds, enzymes, and pathway topology. How to design algorithms for the alignment problem of multiple metabolic pathways based on the similarity of reactions, compounds, and enzymes? It is a difficult computational problem. In this article, we propose an algorithm for the problem of aligning multiple metabolic pathways based on the similarities among reactions, compounds, enzymes, and pathway topology. First, we compute a weight between each pair of like entities in different input pathways based on the entities' similarity score and topological structure using Ay et al.'s methods. We then construct a weighted k-partite graph for the reactions, compounds, and enzymes. We extract a mapping between these entities by solving the maximum-weighted k-partite matching problem by applying a novel heuristic algorithm. By analyzing the alignment results of multiple pathways in different organisms, we show that the alignments found by our algorithm correctly identify common subnetworks among multiple pathways.

Targeting the relaxin hormonal pathway in prostate cancer.

PubMed

Neschadim, Anton; Summerlee, Alastair J S; Silvertown, Joshua D

2015-11-15

Targeting the androgen signalling pathway has long been the hallmark of anti-hormonal therapy for prostate cancer. However, development of androgen-independent prostate cancer is an inevitable outcome to therapies targeting this pathway, in part, owing to the shift from cancer dependence on androgen signalling for growth in favor of augmentation of other cellular pathways that provide proliferation-, survival- and angiogenesis-promoting signals. This review focuses on the role of the hormone relaxin in the development and progression of prostate cancer, prior to and after the onset of androgen independence, as well as its role in cancers of other reproductive tissues. As the body of literature expands, examining relaxin expression in cancerous tissues and its role in a growing number of in vitro and in vivo cancer models, our understanding of the important involvement of this hormone in cancer biology is becoming clearer. Specifically, the pleiotropic functions of relaxin affecting cell growth, angiogenesis, blood flow, cell migration and extracellular matrix remodeling are examined in the context of cancer progression. The interactions and intercepts of the intracellular signalling pathways of relaxin with the androgen pathway are explored in the context of progression of castration-resistant and androgen-independent prostate cancers. We provide an overview of current anti-hormonal therapeutic treatment options for prostate cancer and delve into therapeutic approaches and development of agents aimed at specifically antagonizing relaxin signalling to curb tumor growth. We also discuss the rationale and challenges utilizing such agents as novel anti-hormonals in the clinic, and their potential to supplement current therapeutic modalities. © 2014 UICC.

Integrative analysis of RUNX1 downstream pathways and target genes

PubMed Central

Michaud, Joëlle; Simpson, Ken M; Escher, Robert; Buchet-Poyau, Karine; Beissbarth, Tim; Carmichael, Catherine; Ritchie, Matthew E; Schütz, Frédéric; Cannon, Ping; Liu, Marjorie; Shen, Xiaofeng; Ito, Yoshiaki; Raskind, Wendy H; Horwitz, Marshall S; Osato, Motomi; Turner, David R; Speed, Terence P; Kavallaris, Maria; Smyth, Gordon K; Scott, Hamish S

2008-01-01

Background The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFβ, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFβ. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. Conclusion This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both

Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment.

PubMed

Scala, Stefania

2015-10-01

Evidence suggests that the CXC-chemokine receptor-4 pathway plays a role in cancer cell homing and metastasis, and thus represents a potential target for cancer therapy. The homeostatic microenvironment chemokine CXCL12 binds the CXCR4 and CXCR7 receptors, activating divergent signals on multiple pathways, such as ERK1/2, p38, SAPK/JNK, AKT, mTOR, and the Bruton tyrosine kinase (BTK). An activating mutation in CXCR4 is responsible for a rare disease, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and dominant CXCR4 mutations have also been reported in Waldenstrom macroglobulinemia. The CXCR4-CXCL12 axis regulates the hematopoietic stem cell niche--a property that has led to the approval of the CXCR4 antagonist plerixafor (AMD3100) for mobilization of hematopoietic precursors. In preclinical models, plerixafor has shown antimetastatic potential in vivo, offering proof of concept. Other antagonists are in preclinical and clinical development. Recent evidence demonstrates that inhibiting CXCR4 signaling restores sensitivity to CTLA-4 and PD-1 checkpoint inhibitors, creating a new line for investigation. Targeting the CXCR4-CXCL12 axis thus offers the possibility of affecting CXCR4-expressing primary tumor cells, modulating the immune response, or synergizing with other targeted anticancer therapies. ©2015 American Association for Cancer Research.

SigmaS controls multiple pathways associated with intracellular multiplication of Legionella pneumophila.

PubMed

Hovel-Miner, Galadriel; Pampou, Sergey; Faucher, Sebastien P; Clarke, Margaret; Morozova, Irina; Morozov, Pavel; Russo, James J; Shuman, Howard A; Kalachikov, Sergey

2009-04-01

Legionella pneumophila is the causative agent of the severe and potentially fatal pneumonia Legionnaires' disease. L. pneumophila is able to replicate within macrophages and protozoa by establishing a replicative compartment in a process that requires the Icm/Dot type IVB secretion system. The signals and regulatory pathways required for Legionella infection and intracellular replication are poorly understood. Mutation of the rpoS gene, which encodes sigma(S), does not affect growth in rich medium but severely decreases L. pneumophila intracellular multiplication within protozoan hosts. To gain insight into the intracellular multiplication defect of an rpoS mutant, we examined its pattern of gene expression during exponential and postexponential growth. We found that sigma(S) affects distinct groups of genes that contribute to Legionella intracellular multiplication. We demonstrate that rpoS mutants have a functional Icm/Dot system yet are defective for the expression of many genes encoding Icm/Dot-translocated substrates. We also show that sigma(S) affects the transcription of the cpxR and pmrA genes, which encode two-component response regulators that directly affect the transcription of Icm/Dot substrates. Our characterization of the L. pneumophila small RNA csrB homologs, rsmY and rsmZ, introduces a link between sigma(S) and the posttranscriptional regulator CsrA. We analyzed the network of sigma(S)-controlled genes by mutational analysis of transcriptional regulators affected by sigma(S). One of these, encoding the L. pneumophila arginine repressor homolog gene, argR, is required for maximal intracellular growth in amoebae. These data show that sigma(S) is a key regulator of multiple pathways required for L. pneumophila intracellular multiplication.

MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-β signalling pathway

PubMed Central

Lynch, Jennifer; Fay, Joanna; Meehan, Maria; Bryan, Kenneth; Watters, Karen M.; Murphy, Derek M.; Stallings, Raymond L.

2012-01-01

Transforming growth factor-β (TGF-β) signaling regulates many diverse cellular activities through both canonical (SMAD-dependent) and non-canonical branches, which includes the mitogen-activated protein kinase (MAPK), Rho-like guanosine triphosphatase and phosphatidylinositol-3-kinase/AKT pathways. Here, we demonstrate that miR-335 directly targets and downregulates genes in the TGF-β non-canonical pathways, including the Rho-associated coiled-coil containing protein (ROCK1) and MAPK1, resulting in reduced phosphorylation of downstream pathway members. Specifically, inhibition of ROCK1 and MAPK1 reduces phosphorylation levels of the motor protein myosin light chain (MLC) leading to a significant inhibition of the invasive and migratory potential of neuroblastoma cells. Additionally, miR-335 targets the leucine-rich alpha-2-glycoprotein 1 (LRG1) messenger RNA, which similarly results in a significant reduction in the phosphorylation status of MLC and a decrease in neuroblastoma cell migration and invasion. Thus, we link LRG1 to the migratory machinery of the cell, altering its activity presumably by exerting its effect within the non-canonical TGF-β pathway. Moreover, we demonstrate that the MYCN transcription factor, whose coding sequence is highly amplified in a particularly clinically aggressive neuroblastoma tumor subtype, directly binds to a region immediately upstream of the miR-335 transcriptional start site, resulting in transcriptional repression. We conclude that MYCN contributes to neuroblastoma cell migration and invasion, by directly downregulating miR-335, resulting in the upregulation of the TGF-β signaling pathway members ROCK1, MAPK1 and putative member LRG1, which positively promote this process. Our results provide novel insight into the direct regulation of TGF-β non-canonical signaling by miR-335, which in turn is downregulated by MYCN. PMID:22382496

Can we safely target the WNT pathway?

PubMed Central

Kahn, Michael

2015-01-01

WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective. PMID:24981364

Pathways from Racial Discrimination to Multiple Sexual Partners Among Male African American Adolescents

PubMed Central

Kogan, Steven M.; Yu, Tianyi; Allen, Kimberly A.; Pocock, Alexandra M.; Brody, Gene H.

2014-01-01

African American male adolescents’ involvement with multiple sexual partners has important implications for public health as well as for their development of ideas regarding masculinity and sexuality. The purpose of this study was to test hypotheses regarding the pathways through which racial discrimination affects African American adolescents’ involvement with multiple sexual partners. We hypothesized that racial discrimination would engender psychological distress, which would promote attitudes and peer affiliations conducive to multiple sexual partnerships. The study also examined the protective influence of parenting practices in buffering the influence of contextual stressors. Participants were 221 African American male youth who provided data at ages 16 and 18; their parents provided data on family socioeconomic disadvantages. Of these young men, 18.5% reported having 3 or more sexual partners during the past 3 months. Structural equation models indicated that racial discrimination contributed to sexual activity with multiple partners by inducing psychological distress, which in turn affected attitudes and peer affiliations conducive to multiple partners. The experience of protective parenting, which included racial socialization, closeness and harmony in parent-child relationships, and parental monitoring, buffered the influence of racial discrimination on psychological distress. These findings suggest targets for prevention programming and underscore the importance of efforts to reduce young men’s experience with racial discrimination. PMID:25937821

Signaling pathways relevant to cognition-enhancing drug targets.

PubMed

Ménard, Caroline; Gaudreau, Pierrette; Quirion, Rémi

2015-01-01

Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.

Targeted Quantification of Phosphorylation Dynamics in the Context of EGFR-MAPK Pathway.

PubMed

Yi, Lian; Shi, Tujin; Gritsenko, Marina A; X'avia Chan, Chi-Yuet; Fillmore, Thomas L; Hess, Becky M; Swensen, Adam C; Liu, Tao; Smith, Richard D; Wiley, H Steven; Qian, Wei-Jun

2018-04-17

Large-scale phosphoproteomics with coverage of over 10,000 sites of phosphorylation have now been routinely achieved with advanced mass spectrometry (MS)-based workflows. However, accurate targeted MS-based quantification of phosphorylation dynamics, an important direction for gaining quantitative understanding of signaling pathways or networks, has been much less investigated. Herein, we report an assessment of the targeted workflow in the context of signal transduction pathways, using the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway as our model. A total of 43 phosphopeptides from the EGFR-MAPK pathway were selected for the study. The recovery and sensitivity of two commonly used enrichment methods, immobilized metal affinity chromatography (IMAC) and titanium oxide (TiO 2 ), combined with selected reaction monitoring (SRM)-MS were evaluated. The recovery of phosphopeptides by IMAC and TiO 2 enrichment was quantified to be 38 ± 5% and 58 ± 20%, respectively, based on internal standards. Moreover, both enrichment methods provided comparable sensitivity from 1 to 100 μg starting peptides. Robust quantification was consistently achieved for most targeted phosphopeptides when starting with 25-100 μg peptides. However, the numbers of quantified targets significantly dropped when peptide samples were in the 1-25 μg range. Finally, IMAC-SRM was applied to quantify signaling dynamics of EGFR-MAPK pathway in Hs578T cells following 10 ng/mL EGF treatment. The kinetics of phosphorylation clearly revealed early and late phases of phosphorylation, even for very low abundance proteins. These results demonstrate the feasibility of robust targeted quantification of phosphorylation dynamics for specific pathways, even starting with relatively small amounts of protein.

Targeted Quantification of Phosphorylation Dynamics in the Context of EGFR-MAPK Pathway

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

Yi, Lian; Shi, Tujin; Gritsenko, Marina A.

2018-03-27

Large-scale phosphoproteomics with coverage of over 10,000 sites of phosphorylation have now been routinely achieved with advanced mass spectrometry (MS)-based workflows. However, accurate targeted MS-based quantification of phosphorylation dynamics, an important direction for gaining quantitative understanding of signaling pathways or networks, has been much less investigated. Herein, we report an assessment of the targeted workflow in the context of signal transduction pathways, using the epidermal growth factor receptor (EGFR)–mitogen-activated protein kinase (MAPK) pathway as our model. 43 phosphopeptides from the EGFR–MAPK pathway were selected for the study. The recovery and sensitivity of a workflow consisted of two commonly used enrichmentmore » methods, immobilized metal affinity chromatography (IMAC) and titanium oxide (TiO2), combined with selected reaction monitoring (SRM)-MS, were evaluated. The recovery of phosphopeptides by IMAC and TiO2 enrichment was quantified to be 38 ± 5% and 58 ± 20%, respectively, based on internal standards. Moreover, both enrichment methods provided comparable sensitivity from 1-100 g starting peptides. Robust quantification was consistently achieved for most targeted phosphopeptides when starting with 25-100 g peptides. However, the numbers of quantified targets significantly dropped when peptide samples were in the 1-25g range. Finally, IMAC-SRM was applied to quantify signaling dynamics of EGFR-MAPK pathway in Hs578T cells following 3 ng/mL EGF treatment. The kinetics of phosphorylation clearly revealed early and late phases of phosphorylation, even for very low abundance proteins. These results demonstrate the feasibility of robust targeted quantification of phosphorylation dynamics for specific pathways, even starting with relatively small amounts of protein.« less

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.

Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer.

PubMed

Hwang, Rosa F; Moore, Todd T; Hattersley, Maureen Mertens; Scarpitti, Meghan; Yang, Bin; Devereaux, Erik; Ramachandran, Vijaya; Arumugam, Thiruvengadam; Ji, Baoan; Logsdon, Craig D; Brown, Jeffrey L; Godin, Robert

2012-09-01

The Hedgehog (Hh) pathway has emerged as an important pathway in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. The purpose of this study was to determine the role of pancreatic cancer-associated fibroblasts (human pancreatic stellate cells, HPSCs) in Hh signaling. In addition, we evaluated the efficacy of a novel Hh antagonist, AZD8542, on tumor progression with an emphasis on the role of the stroma compartment. Expression of Hh pathway members and activation of the Hh pathway were analyzed in both HPSCs and pancreatic cancer cells. We tested the effects of Smoothened (SMO) inhibition with AZD8542 on tumor growth in vivo using an orthotopic model of pancreatic cancer containing varying amounts of stroma. HPSCs expressed high levels of SMO receptor and low levels of Hh ligands, whereas cancer cells showed the converse expression pattern. HPSC proliferation was stimulated by Sonic Hedgehog with upregulation of downstream GLI1 mRNA. These effects were abrogated by AZD8542 treatment. In an orthotopic model of pancreatic cancer, AZD8542 inhibited tumor growth only when HPSCs were present, implicating a paracrine signaling mechanism dependent on stroma. Further evidence of paracrine signaling of the Hh pathway in prostate and colon cancer models is provided, demonstrating the broader applicability of our findings. Based on the use of our novel human-derived pancreatic cancer stellate cells, our results suggest that Hh-targeted therapies primarily affect the tumor-associated stroma, rather than the epithelial compartment.

Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand?

PubMed Central

Baig, S; Seevasant, I; Mohamad, J; Mukheem, A; Huri, H Z; Kamarul, T

2016-01-01

Underneath the intricacy of every cancer lies mysterious events that impel the tumour cell and its posterity into abnormal growth and tissue invasion. Oncogenic mutations disturb the regulatory circuits responsible for the governance of versatile cellular functions, permitting tumour cells to endure deregulated proliferation, resist to proapoptotic insults, invade and erode normal tissues and above all escape apoptosis. This disruption of apoptosis has been highly implicated in various malignancies and has been exploited as an anticancer strategy. Owing to the fact that apoptosis causes minimal inflammation and damage to the tissue, apoptotic cell death-based therapy has been the centre of attraction for the development of anticancer drugs. Increased understanding of the molecular pathways underlying apoptosis has enabled scientists to establish unique approaches targeting apoptosis pathways in cancer therapeutics. In this review, we reconnoitre the two major pathways (intrinsic and extrinsic) targeted cancer therapeutics, steering toward chief modulators of these pathways, such as B-cell lymphoma 2 protein family members (pro- and antiapoptotic), inhibitor of apoptosis proteins, and the foremost thespian of extrinsic pathway regulator, tumour necrosis factor-related apoptosis-inducing agent. Together, we also will have a look from clinical perspective to address the agents (drugs) and therapeutic strategies adopted to target these specific proteins/pathways that have entered clinical trials. PMID:26775709

Drug target inference through pathway analysis of genomics data

PubMed Central

Ma, Haisu; Zhao, Hongyu

2013-01-01

Statistical modeling coupled with bioinformatics is commonly used for drug discovery. Although there exist many approaches for single target based drug design and target inference, recent years have seen a paradigm shift to system-level pharmacological research. Pathway analysis of genomics data represents one promising direction for computational inference of drug targets. This article aims at providing a comprehensive review on the evolving issues is this field, covering methodological developments, their pros and cons, as well as future research directions. PMID:23369829

Emerging pathways and future targets for the molecular therapy of pancreatic cancer.

PubMed

Vaccaro, Vanja; Melisi, Davide; Bria, Emilio; Cuppone, Federica; Ciuffreda, Ludovica; Pino, Maria Simona; Gelibter, Alain; Tortora, Giampaolo; Cognetti, Francesco; Milella, Michele

2011-10-01

Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.

Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens

PubMed Central

Thomas, Reuben; Phuong, Jimmy; McHale, Cliona M.; Zhang, Luoping

2012-01-01

We have applied bioinformatic approaches to identify pathways common to chemical leukemogens and to determine whether leukemogens could be distinguished from non-leukemogenic carcinogens. From all known and probable carcinogens classified by IARC and NTP, we identified 35 carcinogens that were associated with leukemia risk in human studies and 16 non-leukemogenic carcinogens. Using data on gene/protein targets available in the Comparative Toxicogenomics Database (CTD) for 29 of the leukemogens and 11 of the non-leukemogenic carcinogens, we analyzed for enrichment of all 250 human biochemical pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The top pathways targeted by the leukemogens included metabolism of xenobiotics by cytochrome P450, glutathione metabolism, neurotrophin signaling pathway, apoptosis, MAPK signaling, Toll-like receptor signaling and various cancer pathways. The 29 leukemogens formed 18 distinct clusters comprising 1 to 3 chemicals that did not correlate with known mechanism of action or with structural similarity as determined by 2D Tanimoto coefficients in the PubChem database. Unsupervised clustering and one-class support vector machines, based on the pathway data, were unable to distinguish the 29 leukemogens from 11 non-leukemogenic known and probable IARC carcinogens. However, using two-class random forests to estimate leukemogen and non-leukemogen patterns, we estimated a 76% chance of distinguishing a random leukemogen/non-leukemogen pair from each other. PMID:22851955

Molecular Pathways: Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer

PubMed Central

Previs, Rebecca A.; Coleman, Robert L.; Harris, Adrian L.; Sood, Anil K.

2014-01-01

Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and crosstalk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3–4, Jagged 1–2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Since the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway. PMID:25388163

An Assessment of Database-Validated microRNA Target Genes in Normal Colonic Mucosa: Implications for Pathway Analysis.

PubMed

Slattery, Martha L; Herrick, Jennifer S; Stevens, John R; Wolff, Roger K; Mullany, Lila E

2017-01-01

Determination of functional pathways regulated by microRNAs (miRNAs), while an essential step in developing therapeutics, is challenging. Some miRNAs have been studied extensively; others have limited information. In this study, we focus on 254 miRNAs previously identified as being associated with colorectal cancer and their database-identified validated target genes. We use RNA-Seq data to evaluate messenger RNA (mRNA) expression for 157 subjects who also had miRNA expression data. In the replication phase of the study, we replicated associations between 254 miRNAs associated with colorectal cancer and mRNA expression of database-identified target genes in normal colonic mucosa. In the discovery phase of the study, we evaluated expression of 18 miR-NAs (those with 20 or fewer database-identified target genes along with miR-21-5p, miR-215-5p, and miR-124-3p which have more than 500 database-identified target genes) with expression of 17 434 mRNAs to identify new targets in colon tissue. Seed region matches between miRNA and newly identified targeted mRNA were used to help determine direct miRNA-mRNA associations. From the replication of the 121 miRNAs that had at least 1 database-identified target gene using mRNA expression methods, 97.9% were expressed in normal colonic mucosa. Of the 8622 target miRNA-mRNA associations identified in the database, 2658 (30.2%) were associated with gene expression in normal colonic mucosa after adjusting for multiple comparisons. Of the 133 miRNAs with database-identified target genes by non-mRNA expression methods, 97.2% were expressed in normal colonic mucosa. After adjustment for multiple comparisons, 2416 miRNA-mRNA associations remained significant (19.8%). Results from the discovery phase based on detailed examination of 18 miRNAs identified more than 80 000 miRNA-mRNA associations that had not previously linked to the miRNA. Of these miRNA-mRNA associations, 15.6% and 14.8% had seed matches for CRCh38 and CRCh37

Drug targeting of oncogenic pathways in melanoma.

PubMed

Fecher, Leslie A; Amaravadi, Ravi K; Schuchter, Lynn M; Flaherty, Keith T

2009-06-01

Melanoma continues to be one of the most aggressive and morbid malignancies once metastatic. Overall survival for advanced unresectable melanoma has not changed over the past several decades. However, the presence of some long-term survivors of metastatic melanoma highlights the heterogeneity of this disease and the potential for improved outcomes. Current research is uncovering the molecular and genetic scaffolding of normal and aberrant cell function. The known oncogenic pathways in melanoma and the attempts to develop therapy for them are discussed. The targeting of certain cellular processes, downstream of the common genetic alterations, for which the issues of target and drug validation are somewhat distinct, are also highlighted.

Costs of California Multiple Pathway Programs. Policy Report

ERIC Educational Resources Information Center

Parsi, Ace; Plank, David; Stern, David

2010-01-01

There is widespread agreement that many of California's high schools are doing a poor job of preparing their students for college and careers. The James Irvine Foundation is sponsoring a major initiative to develop "Multiple Pathways"--now called the Linked Learning approach--as a strategy for improving the performance of California high…

Managing patient pathways to achieve lung cancer waiting time targets: mixed methods study

PubMed Central

Ip, Hugh; Amer, Tarik; Dangoor, Michael; Zamir, Affan; Gibbings-Isaac, Darryl; Kochhar, Ranjeev; Heymann, Timothy

2012-01-01

Objectives England's National Health Service (NHS) introduced a 62-day target, from referral to treatment, to make lung cancer patient pathways more efficient. This study aims to understand pathway delays that lead to breaches of the target when patients need care in both secondary and tertiary setting, so more than one institution is involved. Design Mixed methods cross case analysis. Setting Two tertiary referral hospitals in London. Participants Database records of 53 patients were analysed. Nineteen sets of patient notes were used for pathway mapping. Seventeen doctors, four nurses, eight managers and administrators were interviewed. Main outcome measures Qualitative methods include pathway mapping and semi-structured interviews. Quantitative analysis of patient pathway times from cancer services records. Results The majority of the patient pathway (68.4%) is spent in secondary centres. There is more variability in the processes of secondary centres but tertiary centres do not have perfect processes either. Three themes emerged from discussions: information flows, pathway performance and the role of the multidisciplinary approach. Conclusions The actions of secondary centres have a greater influence on whether a patient breaches the 62-day target, compared with tertiary centres. Nevertheless variability exists in both, with potential for improvement. PMID:23162682

Reliable pre-eclampsia pathways based on multiple independent microarray data sets.

PubMed

Kawasaki, Kaoru; Kondoh, Eiji; Chigusa, Yoshitsugu; Ujita, Mari; Murakami, Ryusuke; Mogami, Haruta; Brown, J B; Okuno, Yasushi; Konishi, Ikuo

2015-02-01

Pre-eclampsia is a multifactorial disorder characterized by heterogeneous clinical manifestations. Gene expression profiling of preeclamptic placenta have provided different and even opposite results, partly due to data compromised by various experimental artefacts. Here we aimed to identify reliable pre-eclampsia-specific pathways using multiple independent microarray data sets. Gene expression data of control and preeclamptic placentas were obtained from Gene Expression Omnibus. Single-sample gene-set enrichment analysis was performed to generate gene-set activation scores of 9707 pathways obtained from the Molecular Signatures Database. Candidate pathways were identified by t-test-based screening using data sets, GSE10588, GSE14722 and GSE25906. Additionally, recursive feature elimination was applied to arrive at a further reduced set of pathways. To assess the validity of the pre-eclampsia pathways, a statistically-validated protocol was executed using five data sets including two independent other validation data sets, GSE30186, GSE44711. Quantitative real-time PCR was performed for genes in a panel of potential pre-eclampsia pathways using placentas of 20 women with normal or severe preeclamptic singleton pregnancies (n = 10, respectively). A panel of ten pathways were found to discriminate women with pre-eclampsia from controls with high accuracy. Among these were pathways not previously associated with pre-eclampsia, such as the GABA receptor pathway, as well as pathways that have already been linked to pre-eclampsia, such as the glutathione and CDKN1C pathways. mRNA expression of GABRA3 (GABA receptor pathway), GCLC and GCLM (glutathione metabolic pathway), and CDKN1C was significantly reduced in the preeclamptic placentas. In conclusion, ten accurate and reliable pre-eclampsia pathways were identified based on multiple independent microarray data sets. A pathway-based classification may be a worthwhile approach to elucidate the pathogenesis of pre

Combining qualitative and quantitative operational research methods to inform quality improvement in pathways that span multiple settings

PubMed Central

Crowe, Sonya; Brown, Katherine; Tregay, Jenifer; Wray, Jo; Knowles, Rachel; Ridout, Deborah A; Bull, Catherine; Utley, Martin

2017-01-01

Background Improving integration and continuity of care across sectors within resource constraints is a priority in many health systems. Qualitative operational research methods of problem structuring have been used to address quality improvement in services involving multiple sectors but not in combination with quantitative operational research methods that enable targeting of interventions according to patient risk. We aimed to combine these methods to augment and inform an improvement initiative concerning infants with congenital heart disease (CHD) whose complex care pathway spans multiple sectors. Methods Soft systems methodology was used to consider systematically changes to services from the perspectives of community, primary, secondary and tertiary care professionals and a patient group, incorporating relevant evidence. Classification and regression tree (CART) analysis of national audit datasets was conducted along with data visualisation designed to inform service improvement within the context of limited resources. Results A ‘Rich Picture’ was developed capturing the main features of services for infants with CHD pertinent to service improvement. This was used, along with a graphical summary of the CART analysis, to guide discussions about targeting interventions at specific patient risk groups. Agreement was reached across representatives of relevant health professions and patients on a coherent set of targeted recommendations for quality improvement. These fed into national decisions about service provision and commissioning. Conclusions When tackling complex problems in service provision across multiple settings, it is important to acknowledge and work with multiple perspectives systematically and to consider targeting service improvements in response to confined resources. Our research demonstrates that applying a combination of qualitative and quantitative operational research methods is one approach to doing so that warrants further

MicroRNA-1271 inhibits proliferation and promotes apoptosis of multiple myeloma cells through inhibiting smoothened-mediated Hedgehog signaling pathway.

PubMed

Xu, Zhengwei; Huang, Chen; Hao, Dingjun

2017-02-01

MicroRNAs (miRNAs) have emerged as important regulators in multiple myeloma (MM). miR-1271 is a tumor suppressor in many cancer types. However, the biological role of miR-1271 in MM remains unclear. In the present study, we elucidated the biological role of miR-1271 in MM. Results showed that miR-1271 was significantly decreased in primary MM cells from MM patients and MM cell lines. Overexpression of miR-1271 inhibited proliferation and promoted apoptosis of MM cells. Conversely, suppression of miR-1271 showed the opposite effect. Bioinformatics algorithm analysis predicted that smoothened (SMO), the activator of Hedgehog (HH) signaling pathway, was a direct target of miR-1271 that was experimentally verified by a dual-luciferase reporter assay. Furthermore, overexpression of miR-1271 inhibited SMO expression and HH signaling pathway. Conversely, the restoration of SMO expression markedly abolished the effect of miR-1271 overexpression on cell proliferation, apoptosis and HH signaling pathway in MM cells. Taken together, the present study suggests that miR-1271 functions as a tumor suppressor that inhibits proliferation and promotes apoptosis of MM cells through inhibiting SMO-mediated HH signaling pathway. This finding implies that miR-1271 is a potential therapeutic target for the treatment of MM.

Approaches for targeting self-renewal pathways in cancer stem cells: implications for hematological treatments.

PubMed

Horne, Gillian A; Copland, Mhairi

2017-05-01

Self-renewal is considered a defining property of stem cells. Self-renewal is essential in embryogenesis and normal tissue repair and homeostasis. However, in cancer, self-renewal pathways, e.g. WNT, NOTCH, Hedgehog and BMP, frequently become de-regulated in stem cells, or more mature progenitor cells acquire self-renewal properties, resulting in abnormal tissue growth and tumorigenesis. Areas covered: This review considers the conserved embryonic self-renewal pathways, including WNT, NOTCH, Hedgehog and BMP. The article describes recent advances in our understanding of these pathways in leukemia and, more specifically, leukemia stem cells (LSC), how these pathways cross-talk and interact with the LSC microenvironment, and discusses the clinical implications and potential therapeutic strategies, both in preclinical and in clinical trials for hematological malignancies. Expert opinion: The conserved embryonic self-renewal pathways are frequently de-regulated in cancer stem cells (CSC), including LSCs. There is significant cross-talk between self-renewal pathways, and their downstream targets, and the microenvironment. Effective targeting of these pathways is challenging due to cross-talk, and importantly, because these pathways are important for normal stem cells as well as CSC, adverse effects on normal tissues may mean a therapeutic window cannot be identified. Nonetheless, several agents targeting these pathways are currently in clinical trials in hematological malignancies.

Pathways and therapeutic targets in melanoma

PubMed Central

Shtivelman, Emma; Davies, Michael A.; Hwu, Patrick; Yang, James; Lotem, Michal; Oren, Moshe; Flaherty, Keith T.; Fisher, David E.

2014-01-01

This review aims to summarize the current knowledge of molecular pathways and their clinical relevance in melanoma. Metastatic melanoma was a grim diagnosis, but in recent years tremendous advances have been made in treatments. Chemotherapy provided little benefit in these patients, but development of targeted and new immune approaches made radical changes in prognosis. This would not have happened without remarkable advances in understanding the biology of disease and tremendous progress in the genomic (and other “omics”) scale analyses of tumors. The big problems facing the field are no longer focused exclusively on the development of new treatment modalities, though this is a very busy area of clinical research. The focus shifted now to understanding and overcoming resistance to targeted therapies, and understanding the underlying causes of the heterogeneous responses to immune therapy. PMID:24743024

Phytochemicals as multi-target inhibitors of the inflammatory pathway- A modeling and experimental study.

PubMed

Devi, Nisha S; Ramanan, Meera; Paragi-Vedanthi, Padmapriya; Doble, Mukesh

2017-03-11

The arachidonic acid pathway consists of several enzymes and targeting them is favored for developing anti-inflammatory drugs. However, till date the current drugs are generally active against a single target, leading to undesirable side-effects. Phytochemicals are known to inhibit multiple targets simultaneously and hence, an attempt is made here to investigate their suitability. A pharmacophore based study is performed with three sets of reported phytochemicals namely, dual 5-LOX/mPGES1, alkaloids and FLAP inhibitors. The analysis indicated that phenylpropanoids (including ferulic acid) and benzoic acids derivatives, and berberine mapped onto these pharmacophores with three hydrophobic centroids and an acceptor feature. 2,4,5-trimethoxy (7) and 3,4-dimethoxy cinnamic acids (8) mapped onto all the three pharmacophores. Experimental studies indicated that berberine inhibited 5-LOX (100 μM) and PGE 2 (50 μM) production by 72.2 and 72.0% and ferulic acid by 74.3 and 54.4% respectively. This approach offers a promising theoretical combined with experimental strategy for designing novel molecules against inflammatory enzymes. Copyright © 2017 Elsevier Inc. All rights reserved.

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

PubMed Central

Miele, Lucio; Harris, Pamela Jo; Jeong, Woondong; Bando, Hideaki; Kahn, Michael; Yang, Sherry X.

2015-01-01

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents. PMID:25850553

Avalanche multiplication and impact ionization in amorphous selenium photoconductive target

NASA Astrophysics Data System (ADS)

Park, Wug-Dong; Tanioka, Kenkichi

2014-03-01

The avalanche multiplication factor and the hole ionization coefficient in the amorphous selenium (a-Se) high-gain avalanche rushing amorphous photoconductor (HARP) target depend on the electric field. The phenomenon of avalanche multiplication and impact ionization in the 0.4-µm-thick a-Se HARP target is investigated. The hot carrier energy in the 0.4-µm-thick a-Se HARP target increases linearly as the target voltage increases. The energy relaxation length of hot carriers in the a-Se photoconductor of the 0.4-µm-thick HARP target saturates as the electric field increases. The average energy Eav of a hot carrier and the energy relaxation length λE in the a-Se photoconductor of the 0.4-µm-thick HARP target at 1 × 108 V/m were 0.25 eV and 2.5 nm, respectively. In addition, the hole ionization coefficient β and the avalanche multiplication factor M are derived as a function of the electric field, the average energy of a hot carrier, and the impact ionization energy. The experimental hole ionization coefficient β and the avalanche multiplication factor M in the 0.4-µm-thick a-Se HARP target agree with the theoretical results.

Multiple Sensory-Motor Pathways Lead to Coordinated Visual Attention

PubMed Central

Yu, Chen; Smith, Linda B.

2016-01-01

Joint attention has been extensively studied in the developmental literature because of overwhelming evidence that the ability to socially coordinate visual attention to an object is essential to healthy developmental outcomes, including language learning. The goal of the present study is to understand the complex system of sensory-motor behaviors that may underlie the establishment of joint attention between parents and toddlers. In an experimental task, parents and toddlers played together with multiple toys. We objectively measured joint attention – and the sensory-motor behaviors that underlie it – using a dual head-mounted eye-tracking system and frame-by-frame coding of manual actions. By tracking the momentary visual fixations and hand actions of each participant, we precisely determined just how often they fixated on the same object at the same time, the visual behaviors that preceded joint attention, and manual behaviors that preceded and co-occurred with joint attention. We found that multiple sequential sensory-motor patterns lead to joint attention. In addition, there are developmental changes in this multi-pathway system evidenced as variations in strength among multiple routes. We propose that coordinated visual attention between parents and toddlers is primarily a sensory-motor behavior. Skill in achieving coordinated visual attention in social settings – like skills in other sensory-motor domains – emerges from multiple pathways to the same functional end. PMID:27016038

Multiple Sensory-Motor Pathways Lead to Coordinated Visual Attention.

PubMed

Yu, Chen; Smith, Linda B

2017-02-01

Joint attention has been extensively studied in the developmental literature because of overwhelming evidence that the ability to socially coordinate visual attention to an object is essential to healthy developmental outcomes, including language learning. The goal of this study was to understand the complex system of sensory-motor behaviors that may underlie the establishment of joint attention between parents and toddlers. In an experimental task, parents and toddlers played together with multiple toys. We objectively measured joint attention-and the sensory-motor behaviors that underlie it-using a dual head-mounted eye-tracking system and frame-by-frame coding of manual actions. By tracking the momentary visual fixations and hand actions of each participant, we precisely determined just how often they fixated on the same object at the same time, the visual behaviors that preceded joint attention and manual behaviors that preceded and co-occurred with joint attention. We found that multiple sequential sensory-motor patterns lead to joint attention. In addition, there are developmental changes in this multi-pathway system evidenced as variations in strength among multiple routes. We propose that coordinated visual attention between parents and toddlers is primarily a sensory-motor behavior. Skill in achieving coordinated visual attention in social settings-like skills in other sensory-motor domains-emerges from multiple pathways to the same functional end. Copyright © 2016 Cognitive Science Society, Inc.

Seeking unique and common biological themes in multiple gene lists or datasets: pathway pattern extraction pipeline for pathway-level comparative analysis.

PubMed

Yi, Ming; Mudunuri, Uma; Che, Anney; Stephens, Robert M

2009-06-29

One of the challenges in the analysis of microarray data is to integrate and compare the selected (e.g., differential) gene lists from multiple experiments for common or unique underlying biological themes. A common way to approach this problem is to extract common genes from these gene lists and then subject these genes to enrichment analysis to reveal the underlying biology. However, the capacity of this approach is largely restricted by the limited number of common genes shared by datasets from multiple experiments, which could be caused by the complexity of the biological system itself. We now introduce a new Pathway Pattern Extraction Pipeline (PPEP), which extends the existing WPS application by providing a new pathway-level comparative analysis scheme. To facilitate comparing and correlating results from different studies and sources, PPEP contains new interfaces that allow evaluation of the pathway-level enrichment patterns across multiple gene lists. As an exploratory tool, this analysis pipeline may help reveal the underlying biological themes at both the pathway and gene levels. The analysis scheme provided by PPEP begins with multiple gene lists, which may be derived from different studies in terms of the biological contexts, applied technologies, or methodologies. These lists are then subjected to pathway-level comparative analysis for extraction of pathway-level patterns. This analysis pipeline helps to explore the commonality or uniqueness of these lists at the level of pathways or biological processes from different but relevant biological systems using a combination of statistical enrichment measurements, pathway-level pattern extraction, and graphical display of the relationships of genes and their associated pathways as Gene-Term Association Networks (GTANs) within the WPS platform. As a proof of concept, we have used the new method to analyze many datasets from our collaborators as well as some public microarray datasets. This tool provides a

ACTP: A webserver for predicting potential targets and relevant pathways of autophagy-modulating compounds

PubMed Central

Ouyang, Liang; Cai, Haoyang; Liu, Bo

2016-01-01

Autophagy (macroautophagy) is well known as an evolutionarily conserved lysosomal degradation process for long-lived proteins and damaged organelles. Recently, accumulating evidence has revealed a series of small-molecule compounds that may activate or inhibit autophagy for therapeutic potential on human diseases. However, targeting autophagy for drug discovery still remains in its infancy. In this study, we developed a webserver called Autophagic Compound-Target Prediction (ACTP) (http://actp.liu-lab.com/) that could predict autophagic targets and relevant pathways for a given compound. The flexible docking of submitted small-molecule compound (s) to potential autophagic targets could be performed by backend reverse docking. The webpage would return structure-based scores and relevant pathways for each predicted target. Thus, these results provide a basis for the rapid prediction of potential targets/pathways of possible autophagy-activating or autophagy-inhibiting compounds without labor-intensive experiments. Moreover, ACTP will be helpful to shed light on identifying more novel autophagy-activating or autophagy-inhibiting compounds for future therapeutic implications. PMID:26824420

Targeting the Hedgehog pathway in cancer: can the spines be smoothened?

PubMed

Ailles, Laurie; Siu, Lillian L

2011-04-15

Aberrant Hedgehog (Hh) pathway signaling has been suggested to play a role in the development of multiple solid tumors and hematologic malignancies. GDC-0449 is a novel first-in-human, first-in-class smoothened (SMO) inhibitor, which has completed its phase I evaluation and achieved proof of concept in tumors with Hh pathway mutations. ©2011 AACR.

MicroRNA expression, target genes, and signaling pathways in infants with a ventricular septal defect.

PubMed

Chai, Hui; Yan, Zhaoyuan; Huang, Ke; Jiang, Yuanqing; Zhang, Lin

2018-02-01

This study aimed to systematically investigate the relationship between miRNA expression and the occurrence of ventricular septal defect (VSD), and characterize the miRNA target genes and pathways that can lead to VSD. The miRNAs that were differentially expressed in blood samples from VSD and normal infants were screened and validated by implementing miRNA microarrays and qRT-PCR. The target genes regulated by differentially expressed miRNAs were predicted using three target gene databases. The functions and signaling pathways of the target genes were enriched using the GO database and KEGG database, respectively. The transcription and protein expression of specific target genes in critical pathways were compared in the VSD and normal control groups using qRT-PCR and western blotting, respectively. Compared with the normal control group, the VSD group had 22 differentially expressed miRNAs; 19 were downregulated and three were upregulated. The 10,677 predicted target genes participated in many biological functions related to cardiac development and morphogenesis. Four target genes (mGLUR, Gq, PLC, and PKC) were involved in the PKC pathway and four (ECM, FAK, PI3 K, and PDK1) were involved in the PI3 K-Akt pathway. The transcription and protein expression of these eight target genes were significantly upregulated in the VSD group. The 22 miRNAs that were dysregulated in the VSD group were mainly downregulated, which may result in the dysregulation of several key genes and biological functions related to cardiac development. These effects could also be exerted via the upregulation of eight specific target genes, the subsequent over-activation of the PKC and PI3 K-Akt pathways, and the eventual abnormal cardiac development and VSD.

Making assessments while taking repeated risks: a pattern of multiple response pathways.

PubMed

Pleskac, Timothy J; Wershbale, Avishai

2014-02-01

Beyond simply a decision process, repeated risky decisions also require a number of cognitive processes including learning, search and exploration, and attention. In this article, we examine how multiple response pathways develop over repeated risky decisions. Using the Balloon Analogue Risk Task (BART) as a case study, we show that 2 different response pathways emerge over the course of the task. The assessment pathway is a slower, more controlled pathway where participants deliberate over taking a risk. The 2nd pathway is a faster, more automatic process where no deliberation occurs. Results imply the slower assessment pathway is taken as choice conflict increases and that the faster automatic response is a learned response. Based on these results, we modify an existing formal cognitive model of decision making during the BART to account for these dual response pathways. The slower more deliberative response process is modeled with a sequential sampling process where evidence is accumulated to a threshold, while the other response is given automatically. We show that adolescents with conduct disorder and substance use disorder symptoms not only evaluate risks differently during the BART but also differ in the rate at which they develop the more automatic response. More broadly, our results suggest cognitive models of judgment decision making need to transition from treating observed decisions as the result of a single response pathway to the result of multiple response pathways that change and develop over time.

Novel Hedgehog pathway targets against basal cell carcinoma

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

Tang, Jean Y.; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA; So, P.-L.

2007-11-01

The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastrointestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting thatmore » agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.« less

Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways

PubMed Central

Jain, Payal; Silva, Amanda; Han, Harry J.; Lang, Shih-Shan; Zhu, Yuankun; Boucher, Katie; Smith, Tiffany E.; Vakil, Aesha; Diviney, Patrick; Choudhari, Namrata; Raman, Pichai; Busch, Christine M.; Delaney, Tim; Yang, Xiaodong; Olow, Aleksandra K.; Mueller, Sabine; Haas-Kogan, Daphne; Fox, Elizabeth; Storm, Phillip B.; Resnick, Adam C.; Waanders, Angela J.

2017-01-01

Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs. PMID:29156677

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

PubMed Central

Abraham, Clara; Dulai, Parambir S.; Vermeire, Séverine; Sandborn, William J.

2016-01-01

Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics. PMID:27780712

Targeting fibroblast growth factor pathways in endometrial cancer.

PubMed

Winterhoff, Boris; Konecny, Gottfried E

Novel treatments that improve outcomes for patients with recurrent or metastatic endometrial cancer (EC) remain an unmet need. Aberrant signaling by fibroblast growth factors (FGFs) and FGF receptors (FGFRs) has been implicated in several human cancers. Activating mutations in FGFR2 have been found in up to 16% of ECs, suggesting an opportunity for targeted therapy. This review summarizes the role of the FGF pathway in angiogenesis and EC, and provides an overview of FGFR-targeted therapies under clinical development for the treatment of EC. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Examining perceptual and conceptual set biases in multiple-target visual search.

PubMed

Biggs, Adam T; Adamo, Stephen H; Dowd, Emma Wu; Mitroff, Stephen R

2015-04-01

Visual search is a common practice conducted countless times every day, and one important aspect of visual search is that multiple targets can appear in a single search array. For example, an X-ray image of airport luggage could contain both a water bottle and a gun. Searchers are more likely to miss additional targets after locating a first target in multiple-target searches, which presents a potential problem: If airport security officers were to find a water bottle, would they then be more likely to miss a gun? One hypothetical cause of multiple-target search errors is that searchers become biased to detect additional targets that are similar to a found target, and therefore become less likely to find additional targets that are dissimilar to the first target. This particular hypothesis has received theoretical, but little empirical, support. In the present study, we tested the bounds of this idea by utilizing "big data" obtained from the mobile application Airport Scanner. Multiple-target search errors were substantially reduced when the two targets were identical, suggesting that the first-found target did indeed create biases during subsequent search. Further analyses delineated the nature of the biases, revealing both a perceptual set bias (i.e., a bias to find additional targets with features similar to those of the first-found target) and a conceptual set bias (i.e., a bias to find additional targets with a conceptual relationship to the first-found target). These biases are discussed in terms of the implications for visual-search theories and applications for professional visual searchers.

Engineered bifunctional proteins and stem cells: next generation of targeted cancer therapeutics.

PubMed

Choi, Sung Hugh; Shah, Khalid

2016-09-01

Redundant survival signaling pathways and their crosstalk within tumor and/or between tumor and their microenvironment are key impediments to developing effective targeted therapies for cancer. Therefore developing therapeutics that target multiple receptor signaling pathways in tumors and utilizing efficient platforms to deliver such therapeutics are critical to the success of future targeted therapies. During the past two decades, a number of bifunctional multi-targeting antibodies, fusion proteins, and oncolytic viruses have been developed and various stem cell types have been engineered to efficiently deliver them to tumors. In this review, we discuss the design and efficacy of therapeutics targeting multiple pathways in tumors and the therapeutic potential of therapeutic stem cells engineered with bifunctional agents.

Combining qualitative and quantitative operational research methods to inform quality improvement in pathways that span multiple settings.

PubMed

Crowe, Sonya; Brown, Katherine; Tregay, Jenifer; Wray, Jo; Knowles, Rachel; Ridout, Deborah A; Bull, Catherine; Utley, Martin

2017-08-01

Improving integration and continuity of care across sectors within resource constraints is a priority in many health systems. Qualitative operational research methods of problem structuring have been used to address quality improvement in services involving multiple sectors but not in combination with quantitative operational research methods that enable targeting of interventions according to patient risk. We aimed to combine these methods to augment and inform an improvement initiative concerning infants with congenital heart disease (CHD) whose complex care pathway spans multiple sectors. Soft systems methodology was used to consider systematically changes to services from the perspectives of community, primary, secondary and tertiary care professionals and a patient group, incorporating relevant evidence. Classification and regression tree (CART) analysis of national audit datasets was conducted along with data visualisation designed to inform service improvement within the context of limited resources. A 'Rich Picture' was developed capturing the main features of services for infants with CHD pertinent to service improvement. This was used, along with a graphical summary of the CART analysis, to guide discussions about targeting interventions at specific patient risk groups. Agreement was reached across representatives of relevant health professions and patients on a coherent set of targeted recommendations for quality improvement. These fed into national decisions about service provision and commissioning. When tackling complex problems in service provision across multiple settings, it is important to acknowledge and work with multiple perspectives systematically and to consider targeting service improvements in response to confined resources. Our research demonstrates that applying a combination of qualitative and quantitative operational research methods is one approach to doing so that warrants further consideration. Published by the BMJ Publishing Group

Predicting Drug Combination Index and Simulating the Network-Regulation Dynamics by Mathematical Modeling of Drug-Targeted EGFR-ERK Signaling Pathway

NASA Astrophysics Data System (ADS)

Huang, Lu; Jiang, Yuyang; Chen, Yuzong

2017-01-01

Synergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect. The predicted CIs and combination therapeutic effects of the EGFR-BRaf, BRaf-MEK, FTI-MEK, and FTI-BRaf inhibitor combinations showed consistent synergism. Our results suggest that existing pathway models may be potentially extended for developing drug-targeted pathway models to predict drug combination CI values, isobolograms, and drug-response surfaces as well as to analyze the dynamics of individual and combinations of drugs. With our model, the efficacy of potential drug combinations can be predicted. Our method complements the developed in-silico methods (e.g. the chemogenomic profile and the statistically-inferenced network models) by predicting drug combination effects from the perspectives of pathway dynamics using experimental or validated molecular kinetic constants, thereby facilitating the collective prediction of drug combination effects in diverse ranges of disease systems.

An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes

PubMed Central

Huard, Jérémy; Mueller, Stephanie; Gilles, Ernst D; Klingmüller, Ursula; Klamt, Steffen

2012-01-01

During liver regeneration, quiescent hepatocytes re-enter the cell cycle to proliferate and compensate for lost tissue. Multiple signals including hepatocyte growth factor, epidermal growth factor, tumor necrosis factor α, interleukin-6, insulin and transforming growth factor β orchestrate these responses and are integrated during the G1 phase of the cell cycle. To investigate how these inputs influence DNA synthesis as a measure for proliferation, we established a large-scale integrated logical model connecting multiple signaling pathways and the cell cycle. We constructed our model based upon established literature knowledge, and successively improved and validated its structure using hepatocyte-specific literature as well as experimental DNA synthesis data. Model analyses showed that activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways was sufficient and necessary for triggering DNA synthesis. In addition, we identified key species in these pathways that mediate DNA replication. Our model predicted oncogenic mutations that were compared with the COSMIC database, and proposed intervention targets to block hepatocyte growth factor-induced DNA synthesis, which we validated experimentally. Our integrative approach demonstrates that, despite the complexity and size of the underlying interlaced network, logical modeling enables an integrative understanding of signaling-controlled proliferation at the cellular level, and thus can provide intervention strategies for distinct perturbation scenarios at various regulatory levels. PMID:22443451

An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway

PubMed Central

Robertson, Kevin A.; Hsieh, Wei Yuan; Forster, Thorsten; Blanc, Mathieu; Lu, Hongjin; Crick, Peter J.; Yutuc, Eylan; Watterson, Steven; Martin, Kimberly; Griffiths, Samantha J.; Enright, Anton J.; Yamamoto, Mami; Pradeepa, Madapura M.; Lennox, Kimberly A.; Behlke, Mark A.; Talbot, Simon; Haas, Jürgen; Dölken, Lars; Griffiths, William J.; Wang, Yuqin; Angulo, Ana; Ghazal, Peter

2016-01-01

In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway. PMID:26938778

An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway.

PubMed

Robertson, Kevin A; Hsieh, Wei Yuan; Forster, Thorsten; Blanc, Mathieu; Lu, Hongjin; Crick, Peter J; Yutuc, Eylan; Watterson, Steven; Martin, Kimberly; Griffiths, Samantha J; Enright, Anton J; Yamamoto, Mami; Pradeepa, Madapura M; Lennox, Kimberly A; Behlke, Mark A; Talbot, Simon; Haas, Jürgen; Dölken, Lars; Griffiths, William J; Wang, Yuqin; Angulo, Ana; Ghazal, Peter

2016-03-01

In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.

Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations

PubMed Central

LoPiccolo, Jaclyn; Blumenthal, Gideon M.; Bernstein, Wendy B.; Dennis, Phillip A.

2008-01-01

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection. PMID:18166498

NF-κB Signaling Pathway and its Potential as a Target for Therapy in Lymphoid Neoplasms

PubMed Central

Yu, Li; Li, Ling; Medeiros, L. Jeffrey; Young, Ken H.

2016-01-01

The NF-κB pathway, a critical regulator of apoptosis, plays a key role in many normal cellular functions. Genetic alterations and other mechanisms leading to constitutive activation of the NF-κB pathway contribute to cancer development, progression and therapy resistance by activation of downstream anti-apoptotic pathways, unfavorable microenvironment interactions, and gene dysregulation. Not surprisingly, given its importance to normal and cancer cell function, the NF-κB pathway has emerged as a target for therapy. In the review, we present the physiologic role of the NF-κB pathway and recent advances in better understanding of the pathologic roles of the NF-κB pathway in major types of lymphoid neoplasms. We also provide an update of clinical trials that use NF-κB pathway inhibitors. These trials are exploring the clinical efficiency of combining NF-κB pathway inhibitors with various agents that target diverse mechanisms of action with the goal being to optimize novel therapeutic opportunities for targeting oncogenic pathways to eradicate cancer cells. PMID:27773462

Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease

DTIC Science & Technology

2017-09-01

AWARD NUMBER: W81XWH-15-1-0419 TITLE: Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease...COVERED 1 Sep 2016 - 31 Aug 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal...inappropriate cell growth, fluid secretion, and dysregulation of cellular energy metabolism. The enzyme AMPK regulates a number of cellular pathways, including

Selective Targeting of Proteins within Secretory Pathway for Endoplasmic Reticulum-associated Degradation

PubMed Central

Vecchi, Lara; Petris, Gianluca; Bestagno, Marco; Burrone, Oscar R.

2012-01-01

The endoplasmic reticulum-associated degradation (ERAD) is a cellular quality control mechanism to dispose of misfolded proteins of the secretory pathway via proteasomal degradation. SEL1L is an ER-resident protein that participates in identification of misfolded molecules as ERAD substrates, therefore inducing their ER-to-cytosol retrotranslocation and degradation. We have developed a novel class of fusion proteins, termed degradins, composed of a fragment of SEL1L fused to a target-specific binding moiety located on the luminal side of the ER. The target-binding moiety can be a ligand of the target or derived from specific mAbs. Here, we describe the ability of degradins with two different recognition moieties to promote degradation of a model target. Degradins recognize the target protein within the ER both in secretory and membrane-bound forms, inducing their degradation following retrotranslocation to the cytosol. Thus, degradins represent an effective technique to knock-out proteins within the secretory pathway with high specificity. PMID:22523070

Targeting kinase signaling pathways with constrained peptide scaffolds

PubMed Central

Hanold, Laura E.; Fulton, Melody D.; Kennedy, Eileen J.

2017-01-01

Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles. Constrained peptide inhibitors have emerged as an alternative strategy for kinase inhibition. Distinct from small molecule inhibitors, peptides can provide a large binding surface area that allows them to bind shallow protein surfaces rather than defined pockets within the target protein structure. By including chemical constraints within the peptide sequence, additional benefits can be bestowed onto the peptide scaffold such as improved target affinity and target selectivity, cell permeability and proteolytic resistance. In this review, we highlight examples of diverse chemistries that are being employed to constrain kinase-targeting peptide scaffolds and highlight their application to modulate kinase signaling as well as their potential clinical implications. PMID:28185915

Molecular evolution of multiple-level control of heme biosynthesis pathway in animal kingdom.

PubMed

Tzou, Wen-Shyong; Chu, Ying; Lin, Tzung-Yi; Hu, Chin-Hwa; Pai, Tun-Wen; Liu, Hsin-Fu; Lin, Han-Jia; Cases, Ildeofonso; Rojas, Ana; Sanchez, Mayka; You, Zong-Ye; Hsu, Ming-Wei

2014-01-01

Adaptation of enzymes in a metabolic pathway can occur not only through changes in amino acid sequences but also through variations in transcriptional activation, mRNA splicing and mRNA translation. The heme biosynthesis pathway, a linear pathway comprised of eight consecutive enzymes in animals, provides researchers with ample information for multiple types of evolutionary analyses performed with respect to the position of each enzyme in the pathway. Through bioinformatics analysis, we found that the protein-coding sequences of all enzymes in this pathway are under strong purifying selection, from cnidarians to mammals. However, loose evolutionary constraints are observed for enzymes in which self-catalysis occurs. Through comparative genomics, we found that in animals, the first intron of the enzyme-encoding genes has been co-opted for transcriptional activation of the genes in this pathway. Organisms sense the cellular content of iron, and through iron-responsive elements in the 5' untranslated regions of mRNAs and the intron-exon boundary regions of pathway genes, translational inhibition and exon choice in enzymes may be enabled, respectively. Pathway product (heme)-mediated negative feedback control can affect the transport of pathway enzymes into the mitochondria as well as the ubiquitin-mediated stability of enzymes. Remarkably, the positions of these controls on pathway activity are not ubiquitous but are biased towards the enzymes in the upstream portion of the pathway. We revealed that multiple-level controls on the activity of the heme biosynthesis pathway depend on the linear depth of the enzymes in the pathway, indicating a new strategy for discovering the molecular constraints that shape the evolution of a metabolic pathway.

Estradiol targets T cell signaling pathways in human systemic lupus.

PubMed

Walters, Emily; Rider, Virginia; Abdou, Nabih I; Greenwell, Cindy; Svojanovsky, Stan; Smith, Peter; Kimler, Bruce F

2009-12-01

The major risk factor for developing systemic lupus erythematosus (SLE) is being female. The present study utilized gene profiles of activated T cells from females with SLE and healthy controls to identify signaling pathways uniquely regulated by estradiol that could contribute to SLE pathogenesis. Selected downstream pathway genes (+/- estradiol) were measured by real time polymerase chain amplification. Estradiol uniquely upregulated six pathways in SLE T cells that control T cell function including interferon-alpha signaling. Measurement of interferon-alpha pathway target gene expression revealed significant differences (p= 0.043) in DRIP150 (+/- estradiol) in SLE T cell samples while IFIT1 expression was bimodal and correlated moderately (r= 0.55) with disease activity. The results indicate that estradiol alters signaling pathways in activated SLE T cells that control T cell function. Differential expression of transcriptional coactivators could influence estrogen-dependent gene regulation in T cell signaling and contribute to SLE onset and disease pathogenesis.

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer

PubMed Central

Niiro, Emiko; Morioka, Sachiko; Iwai, Kana; Yamada, Yuki; Ogawa, Kenji; Kawahara, Naoki; Kobayashi, Hiroshi

2018-01-01

Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer. PMID:29564122

Retrodiction for Bayesian multiple-hypothesis/multiple-target tracking in densely cluttered environment

NASA Astrophysics Data System (ADS)

Koch, Wolfgang

1996-05-01

Sensor data processing in a dense target/dense clutter environment is inevitably confronted with data association conflicts which correspond with the multiple hypothesis character of many modern approaches (MHT: multiple hypothesis tracking). In this paper we analyze the efficiency of retrodictive techniques that generalize standard fixed interval smoothing to MHT applications. 'Delayed estimation' based on retrodiction provides uniquely interpretable and accurate trajectories from ambiguous MHT output if a certain time delay is tolerated. In a Bayesian framework the theoretical background of retrodiction and its intimate relation to Bayesian MHT is sketched. By a simulated example with two closely-spaced targets, relatively low detection probabilities, and rather high false return densities, we demonstrate the benefits of retrodiction and quantitatively discuss the achievable track accuracies and the time delays involved for typical radar parameters.

Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment

PubMed Central

Zhang, Yilong; Jain, Rajul K.; Zhu, Min

2015-01-01

The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents—either as therapeutic proteins or small molecules that target the HGF/MET pathway—have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed. PMID:28536405

Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways.

PubMed

Mijatovic, Tatjana; Kiss, Robert

2013-03-01

Many cancer patients fail to respond to chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli or the acquisition of the multidrug resistant phenotype during chronic treatment. Previous data from our groups and from others point to the sodium/potassium pump (the Na+/K+-ATPase, i.e., NaK) with its highly specific ligands (i.e., cardiotonic steroids) as a new target for combating cancers associated with dismal prognoses, including gliomas, melanomas, non-small cell lung cancers, renal cell carcinomas, and colon cancers. Cardiotonic steroid-mediated Na+/K+-ATPase targeting could circumvent various resistance pathways. The most probable pathways include the involvement of Na+/K+-ATPase β subunits in invasion features and Na+/K+-ATPase α subunits in chemosensitisation by specific cardiotonic steroid-mediated apoptosis and anoïkis-sensitisation; the regulation of the expression of multidrug resistant-related genes; post-translational regulation, including glycosylation and ubiquitinylation of multidrug resistant-related proteins; c-Myc downregulation; hypoxia-inducible factor downregulation; NF-κB downregulation and deactivation; the inhibition of the glycolytic pathway with a reduction of intra-cellular ATP levels and an induction of non-apoptotic cell death. The aims of this review are to examine the various molecular pathways by which the NaK targeting can be more deleterious to biologically aggressive cancer cells than to normal cells. Georg Thieme Verlag KG Stuttgart · New York.

Assessing natural direct and indirect effects through multiple pathways.

PubMed

Lange, Theis; Rasmussen, Mette; Thygesen, Lau Caspar

2014-02-15

Within the fields of epidemiology, interventions research and social sciences researchers are often faced with the challenge of decomposing the effect of an exposure into different causal pathways working through defined mediator variables. The goal of such analyses is often to understand the mechanisms of the system or to suggest possible interventions. The case of a single mediator, thus implying only 2 causal pathways (direct and indirect) from exposure to outcome, has been extensively studied. By using the framework of counterfactual variables, researchers have established theoretical properties and developed powerful tools. However, in practical problems, it is not uncommon to have several distinct causal pathways from exposure to outcome operating through different mediators. In this article, we suggest a widely applicable approach to quantifying and ranking different causal pathways. The approach is an extension of the natural effect models proposed by Lange et al. (Am J Epidemiol. 2012;176(3):190-195). By allowing the analysis of distinct multiple pathways, the suggested approach adds to the capabilities of modern mediation techniques. Furthermore, the approach can be implemented using standard software, and we have included with this article implementation examples using R (R Foundation for Statistical Computing, Vienna, Austria) and Stata software (StataCorp LP, College Station, Texas).

MGAT1 is a novel transcriptional target of Wnt/β-catenin signaling pathway.

PubMed

Akiva, Izzet; Birgül Iyison, Necla

2018-01-08

The Wnt/β-catenin signaling pathway is an evolutionary conserved pathway, which has important functions in vertebrate early development, axis formation, cellular proliferation and morphogenesis. Additionally, Wnt/β-catenin signaling pathway is one of the most important intracellular pathways that controls cancer progression. To date most of the identified targets of this pathway are shown to harbor tumorigenic properties. We previously showed that Mannosyl glycoprotein acetylglucosaminyl-transferase (MGAT1) enzyme is among the Wnt/β-catenin signaling putative target genes in hepatocellular carcinoma cell lines (Huh7). MGAT1 protein levels were determined by Western Blotting from Huh7 cell lines in which Wnt/β-catenin pathway was activated by means of different approaches such as LiCl treatment and mutant β-catenin overexpression. Luciferase reporter assay was used to analyze the promoter activity of MGAT1. The mRNA levels of MGAT1 were determined by quantitative real-time PCR from Huh7 cells that were treated with either Wnt agonist or GSK-3β inhibitor. Wound healing and XTT cell proliferation assays were performed in order to determine the proliferation and migration capacities of MGAT1 overexpressing stable Huh7 cells. Finally, xenograft experiments were carried out to measure the tumor formation capacities in vivo. In this study we showed that the activation of Wnt/β-catenin pathway culminates in the upregulation of MGAT1 enzyme both at transcriptional and post-transcriptional levels. We also showed that overexpression of the β-catenin gene (CTNNB1) increased the promoter activity of MGAT1. We applied a set of complementary approaches to elucidate the functional importance of MGAT1 as a vital target of Wnt/β-catenin signaling in Huh7 cells. Our analyses related to cell proliferation and migration assays showed that in comparison to the control cells, MGAT1 expressing Huh7 cells have greater proliferative and invasive capabilities. Furthermore, the

Anti-inflammatory function of Withangulatin A by targeted inhibiting COX-2 expression via MAPK and NF-kappaB pathways.

PubMed

Sun, Lijuan; Liu, Jianwen; Cui, Daling; Li, Jiyu; Yu, Youjun; Ma, Lei; Hu, Lihong

2010-02-15

Withangulatin A (WA), an active component isolated from Physalis angulata L., has been reported to possess anti-tumor and trypanocidal activities in model systems via multiple biochemical mechanisms. The aim of this study is to investigate its anti-inflammatory potential and the possible underlying mechanisms. In the current study, WA significantly suppressed mice T lymphocytes proliferation stimulated with LPS in a dose- and time-dependent manner and inhibited pro-inflammation cytokines (IL-2, IFN-gamma, and IL-6) dramatically. Moreover, WA targeted inhibited COX-2 expression mediated by MAPKs and NF-kappaB nuclear translocation pathways in mice T lymphocytes, and this result was further confirmed by the COX-1/2 luciferase reporter assay. Intriguingly, administration of WA inhibited the extent of mice ear swelling and decreased pro-inflammatory cytokines production in mice blood serum. Based on these evidences, WA influences the mice T lymphocytes function through targeted inhibiting COX-2 expression via MAPKs and NF-kappaB nuclear translocation signaling pathways, and this would make WA a strong candidate for further study as an anti-inflammatory agent. (c) 2009 Wiley-Liss, Inc.

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

PubMed Central

Dailey, Tamara A.; Gerdes, Svetlana; Jahn, Dieter; O'Brian, Mark R.; Warren, Martin J.

2017-01-01

SUMMARY The advent of heme during evolution allowed organisms possessing this compound to safely and efficiently carry out a variety of chemical reactions that otherwise were difficult or impossible. While it was long assumed that a single heme biosynthetic pathway existed in nature, over the past decade, it has become clear that there are three distinct pathways among prokaryotes, although all three pathways utilize a common initial core of three enzymes to produce the intermediate uroporphyrinogen III. The most ancient pathway and the only one found in the Archaea converts siroheme to protoheme via an oxygen-independent four-enzyme-step process. Bacteria utilize the initial core pathway but then add one additional common step to produce coproporphyrinogen III. Following this step, Gram-positive organisms oxidize coproporphyrinogen III to coproporphyrin III, insert iron to make coproheme, and finally decarboxylate coproheme to protoheme, whereas Gram-negative bacteria first decarboxylate coproporphyrinogen III to protoporphyrinogen IX and then oxidize this to protoporphyrin IX prior to metal insertion to make protoheme. In order to adapt to oxygen-deficient conditions, two steps in the bacterial pathways have multiple forms to accommodate oxidative reactions in an anaerobic environment. The regulation of these pathways reflects the diversity of bacterial metabolism. This diversity, along with the late recognition that three pathways exist, has significantly slowed advances in this field such that no single organism's heme synthesis pathway regulation is currently completely characterized. PMID:28123057

Chemogenomics profiling of drug targets of peptidoglycan biosynthesis pathway in Leptospira interrogans by virtual screening approaches.

PubMed

Bhattacharjee, Biplab; Simon, Rose Mary; Gangadharaiah, Chaithra; Karunakar, Prashantha

2013-06-28

Leptospirosis is a worldwide zoonosis of global concern caused by Leptospira interrogans. The availability of ligand libraries has facilitated the search for novel drug targets using chemogenomics approaches, compared with the traditional method of drug discovery, which is time consuming and yields few leads with little intracellular information for guiding target selection. Recent subtractive genomics studies have revealed the putative drug targets in peptidoglycan biosynthesis pathways in Leptospira interrogans. Aligand library for the murD ligase enzyme in the peptidoglycan pathway has also been identified. Our approach in this research involves screening of the pre-existing ligand library of murD with related protein family members in the putative drug target assembly in the peptidoglycan biosynthesis pathway. A chemogenomics approach has been implemented here, which involves screening of known ligands of a protein family having analogous domain architecture for identification of leads for existing druggable protein family members. By means of this approach, one murC and one murF inhibitor were identified, providing a platform for developing an antileptospirosis drug targeting the peptidoglycan biosynthesis pathway. Given that the peptidoglycan biosynthesis pathway is exclusive to bacteria, the in silico identified mur ligase inhibitors are expected to be broad-spectrum Gram-negative inhibitors if synthesized and tested in in vitro and in vivo assays.

Targeting G protein coupled receptor-related pathways as emerging molecular therapies

PubMed Central

Ghanemi, Abdelaziz

2013-01-01

G protein coupled receptors (GPCRs) represent the most important targets in modern pharmacology because of the different functions they mediate, especially within brain and peripheral nervous system, and also because of their functional and stereochemical properties. In this paper, we illustrate, via a variety of examples, novel advances about the GPCR-related molecules that have been shown to play diverse roles in GPCR pathways and in pathophysiological phenomena. We have exemplified how those GPCRs’ pathways are, or might constitute, potential targets for different drugs either to stimulate, modify, regulate or inhibit the cellular mechanisms that are hypothesized to govern some pathologic, physiologic, biologic and cellular or molecular aspects both in vivo and in vitro. Therefore, influencing such pathways will, undoubtedly, lead to different therapeutical applications based on the related pharmacological implications. Furthermore, such new properties can be applied in different fields. In addition to offering fruitful directions for future researches, we hope the reviewed data, together with the elements found within the cited references, will inspire clinicians and researchers devoted to the studies on GPCR’s properties. PMID:25972730

Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells

PubMed Central

Pan, Jing-Xuan; Ding, Ke; Wang, Cheng-Yan

2012-01-01

Niclosamide, an oral antihelminthic drug, has been used to treat tapeworm infection for about 50 years. Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs. Recently, several groups have independently discovered that niclosamide is also active against cancer cells, but its precise mechanism of antitumor action is not fully understood. Evidence supports that niclosamide targets multiple signaling pathways (NF-κB, Wnt/β-catenin, Notch, ROS, mTORC1, and Stat3), most of which are closely involved with cancer stem cells. The exciting advances in elucidating the antitumor activity and the molecular targets of this drug will be discussed. A method for synthesizing a phosphate pro-drug of niclosamide is provided. Given its potential antitumor activity, clinical trials for niclosamide and its derivatives are warranted for cancer treatment. PMID:22237038

Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways.

PubMed

Liu, Guiyou; Zhang, Fang; Jiang, Yongshuai; Hu, Yang; Gong, Zhongying; Liu, Shoufeng; Chen, Xiuju; Jiang, Qinghua; Hao, Junwei

2017-02-01

Much effort has been expended on identifying the genetic determinants of multiple sclerosis (MS). Existing large-scale genome-wide association study (GWAS) datasets provide strong support for using pathway and network-based analysis methods to investigate the mechanisms underlying MS. However, no shared genetic pathways have been identified to date. We hypothesize that shared genetic pathways may indeed exist in different MS-GWAS datasets. Here, we report results from a three-stage analysis of GWAS and expression datasets. In stage 1, we conducted multiple pathway analyses of two MS-GWAS datasets. In stage 2, we performed a candidate pathway analysis of the large-scale MS-GWAS dataset. In stage 3, we performed a pathway analysis using the dysregulated MS gene list from seven human MS case-control expression datasets. In stage 1, we identified 15 shared pathways. In stage 2, we successfully replicated 14 of these 15 significant pathways. In stage 3, we found that dysregulated MS genes were significantly enriched in 10 of 15 MS risk pathways identified in stages 1 and 2. We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.

Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

Award Number: W81XWH-12-1-0275 TITLE: Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer PRINCIPAL...Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Dual-Targeting of AR and Akt Pathways by Berberine in Castration- Resistant Prostate Cancer 5b. GRANT NUMBER

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.

Multiple-Targeted Graphene-based Nanocarrier for Intracellular Imaging of mRNAs

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

Wang, Ying; Li, Zhaohui; Liu, Misha

Simultaneous detection and imaging of multiple intracellular messenger RNA (mRNAs) hold great significant for early cancer diagnostics and preventive medicine development. Herein, we propose a multiple-targeted graphene oxide (GO) nanocarrier that can simultaneously detect and image different type mRNAs in living cells. First of all, in vitro detection of multiple targets have been realized successfully based on the multiple-targeted GO nanocarrier with linear relationship ranging from 3 nM to 200 nM, as well as sensitive detection limit of 1.84 nM for manganese superoxide dismutase (Mn-SOD) mRNA and 2.45 nM for β-actin mRNA. Additionally, this nanosensing platform composed of fluorescent labeledmore » single strand DNA probes and GO nanocarrier can identify Mn-SOD mRNA and endogenous mRNA of β-actin in living cancer cells, showing rapid response, high specificity, nuclease stability, and good biocompatibility during the cell imaging. Thirdly, changes of the expression levels of mRNA in living cells before or after the drug treatment can be monitored successfully. By using multiple ssDNA as probes and GO nanocarrier as the cellular delivery cargo, the proposed simultaneous multiple-targeted sensing platform will be of great potential as a powerful tool for intracellular trafficking process from basic research to clinical diagnosis.« less

A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs

PubMed Central

McKinsey, EL; Parrish, JK; Irwin, AE; Niemeyer, BF; Kern, HB; Birks, DK; Jedlicka, P

2015-01-01

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with critical functions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences. However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven by EWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, all of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGF signaling. PMID:21643012

A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs.

PubMed

McKinsey, E L; Parrish, J K; Irwin, A E; Niemeyer, B F; Kern, H B; Birks, D K; Jedlicka, P

2011-12-08

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with critical functions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences. However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven by EWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, all of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGF signaling.

Developing Teacher Leadership in Singapore: Multiple Pathways for Differentiated Journeys

ERIC Educational Resources Information Center

Goodwin, A. Lin; Low, Ee Ling; Ng, Pak Tee

2015-01-01

In this article, we examine quality teachers through teacher leadership development. Using Singapore as an illustrative case, we describe the redefinition of the teaching profession to include deliberate structures and multiple pathways designed to nurture teacher leaders, and the role of teacher leaders in supporting education reform. We go on to…

Role of the phosphatidylinositol-3-kinase/Akt/target of rapamycin pathway during ambidensovirus infection of insect cells.

PubMed

Salasc, F; Mutuel, D; Debaisieux, S; Perrin, A; Dupressoir, T; Grenet, A-S Gosselin; Ogliastro, M

2016-01-01

The phosphatidylinositol-3-kinase (PI3K)/Akt/target of rapamycin (TOR) signalling pathway controls cell growth and survival, and is targeted by a number of viruses at different phases of their infection cycle to control translation. Whether and how insect viruses interact with this pathway remain poorly addressed. Here, we investigated the role of PI3K/Akt/TOR signalling during lethal infection of insect cells with an insect parvovirus. Using Junonia coenia densovirus (JcDV; lepidopteran ambidensovirus 1) and susceptible insect cells as experimental models, we first described JcDV cytopathology, and showed that viral infection affects cell size, cell proliferation and survival. We deciphered the role of PI3K/Akt/TOR signalling in the course of infection and found that non-structural (NS) protein expression correlates with the inhibition of TOR and the shutdown of cellular synthesis, concomitant with the burst of viral protein expression. Together, these results suggest that NS proteins control the cellular translational machinery to favour the translation of viral mRNAs at the expense of cellular mRNAs. As a consequence of TOR inhibition, cell autophagy is activated. These results highlight new functions for NS proteins in the course of multiplication of an insect parvovirus.

Hedgehog pathway as a potential treatment target in human cholangiocarcinoma.

PubMed

Riedlinger, Dorothee; Bahra, Marcus; Boas-Knoop, Sabine; Lippert, Steffen; Bradtmöller, Maren; Guse, Katrin; Seehofer, Daniel; Bova, Roberta; Sauer, Igor M; Neuhaus, Peter; Koch, Arend; Kamphues, Carsten

2014-08-01

Innovative treatment concepts targeting essential signaling pathways may offer new chances for patients suffering from cholangiocarcinoma (CCC). For that, we performed a systematic molecular genetic analysis concerning the Hedgehog activity in human CCC samples and analyzed the effect of Hh inhibition on CCC cells in vitro and in vivo. Activation of the Hh pathway was analyzed in 50 human CCC samples using quantitative polymerase chain reaction (qPCR). The efficacy of Hh inhibition using cyclopamine and BMS-833923 was evaluated in vitro. In addition, the effect of BMS-833923, alone or in combination with gemcitabine, was analyzed in vivo in a murine subcutaneous xenograft model. Expression analysis revealed a significant activation of the Hh-signaling pathway in nearly 50% of CCCs. Hh inhibition resulted in a significant decrease in cell proliferation of CCC cells. Moreover, a distinct inhibition of tumor growth could be seen as a result of a combined therapy with BMS-833923 and gemcitabine in CCC xenografts. The results of our study suggest that the Hh pathway plays a relevant role at least in a subset of human CCC. Inhibition of this pathway may represent a possible treatment option for CCC patients in which the Hh pathway is activated. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Plant targets for Pseudomonas syringae type III effectors: virulence targets or guarded decoys?

PubMed

Block, Anna; Alfano, James R

2011-02-01

The phytopathogenic bacterium Pseudomonas syringae can suppress both pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) by the injection of type III effector (T3E) proteins into host cells. T3Es achieve immune suppression using a variety of strategies including interference with immune receptor signaling, blocking RNA pathways and vesicle trafficking, and altering organelle function. T3Es can be recognized indirectly by resistance proteins monitoring specific T3E targets resulting in ETI. It is presently unclear whether the monitored targets represent bona fide virulence targets or guarded decoys. Extensive overlap between PTI and ETI signaling suggests that T3Es may suppress both pathways through common targets and by possessing multiple activities. Copyright © 2010 Elsevier Ltd. All rights reserved.

Safety and feasibility of targeted agent combinations in solid tumours.

PubMed

Park, Sook Ryun; Davis, Myrtle; Doroshow, James H; Kummar, Shivaani

2013-03-01

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy.

PubMed

Juan, Wen Chun; Hong, Wanjin

2016-08-30

The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy.

A compound chimeric antigen receptor strategy for targeting multiple myeloma.

PubMed

Chen, K H; Wada, M; Pinz, K G; Liu, H; Shuai, X; Chen, X; Yan, L E; Petrov, J C; Salman, H; Senzel, L; Leung, E L H; Jiang, X; Ma, Y

2018-02-01

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

In silico database screening of potential targets and pathways of compounds contained in plants used for psoriasis vulgaris.

PubMed

May, Brian H; Deng, Shiqiang; Zhang, Anthony L; Lu, Chuanjian; Xue, Charlie C L

2015-09-01

Reviews and meta-analyses of clinical trials identified plants used as traditional medicines (TMs) that show promise for psoriasis. These include Rehmannia glutinosa, Camptotheca acuminata, Indigo naturalis and Salvia miltiorrhiza. Compounds contained in these TMs have shown activities of relevance to psoriasis in experimental models. To further investigate the likely mechanisms of action of the multiple compounds in these TMs, we undertook a computer-based in silico investigation of the proteins known to be regulated by these compounds and their associated biological pathways. The proteins reportedly regulated by compounds in these four TMs were identified using the HIT (Herbal Ingredients' Targets) database. The resultant data were entered into the PANTHER (Protein ANnotation THrough Evolutionary Relationship) database to identify the pathways in which the proteins could be involved. The study identified 237 compounds in the TMs and these retrieved 287 proteins from HIT. These proteins identified 59 pathways in PANTHER with most proteins being located in the Apoptosis, Angiogenesis, Inflammation mediated by chemokine and cytokine, Gonadotropin releasing hormone receptor, and/or Interleukin signaling pathways. All four TMs contained compounds that had regulating effects on Apoptosis regulator BAX, Apoptosis regulator Bcl-2, Caspase-3, Tumor necrosis factor (TNF) or Prostaglandin G/H synthase 2 (COX2). The main proteins and pathways are primarily related to inflammation, proliferation and angiogenesis which are all processes involved in psoriasis. Experimental studies have reported that certain compounds from these TMs can regulate the expression of proteins involved in each of these pathways.

Genetic and Epigenetic Events Generate Multiple Pathways in Colorectal Cancer Progression

PubMed Central

Pancione, Massimo; Remo, Andrea; Colantuoni, Vittorio

2012-01-01

Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment. PMID:22888469

Identification of key target genes and pathways in laryngeal carcinoma

PubMed Central

Liu, Feng; Du, Jintao; Liu, Jun; Wen, Bei

2016-01-01

The purpose of the present study was to screen the key genes associated with laryngeal carcinoma and to investigate the molecular mechanism of laryngeal carcinoma progression. The gene expression profile of GSE10935 [Gene Expression Omnibus (GEO) accession number], including 12 specimens from laryngeal papillomas and 12 specimens from normal laryngeal epithelia controls, was downloaded from the GEO database. Differentially expressed genes (DEGs) were screened in laryngeal papillomas compared with normal controls using Limma package in R language, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed using Cytoscape software and modules were analyzed using MCODE plugin from the PPI network. Furthermore, significant biological pathway regions (sub-pathway) were identified by using iSubpathwayMiner analysis. A total of 67 DEGs were identified, including 27 up-regulated genes and 40 down-regulated genes and they were involved in different GO terms and pathways. PPI network analysis revealed that Ras association (RalGDS/AF-6) domain family member 1 (RASSF1) was a hub protein. The sub-pathway analysis identified 9 significantly enriched sub-pathways, including glycolysis/gluconeogenesis and nitrogen metabolism. Genes such as phosphoglycerate kinase 1 (PGK1), carbonic anhydrase II (CA2), and carbonic anhydrase XII (CA12) whose node degrees were >10 were identified in the disease risk sub-pathway. Genes in the sub-pathway, such as RASSF1, PGK1, CA2 and CA12 were presumed to serve critical roles in laryngeal carcinoma. The present study identified DEGs and their sub-pathways in the disease, which may serve as potential targets for treatment of laryngeal carcinoma. PMID:27446427

Tracking Multiple Video Targets with an Improved GM-PHD Tracker

PubMed Central

Zhou, Xiaolong; Yu, Hui; Liu, Honghai; Li, Youfu

2015-01-01

Tracking multiple moving targets from a video plays an important role in many vision-based robotic applications. In this paper, we propose an improved Gaussian mixture probability hypothesis density (GM-PHD) tracker with weight penalization to effectively and accurately track multiple moving targets from a video. First, an entropy-based birth intensity estimation method is incorporated to eliminate the false positives caused by noisy video data. Then, a weight-penalized method with multi-feature fusion is proposed to accurately track the targets in close movement. For targets without occlusion, a weight matrix that contains all updated weights between the predicted target states and the measurements is constructed, and a simple, but effective method based on total weight and predicted target state is proposed to search the ambiguous weights in the weight matrix. The ambiguous weights are then penalized according to the fused target features that include spatial-colour appearance, histogram of oriented gradient and target area and further re-normalized to form a new weight matrix. With this new weight matrix, the tracker can correctly track the targets in close movement without occlusion. For targets with occlusion, a robust game-theoretical method is used. Finally, the experiments conducted on various video scenarios validate the effectiveness of the proposed penalization method and show the superior performance of our tracker over the state of the art. PMID:26633422

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

Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma.

PubMed

Tagde, Ashujit; Markert, Tahireh; Rajabi, Hasan; Hiraki, Masayuki; Alam, Maroof; Bouillez, Audrey; Avigan, David; Anderson, Kenneth; Kufe, Donald

2017-09-19

The polycomb repressive complex 1 (PRC1) includes the BMI1, RING1 and RING2 proteins. BMI1 is required for survival of multiple myeloma (MM) cells. The MUC1-C oncoprotein is aberrantly expressed by MM cells, activates MYC and is also necessary for MM cell survival. The present studies show that targeting MUC1-C with (i) stable and inducible silencing and CRISPR/Cas9 editing and (ii) the pharmacologic inhibitor GO-203, which blocks MUC1-C function, downregulates BMI1, RING1 and RING2 expression. The results demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism. MUC1-C thus promotes MYC occupancy on the BMI1 promoter and thereby activates BMI1 expression. We also show that the MUC1-C→MYC pathway induces RING2 expression. Moreover, in contrast to BMI1 and RING2, we found that MUC1-C drives RING1 by an NF-κB p65-dependent mechanism. Targeting MUC1-C and thereby the suppression of these key PRC1 proteins was associated with downregulation of the PRC1 E3 ligase activity as evidenced by decreases in ubiquitylation of histone H2A. Targeting MUC1-C also resulted in activation of the PRC1-repressed tumor suppressor genes, PTEN, CDNK2A and BIM . These findings identify a heretofore unrecognized role for MUC1-C in the epigenetic regulation of MM cells.

Additional targets of the Arabidopsis autonomous pathway members, FCA and FY.

PubMed

Marquardt, S; Boss, P K; Hadfield, J; Dean, C

2006-01-01

A central player in the Arabidopsis floral transition is the floral repressor FLC, the MADS-box transcriptional regulator that inhibits the activity of genes required to switch the meristem from vegetative to floral development. One of the many pathways that regulate FLC expression is the autonomous promotion pathway composed of FCA, FY, FLD, FPA, FVE, LD, and FLK. Rather than a hierarchical set of activities the autonomous promotion pathway comprises sub-pathways of genes with different biochemical functions that all share FLC as a target. One sub-pathway involves FCA and FY, which interact to regulate RNA processing of FLC. Several of the identified components (FY, FVE, and FLD) are homologous to yeast and mammalian proteins with rather generic roles in gene regulation. So why do mutations in these genes specifically show a late-flowering phenotype in Arabidopsis? One reason, found during the analysis of fy alleles, is that the mutant alleles identified in flowering screens can be hypomorphic, they still have partial function. A broader role for the autonomous promotion pathway is supported by a microarray analysis which has identified genes mis-regulated in fca mutants, and whose expression is also altered in fy mutants.

The use of functional chemical-protein associations to identify multi-pathway renoprotectants.

PubMed

Xu, Jia; Meng, Kexin; Zhang, Rui; Yang, He; Liao, Chang; Zhu, Wenliang; Jiao, Jundong

2014-01-01

Typically, most nephropathies can be categorized as complex human diseases in which the cumulative effect of multiple minor genes, combined with environmental and lifestyle factors, determines the disease phenotype. Thus, multi-target drugs would be more likely to facilitate comprehensive renoprotection than single-target agents. In this study, functional chemical-protein association analysis was performed to retrieve multi-target drugs of high pathway wideness from the STITCH 3.1 database. Pathway wideness of a drug evaluated the efficiency of regulation of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in quantity. We identified nine experimentally validated renoprotectants that exerted remarkable impact on KEGG pathways by targeting a limited number of proteins. We selected curcumin as an illustrative compound to display the advantage of multi-pathway drugs on renoprotection. We compared curcumin with hemin, an agonist of heme oxygenase-1 (HO-1), which significantly affects only one KEGG pathway, porphyrin and chlorophyll metabolism (adjusted p = 1.5×10-5). At the same concentration (10 µM), both curcumin and hemin equivalently mitigated oxidative stress in H2O2-treated glomerular mesangial cells. The benefit of using hemin was derived from its agonistic effect on HO-1, providing relief from oxidative stress. Selective inhibition of HO-1 completely blocked the action of hemin but not that of curcumin, suggesting simultaneous multi-pathway intervention by curcumin. Curcumin also increased cellular autophagy levels, enhancing its protective effect; however, hemin had no effects. Based on the fact that the dysregulation of multiple pathways is implicated in the etiology of complex diseases, we proposed a feasible method for identifying multi-pathway drugs from compounds with validated targets. Our efforts will help identify multi-pathway agents capable of providing comprehensive protection against renal injuries.

Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy

PubMed Central

Juan, Wen Chun; Hong, Wanjin

2016-01-01

The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy. PMID:27589805

Multiple Regression Analysis of mRNA-miRNA Associations in Colorectal Cancer Pathway

PubMed Central

Wang, Fengfeng; Wong, S. C. Cesar; Chan, Lawrence W. C.; Cho, William C. S.; Yip, S. P.; Yung, Benjamin Y. M.

2014-01-01

Background. MicroRNA (miRNA) is a short and endogenous RNA molecule that regulates posttranscriptional gene expression. It is an important factor for tumorigenesis of colorectal cancer (CRC), and a potential biomarker for diagnosis, prognosis, and therapy of CRC. Our objective is to identify the related miRNAs and their associations with genes frequently involved in CRC microsatellite instability (MSI) and chromosomal instability (CIN) signaling pathways. Results. A regression model was adopted to identify the significantly associated miRNAs targeting a set of candidate genes frequently involved in colorectal cancer MSI and CIN pathways. Multiple linear regression analysis was used to construct the model and find the significant mRNA-miRNA associations. We identified three significantly associated mRNA-miRNA pairs: BCL2 was positively associated with miR-16 and SMAD4 was positively associated with miR-567 in the CRC tissue, while MSH6 was positively associated with miR-142-5p in the normal tissue. As for the whole model, BCL2 and SMAD4 models were not significant, and MSH6 model was significant. The significant associations were different in the normal and the CRC tissues. Conclusion. Our results have laid down a solid foundation in exploration of novel CRC mechanisms, and identification of miRNA roles as oncomirs or tumor suppressor mirs in CRC. PMID:24895601

Targeting the Autophagy/Lysosomal Degradation Pathway in Parkinson's Disease.

PubMed

Rivero-Ríos, Pilar; Madero-Pérez, Jesús; Fernández, Belén; Hilfiker, Sabine

2016-01-01

Autophagy is a cellular quality control mechanism crucial for neuronal homeostasis. Defects in autophagy are critically associated with mechanisms underlying Parkinson's disease (PD), a common and debilitating neurodegenerative disorder. Autophagic dysfunction in PD can occur at several stages of the autophagy/lysosomal degradative machinery, contributing to the formation of intracellular protein aggregates and eventual neuronal cell death. Therefore, autophagy inducers may comprise a promising new therapeutic approach to combat neurodegeneration in PD. Several currently available FDA-approved drugs have been shown to enhance autophagy, which may allow for their repurposing for use in novel clinical conditions including PD. This review summarizes our current knowledge of deficits in the autophagy/lysosomal degradation pathways associated with PD, and highlight current approaches which target this pathway as possible means towards novel therapeutic strategies.

Incorporating multiple secondary targets into learning trials for individuals with autism spectrum disorder.

PubMed

Nottingham, Casey L; Vladescu, Jason C; Kodak, Tiffany; Kisamore, April N

2017-07-01

The current study examined the outcome of presenting multiple secondary targets in learning trials for individuals with autism spectrum disorder. We compared conditions in which (a) a secondary target was presented in the antecedent and consequence of trials, (b) two secondary targets were presented in the consequence of trials, (c) one secondary target was presented in the consequence of each trial, and (d) no additional targets were presented trials. The participants acquired the majority of secondary targets. Presenting one or multiple secondary targets per trial, regardless of the location of these secondary targets, increased the efficiency of instruction in comparison to a condition with no secondary target. © 2017 Society for the Experimental Analysis of Behavior.

Optoelectronic System Measures Distances to Multiple Targets

NASA Technical Reports Server (NTRS)

Liebe, Carl Christian; Abramovici, Alexander; Bartman, Randall; Chapsky, Jacob; Schmalz, John; Coste, Keith; Litty, Edward; Lam, Raymond; Jerebets, Sergei

2007-01-01

An optoelectronic metrology apparatus now at the laboratory-prototype stage of development is intended to repeatedly determine distances of as much as several hundred meters, at submillimeter accuracy, to multiple targets in rapid succession. The underlying concept of optoelectronic apparatuses that can measure distances to targets is not new; such apparatuses are commonly used in general surveying and machining. However, until now such apparatuses have been, variously, constrained to (1) a single target or (2) multiple targets with a low update rate and a requirement for some a priori knowledge of target geometry. When fully developed, the present apparatus would enable measurement of distances to more than 50 targets at an update rate greater than 10 Hz, without a requirement for a priori knowledge of target geometry. The apparatus (see figure) includes a laser ranging unit (LRU) that includes an electronic camera (photo receiver), the field of view of which contains all relevant targets. Each target, mounted at a fiducial position on an object of interest, consists of a small lens at the output end of an optical fiber that extends from the object of interest back to the LRU. For each target and its optical fiber, there is a dedicated laser that is used to illuminate the target via the optical fiber. The targets are illuminated, one at a time, with laser light that is modulated at a frequency of 10.01 MHz. The modulated laser light is emitted by the target, from where it returns to the camera (photodetector), where it is detected. Both the outgoing and incoming 10.01-MHz laser signals are mixed with a 10-MHz local-oscillator to obtain beat notes at 10 kHz, and the difference between the phases of the beat notes is measured by a phase meter. This phase difference serves as a measure of the total length of the path traveled by light going out through the optical fiber and returning to the camera (photodetector) through free space. Because the portion of the path

Curation of inhibitor-target data: process and impact on pathway analysis.

PubMed

Devidas, Sreenivas

2009-01-01

The past decade has seen a significant emergence in the availability and use of pathway analysis tools. The workflow that is supported by most of the pathway analysis tools is limited to either of the following: a. a network of genes based on the input data set, or b. the resultant network filtered down by a few criteria such as (but not limited to) i. disease association of the genes in the network; ii. targets known to be the target of one or more launched drugs; iii. targets known to be the target of one or more compounds in clinical trials; and iv. targets reasonably known to be potential candidate or clinical biomarkers. Almost all the tools in use today are biased towards the biological side and contain little, if any, information on the chemical inhibitors associated with the components of a given biological network. The limitation resides as follows: The fact that the number of inhibitors that have been published or patented is probably several fold (probably greater than 10-fold) more than the number of published protein-protein interactions. Curation of such data is both expensive and time consuming and could impact ROI significantly. The non-standardization associated with protein and gene names makes mapping reasonably non-straightforward. The number of patented and published inhibitors across target classes increases by over a million per year. Therefore, keeping the databases current becomes a monumental problem. Modifications required in the product architectures to accommodate chemistry-related content. GVK Bio has, over the past 7 years, curated the compound-target data that is necessary for the addition of such compound-centric workflows. This chapter focuses on identification, curation and utility of such data.

Cell Death Pathways in Mutant Rhodopsin Rat Models Identifies Genotype-Specific Targets Controlling Retinal Degeneration.

PubMed

Viringipurampeer, Ishaq A; Gregory-Evans, Cheryl Y; Metcalfe, Andrew L; Bashar, Emran; Moritz, Orson L; Gregory-Evans, Kevin

2018-06-18

Retinitis pigmentosa (RP) is a group of inherited neurological disorders characterized by rod photoreceptor cell death, followed by secondary cone cell death leading to progressive blindness. Currently, there are no viable treatment options for RP. Due to incomplete knowledge of the molecular signaling pathways associated with RP pathogenesis, designing therapeutic strategies remains a challenge. In particular, preventing secondary cone photoreceptor cell loss is a key goal in designing potential therapies. In this study, we identified the main drivers of rod cell death and secondary cone loss in the transgenic S334ter rhodopsin rat model, tested the efficacy of specific cell death inhibitors on retinal function, and compared the effect of combining drugs to target multiple pathways in the S334ter and P23H rhodopsin rat models. The primary driver of early rod cell death in the S334ter model was a caspase-dependent process, whereas cone cell death occurred though RIP3-dependent necroptosis. In comparison, rod cell death in the P23H model was via necroptotic signaling, whereas cone cell loss occurred through inflammasome activation. Combination therapy of four drugs worked better than the individual drugs in the P23H model but not in the S334ter model. These differences imply that treatment modalities need to be tailored for each genotype. Taken together, our data demonstrate that rationally designed genotype-specific drug combinations will be an important requisite to effectively target primary rod cell loss and more importantly secondary cone survival.

A covariant multiple scattering series for elastic projectile-target scattering

NASA Technical Reports Server (NTRS)

Gross, Franz; Maung-Maung, Khin

1989-01-01

A covariant formulation of the multiple scattering series for the optical potential is presented. The case of a scalar nucleon interacting with a spin zero isospin zero A-body target through meson exchange, is considered. It is shown that a covariant equation for the projectile-target t-matrix can be obtained which sums the ladder and crossed ladder diagrams efficiently. From this equation, a multiple scattering series for the optical potential is derived, and it is shown that in the impulse approximation, the two-body t-matrix associated with the first order optical potential is the one in which one particle is kept on mass-shell. The meaning of various terms in the multiple scattering series is given. The construction of the first-order optical potential for elastic scattering calculations is described.

Multiple pathway asbestos exposure assessment for a Superfund community.

PubMed

Noonan, Curtis W; Conway, Kathrene; Landguth, Erin L; McNew, Tracy; Linker, Laura; Pfau, Jean; Black, Brad; Szeinuk, Jaime; Flores, Raja

2015-01-01

Libby, MT, USA, was the home to workers at a historical vermiculite mining facility and served as the processing and distribution center for this industrial product that was contaminated with amphibole asbestos. Several pathways of environmental asbestos exposure to the general population have been identified. The local clinic and health screening program collects data from participants on past occupational and environmental exposures to vermiculite and asbestos. Health studies among this population have demonstrated associations between amphibole exposure and health outcomes, but critical questions regarding the nature and level of exposure associated with specific outcomes remain unanswered. The objective of this study was to develop a comprehensive exposure assessment approach that integrates information on individuals' contact frequency with multiple exposure pathways. For 3031 participants, we describe cumulative exposure metrics for environmental exposures, occupational exposures, and residents' contact with carry-home asbestos from household workers. As expected, cumulative exposures for all three occupational categories were higher among men compared with women, and cumulative exposures for household contact and environmental pathways were higher among women. The comprehensive exposure assessment strategies will advance health studies and risk assessment approaches in this population with a complex history of both occupational and environmental asbestos exposure.

Quantum partial search for uneven distribution of multiple target items

NASA Astrophysics Data System (ADS)

Zhang, Kun; Korepin, Vladimir

2018-06-01

Quantum partial search algorithm is an approximate search. It aims to find a target block (which has the target items). It runs a little faster than full Grover search. In this paper, we consider quantum partial search algorithm for multiple target items unevenly distributed in a database (target blocks have different number of target items). The algorithm we describe can locate one of the target blocks. Efficiency of the algorithm is measured by number of queries to the oracle. We optimize the algorithm in order to improve efficiency. By perturbation method, we find that the algorithm runs the fastest when target items are evenly distributed in database.

Convergent pathogenic pathways in Alzheimer’s and Huntington disease: Shared targets for drug development

PubMed Central

Ehrnhoefer, Dagmar E.; Wong, Bibiana K.Y.; Hayden, Michael R.

2011-01-01

Neurodegenerative diseases exemplified by Alzheimer’s and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a ‘model’ for Alzheimer’s disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways. PMID:22015920

Deciphering the biological effects of acupuncture treatment modulating multiple metabolism pathways.

PubMed

Zhang, Aihua; Yan, Guangli; Sun, Hui; Cheng, Weiping; Meng, Xiangcai; Liu, Li; Xie, Ning; Wang, Xijun

2016-02-16

Acupuncture is an alternative therapy that is widely used to treat various diseases. However, detailed biological interpretation of the acupuncture stimulations is limited. We here used metabolomics and proteomics technology, thereby identifying the serum small molecular metabolites into the effect and mechanism pathways of standardized acupuncture treatments at 'Zusanli' acupoint which was the most often used acupoint in previous reports. Comprehensive overview of serum metabolic profiles during acupuncture stimulation was investigated. Thirty-four differential metabolites were identified in serum metabolome and associated with ten metabolism pathways. Importantly, we have found that high impact glycerophospholipid metabolism, fatty acid metabolism, ether lipid metabolism were acutely perturbed by acupuncture stimulation. As such, these alterations may be useful to clarify the biological mechanism of acupuncture stimulation. A series of differentially expressed proteins were identified and such effects of acupuncture stimulation were found to play a role in transport, enzymatic activity, signaling pathway or receptor interaction. Pathway analysis further revealed that most of these proteins were found to play a pivotal role in the regulation of multiple metabolism pathways. It demonstrated that the metabolomics coupled with proteomics as a powerful approach for potential applications in understanding the biological effects of acupuncture stimulation.

A novel controlled release formulation of the Pin1 inhibitor ATRA to improve liver cancer therapy by simultaneously blocking multiple cancer pathways.

PubMed

Yang, Dayun; Luo, Wensong; Wang, Jichuang; Zheng, Min; Liao, Xin-Hua; Zhang, Nan; Lu, Wenxian; Wang, Long; Chen, Ai-Zheng; Wu, Wen-Guo; Liu, Hekun; Wang, Shi-Bin; Zhou, Xiao Zhen; Lu, Kun Ping

2018-01-10

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide largely due to lack of effective targeted drugs to simultaneously block multiple cancer-driving pathways. The identification of all-trans retinoic acid (ATRA) as a potent Pin1 inhibitor provides a promising candidate for HCC targeted therapy because Pin1 is overexpressed in most HCC and activates numerous cancer-driving pathways. However, the efficacy of ATRA against solid tumors is limited due to its short half-life of 45min in humans. A slow-releasing ATRA formulation inhibits solid tumors such as HCC, but can be used only in animals. Here, we developed a one-step, cost-effective route to produce a novel biocompatible, biodegradable, and non-toxic controlled release formulation of ATRA for effective HCC therapy. We used supercritical carbon dioxide process to encapsulate ATRA in largely uniform poly L-lactic acid (PLLA) microparticles, with the efficiency of 91.4% and yield of 68.3%, and ~4-fold higher C max and AUC over the slow-releasing ATRA formulation. ATRA-PLLA microparticles had good biocompatibility, and significantly enhanced the inhibitory potency of ATRA on HCC cell growth, improving IC 50 by over 3-fold. ATRA-PLLA microparticles exerted its efficacy likely through degrading Pin1 and inhibiting multiple Pin1-regulated cancer pathways and cell cycle progression. Indeed, Pin1 knock-down abolished ATRA inhibitory effects on HCC cells and ATRA-PLLA did not inhibit normal liver cells, as expected because ATRA selectively inhibits active Pin1 in cancer cells. Moreover ATRA-PLLA microparticles significantly enhanced the efficacy of ATRA against HCC tumor growth in mice through reducing Pin1, with a better potency than the slow-releasing ATRA formulation, consistent with its improved pharmacokinetic profiles. This study illustrates an effective platform to produce controlled release formulation of anti-cancer drugs, and ATRA-PLLA microparticles might be a promising targeted

The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS.

PubMed

Martínez-Lapiscina, Elena H; Fraga-Pumar, Elena; Gabilondo, Iñigo; Martínez-Heras, Eloy; Torres-Torres, Ruben; Ortiz-Pérez, Santiago; Llufriu, Sara; Tercero, Ana; Andorra, Magi; Roca, Marc Figueras; Lampert, Erika; Zubizarreta, Irati; Saiz, Albert; Sanchez-Dalmau, Bernardo; Villoslada, Pablo

2014-12-15

Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway. The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients.

Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma.

PubMed

Beck, Joseph Thaddeus; Ismail, Amen; Tolomeo, Christina

2014-09-01

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hyperspectral target detection using manifold learning and multiple target spectra

DOE PAGES

Ziemann, Amanda K.; Theiler, James; Messinger, David W.

2016-03-31

Imagery collected from satellites and airborne platforms provides an important tool for remotely analyzing the content of a scene. In particular, the ability to remotely detect a specific material within a scene is of critical importance in nonproliferation and other applications. The sensor systems that process hyperspectral images collect the high-dimensional spectral information necessary to perform these detection analyses. For a d-dimensional hyperspectral image, however, where d is the number of spectral bands, it is common for the data to inherently occupy an m-dimensional space with m << d. In the remote sensing community, this has led to recent interestmore » in the use of manifold learning, which seeks to characterize the embedded lower-dimensional, nonlinear manifold that the data discretely approximate. The research presented in this paper focuses on a graph theory and manifold learning approach to target detection, using an adaptive version of locally linear embedding that is biased to separate target pixels from background pixels. Finally, this approach incorporates multiple target signatures for a particular material, accounting for the spectral variability that is often present within a solid material of interest.« less

Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis.

PubMed

Antoniou, Katerina M; Pataka, Athanasia; Bouros, Demosthenes; Siafakas, Nikolaos M

2007-01-01

Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that usually leads to death within 5 years of diagnosis. Despite our better understanding of IPF pathogenesis, the etiology and the precise cellular and molecular mechanisms involved are not well known. Current therapies are of unproven benefit. The aim of this review is to identify possible candidate pathways that might offer novel therapeutic targets changing the natural course of this disease. Current therapeutic approaches target at apoptosis, epithelial replacement, fibroblasts/myofibroblasts, procoagulant activity, growth factors production, angiogenesis, Th1 and Th2 cytokines and oxidative stress. Increased epithelial cells apoptosis can contribute to fibrosis, while on the other hand, decreased fibroblast or myofibroblast apoptosis promotes fibrosis. Recent findings support the notion that therapy directed at either inhibition of angiogenic or augmentation of angiostatic CXC chemokines may be a novel approach in the treatment of IPF. Additionally, there is little doubt that the development of novel therapeutic strategies for pulmonary fibrosis should target some profibrotic growth factors and key type II cytokines, such as inteleukin-13. Importantly, persistent activation of intra-alveolar procoagulant activity and subsequent abnormal fibrin turnover enhances a fibrotic response. Furthermore, increased procoagulant activity may interfere with fibrin accumulation and lack of activation of some matrix metalloproteinases responsible for an imbalance in matrix turnover. Finally, oxidative stress with increased production of oxidants in IPF is an additional mechanism proposed to explain epithelial cell apoptosis in this disease. The challenge of future targets for therapeutic intervention is to reconcile different pathogenetic pathways, and we strongly suspect that no single approach will be sufficient for a lethal disease with few therapeutic options.

Molecular pathways and targets in prostate cancer

PubMed Central

Shtivelman, Emma; Beer, Tomasz M.; Evans, Christopher P.

2014-01-01

Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge. PMID:25277175

Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

PubMed Central

Bruntz, Ronald C.; Lindsley, Craig W.

2014-01-01

Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein–coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions. PMID:25244928

Multiple parietal-frontal pathways mediate grasping in macaque monkeys

PubMed Central

Gharbawie, Omar A.; Stepniewska, Iwona; Qi, Huixin; Kaas, Jon H.

2011-01-01

The nodes of a parietal-frontal pathway that mediates grasping in primates are in anterior intraparietal area (AIP) and ventral premotor cortex (PMv). Nevertheless, multiple somatosensory and motor representations of the hand, respectively in parietal and frontal cortex, suggest that additional pathways remain unrealized. We explored this possibility in macaque monkeys by injecting retrograde tracers into grasp zones identified in M1, PMv, and area 2 with long train electrical stimulation. The M1 grasp zone was densely connected with other frontal cortex motor regions. The remainder of the connections originated from somatosensory areas 3a and S2/PV, and from the medial bank and fundus of the intraparietal sulcus (IPS). The PMv grasp zone was also densely connected with frontal cortex motor regions, albeit to a lesser extent than the M1 grasp zone. The remainder of the connections originated from areas S2/PV and aspects of the inferior parietal lobe such as PF, PFG, AIP, and the tip of the IPS. The area 2 grasp zone was densely connected with the hand representations of somatosensory areas 3b, 1, and S2/PV. The remainder of the connections was with areas 3a and 5 and the medial bank and fundus of the IPS. Connections with frontal cortex were relatively weak and concentrated in caudal M1. Thus, the three grasp zones may be nodes of parallel parietal-frontal pathways. Differential points of origin and termination of each pathway suggest varying functional specializations. Direct and indirect connections between those parietal-frontal pathways likely coordinate their respective functions into an accurate grasp. PMID:21832196

Molecular design and nanoparticle-mediated intracellular delivery of functional proteins to target cellular pathways

NASA Astrophysics Data System (ADS)

Shah, Dhiral Ashwin

Intracellular delivery of specific proteins and peptides represents a novel method to influence stem cells for gain-of-function and loss-of-function. Signaling control is vital in stem cells, wherein intricate control of and interplay among critical pathways directs the fate of these cells into either self-renewal or differentiation. The most common route to manipulate cellular function involves the introduction of genetic material such as full-length genes and shRNA into the cell to generate (or prevent formation of) the target protein, and thereby ultimately alter cell function. However, viral-mediated gene delivery may result in relatively slow expression of proteins and prevalence of oncogene insertion into the cell, which can alter cell function in an unpredictable fashion, and non-viral delivery may lead to low efficiency of genetic delivery. For example, the latter case plagues the generation of induced pluripotent stem cells (iPSCs) and hinders their use for in vivo applications. Alternatively, introducing proteins into cells that specifically recognize and influence target proteins, can result in immediate deactivation or activation of key signaling pathways within the cell. In this work, we demonstrate the cellular delivery of functional proteins attached to hydrophobically modified silica (SiNP) nanoparticles to manipulate specifically targeted cell signaling proteins. In the Wnt signaling pathway, we have targeted the phosphorylation activity of glycogen synthase kinase-3beta (GSK-3beta) by designing a chimeric protein and delivering it in neural stem cells. Confocal imaging indicates that the SiNP-chimeric protein conjugates were efficiently delivered to the cytosol of human embryonic kidney cells and rat neural stem cells, presumably via endocytosis. This uptake impacted the Wnt signaling cascade, indicated by the elevation of beta-catenin levels, and increased transcription of Wnt target genes, such as c-MYC. The results presented here suggest that

Tributyltin engages multiple nuclear receptor pathways and suppresses osteogenesis in bone marrow multipotent stromal cells.

PubMed

Baker, Amelia H; Watt, James; Huang, Cassie K; Gerstenfeld, Louis C; Schlezinger, Jennifer J

2015-06-15

Organotins are members of the environmental obesogen class of contaminants because they activate peroxisome proliferator-activated receptor γ (PPARγ), the essential regulator of adipogenesis. Exposure to thiazolidinediones (PPARγ ligands used to treat type 2 diabetes) is associated with increased fractures. Diminished bone quality likely results from PPARγ's role in promoting adipogenesis while suppressing osteogenesis of bone marrow multipotent mesenchymal stromal cells (BM-MSC). We hypothesized that tributyltin (TBT) would be a potent modifier of BM-MSC differentiation and a negative regulator of bone formation. Organotins interact with both PPARγ and retinoid X receptors (RXR), suggesting that they activate multiple nuclear receptor pathways. To investigate the role of RXR in the actions of TBT, the effects of PPARγ (rosiglitazone) and RXR (bexarotene, LG100268) agonists were compared to the effects of TBT in BMS2 cells and primary mouse BM-MSC cultures. In BMS2 cells, TBT induced the expression of Fabp4, Abca1, and Tgm2 in an RXR-dependent manner. All agonists suppressed osteogenesis in primary mouse BM-MSC cultures, based on decreased alkaline phosphatase activity, mineralization, and expression of osteoblast-related genes. While rosiglitazone and TBT strongly activated adipogenesis, based on lipid accumulation and expression of adipocyte-related genes, the RXR agonists did not. Extending these analyses to other RXR heterodimers showed that TBT and the RXR agonists activated the liver X receptor pathway, whereas rosiglitazone did not. Application of either a PPARγ antagonist (T0070907) or an RXR antagonist (HX531) significantly reduced rosiglitazone-induced suppression of bone nodule formation. Only the RXR antagonist significantly reduced LG100268- and TBT-induced bone suppression. The RXR antagonist also inhibited LG100268- and TBT-induced expression of Abca1, an LXR target gene, in primary BM-MSC cultures. These results provide novel evidence that

Extracellular Calcium Has Multiple Targets to Control Cell Proliferation.

PubMed

Capiod, Thierry

2016-01-01

Calcium channels and the two G-protein coupled receptors sensing extracellular calcium, calcium-sensing receptor (CaSR) and GPRC6a, are the two main means by which extracellular calcium can signal to cells and regulate many cellular processes including cell proliferation, migration and invasion of tumoral cells. Many intracellular signaling pathways are sensitive to cytosolic calcium rises and conversely intracellular signaling pathways can modulate calcium channel expression and activity. Calcium channels are undoubtedly involved in the former while the CaSR and GPRC6a are most likely to interfere with the latter. As for neurotransmitters, calcium ions use plasma membrane channels and GPCR to trigger cytosolic free calcium concentration rises and intracellular signaling and regulatory pathways activation. Calcium sensing GPCR, CaSR and GPRC6a, allow a supplemental degree of control and as for metabotropic receptors, they not only modulate calcium channel expression but they may also control calcium-dependent K+ channels. The multiplicity of intracellular signaling pathways involved, their sensitivity to local and global intracellular calcium increase and to CaSR and GPRC6a stimulation, the presence of membrane signalplex, all this confers the cells the plasticity they need to convert the effects of extracellular calcium into complex physiological responses and therefore determine their fate.

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.

Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation.

PubMed

Choi, Dongsic; Lee, Tae Hoon; Spinelli, Cristiana; Chennakrishnaiah, Shilpa; D'Asti, Esterina; Rak, Janusz

2017-07-01

Pathogenesis of human cancers bridges intracellular oncogenic driver events and their impact on intercellular communication. Among multiple mediators of this 'pathological connectivity' the role of extracellular vesicles (EVs) and their subsets (exosomes, ectosomes, oncosomes) is of particular interest for several reasons. The release of EVs from cancer cells represents a unique mechanism of regulated expulsion of bioactive molecules, a process that also mediates cell-to-cell transfer of lipids, proteins, and nucleic acids. Biological effects of these processes have been implicated in several aspects of cancer-related pathology, including tumour growth, invasion, angiogenesis, metastasis, immunity and thrombosis. Notably, the emerging evidence suggests that oncogenic mutations may impact several aspects of EV-mediated cell-cell communication including: (i) EV release rate and protein content; (ii) molecular composition of cancer EVs; (iii) the inclusion of oncogenic and mutant macromolecules in the EV cargo; (iv) EV-mediated release of genomic DNA; (v) deregulation of mechanisms responsible for EV biogenesis (vesiculome) and (vi) mechanisms of EV uptake by cancer cells. Intriguingly, EV-mediated intercellular transfer of mutant and oncogenic molecules between subpopulations of cancer cells, their indolent counterparts and stroma may exert profound biological effects that often resemble (but are not tantamount to) oncogenic transformation, including changes in cell growth, clonogenicity and angiogenic phenotype, or cause cell stress and death. However, several biological barriers likely curtail a permanent horizontal transformation of normal cells through EV-mediated mechanisms. The ongoing analysis and targeting of EV-mediated intercellular communication pathways can be viewed as a new therapeutic paradigm in cancer, while the analysis of oncogenic cargo contained in EVs released from cancer cells into biofluids is being developed for clinical use as a biomarker

Epigenetic identification of ZNF545 as a functional tumor suppressor in multiple myeloma via activation of p53 signaling pathway

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

Fan, Yu; Zhan, Qian; Xu, Hongying

The KRAB–zinc-finger protein ZNF545 was recently identified as a potential suppressor gene in several tumors. However, the regulatory mechanisms of ZNF545 in tumorigenesis remain unclear. In this study, we investigated the expression and roles of ZNF545 in multiple myeloma (MM). ZNF545 was frequently downregulated in MM tissues compared with non-tumor bone marrow tissues. ZNF545 expression was silenced by promoter methylation in MM cell lines, and could be restored by demethylation treatment. ZNF545 methylation was detected in 28.3% of MM tissues, compared with 4.3% of normal bone marrow tissues. ZNF545 transcriptionally activated the p53 signaling pathway but had no effect onmore » Akt in MM, whereas ectopic expression of ZNF545 in silenced cells suppressed their proliferation and induced apoptosis. We therefore identified ZNF545 as a novel tumor suppressor inhibiting tumor growth through activation of the p53 pathway in MM. Moreover, tumor-specific methylation of ZNF545 may represent an epigenetic biomarker for MM diagnosis, and a potential target for specific therapy. -- Highlights: •Downregulated ZNF545 in MM tissues and cell lines and ectopic expression of ZNF545 suppresses tumor growth. •Tumor-specific methylation of ZNF545 represents an epigenetic biomarker for MM diagnosis, and a potential target for specific therapy. •ZNF545 exerts its tumor suppressive effects via transcriptional activating p53 pathway.« less

Regulation of the Hippo signaling pathway by ubiquitin modification.

PubMed

Kim, Youngeun; Jho, Eek-Hoon

2018-03-01

The Hippo signaling pathway plays an essential role in adult tissue homeostasis and organ size control. Abnormal regulation of Hippo signaling can be a cause for multiple types of human cancers. Since the awareness of the importance of the Hippo signaling in a wide range of biological fields has been continually grown, it is also understood that a thorough and well-rounded comprehension of the precise dynamics could provide fundamental insights for therapeutic applications. Several components in the Hippo signaling pathway are known to be targeted for proteasomal degradation via ubiquitination by E3 ligases. β-TrCP is a well-known E3 ligase of YAP/TAZ, which leads to the reduction of YAP/TAZ levels. The Hippo signaling pathway can also be inhibited by the E3 ligases (such as ITCH) which target LATS1/2 for degradation. Regulation via ubiquitination involves not only complex network of E3 ligases but also deubiquitinating enzymes (DUBs), which remove ubiquitin from its targets. Interestingly, non-degradative ubiquitin modifications are also known to play important roles in the regulation of Hippo signaling. Although there has been much advanced progress in the investigation of ubiquitin modifications acting as regulators of the Hippo signaling pathway, research done to date still remains inadequate due to the sheer complexity and diversity of the subject. Herein, we review and discuss recent developments that implicate ubiquitin-mediated regulatory mechanisms at multiple steps of the Hippo signaling pathway. [BMB Reports 2018; 51(3): 143-150].

Triptolide prevents extracellular matrix accumulation in experimental diabetic kidney disease by targeting microRNA-137/Notch1 pathway.

PubMed

Han, Fei; Wang, Shanshan; Chang, Yunpeng; Li, Chunjun; Yang, Juhong; Han, Zhe; Chang, Baocheng; Sun, Bei; Chen, Liming

2018-03-01

MicroRNAs (miRNAs) are involved in multiple biological functions via suppressing target genes. Triptolide is a monomeric compound isolated from a traditional Chinese herb, which exerts protective roles in many kinds of glomerular diseases. However, our understanding of the triptolide effect on miRNAome is still limited. In this study, we found that triptolide significantly decreased albuminuria and improved glomerulosclerosis in rats with diabetic kidney disease (DKD). And triptolide also inhibited extracellular matrix (ECM) protein accumulation and the notch1 pathway activation under diabetic conditions. MiR-137 was significantly decreased in the HG (high glucose)-treated HRMCs and in the kidney tissues of the diabetic rats, but was upregulated by triptolide. In addition, overexpression of miR-137 exerted similar effects to those of triptolide, while miR-137 inhibition aggravated ECM protein accumulation. Luciferase reporter assay results demonstrated that miR-137 directly targets Notch1. Furthermore, the miR-137-dependent effects were due to Notch1 suppression that in turn inhibited ECM protein expression, key mediators of glomerulosclerosis. Finally, downregulation of miR-137 reversed the ECM inhibition role of triptolide in HG cultured HRMCs. Taken together, these findings indicate that triptolide is a potential therapeutic option for DKD and that miR-137/Notch1 pathway play roles in the anti-glomerulosclerosis mechanism of triptolide. © 2017 Wiley Periodicals, Inc.

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.

MicroRNA-188 suppresses G1/S transition by targeting multiple cyclin/CDK complexes.

PubMed

Wu, Jiangbin; Lv, Qing; He, Jie; Zhang, Haoxiang; Mei, Xueshuang; Cui, Kai; Huang, Nunu; Xie, Weidong; Xu, Naihan; Zhang, Yaou

2014-10-11

Accelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. It has been shown that miR-188 is upregulated in UVB-irradiated mouse skin and human nasopharyngeal carcinoma CNE cells under hypoxic stress. However, little is known about the function of miR-188 in cell proliferation and growth control. Overexpression of miR-188 inhibits cell proliferation, tumor colony formation and G1/S cell cycle transition in human nasopharyngeal carcinoma CNE cells. Using bioinformatics approach, we identify a series of genes regulating G1/S transition as putative miR-188 targets. MiR-188 inhibits both mRNA and protein expression of CCND1, CCND3, CCNE1, CCNA2, CDK4 and CDK2, suppresses Rb phosphorylation and downregulates E2F transcriptional activity. The expression level of miR-188 also inversely correlates with the expression of miR-188 targets in human nasopharyngeal carcinoma (NPC) tissues. Moreover, studies in xenograft mouse model reveal that miR-188 is capable of inhibiting tumor initiation and progression by suppressing target genes expression and Rb phosphorylation. This study demonstrates that miR-188 exerts anticancer effects, via downregulation of multiple G1/S related cyclin/CDKs and Rb/E2F signaling pathway.

A unique role of endogenous visual-spatial attention in rapid processing of multiple targets

PubMed Central

Guzman, Emmanuel; Grabowecky, Marcia; Palafox, German; Suzuki, Satoru

2012-01-01

Visual spatial attention can be exogenously captured by a salient stimulus or can be endogenously allocated by voluntary effort. Whether these two attention modes serve distinctive functions is debated, but for processing of single targets the literature suggests superiority of exogenous attention (it is faster acting and serves more functions). We report that endogenous attention uniquely contributes to processing of multiple targets. For speeded visual discrimination, response times are faster for multiple redundant targets than for single targets due to probability summation and/or signal integration. This redundancy gain was unaffected when attention was exogenously diverted from the targets, but was completely eliminated when attention was endogenously diverted. This was not due to weaker manipulation of exogenous attention because our exogenous and endogenous cues similarly affected overall response times. Thus, whereas exogenous attention is superior for processing single targets, endogenous attention plays a unique role in allocating resources crucial for rapid concurrent processing of multiple targets. PMID:21517209

Posterior Orbitofrontal and Anterior Cingulate Pathways to the Amygdala Target Inhibitory and Excitatory Systems with Opposite Functions.

PubMed

Zikopoulos, Basilis; Höistad, Malin; John, Yohan; Barbas, Helen

2017-05-17

The bidirectional dialogue of the primate posterior orbitofrontal cortex (pOFC) with the amygdala is essential in cognitive-emotional functions. The pOFC also sends a uniquely one-way excitatory pathway to the amygdalar inhibitory intercalated masses (IM), which inhibit the medial part of the central amygdalar nucleus (CeM). Inhibition of IM has the opposite effect, allowing amygdalar activation of autonomic structures and emotional arousal. Using multiple labeling approaches to identify pathways and their postsynaptic sites in the amygdala in rhesus monkeys, we found that the anterior cingulate cortex innervated mostly the basolateral and CeM amygdalar nuclei, poised to activate CeM for autonomic arousal. By contrast, a pathway from pOFC to IM exceeded all other pathways to the amygdala by density and size and proportion of large and efficient terminals. Moreover, whereas pOFC terminals in IM innervated each of the three distinct classes of inhibitory neurons, most targeted neurons expressing dopamine- and cAMP-regulated phosphoprotein (DARPP-32+), known to be modulated by dopamine. The predominant pOFC innervation of DARPP-32+ neurons suggests activation of IM and inhibition of CeM, resulting in modulated autonomic function. By contrast, inhibition of DARPP-32 neurons in IM by high dopamine levels disinhibits CeM and triggers autonomic arousal. The findings provide a mechanism to help explain how a strong pOFC pathway, which is poised to moderate activity of CeM, through IM, can be undermined by the high level of dopamine during stress, resulting in collapse of potent inhibitory mechanisms in the amygdala and heightened autonomic drive, as seen in chronic anxiety disorders. SIGNIFICANCE STATEMENT The dialogue between prefrontal cortex and amygdala allows thoughts and emotions to influence actions. The posterior orbitofrontal cortex sends a powerful pathway that targets a special class of amygdalar intercalated mass (IM) inhibitory neurons, whose wiring may help

Multiple operating system rotation environment moving target defense

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

Evans, Nathaniel; Thompson, Michael

Systems and methods for providing a multiple operating system rotation environment ("MORE") moving target defense ("MTD") computing system are described. The MORE-MTD system provides enhanced computer system security through a rotation of multiple operating systems. The MORE-MTD system increases attacker uncertainty, increases the cost of attacking the system, reduces the likelihood of an attacker locating a vulnerability, and reduces the exposure time of any located vulnerability. The MORE-MTD environment is effectuated by rotation of the operating systems at a given interval. The rotating operating systems create a consistently changing attack surface for remote attackers.

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

PubMed

Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A; Cornelissen-Steijger, Paulien D M; Geukes Foppen, Marnix H; Kemper, Kristel; Goding, Colin R; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G; Ribas, Antoni; Lo, Roger S; Peeper, Daniel S

2014-12-15

Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

[Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

PubMed

Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

2015-01-01

Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

Multi-target detection and positioning in crowds using multiple camera surveillance

NASA Astrophysics Data System (ADS)

Huang, Jiahu; Zhu, Qiuyu; Xing, Yufeng

2018-04-01

In this study, we propose a pixel correspondence algorithm for positioning in crowds based on constraints on the distance between lines of sight, grayscale differences, and height in a world coordinates system. First, a Gaussian mixture model is used to obtain the background and foreground from multi-camera videos. Second, the hair and skin regions are extracted as regions of interest. Finally, the correspondences between each pixel in the region of interest are found under multiple constraints and the targets are positioned by pixel clustering. The algorithm can provide appropriate redundancy information for each target, which decreases the risk of losing targets due to a large viewing angle and wide baseline. To address the correspondence problem for multiple pixels, we construct a pixel-based correspondence model based on a similar permutation matrix, which converts the correspondence problem into a linear programming problem where a similar permutation matrix is found by minimizing an objective function. The correct pixel correspondences can be obtained by determining the optimal solution of this linear programming problem and the three-dimensional position of the targets can also be obtained by pixel clustering. Finally, we verified the algorithm with multiple cameras in experiments, which showed that the algorithm has high accuracy and robustness.

Investigating multiple dysregulated pathways in rheumatoid arthritis based on pathway interaction network.

PubMed

Song, Xian-Dong; Song, Xian-Xu; Liu, Gui-Bo; Ren, Chun-Hui; Sun, Yuan-Bo; Liu, Ke-Xin; Liu, Bo; Liang, Shuang; Zhu, Zhu

2018-03-01

The traditional methods of identifying biomarkers in rheumatoid arthritis (RA) have focussed on the differentially expressed pathways or individual pathways, which however, neglect the interactions between pathways. To better understand the pathogenesis of RA, we aimed to identify dysregulated pathway sets using a pathway interaction network (PIN), which considered interactions among pathways. Firstly, RA-related gene expression profile data, protein-protein interactions (PPI) data and pathway data were taken up from the corresponding databases. Secondly, principal component analysis method was used to calculate the pathway activity of each of the pathway, and then a seed pathway was identified using data gleaned from the pathway activity. A PIN was then constructed based on the gene expression profile, pathway data, and PPI information. Finally, the dysregulated pathways were extracted from the PIN based on the seed pathway using the method of support vector machines and an area under the curve (AUC) index. The PIN comprised of a total of 854 pathways and 1064 pathway interactions. The greatest change in the activity score between RA and control samples was observed in the pathway of epigenetic regulation of gene expression, which was extracted and regarded as the seed pathway. Starting with this seed pathway, one maximum pathway set containing 10 dysregulated pathways was extracted from the PIN, having an AUC of 0.8249, and the result indicated that this pathway set could distinguish RA from the controls. These 10 dysregulated pathways might be potential biomarkers for RA diagnosis and treatment in the future.

Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer.

PubMed

Bruntz, Ronald C; Lindsley, Craig W; Brown, H Alex

2014-10-01

Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein-coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

An Interactive Platform to Visualize Data-Driven Clinical Pathways for the Management of Multiple Chronic Conditions.

PubMed

Zhang, Yiye; Padman, Rema

2017-01-01

Patients with multiple chronic conditions (MCC) pose an increasingly complex health management challenge worldwide, particularly due to the significant gap in our understanding of how to provide coordinated care. Drawing on our prior research on learning data-driven clinical pathways from actual practice data, this paper describes a prototype, interactive platform for visualizing the pathways of MCC to support shared decision making. Created using Python web framework, JavaScript library and our clinical pathway learning algorithm, the visualization platform allows clinicians and patients to learn the dominant patterns of co-progression of multiple clinical events from their own data, and interactively explore and interpret the pathways. We demonstrate functionalities of the platform using a cluster of 36 patients, identified from a dataset of 1,084 patients, who are diagnosed with at least chronic kidney disease, hypertension, and diabetes. Future evaluation studies will explore the use of this platform to better understand and manage MCC.

Programmed Cell Death-1/Programmed Death-ligand 1 Pathway: A New Target for Sepsis.

PubMed

Liu, Qiang; Li, Chun-Sheng

2017-04-20

Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment. Studies of the association between PD-1/PD-L1 and sepsis published up to January 31, 2017, were obtained by searching the PubMed database. English language studies, including those based on animal models, clinical research, and reviews, with data related to PD-1/PD-L1 and sepsis, were evaluated. Immunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of the PD-1/PD-L1 pathway could reduce the exhaustion of T-cells and enhance the proliferation and activation of T-cells. The anti-PD-1/PD-L1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and future studies aimed at revaluating the efficacy and safety of this targeted approach.

Creating Multiple Pathways in the Arts: A New York City Case Study

ERIC Educational Resources Information Center

Maguire, Cindy; Mishook, Jacob; Garcia, Ivonne; de Gaillande, Genevieve

2013-01-01

Increasingly, education policy makers understand the importance of students and families having access to a range of high quality educational opportunities inside and outside of school, 365 days a year. This paper explores the concept of multiple pathways in arts education to further conceptualize and build upon such opportunities, inside and…

Multiple targets detection method in detection of UWB through-wall radar

NASA Astrophysics Data System (ADS)

Yang, Xiuwei; Yang, Chuanfa; Zhao, Xingwen; Tian, Xianzhong

2017-11-01

In this paper, the problems and difficulties encountered in the detection of multiple moving targets by UWB radar are analyzed. The experimental environment and the penetrating radar system are established. An adaptive threshold method based on local area is proposed to effectively filter out clutter interference The objective of the moving target is analyzed, and the false target is further filtered out by extracting the target feature. Based on the correlation between the targets, the target matching algorithm is proposed to improve the detection accuracy. Finally, the effectiveness of the above method is verified by practical experiment.

Waveform Optimization for Target Estimation by Cognitive Radar with Multiple Antennas.

PubMed

Yao, Yu; Zhao, Junhui; Wu, Lenan

2018-05-29

A new scheme based on Kalman filtering to optimize the waveforms of an adaptive multi-antenna radar system for target impulse response (TIR) estimation is presented. This work aims to improve the performance of TIR estimation by making use of the temporal correlation between successive received signals, and minimize the mean square error (MSE) of TIR estimation. The waveform design approach is based upon constant learning from the target feature at the receiver. Under the multiple antennas scenario, a dynamic feedback loop control system is established to real-time monitor the change in the target features extracted form received signals. The transmitter adapts its transmitted waveform to suit the time-invariant environment. Finally, the simulation results show that, as compared with the waveform design method based on the MAP criterion, the proposed waveform design algorithm is able to improve the performance of TIR estimation for extended targets with multiple iterations, and has a relatively lower level of complexity.

49 CFR 234.306 - Multiple dispatching or maintaining railroads with respect to the same highway-rail or pathway...

Code of Federal Regulations, 2012 CFR

2012-10-01

... respect to the same highway-rail or pathway grade crossing; appointment of responsible railroad. 234.306... Conditions at Highway-Rail and Pathway Grade Crossings § 234.306 Multiple dispatching or maintaining railroads with respect to the same highway-rail or pathway grade crossing; appointment of responsible...

49 CFR 234.306 - Multiple dispatching or maintaining railroads with respect to the same highway-rail or pathway...

Code of Federal Regulations, 2013 CFR

2013-10-01

... respect to the same highway-rail or pathway grade crossing; appointment of responsible railroad. 234.306... Conditions at Highway-Rail and Pathway Grade Crossings § 234.306 Multiple dispatching or maintaining railroads with respect to the same highway-rail or pathway grade crossing; appointment of responsible...

49 CFR 234.306 - Multiple dispatching or maintaining railroads with respect to the same highway-rail or pathway...

Code of Federal Regulations, 2014 CFR

2014-10-01

... respect to the same highway-rail or pathway grade crossing; appointment of responsible railroad. 234.306... Conditions at Highway-Rail and Pathway Grade Crossings § 234.306 Multiple dispatching or maintaining railroads with respect to the same highway-rail or pathway grade crossing; appointment of responsible...

Co-Targeting HER2 and EphB4 Pathways

DTIC Science & Technology

2013-07-01

progress has been made toward the clinic. An IND has been obtained for sEphbB4- HSA, an albumin stabilized soluble EphB4 decoy receptor that efficiently...for activated HER2/HER family receptors , angiogenic markers (EphrinB2, EphB1,2,3,4,6, VEGF, VEGFR-1, 2, 3 and PDGFR), vessel density, signal...ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE 3 . DATES COVERED 4. TITLE AND SUBTITLE Co-Targeting HER2 and EphB4 Pathways 5a. CONTRACT NUMBER 5b

In vitro reconstitution of mevalonate pathway and targeted engineering of farnesene overproduction in Escherichia coli.

PubMed

Zhu, Fayin; Zhong, Xiaofang; Hu, Mengzhu; Lu, Lei; Deng, Zixin; Liu, Tiangang

2014-07-01

Approaches using metabolic engineering and synthetic biology to overproduce terpenoids, such as the precursors of taxol and artemisinin, in microbial systems have achieved initial success. However, due to the lack of steady-state kinetic information and incomplete understanding of the terpenoid biosynthetic pathway, it has been difficult to build a highly efficient, universal system. Here, we reconstituted the mevalonate pathway to produce farnesene (a precursor of new jet fuel) in vitro using purified protein components. The information from this in vitro reconstituted system guided us to rationally optimize farnesene production in E. coli by quantitatively overexpressing each component. Targeted proteomic assays and intermediate assays were used to determine the metabolic status of each mutant. Through targeted engineering, farnesene production could be increased predictably step by step, up to 1.1 g/L (∼ 2,000 fold) 96 h after induction at the shake-flask scale. The strategy developed to release the potential of the mevalonate pathway for terpenoid overproduction should also work in other multistep synthetic pathways. © 2014 Wiley Periodicals, Inc.

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

Molecular Approach to Targeted Therapy for Multiple Sclerosis.

PubMed

Sherbet, Gajanan V

2016-01-01

The development and evolution of targeted therapy to any disease require the identification of targets amenable to treatment of patients. Here the pathogenetic signalling systems involved in multiple sclerosis are scrutinised to locate nodes of deregulation and dysfunction in order to devise strategies of drug development for targeted intervention. Oliogoclonal bands (OCB) are isoelectric focusing profiles of immunoglobulins synthesised in the central nervous system. OCBs enable the diagnosis of multiple sclerosis with high sensitivity and specificity and are related to the course of the disease and progression. The OCB patterns can be linked with the expression of angiogenic molecular species. Angiogenic signalling which has also been implicated in demyelination provides the option of using angiogenesis inhibitors in disease control. The PI3K (phosphoinositide 3-kinase)/Akt axis has emerged with a key role in myelination with its demonstrable links with mTOR mediated transcription of downstream target genes. Inflammatory signals and innate and acquired immunity from the activation of NF-κB (nuclear factor κB) responsive genes are considered. NF-κB signalling could be implicated in myelination. The transcription factor STAT (signal transducers and activators of transcription) and the EBV (Epstein- Barr virus) transcription factor BZLF1 contributing significantly to the disease process are a major environmental factor linked to MS. EBV can activate TGF (transforming growth factor) and VEGF (vascular endothelial growth factor) signalling. EBV microRNAs are reviewed as signalling mediators of pathogenesis. Stem cell transplantation therapy has lately gained much credence, so the current status of mesenchymal and hematopoietic stem cell therapy is reviewed with emphasis on the differential expression immune-related genes and operation of signalling systems.

Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways.

PubMed

An, Songzhu Michael; Ding, Qiang Peter; Li, Ling-song

2013-06-01

One of the most exciting fields in biomedical research over the past few years is stem cell biology, and therapeutic application of stem cells to replace the diseased or damaged tissues is also an active area in development. Although stem cell therapy has a number of technical challenges and regulatory hurdles to overcome, the use of stem cells as tools in drug discovery supported by mature technologies and established regulatory paths is expected to generate more immediate returns. In particular, the targeting of stem cell signaling pathways is opening up a new avenue for drug discovery. Aberrations in these pathways result in various diseases, including cancer, fibrosis and degenerative diseases. A number of drug targets in stem cell signaling pathways have been identified. Among them, WNT and Hedgehog are two most important signaling pathways, which are the focus of this review. A hedgehog pathway inhibitor, vismodegib (Erivedge), has recently been approved by the US FDA for the treatment of skin cancer, while several drug candidates for the WNT pathway are entering clinical trials. We have discovered that the stem cell signaling pathways respond to traditional Chinese medicines. Substances isolated from herbal medicine may act specifically on components of stem cell signaling pathways with high affinities. As many of these events can be explained through molecular interactions, these phenomena suggest that discovery of stem cell-targeting drugs from natural products may prove to be highly successful.

Multiple Pathways and State Policy: Toward Education and Training Beyond High School.

ERIC Educational Resources Information Center

Callan, Patrick M.; Finney, Joni E.

This paper discusses the policy dimensions to increase the nation's educational capital by providing at least two years of education beyond high school for almost every young and working-age adult who is motivated and able to benefit. It focuses on creating multiple pathways resulting from collaborative efforts across educational sectors or…

Regression of Pathological Cardiac Hypertrophy: Signaling Pathways and Therapeutic Targets

PubMed Central

Hou, Jianglong; Kang, Y. James

2012-01-01

Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. PMID:22750195

Fuzzy Neural Network-Based Interacting Multiple Model for Multi-Node Target Tracking Algorithm

PubMed Central

Sun, Baoliang; Jiang, Chunlan; Li, Ming

2016-01-01

An interacting multiple model for multi-node target tracking algorithm was proposed based on a fuzzy neural network (FNN) to solve the multi-node target tracking problem of wireless sensor networks (WSNs). Measured error variance was adaptively adjusted during the multiple model interacting output stage using the difference between the theoretical and estimated values of the measured error covariance matrix. The FNN fusion system was established during multi-node fusion to integrate with the target state estimated data from different nodes and consequently obtain network target state estimation. The feasibility of the algorithm was verified based on a network of nine detection nodes. Experimental results indicated that the proposed algorithm could trace the maneuvering target effectively under sensor failure and unknown system measurement errors. The proposed algorithm exhibited great practicability in the multi-node target tracking of WSNs. PMID:27809271

Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway

PubMed Central

Duffy, Diane M.

2015-01-01

PTGS2 inhibitors alone may be suitable for use as emergency contraceptives. However, drugs of this class are unlikely to be effective as monthly contraceptives. Inhibitors of additional PGE2 synthesis enzymes or modulation of PGE2 metabolism or transport also hold potential for reducing follicular PGE2 and preventing ovulation. Approaches which target multiple components of the PGE2 synthesis-metabolism-transport pathway may be required to effectively block ovulation and lead to the development of novel contraceptive options for women. Therapies which target PGE2 may also impact disorders of the uterus and could also have benefits for women's health in addition to contraception. PMID:26025453

Allowable carbon emissions lowered by multiple climate targets.

PubMed

Steinacher, Marco; Joos, Fortunat; Stocker, Thomas F

2013-07-11

Climate targets are designed to inform policies that would limit the magnitude and impacts of climate change caused by anthropogenic emissions of greenhouse gases and other substances. The target that is currently recognized by most world governments places a limit of two degrees Celsius on the global mean warming since preindustrial times. This would require large sustained reductions in carbon dioxide emissions during the twenty-first century and beyond. Such a global temperature target, however, is not sufficient to control many other quantities, such as transient sea level rise, ocean acidification and net primary production on land. Here, using an Earth system model of intermediate complexity (EMIC) in an observation-informed Bayesian approach, we show that allowable carbon emissions are substantially reduced when multiple climate targets are set. We take into account uncertainties in physical and carbon cycle model parameters, radiative efficiencies, climate sensitivity and carbon cycle feedbacks along with a large set of observational constraints. Within this framework, we explore a broad range of economically feasible greenhouse gas scenarios from the integrated assessment community to determine the likelihood of meeting a combination of specific global and regional targets under various assumptions. For any given likelihood of meeting a set of such targets, the allowable cumulative emissions are greatly reduced from those inferred from the temperature target alone. Therefore, temperature targets alone are unable to comprehensively limit the risks from anthropogenic emissions.

Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis

PubMed Central

Srivastava, Rajneesh; Aslam, Muhammad; Kalluri, Sudhakar Reddy; Schirmer, Lucas; Buck, Dorothea; Tackenberg, Björn; Rothhammer, Veit; Chan, Andrew; Gold, Ralf; Berthele, Achim; Bennett, Jeffrey L.; Korn, Thomas; Hemmer, Bernhard

2016-01-01

BACKGROUND Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known. METHODS We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. RESULTS Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. CONCLUSIONS KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.) PMID:22784115

Multiple-target tracking implementation in the ebCMOS camera system: the LUSIPHER prototype

NASA Astrophysics Data System (ADS)

Doan, Quang Tuyen; Barbier, Remi; Dominjon, Agnes; Cajgfinger, Thomas; Guerin, Cyrille

2012-06-01

The domain of the low light imaging systems progresses very fast, thanks to detection and electronic multiplication technology evolution, such as the emCCD (electron multiplying CCD) or the ebCMOS (electron bombarded CMOS). We present an ebCMOS camera system that is able to track every 2 ms more than 2000 targets with a mean number of photons per target lower than two. The point light sources (targets) are spots generated by a microlens array (Shack-Hartmann) used in adaptive optics. The Multiple-Target-Tracking designed and implemented on a rugged workstation is described. The results and the performances of the system on the identification and tracking are presented and discussed.

Conformational Transition Pathways of Epidermal Growth Factor Receptor Kinase Domain from Multiple Molecular Dynamics Simulations and Bayesian Clustering.

PubMed

Li, Yan; Li, Xiang; Ma, Weiya; Dong, Zigang

2014-08-12

The epidermal growth factor receptor (EGFR) is aberrantly activated in various cancer cells and an important target for cancer treatment. Deep understanding of EGFR conformational changes between the active and inactive states is of pharmaceutical interest. Here we present a strategy combining multiply targeted molecular dynamics simulations, unbiased molecular dynamics simulations, and Bayesian clustering to investigate transition pathways during the activation/inactivation process of EGFR kinase domain. Two distinct pathways between the active and inactive forms are designed, explored, and compared. Based on Bayesian clustering and rough two-dimensional free energy surfaces, the energy-favorable pathway is recognized, though DFG-flip happens in both pathways. In addition, another pathway with different intermediate states appears in our simulations. Comparison of distinct pathways also indicates that disruption of the Lys745-Glu762 interaction is critically important in DFG-flip while movement of the A-loop significantly facilitates the conformational change. Our simulations yield new insights into EGFR conformational transitions. Moreover, our results verify that this approach is valid and efficient in sampling of protein conformational changes and comparison of distinct pathways.

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

Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie

PubMed Central

Parker, Joseph; Struhl, Gary

2015-01-01

Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes—a phenomenon we term “nuclear seclusion.” Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability. PMID:26474042

Multiple target drug cocktail design for attacking the core network markers of four cancers using ligand-based and structure-based virtual screening methods

PubMed Central

2015-01-01

Background Computer-aided drug design has a long history of being applied to discover new molecules to treat various cancers, but it has always been focused on single targets. The development of systems biology has let scientists reveal more hidden mechanisms of cancers, but attempts to apply systems biology to cancer therapies remain at preliminary stages. Our lab has successfully developed various systems biology models for several cancers. Based on these achievements, we present the first attempt to combine multiple-target therapy with systems biology. Methods In our previous study, we identified 28 significant proteins--i.e., common core network markers--of four types of cancers as house-keeping proteins of these cancers. In this study, we ranked these proteins by summing their carcinogenesis relevance values (CRVs) across the four cancers, and then performed docking and pharmacophore modeling to do virtual screening on the NCI database for anti-cancer drugs. We also performed pathway analysis on these proteins using Panther and MetaCore to reveal more mechanisms of these cancer house-keeping proteins. Results We designed several approaches to discover targets for multiple-target cocktail therapies. In the first one, we identified the top 20 drugs for each of the 28 cancer house-keeping proteins, and analyzed the docking pose to further understand the interaction mechanisms of these drugs. After screening for duplicates, we found that 13 of these drugs could target 11 proteins simultaneously. In the second approach, we chose the top 5 proteins with the highest summed CRVs and used them as the drug targets. We built a pharmacophore and applied it to do virtual screening against the Life-Chemical library for anti-cancer drugs. Based on these results, wet-lab bio-scientists could freely investigate combinations of these drugs for multiple-target therapy for cancers, in contrast to the traditional single target therapy. Conclusions Combination of systems biology

Protein C receptor stimulates multiple signaling pathways in breast cancer cells.

PubMed

Wang, Daisong; Liu, Chunye; Wang, Jingqiang; Jia, Yingying; Hu, Xin; Jiang, Hai; Shao, Zhi-Ming; Zeng, Yi Arial

2018-01-26

The protein C receptor (PROCR) has emerged as a stem cell marker in several normal tissues and has also been implicated in tumor progression. However, the functional role of PROCR and the signaling mechanisms downstream of PROCR remain poorly understood. Here, we dissected the PROCR signaling pathways in breast cancer cells. Combining protein array, knockdown, and overexpression methods, we found that PROCR concomitantly activates multiple pathways. We also noted that PROCR-dependent ERK and PI3k-Akt-mTOR signaling pathways proceed through Src kinase and transactivation of insulin-like growth factor 1 receptor (IGF-1R). These pathway activities led to the accumulation of c-Myc and cyclin D1. On the other hand, PROCR-dependent RhoA-ROCK-p38 signaling relied on coagulation factor II thrombin receptor (F2R). We confirmed these findings in primary cells isolated from triple-negative breast cancer-derived xenografts (PDX) that have high expression of PROCR. To the best our knowledge, this is the first comprehensive study of PROCR signaling in breast cancer cells, and its findings also shed light on the molecular mechanisms of PROCR in stem cells in normal tissue. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Renal Protective Role of Xiexin Decoction with Multiple Active Ingredients Involves Inhibition of Inflammation through Downregulation of the Nuclear Factor-κB Pathway in Diabetic Rats

PubMed Central

Wu, Jia-sheng; Shi, Rong; Zhong, Jie; Lu, Xiong; Ma, Bing-liang; Wang, Tian-ming; Zan, Bin; Ma, Yue-ming; Cheng, Neng-neng; Qiu, Fu-rong

2013-01-01

In Chinese medicine, Xiexin decoction (XXD) has been used for the clinical treatment of diabetes for at least 1700 years. The present study was conducted to investigate the effective ingredients of XXD and their molecular mechanisms of antidiabetic nephropathy in rats. Rats with diabetes induced by high-fat diet and streptozotocin were treated with XXD extract for 12 weeks. XXD significantly improved the glucolipid metabolism disorder, attenuated albuminuria and renal pathological changes, reduced renal advanced glycation end-products, inhibited receptor for advanced glycation end-product and inflammation factors expression, suppressed renal nuclear factor-κB pathway activity, and downregulated renal transforming growth factor-β1. The concentrations of multiple components in plasma from XXD were determined by liquid chromatography and tandem mass spectrometry. Pharmacokinetic/pharmacodynamic analysis using partial least square regression revealed that 8 ingredients of XXD were responsible for renal protective effects via actions on multiple molecular targets. Our study suggests that the renal protective role of XXD with multiple effective ingredients involves inhibition of inflammation through downregulation of the nuclear factor-κB pathway, reducing renal advanced glycation end-products and receptor for advanced glycation end-product in diabetic rats. PMID:23935673

Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases.

PubMed

Sahakyan, Aleksandr B; Balasubramanian, Shankar

2016-03-12

The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases. We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations. Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired.

Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies.

PubMed

Ruiz Salas, Veronica; Alegre, Marta; Garcés, Joan Ramón; Puig, Lluis

2014-06-01

The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.

Respiratory syncytial virus nonstructural proteins decrease levels of multiple members of the cellular interferon pathways.

PubMed

Swedan, Samer; Musiyenko, Alla; Barik, Sailen

2009-10-01

Viruses of the Paramyxoviridae family, such as the respiratory syncytial virus (RSV), suppress cellular innate immunity represented by type I interferon (IFN) for optimal growth in their hosts. The two unique nonstructural (NS) proteins, NS1 and NS2, of RSV suppress IFN synthesis, as well as IFN function, but their exact targets are still uncharacterized. Here, we investigate if either or both of the NS proteins affect the steady-state levels of key members of the IFN pathway. We found that both NS1 and NS2 decreased the levels of TRAF3, a strategic integrator of multiple IFN-inducing signals, although NS1 was more efficient. Only NS1 reduced IKKepsilon, a key protein kinase that specifically phosphorylates and activates IFN regulatory factor 3. Loss of the TRAF3 and IKKepsilon proteins appeared to involve a nonproteasomal mechanism. Interestingly, NS2 modestly increased IKKepsilon levels. In the IFN response pathway, NS2 decreased the levels of STAT2, the essential transcription factor for IFN-inducible antiviral genes. Preliminary mapping revealed that the C-terminal 10 residues of NS1 were essential for reducing IKKepsilon levels and the C-terminal 10 residues of NS2 were essential for increasing and reducing IKKepsilon and STAT2, respectively. In contrast, deletion of up to 20 residues of the C termini of NS1 and NS2 did not diminish their TRAF3-reducing activity. Coimmunoprecipitation studies revealed that NS1 and NS2 form a heterodimer. Clearly, the NS proteins of RSV, working individually and together, regulate key signaling molecules of both the IFN activation and response pathways.

Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

PubMed

Likus, Wirginia; Siemianowicz, Krzysztof; Bieńk, Konrad; Pakuła, Małgorzata; Pathak, Himani; Dutta, Chhanda; Wang, Qiong; Shojaei, Shahla; Assaraf, Yehuda G; Ghavami, Saeid; Cieślar-Pobuda, Artur; Łos, Marek J

2016-03-01

Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly

Nutrient sensing pathways as therapeutic targets for healthy ageing.

PubMed

Aiello, Anna; Accardi, Giulia; Candore, Giuseppina; Gambino, Caterina Maria; Mirisola, Mario; Taormina, Giusi; Virruso, Claudia; Caruso, Calogero

2017-04-01

In the present paper, the authors have discussed anti-aging strategies which aim to slow the aging process and to delay the onset of age-related diseases, focusing on nutrient sensing pathways (NSPs) as therapeutic targets. Indeed, several studies have already demonstrated that both in animal models and humans, dietary interventions might have a positive impact on the aging process through the modulation of these pathways. Areas covered: Achieving healthy aging is the main challenge of the twenty-first century because lifespan is increasing, but not in tandem with good health. The authors have illustrated different approaches that can act on NSPs, modulating the rate of the aging process. Expert opinion: Humanity's lasting dream is to reverse or, at least, postpone aging. In recent years, increasing attention has been devoted to anti-aging therapies. The subject is very popular among the general public, whose imagination runs wild with all the possible tools to delay aging and to gain immortality. Some approaches discussed in the present review should be able to substantially slow down the aging process, extending our productive, youthful lives, without frailty.

SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

PubMed Central

Wu, Ching-Shyi; Ouyang, Jian; Mori, Eiichiro; Nguyen, Hai Dang; Maréchal, Alexandre; Hallet, Alexander; Chen, David J.; Zou, Lee

2014-01-01

The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR–Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11–RAD50–NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. PMID:24990965

Targeting of a Nuclease to Murine Leukemia Virus Capsids Inhibits Viral Multiplication

NASA Astrophysics Data System (ADS)

Natsoulis, Georges; Seshaiah, Partha; Federspiel, Mark J.; Rein, Alan; Hughes, Stephen H.; Boeke, Jef D.

1995-01-01

Capsid-targeted viral inactivation is an antiviral strategy in which toxic fusion proteins are targeted to virions, where they inhibit viral multiplication by destroying viral components. These fusion proteins consist of a virion structural protein moiety and an enzymatic moiety such as a nuclease. Such fusion proteins can severely inhibit transposition of yeast retrotransposon Ty1, an element whose transposition mechanistically resembles retroviral multiplication. We demonstrate that expression of a murine retrovirus capsid-staphylococcal nuclease fusion protein inhibits multiplication of the corresponding murine leukemia virus by 30- to 100-fold. Staphylococcal nuclease is apparently inactive intracellularly and hence nontoxic to the host cell, but it is active extracellularly because of its requirement for high concentrations of Ca2+ ions. Virions assembled in and shed from cells expressing the fusion protein contain very small amounts of intact viral RNA, as would be predicted for nuclease-mediated inhibition of viral multiplication.

Expression profiling and bioinformatic analyses suggest new target genes and pathways for human hair follicle related microRNAs.

PubMed

Hochfeld, Lara M; Anhalt, Thomas; Reinbold, Céline S; Herrera-Rivero, Marisol; Fricker, Nadine; Nöthen, Markus M; Heilmann-Heimbach, Stefanie

2017-02-22

Human hair follicle (HF) cycling is characterised by the tight orchestration and regulation of signalling cascades. Research shows that micro(mi)RNAs are potent regulators of these pathways. However, knowledge of the expression of miRNAs and their target genes and pathways in the human HF is limited. The objective of this study was to improve understanding of the role of miRNAs and their regulatory interactions in the human HF. Expression levels of ten candidate miRNAs with reported functions in hair biology were assessed in HFs from 25 healthy male donors. MiRNA expression levels were correlated with mRNA-expression levels from the same samples. Identified target genes were tested for enrichment in biological pathways and accumulation in protein-protein interaction (PPI) networks. Expression in the human HF was confirmed for seven of the ten candidate miRNAs, and numerous target genes for miR-24, miR-31, and miR-106a were identified. While the latter include several genes with known functions in hair biology (e.g., ITGB1, SOX9), the majority have not been previously implicated (e.g., PHF1). Target genes were enriched in pathways of interest to hair biology, such as integrin and GnRH signalling, and the respective gene products showed accumulation in PPIs. Further investigation of miRNA expression in the human HF, and the identification of novel miRNA target genes and pathways via the systematic integration of miRNA and mRNA expression data, may facilitate the delineation of tissue-specific regulatory interactions, and improve our understanding of both normal hair growth and the pathobiology of hair loss disorders.

Preclinical evaluation of the PI3K/Akt/mTOR pathway in animal models of multiple sclerosis

PubMed Central

Mammana, Santa; Bramanti, Placido; Mazzon, Emanuela; Cavalli, Eugenio; Basile, Maria Sofia; Fagone, Paolo; Petralia, Maria Cristina; McCubrey, James Andrew; Nicoletti, Ferdinando; Mangano, Katia

2018-01-01

The PI3K/AKT/mTOR pathway is an intracellular signalling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Multiple Sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS and on oligodendrocyte function, making use of currently available whole-genome transcriptomic data. Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aim, the involvement of mTOR was validated on a well-known animal model of MS and in vitro on Th17 cells. Our data indicate that there is a significant involvement of the mTOR network in the etiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in this clinical setting. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury. Overall, our study suggests that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability. PMID:29492193

Protein kinase FgSch9 serves as a mediator of the target of rapamycin and high osmolarity glycerol pathways and regulates multiple stress responses and secondary metabolism in Fusarium graminearum.

PubMed

Gu, Qin; Zhang, Chengqi; Yu, Fangwei; Yin, Yanni; Shim, Won-Bo; Ma, Zhonghua

2015-08-01

Saccharomyces cerevisiae protein kinase Sch9 is one of the downstream effectors of the target of rapamycin (TOR) complex 1 and plays multiple roles in stress resistance, longevity and nutrient sensing. However, the functions of Sch9 orthologs in filamentous fungi, particularly in pathogenic species, have not been characterized to date. Here, we investigated biological and genetic functions of FgSch9 in Fusarium graminearum. The FgSCH9 deletion mutant (ΔFgSch9) was defective in aerial hyphal growth, hyphal branching and conidial germination. The mutant exhibited increased sensitivity to osmotic and oxidative stresses, cell wall-damaging agents, and to rapamycin, while showing increased thermal tolerance. We identified FgMaf1 as one of the FgSch9-interacting proteins that plays an important role in regulating mycotoxin biosynthesis and virulence of F. graminearum. Co-immunoprecipitation and affinity capture-mass spectrometry assays showed that FgSch9 also interacts with FgTor and FgHog1. More importantly, both ΔFgSch9 and FgHog1 null mutant (ΔFgHog1) exhibited increased sensitivity to osmotic and oxidative stresses. This defect was more severe in the FgSch9/FgHog1 double mutant. Taken together, we propose that FgSch9 serves as a mediator of the TOR and high osmolarity glycerol pathways, and regulates vegetative differentiation, multiple stress responses and secondary metabolism in F. graminearum. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

The JAK2/STAT5 signaling pathway as a potential therapeutic target in canine mastocytoma

PubMed Central

Keller, Alexandra; Wingelhofer, Bettina; Peter, Barbara; Bauer, Karin; Berger, Daniela; Gamperl, Susanne; Reifinger, Martin; Cerny-Reiterer, Sabine; Moriggl, Richard; Willmann, Michael; Valent, Peter; Hadzijusufovic, Emir

2018-01-01

Background Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. Materials and Methods We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1. Results Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells. Conclusion The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma. PMID:28397975

Interaction of Herbal Compounds with Biological Targets: A Case Study with Berberine

PubMed Central

Chen, Xiao-Wu; Di, Yuan Ming; Zhang, Jian; Zhou, Zhi-Wei; Li, Chun Guang; Zhou, Shu-Feng

2012-01-01

Berberine is one of the main alkaloids found in the Chinese herb Huang lian (Rhizoma Coptidis), which has been reported to have multiple pharmacological activities. This study aimed to analyze the molecular targets of berberine based on literature data followed by a pathway analysis using the PANTHER program. PANTHER analysis of berberine targets showed that the most classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Based on the biological process classification of in vitro berberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor-linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved. In addition, berberine was found to interact with a mixture of biological pathways, such as Alzheimer's disease-presenilin and -secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Hungtington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways. We also explored the possible mechanism of action for the anti-diabetic effect of berberine. Further studies are warranted to elucidate the mechanisms of action of berberine using systems biology approach. PMID:23213296

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

PubMed

Sanchez-Vega, Francisco; Mina, Marco; Armenia, Joshua; Chatila, Walid K; Luna, Augustin; La, Konnor C; Dimitriadoy, Sofia; Liu, David L; Kantheti, Havish S; Saghafinia, Sadegh; Chakravarty, Debyani; Daian, Foysal; Gao, Qingsong; Bailey, Matthew H; Liang, Wen-Wei; Foltz, Steven M; Shmulevich, Ilya; Ding, Li; Heins, Zachary; Ochoa, Angelica; Gross, Benjamin; Gao, Jianjiong; Zhang, Hongxin; Kundra, Ritika; Kandoth, Cyriac; Bahceci, Istemi; Dervishi, Leonard; Dogrusoz, Ugur; Zhou, Wanding; Shen, Hui; Laird, Peter W; Way, Gregory P; Greene, Casey S; Liang, Han; Xiao, Yonghong; Wang, Chen; Iavarone, Antonio; Berger, Alice H; Bivona, Trever G; Lazar, Alexander J; Hammer, Gary D; Giordano, Thomas; Kwong, Lawrence N; McArthur, Grant; Huang, Chenfei; Tward, Aaron D; Frederick, Mitchell J; McCormick, Frank; Meyerson, Matthew; Van Allen, Eliezer M; Cherniack, Andrew D; Ciriello, Giovanni; Sander, Chris; Schultz, Nikolaus

2018-04-05

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. Copyright © 2018. Published by Elsevier Inc.

Feature-aided multiple target tracking in the image plane

NASA Astrophysics Data System (ADS)

Brown, Andrew P.; Sullivan, Kevin J.; Miller, David J.

2006-05-01

Vast quantities of EO and IR data are collected on airborne platforms (manned and unmanned) and terrestrial platforms (including fixed installations, e.g., at street intersections), and can be exploited to aid in the global war on terrorism. However, intelligent preprocessing is required to enable operator efficiency and to provide commanders with actionable target information. To this end, we have developed an image plane tracker which automatically detects and tracks multiple targets in image sequences using both motion and feature information. The effects of platform and camera motion are compensated via image registration, and a novel change detection algorithm is applied for accurate moving target detection. The contiguous pixel blob on each moving target is segmented for use in target feature extraction and model learning. Feature-based target location measurements are used for tracking through move-stop-move maneuvers, close target spacing, and occlusion. Effective clutter suppression is achieved using joint probabilistic data association (JPDA), and confirmed target tracks are indicated for further processing or operator review. In this paper we describe the algorithms implemented in the image plane tracker and present performance results obtained with video clips from the DARPA VIVID program data collection and from a miniature unmanned aerial vehicle (UAV) flight.

Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway.

PubMed

Le Sage, Valerie; Cinti, Alessandro; Amorim, Raquel; Mouland, Andrew J

2016-05-24

The mammalian target of rapamycin (mTOR) is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors) and intracellular (energy status) molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs.

Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway

PubMed Central

Le Sage, Valerie; Cinti, Alessandro; Amorim, Raquel; Mouland, Andrew J.

2016-01-01

The mammalian target of rapamycin (mTOR) is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors) and intracellular (energy status) molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs. PMID:27231932

Long Non-Coding RNA in Glioma: Target miRNA and Signaling Pathways.

PubMed

Dang, Yuan; Wei, Xudong; Xue, Laien; Wen, Fuli; Gu, Jianjun; Zheng, Heping

2018-06-01

Glioma is one of the most common and aggressive malignant tumors of the central nervous system. Here, we review and explore the use of long noncoding RNA (lncRNA) as a therapeutic strategy for the targeting of gliomas. LncRNA is a functional RNA molecule with no protein coding function and is involved in the occurrence and progression of glioma. It is reported that the activation of several signaling pathways, including the MAPK, p53, Wnt/β-catenin, PI3K/AKT/mTOR, and epithelial mesenchymal transformation (EMT) pathways, are involved in the regulation of gliomas. In addition, microRNAs in glioma may also interact with lncRNAs and affect tumor growth and progression. Therefore, the exploration of lncRNA participation in signaling pathway regulatory mechanisms and the determination of the interaction between lncRNA and miRNA may help to develop new effective therapies for the treatment of glioma.

MiR-592 Promotes Gastric Cancer Proliferation, Migration, and Invasion Through the PI3K/AKT and MAPK/ERK Signaling Pathways by Targeting Spry2.

PubMed

He, Yu; Ge, Yugang; Jiang, Mingkun; Zhou, Jundong; Luo, Dakui; Fan, Hao; Shi, Liang; Lin, Linling; Yang, Li

2018-06-21

Gastric cancer (GC) is one of the most prevalent digestive malignancies. MicroRNAs (miRNAs) are involved in multiple cellular processes, including oncogenesis, and miR-592 itself participates in many malignancies; however, its role in GC remains unknown. In this study, we investigated the expression and molecular mechanisms of miR-592 in GC. Quantitative real-time PCR and immunohistochemistry were performed to determine the expression of miR-592 and its putative targets in human tissues and cell lines. Proliferation, migration, and invasion were evaluated by Cell Counting Kit-8, population doubling time, colony formation, Transwell, and wound-healing assays in transfected GC cells in vitro. A dual-luciferase reporter assay was used to determine whether miR-592 could directly bind its target. A tumorigenesis assay was used to study whether miR-592 affected GC growth in vivo. Proteins involved in signaling pathways and the epithelial-mesenchymal transition (EMT) were detected with western blot. The ectopic expression of miR-592 promoted GC proliferation, migration, and invasion in vitro and facilitated tumorigenesis in vivo. Spry2 was a direct target of miR-592 and Spry2 overexpression partially counteracted the effects of miR-592. miR-592 induced the EMT and promoted its progression in GC via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2. Overexpression of miR-592 promotes GC proliferation, migration, and invasion and induces the EMT via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2, suggesting a potential therapeutic target for GC. © 2018 The Author(s). Published by S. Karger AG, Basel.

Dynamics Sampling in Transition Pathway Space.

PubMed

Zhou, Hongyu; Tao, Peng

2018-01-09

The minimum energy pathway contains important information describing the transition between two states on a potential energy surface (PES). Chain-of-states methods were developed to efficiently calculate minimum energy pathways connecting two stable states. In the chain-of-states framework, a series of structures are generated and optimized to represent the minimum energy pathway connecting two states. However, multiple pathways may exist connecting two existing states and should be identified to obtain a full view of the transitions. Therefore, we developed an enhanced sampling method, named as the direct pathway dynamics sampling (DPDS) method, to facilitate exploration of a PES for multiple pathways connecting two stable states as well as addition minima and their associated transition pathways. In the DPDS method, molecular dynamics simulations are carried out on the targeting PES within a chain-of-states framework to directly sample the transition pathway space. The simulations of DPDS could be regulated by two parameters controlling distance among states along the pathway and smoothness of the pathway. One advantage of the chain-of-states framework is that no specific reaction coordinates are necessary to generate the reaction pathway, because such information is implicitly represented by the structures along the pathway. The chain-of-states setup in a DPDS method greatly enhances the sufficient sampling in high-energy space between two end states, such as transition states. By removing the constraint on the end states of the pathway, DPDS will also sample pathways connecting minima on a PES in addition to the end points of the starting pathway. This feature makes DPDS an ideal method to directly explore transition pathway space. Three examples demonstrate the efficiency of DPDS methods in sampling the high-energy area important for reactions on the PES.

Efficient search of multiple types of targets

NASA Astrophysics Data System (ADS)

Wosniack, M. E.; Raposo, E. P.; Viswanathan, G. M.; da Luz, M. G. E.

2015-12-01

Random searches often take place in fragmented landscapes. Also, in many instances like animal foraging, significant benefits to the searcher arise from visits to a large diversity of patches with a well-balanced distribution of targets found. Up to date, such aspects have been widely ignored in the usual single-objective analysis of search efficiency, in which one seeks to maximize just the number of targets found per distance traversed. Here we address the problem of determining the best strategies for the random search when these multiple-objective factors play a key role in the process. We consider a figure of merit (efficiency function), which properly "scores" the mentioned tasks. By considering random walk searchers with a power-law asymptotic Lévy distribution of step lengths, p (ℓ ) ˜ℓ-μ , with 1 <μ ≤3 , we show that the standard optimal strategy with μopt≈2 no longer holds universally. Instead, optimal searches with enhanced superdiffusivity emerge, including values as low as μopt≈1.3 (i.e., tending to the ballistic limit). For the general theory of random search optimization, our findings emphasize the necessity to correctly characterize the multitude of aims in any concrete metric to compare among possible candidates to efficient strategies. In the context of animal foraging, our results might explain some empirical data pointing to stronger superdiffusion (μ <2 ) in the search behavior of different animal species, conceivably associated to multiple goals to be achieved in fragmented landscapes.

A pathway of targeted autophagy is induced by DNA damage in budding yeast

PubMed Central

Eapen, Vinay V.; Waterman, David P.; Bernard, Amélie; Schiffmann, Nathan; Sayas, Enrich; Kamber, Roarke; Lemos, Brenda; Memisoglu, Gonen; Ang, Jessie; Mazella, Allison; Chuartzman, Silvia G.; Loewith, Robbie J.; Schuldiner, Maya; Denic, Vladimir; Klionsky, Daniel J.; Haber, James E.

2017-01-01

Autophagy plays a central role in the DNA damage response (DDR) by controlling the levels of various DNA repair and checkpoint proteins; however, how the DDR communicates with the autophagy pathway remains unknown. Using budding yeast, we demonstrate that global genotoxic damage or even a single unrepaired double-strand break (DSB) initiates a previously undescribed and selective pathway of autophagy that we term genotoxin-induced targeted autophagy (GTA). GTA requires the action primarily of Mec1/ATR and Rad53/CHEK2 checkpoint kinases, in part via transcriptional up-regulation of central autophagy proteins. GTA is distinct from starvation-induced autophagy. GTA requires Atg11, a central component of the selective autophagy machinery, but is different from previously described autophagy pathways. By screening a collection of ∼6,000 yeast mutants, we identified genes that control GTA but do not significantly affect rapamycin-induced autophagy. Overall, our findings establish a pathway of autophagy specific to the DNA damage response. PMID:28154131

A pathway of targeted autophagy is induced by DNA damage in budding yeast.

PubMed

Eapen, Vinay V; Waterman, David P; Bernard, Amélie; Schiffmann, Nathan; Sayas, Enrich; Kamber, Roarke; Lemos, Brenda; Memisoglu, Gonen; Ang, Jessie; Mazella, Allison; Chuartzman, Silvia G; Loewith, Robbie J; Schuldiner, Maya; Denic, Vladimir; Klionsky, Daniel J; Haber, James E

2017-02-14

Autophagy plays a central role in the DNA damage response (DDR) by controlling the levels of various DNA repair and checkpoint proteins; however, how the DDR communicates with the autophagy pathway remains unknown. Using budding yeast, we demonstrate that global genotoxic damage or even a single unrepaired double-strand break (DSB) initiates a previously undescribed and selective pathway of autophagy that we term genotoxin-induced targeted autophagy (GTA). GTA requires the action primarily of Mec1/ATR and Rad53/CHEK2 checkpoint kinases, in part via transcriptional up-regulation of central autophagy proteins. GTA is distinct from starvation-induced autophagy. GTA requires Atg11, a central component of the selective autophagy machinery, but is different from previously described autophagy pathways. By screening a collection of ∼6,000 yeast mutants, we identified genes that control GTA but do not significantly affect rapamycin-induced autophagy. Overall, our findings establish a pathway of autophagy specific to the DNA damage response.

Targeting inflammatory pathways in myocardial infarction

PubMed Central

Christia, Panagiota; Frangogiannis, Nikolaos G

2013-01-01

Acute cardiomyocyte necrosis in the infarcted heart generates Damage-Associated Molecular Patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, and triggering an intense inflammatory reaction. Infiltrating leukocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels; the geometric, functional and molecular alterations associated with post-infarction remodeling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the post-infarction inflammatory reaction may be crucial to protect the myocardium from dilative remodeling and progressive dysfunction. Inhibition and resolution of post-infarction inflammation involves mobilization of inhibitory mononuclear cell subsets and requires activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the post-infarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodeling. Given the pathophysiologic complexity of post-infarction remodeling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and Monocyte Chemoattractant Protein-1) may be effective in patients with defective resolution of post-infarction inflammation who exhibit progressive dilative remodeling. In contrast, patients with predominant

A Network Pharmacology Approach to Determine the Active Components and Potential Targets of Curculigo Orchioides in the Treatment of Osteoporosis.

PubMed

Wang, Nani; Zhao, Guizhi; Zhang, Yang; Wang, Xuping; Zhao, Lisha; Xu, Pingcui; Shou, Dan

2017-10-27

BACKGROUND Osteoporosis is a complex bone disorder with a genetic predisposition, and is a cause of health problems worldwide. In China, Curculigo orchioides (CO) has been widely used as a herbal medicine in the prevention and treatment of osteoporosis. However, research on the mechanism of action of CO is still lacking. The aim of this study was to identify the absorbable components, potential targets, and associated treatment pathways of CO using a network pharmacology approach. MATERIAL AND METHODS We explored the chemical components of CO and used the five main principles of drug absorption to identify absorbable components. Targets for the therapeutic actions of CO were obtained from the PharmMapper server database. Pathway enrichment analysis was performed using the Comparative Toxicogenomics Database (CTD). Cytoscape was used to visualize the multiple components-multiple target-multiple pathways-multiple disease network for CO. RESULTS We identified 77 chemical components of CO, of which 32 components could be absorbed in the blood. These potential active components of CO regulated 83 targets and affected 58 pathways. Data analysis showed that the genes for estrogen receptor alpha (ESR1) and beta (ESR2), and the gene for 11 beta-hydroxysteroid dehydrogenase type 1, or cortisone reductase (HSD11B1) were the main targets of CO. Endocrine regulatory factors and factors regulating calcium reabsorption, steroid hormone biosynthesis, and metabolic pathways were related to these main targets and to ten corresponding compounds. CONCLUSIONS The network pharmacology approach used in our study has attempted to explain the mechanisms for the effects of CO in the prevention and treatment of osteoporosis, and provides an alternative approach to the investigation of the effects of this complex compound.

Targeting multiple types of tumors using NKG2D-coated iron oxide nanoparticles

NASA Astrophysics Data System (ADS)

Wu, Ming-Ru; Cook, W. James; Zhang, Tong; Sentman, Charles L.

2014-11-01

Iron oxide nanoparticles (IONPs) hold great potential for cancer therapy. Actively targeting IONPs to tumor cells can further increase therapeutic efficacy and decrease off-target side effects. To target tumor cells, a natural killer (NK) cell activating receptor, NKG2D, was utilized to develop pan-tumor targeting IONPs. NKG2D ligands are expressed on many tumor types and its ligands are not found on most normal tissues under steady state conditions. The data showed that mouse and human fragment crystallizable (Fc)-fusion NKG2D (Fc-NKG2D) coated IONPs (NKG2D/NPs) can target multiple NKG2D ligand positive tumor types in vitro in a dose dependent manner by magnetic cell sorting. Tumor targeting effect was robust even under a very low tumor cell to normal cell ratio and targeting efficiency correlated with NKG2D ligand expression level on tumor cells. Furthermore, the magnetic separation platform utilized to test NKG2D/NP specificity has the potential to be developed into high throughput screening strategies to identify ideal fusion proteins or antibodies for targeting IONPs. In conclusion, NKG2D/NPs can be used to target multiple tumor types and magnetic separation platform can facilitate the proof-of-concept phase of tumor targeting IONP development.

Vitamin D Pathway Status and the Identification of Target Genes in the Mouse Mammary Gland

DTIC Science & Technology

2013-01-01

12 Palmer HG et al. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis...AD_________________ Award Number: W81XWH-11-1-0152 TITLE: Vitamin D pathway status and the...December 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-11-1-0152 Vitamin D pathway status and the identification of target genes in the

Sprouty is a cytoplasmic target of adenoviral E1A oncoproteins to regulate the receptor tyrosine kinase signalling pathway

PubMed Central

2011-01-01

Background Oncoproteins encoded by the early region of adenoviruses have been shown to be powerful tools to study gene regulatory mechanisms, which affect major cellular events such as proliferation, differentiation, apoptosis and oncogenic transformation. They are possesing a key role to favor viral replication via their interaction with multiple cellular proteins. In a yeast two-hybrid screen we have identified Sprouty1 (Spry1) as a target of adenoviral E1A Oncoproteins. Spry proteins are central and complex regulators of the receptor tyrosine kinase (RTK) signalling pathway. The deregulation of Spry family members is often associated with alterations of the RTK signalling and its downstream effectors, leading to the ERK pathway. Results Here, we confirm our yeast two-hybrid data, showing the interaction between Spry1 and E1A in GST pull-down and immunoprecipitation assays. We also demonstrated the interaction of E1A with two further Spry isoforms. Using deletion mutants we identified the N-terminus and the CR conserved region (CR) 3 of E1A- and the C-terminal half of Spry1, which contains the highly conserved Spry domain, as the essential sites for direct interaction between Spry and E1A. Immunofluorescent microscopy data revealed a co-localization of E1A13S with Spry1 in the cytoplasm. SRE and TRE reporter assays demonstrated that co-expression of Spry1 with E1A13S abolishes the inhibitory function of Spry1 in RTK signalling, which is consequently accompanied with a decrease of E1A13S-induced gene expression. Conclusions These results establish Spry1 as a cytoplasmic localized cellular target for E1A oncoproteins to regulate the RTK signalling pathway, and consequently cellular events downstream of RTK that are essential for viral replication and transformation. PMID:21518456

Use of multiple dispersal pathways facilitates amphibian persistence in stream networks.

PubMed

Campbell Grant, Evan H; Nichols, James D; Lowe, Winsor H; Fagan, William F

2010-04-13

Although populations of amphibians are declining worldwide, there is no evidence that salamanders occupying small streams are experiencing enigmatic declines, and populations of these species seem stable. Theory predicts that dispersal through multiple pathways can stabilize populations, preventing extinction in habitat networks. However, empirical data to support this prediction are absent for most species, especially those at risk of decline. Our mark-recapture study of stream salamanders reveals both a strong upstream bias in dispersal and a surprisingly high rate of overland dispersal to adjacent headwater streams. This evidence of route-dependent variation in dispersal rates suggests a spatial mechanism for population stability in headwater-stream salamanders. Our results link the movement behavior of stream salamanders to network topology, and they underscore the importance of identifying and protecting critical dispersal pathways when addressing region-wide population declines.

Use of multiple dispersal pathways facilitates amphibian persistence in stream networks

USGS Publications Warehouse

Campbell, Grant E.H.; Nichols, J.D.; Lowe, W.H.; Fagan, W.F.

2010-01-01

Although populations of amphibians are declining worldwide, there is no evidence that salamanders occupying small streams are experiencing enigmatic declines, and populations of these species seem stable. Theory predicts that dispersal through multiple pathways can stabilize populations, preventing extinction in habitat networks. However, empirical data to support this prediction are absent for most species, especially those at risk of decline. Our mark-recapture study of stream salamanders reveals both a strong upstream bias in dispersal and a surprisingly high rate of overland dispersal to adjacent headwater streams. This evidence of route-dependent variation in dispersal rates suggests a spatial mechanism for population stability in headwater-stream salamanders. Our results link the movement behavior of stream salamanders to network topology, and they underscore the importance of identifying and protecting critical dispersal pathways when addressing region-wide population declines.

Use of multiple dispersal pathways facilitates amphibian persistence in stream networks

PubMed Central

Campbell Grant, Evan H.; Nichols, James D.; Lowe, Winsor H.; Fagan, William F.

2010-01-01

Although populations of amphibians are declining worldwide, there is no evidence that salamanders occupying small streams are experiencing enigmatic declines, and populations of these species seem stable. Theory predicts that dispersal through multiple pathways can stabilize populations, preventing extinction in habitat networks. However, empirical data to support this prediction are absent for most species, especially those at risk of decline. Our mark-recapture study of stream salamanders reveals both a strong upstream bias in dispersal and a surprisingly high rate of overland dispersal to adjacent headwater streams. This evidence of route-dependent variation in dispersal rates suggests a spatial mechanism for population stability in headwater-stream salamanders. Our results link the movement behavior of stream salamanders to network topology, and they underscore the importance of identifying and protecting critical dispersal pathways when addressing region-wide population declines. PMID:20351269

Genistein Ameliorates Non-alcoholic Fatty Liver Disease by Targeting the Thromboxane A2 Pathway.

PubMed

Wang, Wenzhe; Chen, Junliang; Mao, Jinyan; Li, Hongling; Wang, Mingfu; Zhang, Hao; Li, Haitao; Chen, Wei

2018-06-13

Non-alcoholic fatty liver disease (NAFLD) is now a public health issue worldwide, but no drug has yet received approval. Genistein, an isoflavonoid derived from soybean, ameliorates high-fat-diet-induced NAFLD in mice, but the molecular underpinnings remain largely elusive. Arachidonic acid (AA) is a major ingredient of animal fats, and the AA cascade has been implicated in chronic inflammation. In this study, we investigated whether genistein was against NAFLD by targeting the AA cascade. Using a mouse model, we showed that genistein supplementation improved high-fat-diet-induced NAFLD by normalizing hepatomegaly, liver steatosis, aminotransferase abnormalities, and glucose tolerance. The thromboxane A 2 (TXA 2 ) pathway was aberrantly active in NAFLD, evidenced by an elevation of circulating TXA 2 and hepatic thromboxane A 2 receptor expression. Mechanistically, we found that genistein directly targeted cyclooxygenase-1 activity as well as its downstream TXA 2 biosynthesis, while the TXA 2 pathway might mediate NAFLD progression by impairing insulin sensitivity. Taken together, our study revealed a crucial pathophysiological role of the TXA 2 pathway in NAFLD and provided an explanation as to how genistein was against NAFLD progression.

Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA.

PubMed

Ferrer, Miriam; de Winter, Johan P; Mastenbroek, D C Jeroen; Curiel, David T; Gerritsen, Winald R; Giaccone, Giuseppe; Kruyt, Frank A E

2004-08-01

Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin. Here, we studied the use of the FA pathway as a possible target for cancer gene therapy with the aim to sensitize tumor cells for cisplatin by interfering with the FA pathway. As proof-of-principle, FA and non-FA lymphoblast-derived tumors were grown subcutaneously in scid mice and treated with two different concentrations of cisplatin. As predicted, the antitumor response was considerably improved in FA tumors. An adenoviral vector encoding a dominant-negative form of FANCA, FANCA600DN, was generated that interfered with endogenous FANCA-FANCG interaction resulting in the disruption of the FA pathway as illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines, including non-small-cell lung cancer cells, could be sensitized approximately two- to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase upon enhanced infection efficiency. In conclusion, targeting the FA pathway may provide a novel strategy for the sensitization of solid tumors for cisplatin and, in addition, provides a tool for examining the role of the FA pathway in determining chemoresistance in different tumor types.

O-GlcNAcylation of master growth repressor DELLA by SECRET AGENT modulates multiple signaling pathways in Arabidopsis

PubMed Central

Zentella, Rodolfo; Hu, Jianhong; Hsieh, Wen-Ping; Matsumoto, Peter A.; Dawdy, Andrew; Barnhill, Benjamin; Oldenhof, Harriëtte; Hartweck, Lynn M.; Maitra, Sushmit; Thomas, Stephen G.; Cockrell, Shelley; Boyce, Michael; Shabanowitz, Jeffrey; Hunt, Donald F.; Olszewski, Neil E.; Sun, Tai-ping

2016-01-01

The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein–protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors—PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)—that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. PMID:26773002

O-GlcNAcylation of master growth repressor DELLA by SECRET AGENT modulates multiple signaling pathways in Arabidopsis.

PubMed

Zentella, Rodolfo; Hu, Jianhong; Hsieh, Wen-Ping; Matsumoto, Peter A; Dawdy, Andrew; Barnhill, Benjamin; Oldenhof, Harriëtte; Hartweck, Lynn M; Maitra, Sushmit; Thomas, Stephen G; Cockrell, Shelley; Boyce, Michael; Shabanowitz, Jeffrey; Hunt, Donald F; Olszewski, Neil E; Sun, Tai-Ping

2016-01-15

The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein-protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors-PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)-that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. © 2016 Zentella et al.; Published by Cold Spring Harbor Laboratory Press.

Incorporating Multiple Secondary Targets into Learning Trials for Individuals with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Nottingham, Casey L.; Vladescu, Jason C.; Kodak, Tiffany; Kisamore, April N.

2017-01-01

The current study examined the outcome of presenting multiple secondary targets in learning trials for individuals with autism spectrum disorder. We compared conditions in which (a) a secondary target was presented in the antecedent and consequence of trials, (b) two secondary targets were presented in the consequence of trials, (c) one secondary…

Serum Metabolomic Profiling in Acute Alcoholic Hepatitis Identifies Multiple Dysregulated Pathways

PubMed Central

Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit; Bell, Lauren N.; Cooper, Sara; Malik, Shahid; Behari, Jaideep

2014-01-01

Background and Objectives While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. Methods This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Results Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Conclusion Severe AAH is

Core Proteomic Analysis of Unique Metabolic Pathways of Salmonella enterica for the Identification of Potential Drug Targets.

PubMed

Uddin, Reaz; Sufian, Muhammad

2016-01-01

Infections caused by Salmonella enterica, a Gram-negative facultative anaerobic bacteria belonging to the family of Enterobacteriaceae, are major threats to the health of humans and animals. The recent availability of complete genome data of pathogenic strains of the S. enterica gives new avenues for the identification of drug targets and drug candidates. We have used the genomic and metabolic pathway data to identify pathways and proteins essential to the pathogen and absent from the host. We took the whole proteome sequence data of 42 strains of S. enterica and Homo sapiens along with KEGG-annotated metabolic pathway data, clustered proteins sequences using CD-HIT, identified essential genes using DEG database and discarded S. enterica homologs of human proteins in unique metabolic pathways (UMPs) and characterized hypothetical proteins with SVM-prot and InterProScan. Through this core proteomic analysis we have identified enzymes essential to the pathogen. The identification of 73 enzymes common in 42 strains of S. enterica is the real strength of the current study. We proposed all 73 unexplored enzymes as potential drug targets against the infections caused by the S. enterica. The study is comprehensive around S. enterica and simultaneously considered every possible pathogenic strain of S. enterica. This comprehensiveness turned the current study significant since, to the best of our knowledge it is the first subtractive core proteomic analysis of the unique metabolic pathways applied to any pathogen for the identification of drug targets. We applied extensive computational methods to shortlist few potential drug targets considering the druggability criteria e.g. Non-homologous to the human host, essential to the pathogen and playing significant role in essential metabolic pathways of the pathogen (i.e. S. enterica). In the current study, the subtractive proteomics through a novel approach was applied i.e. by considering only proteins of the unique metabolic

From Pathways to Targets: Understanding the Mechanisms behind Polyglutamine Disease

PubMed Central

Weber, Jonasz Jeremiasz; Sowa, Anna Sergeevna

2014-01-01

The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment. PMID:25309920

Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

PubMed Central

Nichols, Daniel Brian; De Martini, William; Cottrell, Jessica

2017-01-01

Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence. PMID:28786952

A Convenient Cas9-based Conditional Knockout Strategy for Simultaneously Targeting Multiple Genes in Mouse.

PubMed

Chen, Jiang; Du, Yinan; He, Xueyan; Huang, Xingxu; Shi, Yun S

2017-03-31

The most powerful way to probe protein function is to characterize the consequence of its deletion. Compared to conventional gene knockout (KO), conditional knockout (cKO) provides an advanced gene targeting strategy with which gene deletion can be performed in a spatially and temporally restricted manner. However, for most species that are amphiploid, the widely used Cre-flox conditional KO (cKO) system would need targeting loci in both alleles to be loxP flanked, which in practice, requires time and labor consuming breeding. This is considerably significant when one is dealing with multiple genes. CRISPR/Cas9 genome modulation system is advantaged in its capability in targeting multiple sites simultaneously. Here we propose a strategy that could achieve conditional KO of multiple genes in mouse with Cre recombinase dependent Cas9 expression. By transgenic construction of loxP-stop-loxP (LSL) controlled Cas9 (LSL-Cas9) together with sgRNAs targeting EGFP, we showed that the fluorescence molecule could be eliminated in a Cre-dependent manner. We further verified the efficacy of this novel strategy to target multiple sites by deleting c-Maf and MafB simultaneously in macrophages specifically. Compared to the traditional Cre-flox cKO strategy, this sgRNAs-LSL-Cas9 cKO system is simpler and faster, and would make conditional manipulation of multiple genes feasible.

Rabies Virus Envelope Glycoprotein Targets Lentiviral Vectors to the Axonal Retrograde Pathway in Motor Neurons*

PubMed Central

Hislop, James N.; Islam, Tarin A.; Eleftheriadou, Ioanna; Carpentier, David C. J.; Trabalza, Antonio; Parkinson, Michael; Schiavo, Giampietro; Mazarakis, Nicholas D.

2014-01-01

Rabies pseudotyped lentiviral vectors have great potential in gene therapy, not least because of their ability to transduce neurons following their distal axonal application. However, very little is known about the molecular processes that underlie their retrograde transport and cell transduction. Using multiple labeling techniques and confocal microscopy, we demonstrated that pseudotyping with rabies virus envelope glycoprotein (RV-G) enabled the axonal retrograde transport of two distinct subtypes of lentiviral vector in motor neuron cultures. Analysis of this process revealed that these vectors trafficked through Rab5-positive endosomes and accumulated within a non-acidic Rab7 compartment. RV-G pseudotyped vectors were co-transported with both the tetanus neurotoxin-binding fragment and the membrane proteins thought to mediate rabies virus endocytosis (neural cell adhesion molecule, nicotinic acetylcholine receptor, and p75 neurotrophin receptor), thus demonstrating that pseudotyping with RV-G targets lentiviral vectors for transport along the same pathway exploited by several toxins and viruses. Using motor neurons cultured in compartmentalized chambers, we demonstrated that axonal retrograde transport of these vectors was rapid and efficient; however, it was not able to transduce the targeted neurons efficiently, suggesting that impairment in processes occurring after arrival of the viral vector in the soma is responsible for the low transduction efficiency seen in vivo, which suggests a novel area for improvement of gene therapy vectors. PMID:24753246

MENA is a transcriptional target of the Wnt/beta-catenin pathway.

PubMed

Najafov, Ayaz; Seker, Tuncay; Even, Ipek; Hoxhaj, Gerta; Selvi, Osman; Ozel, Duygu Esen; Koman, Ahmet; Birgül-İyison, Necla

2012-01-01

Wnt/β-catenin signalling pathway plays important roles in embryonic development and carcinogenesis. Overactivation of the pathway is one of the most common driving forces in major cancers such as colorectal and breast cancers. The downstream effectors of the pathway and its regulation of carcinogenesis and metastasis are still not very well understood. In this study, which was based on two genome-wide transcriptomics screens, we identify MENA (ENAH, Mammalian enabled homologue) as a novel transcriptional target of the Wnt/β-catenin signalling pathway. We show that the expression of MENA is upregulated upon overexpression of degradation-resistant β-catenin. Promoters of all mammalian MENA homologues contain putative binding sites for Tcf4 transcription factor--the primary effector of the Wnt/β-catenin pathway and we demonstrate functionality of these Tcf4-binding sites using luciferase reporter assays and overexpression of β-catenin, Tcf4 and dominant-negative Tcf4. In addition, lithium chloride-mediated inhibition of GSK3β also resulted in increase in MENA mRNA levels. Chromatin immunoprecipitation showed direct interaction between β-catenin and MENA promoter in Huh7 and HEK293 cells and also in mouse brain and liver tissues. Moreover, overexpression of Wnt1 and Wnt3a ligands increased MENA mRNA levels. Additionally, knock-down of MENA ortholog in D. melanogaster eyeful and sensitized eye cancer fly models resulted in increased tumor and metastasis formations. In summary, our study identifies MENA as novel nexus for the Wnt/β-catenin and the Notch signalling cascades.

Targeting metabolic pathways for head and neck cancers therapeutics.

PubMed

Yamamoto, Masashi; Inohara, Hidenori; Nakagawa, Takashi

2017-09-01

Cancer cells have distinctive energy metabolism pathways that support their rapid cell division. The preference for anaerobic glycolysis under the normal oxygen condition is known as the Warburg effect and has been observed in head and neck cancers. These metabolic changes are controlled by cancer-related transcription factors, such as tumor suppressor gene and hypoxia inducible factor 1α. In addition, various metabolic enzymes also actively regulate cancer-specific metabolism including the switch between aerobic and anaerobic glycolysis. For a long time, these metabolic changes in cancer cells have been considered a consequence of transformation required to maintain the high rate of tumor cell replication. However, recent studies indicate that alteration of metabolism is sufficient to initiate tumor transformation. Indeed, oncogenic mutations in the metabolic enzymes, isocitrate dehydrogenase and succinate dehydrogenase, have been increasingly found in various cancers, including head and neck cancers. In the present review, we introduce recent findings regarding the cancer metabolism, including the molecular mechanisms of how they affect cancer pathogenesis and maintenance. We also discuss the current and future perspectives on therapeutics that target metabolic pathways, with an emphasis on head and neck cancer.

Multiple source/multiple target fluid transfer apparatus

DOEpatents

Turner, Terry D.

1997-01-01

A fluid transfer apparatus includes: a) a plurality of orifices for connection with fluid sources; b) a plurality of orifices for connection with fluid targets; c) a set of fluid source conduits and fluid target conduits associated with the orifices; d) a pump fluidically interposed between the source and target conduits to transfer fluid therebetween; e) a purge gas conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass a purge gas under pressure; f) a solvent conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass solvent, the solvent conduit including a solvent valve; g) pump control means for controlling operation of the pump; h) purge gas valve control means for controlling operation of the purge gas valve to selectively impart flow of purge gas to the fluid source conduits, fluid target conduits and pump; i) solvent valve control means for controlling operation of the solvent valve to selectively impart flow of solvent to the fluid source conduits, fluid target conduits and pump; and j) source and target valve control means for controlling operation of the fluid source conduit valves and the fluid target conduit valves to selectively impart passage of fluid between a selected one of the fluid source conduits and a selected one of the fluid target conduits through the pump and to enable passage of solvent or purge gas through selected fluid source conduits and selected fluid target conduits.

Multiple source/multiple target fluid transfer apparatus

DOEpatents

Turner, T.D.

1997-08-26

A fluid transfer apparatus includes: (a) a plurality of orifices for connection with fluid sources; (b) a plurality of orifices for connection with fluid targets; (c) a set of fluid source conduits and fluid target conduits associated with the orifices; (d) a pump fluidically interposed between the source and target conduits to transfer fluid there between; (e) a purge gas conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass a purge gas under pressure; (f) a solvent conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass solvent, the solvent conduit including a solvent valve; (g) pump control means for controlling operation of the pump; (h) purge gas valve control means for controlling operation of the purge gas valve to selectively impart flow of purge gas to the fluid source conduits, fluid target conduits and pump; (i) solvent valve control means for controlling operation of the solvent valve to selectively impart flow of solvent to the fluid source conduits, fluid target conduits and pump; and (j) source and target valve control means for controlling operation of the fluid source conduit valves and the fluid target conduit valves to selectively impart passage of fluid between a selected one of the fluid source conduits and a selected one of the fluid target conduits through the pump and to enable passage of solvent or purge gas through selected fluid source conduits and selected fluid target conduits. 6 figs.

The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy

PubMed Central

Wheeler, Allison P.; Gailani, David

2016-01-01

Plasma coagulation in the activated partial thromboplastin time assay is initiated by sequential activation of coagulation factors XII, XI and IX – the classical intrinsic pathway of coagulation. It is well recognized that this series of proteolytic reactions is not an accurate model for hemostasis in vivo, as factor XII deficiency does not cause abnormal bleeding, and fXI deficiency causes a relatively mild propensity to bleed excessively with injury. Despite their limited roles in hemostasis, there is mounting evidence that fXI and fXII contribute to thrombosis, and that inhibiting them can produce an antithrombotic effect with a relatively small effect on hemostasis. In this chapter the contributions of components of the intrinsic pathway to thrombosis in animal models and humans are discussed, and results of early clinical trials of drugs targeting factors IX, XI and XII are presented. PMID:27637310

Targeting VEGF/VEGFRs Pathway in the Antiangiogenic Treatment of Human Cancers by Traditional Chinese Medicine.

PubMed

Zhang, Cheng; Wang, Ning; Tan, Hor-Yue; Guo, Wei; Li, Sha; Feng, Yibin

2018-05-01

Bearing in mind the doctrine of tumor angiogenesis hypothesized by Folkman several decades ago, the fundamental strategy for alleviating numerous cancer indications may be the strengthening application of notable antiangiogenic therapies to inhibit metastasis-related tumor growth. Under physiological conditions, vascular sprouting is a relatively infrequent event unless when specifically stimulated by pathogenic factors that contribute to the accumulation of angiogenic activators such as the vascular endothelial growth factor (VEGF) family and basic fibroblast growth factor (bFGF). Since VEGFs have been identified as the principal cytokine to initiate angiogenesis in tumor growth, synthetic VEGF-targeting medicines containing bevacizumab and sorafenib have been extensively used, but prominent side effects have concomitantly emerged. Traditional Chinese medicines (TCM)-derived agents with distinctive safety profiles have shown their multitarget curative potential by impairing angiogenic stimulatory signaling pathways directly or eliciting synergistically therapeutic effects with anti-angiogenic drugs mainly targeting VEGF-dependent pathways. This review aims to summarize ( a) the up-to-date understanding of the role of VEGF/VEGFR in correlation with proangiogenic mechanisms in various tissues and cells; ( b) the elaboration of antitumor angiogenesis mechanisms of 4 representative TCMs, including Salvia miltiorrhiza, Curcuma longa, ginsenosides, and Scutellaria baicalensis; and ( c) circumstantial clarification of TCM-driven therapeutic actions of suppressing tumor angiogenesis by targeting VEGF/VEGFRs pathway in recent years, based on network pharmacology.

Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies

PubMed Central

Thaker, Nikhil G; Pollack, Ian F

2010-01-01

Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient’s tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG. PMID:19951140

All set! Evidence of simultaneous attentional control settings for multiple target colors.

PubMed

Irons, Jessica L; Folk, Charles L; Remington, Roger W

2012-06-01

Although models of visual search have often assumed that attention can only be set for a single feature or property at a time, recent studies have suggested that it may be possible to maintain more than one attentional control setting. The aim of the present study was to investigate whether spatial attention could be guided by multiple attentional control settings for color. In a standard spatial cueing task, participants searched for either of two colored targets accompanied by an irrelevantly colored distractor. Across five experiments, results consistently showed that nonpredictive cues matching either target color produced a significant spatial cueing effect, while irrelevantly colored cues did not. This was the case even when the target colors could not be linearly separated from irrelevantly cue colors in color space, suggesting that participants were not simply adopting one general color set that included both target colors. The results could not be explained by intertrial priming by previous targets, nor could they be explained by a single inhibitory set for the distractor color. Overall, the results are most consistent with the maintenance of multiple attentional control settings.

The Akt signaling pathway

PubMed Central

Madhunapantula, SubbaRao V; Mosca, Paul J

2011-01-01

Studies using cultured melanoma cells and patient tumor biopsies have demonstrated deregulated PI3 kinase-Akt3 pathway activity in ∼70% of melanomas. Furthermore, targeting Akt3 and downstream PRAS40 has been shown to inhibit melanoma tumor development in mice. Although these preclinical studies and several other reports using small interfering RNAs and pharmacological agents targeting key members of this pathway have been shown to retard melanoma development, analysis of early Phase I and Phase II clinical trials using pharmacological agents to target this pathway demonstrate the need for (1) selection of patients whose tumors have PI3 kinase-Akt pathway deregulation, (2) further optimization of therapeutic agents for increased potency and reduced toxicity, (3) the identification of additional targets in the same pathway or in other signaling cascades that synergistically inhibit the growth and progression of melanoma, and (4) better methods for targeted delivery of pharmaceutical agents inhibiting this pathway. In this review we discuss key potential targets in PI3K-Akt3 signaling, the status of pharmacological agents targeting these proteins, drugs under clinical development, and strategies to improve the efficacy of therapeutic agents targeting this pathway. PMID:22157148

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.

Targeting protein-trafficking pathways alters melanoma treatment sensitivity

PubMed Central

Huang, Zhi-ming; Chinen, Milka; Chang, Philip J.; Xie, Tong; Zhong, Lily; Demetriou, Stephanie; Patel, Mira P.; Scherzer, Rebecca; Sviderskaya, Elena V.; Bennett, Dorothy C.; Millhauser, Glenn L.; Oh, Dennis H.; Cleaver, James E.; Wei, Maria L.

2012-01-01

Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents. PMID:22203954

Novel targets for prostate cancer chemoprevention

PubMed Central

Sarkar, Fazlul H; Li, Yiwei; Wang, Zhiwei; Kong, Dejuan

2010-01-01

Among many endocrine-related cancers, prostate cancer (PCa) is the most frequent male malignancy, and it is the second most common cause of cancer-related death in men in the United States. Therefore, this review focuses on summarizing the knowledge of molecular signaling pathways in PCa because, in order to better design new preventive strategies for the fight against PCa, documentation of the knowledge on the pathogenesis of PCa at the molecular level is very important. Cancer cells are known to have alterations in multiple cellular signaling pathways; indeed, the development and the progression of PCa are known to be caused by the deregulation of several selective signaling pathways such as the androgen receptor, Akt, nuclear factor-κB, Wnt, Hedgehog, and Notch. Therefore, strategies targeting these important pathways and their upstream and downstream signaling could be promising for the prevention of PCa progression. In this review, we summarize the current knowledge regarding the alterations in cell signaling pathways during the development and progression of PCa, and document compelling evidence showing that these are the targets of several natural agents against PCa progression and its metastases. PMID:20576802

Alternative pathways to the 1.5 °C target reduce the need for negative emission technologies

NASA Astrophysics Data System (ADS)

van Vuuren, Detlef P.; Stehfest, Elke; Gernaat, David E. H. J.; van den Berg, Maarten; Bijl, David L.; de Boer, Harmen Sytze; Daioglou, Vassilis; Doelman, Jonathan C.; Edelenbosch, Oreane Y.; Harmsen, Mathijs; Hof, Andries F.; van Sluisveld, Mariësse A. E.

2018-05-01

Mitigation scenarios that achieve the ambitious targets included in the Paris Agreement typically rely on greenhouse gas emission reductions combined with net carbon dioxide removal (CDR) from the atmosphere, mostly accomplished through large-scale application of bioenergy with carbon capture and storage, and afforestation. However, CDR strategies face several difficulties such as reliance on underground CO2 storage and competition for land with food production and biodiversity protection. The question arises whether alternative deep mitigation pathways exist. Here, using an integrated assessment model, we explore the impact of alternative pathways that include lifestyle change, additional reduction of non-CO2 greenhouse gases and more rapid electrification of energy demand based on renewable energy. Although these alternatives also face specific difficulties, they are found to significantly reduce the need for CDR, but not fully eliminate it. The alternatives offer a means to diversify transition pathways to meet the Paris Agreement targets, while simultaneously benefiting other sustainability goals.

Protein Design for Pathway Engineering

PubMed Central

Eriksen, Dawn T.; Lian, Jiazhang; Zhao, Huimin

2013-01-01

Design and construction of biochemical pathways has increased the complexity of biosynthetically-produced compounds when compared to single enzyme biocatalysis. However, the coordination of multiple enzymes can introduce a complicated set of obstacles to overcome in order to achieve a high titer and yield of the desired compound. Metabolic engineering has made great strides in developing tools to optimize the flux through a target pathway, but the inherent characteristics of a particular enzyme within the pathway can still limit the productivity. Thus, judicious protein design is critical for metabolic and pathway engineering. This review will describe various strategies and examples of applying protein design to pathway engineering to optimize the flux through the pathway. The proteins can be engineered for altered substrate specificity/selectivity, increased catalytic activity, reduced mass transfer limitations through specific protein localization, and reduced substrate/product inhibition. Protein engineering can also be expanded to design biosensors to enable high through-put screening and to customize cell signaling networks. These strategies have successfully engineered pathways for significantly increased productivity of the desired product or in the production of novel compounds. PMID:23558037

Protein design for pathway engineering.

PubMed

Eriksen, Dawn T; Lian, Jiazhang; Zhao, Huimin

2014-02-01

Design and construction of biochemical pathways has increased the complexity of biosynthetically-produced compounds when compared to single enzyme biocatalysis. However, the coordination of multiple enzymes can introduce a complicated set of obstacles to overcome in order to achieve a high titer and yield of the desired compound. Metabolic engineering has made great strides in developing tools to optimize the flux through a target pathway, but the inherent characteristics of a particular enzyme within the pathway can still limit the productivity. Thus, judicious protein design is critical for metabolic and pathway engineering. This review will describe various strategies and examples of applying protein design to pathway engineering to optimize the flux through the pathway. The proteins can be engineered for altered substrate specificity/selectivity, increased catalytic activity, reduced mass transfer limitations through specific protein localization, and reduced substrate/product inhibition. Protein engineering can also be expanded to design biosensors to enable high through-put screening and to customize cell signaling networks. These strategies have successfully engineered pathways for significantly increased productivity of the desired product or in the production of novel compounds. Copyright © 2013 Elsevier Inc. All rights reserved.

VEGF-independent angiogenic pathways induced by PDGF-C

PubMed Central

Kumar, Anil; Zhang, Fan; Lee, Chunsik; Li, Yang; Tang, Zhongshu; Arjunan, Pachiappan

2010-01-01

VEGF is believed to be a master regulator in both developmental and pathological angiogenesis. The role of PDGF-C in angiogenesis, however, is only at the beginning of being revealed. We and others have shown that PDGF-C is a critical player in pathological angiogenesis because of its pleiotropic effects on multiple cellular targets. The angiogenic pathways induced by PDGF-C are, to a large extent, VEGF-independent. These pathways may include, but not limited to, the direct effect of PDGF-C on vascular cells, the effect of PDGF-C on tissue stroma fibroblasts, and its effect on macrophages. Taken together, the pleiotropic, versatile and VEGF-independent angiogenic nature of PDGF-C has placed it among the most important target genes for antiangiogenic therapy. PMID:20871734

Emerging new pathways of pathogenesis and targets for treatment in systemic lupus erythematosus and Sjogren's syndrome.

PubMed

Perl, Andras

2009-09-01

Systemic lupus erythematosus (SLE) and Sjogren's syndrome are chronic inflammatory diseases characterized by the dysfunction of T cells, B cells, and dendritic cells and the production of antinuclear autoantibodies. Here, we evaluate newly discovered molecular and cellular targets for the treatment of SLE and Sjogren's syndrome. The mammalian target of rapamycin in T and B cells has been successfully targeted for treatment of SLE with rapamycin or sirolimus both in patients and animal models. Inhibition of oxidative stress, nitric oxide production, interferon alpha, toll-like receptors 7 and 9, histone deacetylase, spleen tyrosine kinase, proteasome function, lysosome function, endosome recycling, and the nuclear factor kappa B pathway showed efficacy in animal models of lupus. B-cell depletion and blockade of anti-DNA antibodies and T-B cell interaction have shown success in animal models, whereas human studies have so far failed to accomplish clinical endpoints, possibly due to inadequacies in study design. Discovery of novel genes and signaling pathways in lupus pathogenesis offers novel biomarker-targeted approaches for treatment of SLE and Sjogren's syndrome.

Multiple Smaller Missions as a Direct Pathway to Mars Sample Return

NASA Technical Reports Server (NTRS)

Niles, P. B.; Draper, D. S.; Evans, C. A.; Gibson, E. K.; Graham, L. D.; Jones, J. H.; Lederer, S. M.; Ming, D.; Seaman, C. H.; Archer, P. D.;

Competing Pathways and Multiple Folding Nuclei in a Large Multidomain Protein, Luciferase.

PubMed

Scholl, Zackary N; Yang, Weitao; Marszalek, Piotr E

2017-05-09

Proteins obtain their final functional configuration through incremental folding with many intermediate steps in the folding pathway. If known, these intermediate steps could be valuable new targets for designing therapeutics and the sequence of events could elucidate the mechanism of refolding. However, determining these intermediate steps is hardly an easy feat, and has been elusive for most proteins, especially large, multidomain proteins. Here, we effectively map part of the folding pathway for the model large multidomain protein, Luciferase, by combining single-molecule force-spectroscopy experiments and coarse-grained simulation. Single-molecule refolding experiments reveal the initial nucleation of folding while simulations corroborate these stable core structures of Luciferase, and indicate the relative propensities for each to propagate to the final folded native state. Both experimental refolding and Monte Carlo simulations of Markov state models generated from simulation reveal that Luciferase most often folds along a pathway originating from the nucleation of the N-terminal domain, and that this pathway is the least likely to form nonnative structures. We then engineer truncated variants of Luciferase whose sequences corresponded to the putative structure from simulation and we use atomic force spectroscopy to determine their unfolding and stability. These experimental results corroborate the structures predicted from the folding simulation and strongly suggest that they are intermediates along the folding pathway. Taken together, our results suggest that initial Luciferase refolding occurs along a vectorial pathway and also suggest a mechanism that chaperones may exploit to prevent misfolding. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

PubMed

Guan, S-M; Fu, S-M; He, J-J; Zhang, M

2011-01-01

Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

Interacting multiple model forward filtering and backward smoothing for maneuvering target tracking

NASA Astrophysics Data System (ADS)

Nandakumaran, N.; Sutharsan, S.; Tharmarasa, R.; Lang, Tom; McDonald, Mike; Kirubarajan, T.

2009-08-01

The Interacting Multiple Model (IMM) estimator has been proven to be effective in tracking agile targets. Smoothing or retrodiction, which uses measurements beyond the current estimation time, provides better estimates of target states. Various methods have been proposed for multiple model smoothing in the literature. In this paper, a new smoothing method, which involves forward filtering followed by backward smoothing while maintaining the fundamental spirit of the IMM, is proposed. The forward filtering is performed using the standard IMM recursion, while the backward smoothing is performed using a novel interacting smoothing recursion. This backward recursion mimics the IMM estimator in the backward direction, where each mode conditioned smoother uses standard Kalman smoothing recursion. Resulting algorithm provides improved but delayed estimates of target states. Simulation studies are performed to demonstrate the improved performance with a maneuvering target scenario. The comparison with existing methods confirms the improved smoothing accuracy. This improvement results from avoiding the augmented state vector used by other algorithms. In addition, the new technique to account for model switching in smoothing is a key in improving the performance.

HIV dynamics with multiple infections of target cells.

PubMed

Dixit, Narendra M; Perelson, Alan S

2005-06-07

The high incidence of multiple infections of cells by HIV sets the stage for rapid HIV evolution by means of recombination. Yet how HIV dynamics proceeds with multiple infections remains poorly understood. Here, we present a mathematical model that describes the dynamics of viral, target cell, and multiply infected cell subpopulations during HIV infection. Model calculations reproduce several experimental observations and provide key insights into the influence of multiple infections on HIV dynamics. We find that the experimentally observed scaling law, that the number of cells coinfected with two distinctly labeled viruses is proportional to the square of the total number of infected cells, can be generalized so that the number of triply infected cells is proportional to the cube of the number of infected cells, etc. Despite the expectation from Poisson statistics, we find that this scaling relationship only holds under certain conditions, which we predict. We also find that multiple infections do not influence viral dynamics when the rate of viral production from infected cells is independent of the number of times the cells are infected, a regime expected when viral production is limited by cellular rather than viral factors. This result may explain why extant models, which ignore multiple infections, successfully describe viral dynamics in HIV patients. Inhibiting CD4 down-modulation increases the average number of infections per cell. Consequently, altering CD4 down-modulation may allow for an experimental determination of whether viral or cellular factors limit viral production.

HIV dynamics with multiple infections of target cells

PubMed Central

Dixit, Narendra M.; Perelson, Alan S.

2005-01-01

The high incidence of multiple infections of cells by HIV sets the stage for rapid HIV evolution by means of recombination. Yet how HIV dynamics proceeds with multiple infections remains poorly understood. Here, we present a mathematical model that describes the dynamics of viral, target cell, and multiply infected cell subpopulations during HIV infection. Model calculations reproduce several experimental observations and provide key insights into the influence of multiple infections on HIV dynamics. We find that the experimentally observed scaling law, that the number of cells coinfected with two distinctly labeled viruses is proportional to the square of the total number of infected cells, can be generalized so that the number of triply infected cells is proportional to the cube of the number of infected cells, etc. Despite the expectation from Poisson statistics, we find that this scaling relationship only holds under certain conditions, which we predict. We also find that multiple infections do not influence viral dynamics when the rate of viral production from infected cells is independent of the number of times the cells are infected, a regime expected when viral production is limited by cellular rather than viral factors. This result may explain why extant models, which ignore multiple infections, successfully describe viral dynamics in HIV patients. Inhibiting CD4 down-modulation increases the average number of infections per cell. Consequently, altering CD4 down-modulation may allow for an experimental determination of whether viral or cellular factors limit viral production. PMID:15928092

Signaling Pathways in Cardiac Myocyte Apoptosis

PubMed Central

Xia, Peng; Liu, Yuening

2016-01-01

Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

A Novel Uveolymphatic Drainage Pathway-Possible New Target for Glaucoma Treatment.

PubMed

Tomczyk-Socha, Martyna; Turno-Kręcicka, Anna

2017-12-01

Glaucoma is a heterogeneous group of ophthalmic diseases leading to irreversible damage to the optic nerve. While the overall mechanism responsible for glaucoma remains obscure, the most important risk factor is elevated intraocular pressure. The current therapies, whether pharmacological or surgical, are primarily symptomatic with the aim to lower the intraocular pressure (IOP). Poorer response to treatment is associated, for example, with pseudoexfoliation glaucoma, which is determined by blocking the trabecular meshwork (TM) both by pigment grains and the pseudoexfoliation material. It was thought that aqueous humor is drained from the eye by two main pathways: conventional outflow through the TM and Schlemm's canal; and unconventional outflow through the ciliary body through uveal tissue. In 2009 Yucel et al. described and proved the presence of a third pathway for aqueous humor drainage using two specific lymphatic markers: podoplanin, and lymphatic vessel endothelial hyaluronan receptor-1 to identify lymphatic channels in the human ciliary body. The discovery identifies a novel target for IOP-lowering therapies. The most promising group are prostaglandins, which are widely prescribed for glaucoma patients. An intriguing new possibility in glaucoma therapy is using ANGPT agonist. It is still not known if the lymphatic drainage in glaucoma is decreased or dysfunctional and whether lymphatic stimulation can help in removing the improperly accumulated substances, as is seen in pseudoexfoliation glaucoma. However, this new target for glaucoma treatment appears very promising.

Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukemia cells.

PubMed

Chen, Jian; Mu, Qitian; Li, Xia; Yin, Xiufeng; Yu, Mengxia; Jin, Jing; Li, Chenying; Zhou, Yile; Zhou, Jiani; Suo, Shanshan; Lu, Demin; Jin, Jie

2017-06-20

Homoharringtonine (HHT) has long and widely been used in China for the treatment of acute myeloid leukemia (AML), the clinical therapeutic effect is significant but the working mechanism is poorly understood. The purpose of this study is to screen the possible target for HHT with virtual screening and verify the findings by cell experiments. Software including Autodock, Python, and MGL tools were used, with HHT being the ligand and proteins from PI3K-Akt pathway, Jak-stat pathway, TGF-β pathway and NK-κB pathway as the receptors. Human AML cell lines including U937, KG-1, THP-1 were cultured and used as the experiment cell lines. MTT assay was used for proliferation detection, flowcytometry was used to detect apoptosis and cell cycle arrest upon HHT functioning, western blotting was used to detect the protein level changes, viral shRNA transfection was used to suppress the expression level of the target protein candidate, and viral mRNA transfection was used for over-expression. Virtual screening revealed that smad3 from TGF-β pathway might be the candidate for HHT binding. In AML cell line U937 and KG-1, HHT can induce the Ser423/425 phosphorylation of smad3, and this phosphorylation can subsequently activate the TGF-β pathway, causing cell cycle arrest at G1 phase in U937 cells and apoptosis in KG-1 cells, knockdown of smad3 can impair the sensitivity of U937 cell to HHT, and over-expression of smad3 can re-establish the sensitivity in both cell lines. We conclude that smad3 is the probable target protein of HHT and plays an important role in the functioning mechanism of HHT.

Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukemia cells

PubMed Central

Yin, Xiufeng; Yu, Mengxia; Jin, Jing; Li, Chenying; Zhou, Yile; Zhou, Jiani; Suo, Shanshan; Lu, Demin; Jin, Jie

2017-01-01

Homoharringtonine (HHT) has long and widely been used in China for the treatment of acute myeloid leukemia (AML), the clinical therapeutic effect is significant but the working mechanism is poorly understood. The purpose of this study is to screen the possible target for HHT with virtual screening and verify the findings by cell experiments. Software including Autodock, Python, and MGL tools were used, with HHT being the ligand and proteins from PI3K-Akt pathway, Jak-stat pathway, TGF-β pathway and NK-κB pathway as the receptors. Human AML cell lines including U937, KG-1, THP-1 were cultured and used as the experiment cell lines. MTT assay was used for proliferation detection, flowcytometry was used to detect apoptosis and cell cycle arrest upon HHT functioning, western blotting was used to detect the protein level changes, viral shRNA transfection was used to suppress the expression level of the target protein candidate, and viral mRNA transfection was used for over-expression. Virtual screening revealed that smad3 from TGF-β pathway might be the candidate for HHT binding. In AML cell line U937 and KG-1, HHT can induce the Ser423/425 phosphorylation of smad3, and this phosphorylation can subsequently activate the TGF-β pathway, causing cell cycle arrest at G1 phase in U937 cells and apoptosis in KG-1 cells, knockdown of smad3 can impair the sensitivity of U937 cell to HHT, and over-expression of smad3 can re-establish the sensitivity in both cell lines. We conclude that smad3 is the probable target protein of HHT and plays an important role in the functioning mechanism of HHT. PMID:28454099

Forward-backward multiplicity correlations of target fragments in nucleus-emulsion collisions at a few hundred MeV/u

NASA Astrophysics Data System (ADS)

Zhang, Dong-Hai; Chen, Yan-Ling; Wang, Guo-Rong; Li, Wang-Dong; Wang, Qing; Yao, Ji-Jie; Zhou, Jian-Guo; Li, Rong; Li, Jun-Sheng; Li, Hui-Ling

2015-01-01

The forward-backward multiplicity and correlations of a target evaporated fragment (black track particle) and target recoiled proton (grey track particle) emitted from 150 A MeV 4He, 290 A MeV 12C, 400 A MeV 12C, 400 A MeV 20Ne and 500 A MeV 56Fe induced different types of nuclear emulsion target interactions are investigated. It is found that the forward and backward averaged multiplicity of a grey, black and heavily ionized track particle increases with the increase of the target size. The averaged multiplicity of a forward black track particle, backward black track particle, and backward grey track particle do not depend on the projectile size and energy, but the averaged multiplicity of a forward grey track particle increases with an increase of projectile size and energy. The backward grey track particle multiplicity distribution follows an exponential decay law and the decay constant decreases with an increase of target size. The backward-forward multiplicity correlations follow linear law which is independent of the projectile size and energy, and the saturation effect is observed in some heavy target data sets.

Fisetin Inhibits Human Melanoma Cell Invasion through Promotion of Mesenchymal to Epithelial Transition and by Targeting MAPK and NFκB Signaling Pathways

PubMed Central

Pal, Harish Chandra; Sharma, Samriti; Strickland, Leah Ray; Katiyar, Santosh K.; Ballestas, Mary E.; Athar, Mohammad; Elmets, Craig A.; Afaq, Farrukh

2014-01-01

Malignant melanoma is responsible for approximately 75% of skin cancer-related deaths. BRAF plays an important role in regulating the mitogen-activated protein kinase (MAPK) signaling cascade in melanoma with activating mutations in the serine/threonine kinase BRAF occurring in 60–70% of malignant melanomas. The BRAF-MEK-ERK (MAPK) pathway is a key regulator of melanoma cell invasion. In addition, activation of NFκB via the MAPK pathway is regulated through MEK-induced activation of IKK. These pathways are potential targets for prevention and treatment of melanoma. In this study, we investigated the effect of fisetin, a phytochemical present in fruits and vegetables, on melanoma cell invasion and epithelial-mesenchymal transition, and delineated the underlying molecular mechanism. Treatment of multiple human malignant melanoma cell lines with fisetin (5–20 µM) resulted in inhibition of cell invasion. BRAF mutated melanoma cells were more sensitive to fisetin treatment, and this was associated with a decrease in the phosphorylation of MEK1/2 and ERK1/2. In addition, fisetin inhibited the activation of IKK leading to a reduction in the activation of the NFκB signaling pathway. Treatment of cells with an inhibitor of MEK1/2 (PD98059) or of NFκB (caffeic acid phenethyl ester) also reduced melanoma cell invasion. Furthermore, treatment of fisetin promoted mesenchymal to epithelial transition in melanoma cells, which was associated with a decrease in mesenchymal markers (N-cadherin, vimentin, snail and fibronectin) and an increase in epithelial markers (E-cadherin and desmoglein). Employing three dimensional skin equivalents consisting of A375 cells admixed with normal human keratinocytes embedded onto a collagen-constricted fibroblast matrix, we found that treatment of fisetin reduced the invasive potential of melanoma cells into the dermis and increased the expression of E-cadherin with a concomitant decrease in vimentin. These results indicate that fisetin

MiR-191 Regulates Primary Human Fibroblast Proliferation and Directly Targets Multiple Oncogenes

PubMed Central

Polioudakis, Damon; Abell, Nathan S.; Iyer, Vishwanath R.

2015-01-01

miRNAs play a central role in numerous pathologies including multiple cancer types. miR-191 has predominantly been studied as an oncogene, but the role of miR-191 in the proliferation of primary cells is not well characterized, and the miR-191 targetome has not been experimentally profiled. Here we utilized RNA induced silencing complex immunoprecipitations as well as gene expression profiling to construct a genome wide miR-191 target profile. We show that miR-191 represses proliferation in primary human fibroblasts, identify multiple proto-oncogenes as novel miR-191 targets, including CDK9, NOTCH2, and RPS6KA3, and present evidence that miR-191 extensively mediates target expression through coding sequence (CDS) pairing. Our results provide a comprehensive genome wide miR-191 target profile, and demonstrate miR-191’s regulation of primary human fibroblast proliferation. PMID:25992613

Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma

PubMed Central

Meads, MB; Fang, B; Mathews, L; Gemmer, J; Nong, L; Rosado-Lopez, I; Nguyen, T; Ring, JE; Matsui, W; MacLeod, AR; Pachter, JA; Hazlehurst, LA; Koomen, JM; Shain, KH

2015-01-01

Multiple myeloma (MM) remains an incurable malignancy due, in part, to the influence of the bone marrow microenvironment on survival and drug response. Identification of microenvironment-specific survival signaling determinants is critical for the rational design of therapy and elimination of MM. Previously, we have shown that collaborative signaling between β1 integrin-mediated adhesion to fibronectin and interleukin-6 confers a more malignant phenotype via amplification of signal transducer and activator of transcription 3 (STAT3) activation. Further characterization of the events modulated under these conditions with quantitative phosphotyrosine profiling identified 193 differentially phosphorylated peptides. Seventy-seven phosphorylations were upregulated upon adhesion, including PYK2/FAK2, Paxillin, CASL and p130CAS consistent with focal adhesion (FA) formation. We hypothesized that the collaborative signaling between β1 integrin and gp130 (IL-6 beta receptor, IL-6 signal transducer) was mediated by FA formation and proline-rich tyrosine kinase 2 (PYK2) activity. Both pharmacological and molecular targeting of PYK2 attenuated the amplification of STAT3 phosphorylation under co-stimulatory conditions. Co-culture of MM cells with patient bone marrow stromal cells (BMSC) showed similar β1 integrin-specific enhancement of PYK2 and STAT3 signaling. Molecular and pharmacological targeting of PYK2 specifically induced cell death and reduced clonogenic growth in BMSC-adherent myeloma cell lines, aldehyde dehydrogenase-positive MM cancer stem cells and patient specimens. Finally, PYK2 inhibition similarly attenuated MM progression in vivo. These data identify a novel PYK2-mediated survival pathway in MM cells and MM cancer stem cells within the context of microenvironmental cues, providing preclinical support for the use of the clinical stage FAK/PYK2 inhibitors for treatment of MM, especially in a minimal residual disease setting. PMID:26387544

Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer

PubMed Central

Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang

2015-01-01

Two decades of studies in multiple model organisms have established the Hippo pathway as a key regulator of organ size and tissue homeostasis. By inhibiting YAP and TAZ transcription co-activators, the Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein coupled receptors, and cellular energy status. Dysregulation of the Hippo pathway exerts a significant impact on cancer development. Further investigation of the functions and regulatory mechanisms of this pathway will help uncovering the mystery of organ size control and identify new targets for cancer treatment. PMID:26544935

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.

Targeted quantitative analysis of Streptococcus pyogenes virulence factors by multiple reaction monitoring.

PubMed

Lange, Vinzenz; Malmström, Johan A; Didion, John; King, Nichole L; Johansson, Björn P; Schäfer, Juliane; Rameseder, Jonathan; Wong, Chee-Hong; Deutsch, Eric W; Brusniak, Mi-Youn; Bühlmann, Peter; Björck, Lars; Domon, Bruno; Aebersold, Ruedi

2008-08-01

In many studies, particularly in the field of systems biology, it is essential that identical protein sets are precisely quantified in multiple samples such as those representing differentially perturbed cell states. The high degree of reproducibility required for such experiments has not been achieved by classical mass spectrometry-based proteomics methods. In this study we describe the implementation of a targeted quantitative approach by which predetermined protein sets are first identified and subsequently quantified at high sensitivity reliably in multiple samples. This approach consists of three steps. First, the proteome is extensively mapped out by multidimensional fractionation and tandem mass spectrometry, and the data generated are assembled in the PeptideAtlas database. Second, based on this proteome map, peptides uniquely identifying the proteins of interest, proteotypic peptides, are selected, and multiple reaction monitoring (MRM) transitions are established and validated by MS2 spectrum acquisition. This process of peptide selection, transition selection, and validation is supported by a suite of software tools, TIQAM (Targeted Identification for Quantitative Analysis by MRM), described in this study. Third, the selected target protein set is quantified in multiple samples by MRM. Applying this approach we were able to reliably quantify low abundance virulence factors from cultures of the human pathogen Streptococcus pyogenes exposed to increasing amounts of plasma. The resulting quantitative protein patterns enabled us to clearly define the subset of virulence proteins that is regulated upon plasma exposure.

Evolution-guided optimization of biosynthetic pathways.

PubMed

Raman, Srivatsan; Rogers, Jameson K; Taylor, Noah D; Church, George M

2014-12-16

Engineering biosynthetic pathways for chemical production requires extensive optimization of the host cellular metabolic machinery. Because it is challenging to specify a priori an optimal design, metabolic engineers often need to construct and evaluate a large number of variants of the pathway. We report a general strategy that combines targeted genome-wide mutagenesis to generate pathway variants with evolution to enrich for rare high producers. We convert the intracellular presence of the target chemical into a fitness advantage for the cell by using a sensor domain responsive to the chemical to control a reporter gene necessary for survival under selective conditions. Because artificial selection tends to amplify unproductive cheaters, we devised a negative selection scheme to eliminate cheaters while preserving library diversity. This scheme allows us to perform multiple rounds of evolution (addressing ∼10(9) cells per round) with minimal carryover of cheaters after each round. Based on candidate genes identified by flux balance analysis, we used targeted genome-wide mutagenesis to vary the expression of pathway genes involved in the production of naringenin and glucaric acid. Through up to four rounds of evolution, we increased production of naringenin and glucaric acid by 36- and 22-fold, respectively. Naringenin production (61 mg/L) from glucose was more than double the previous highest titer reported. Whole-genome sequencing of evolved strains revealed additional untargeted mutations that likely benefit production, suggesting new routes for optimization.

Identifying Drug-Target Interactions with Decision Templates.

PubMed

Yan, Xiao-Ying; Zhang, Shao-Wu

2018-01-01

During the development process of new drugs, identification of the drug-target interactions wins primary concerns. However, the chemical or biological experiments bear the limitation in coverage as well as the huge cost of both time and money. Based on drug similarity and target similarity, chemogenomic methods can be able to predict potential drug-target interactions (DTIs) on a large scale and have no luxurious need about target structures or ligand entries. In order to reflect the cases that the drugs having variant structures interact with common targets and the targets having dissimilar sequences interact with same drugs. In addition, though several other similarity metrics have been developed to predict DTIs, the combination of multiple similarity metrics (especially heterogeneous similarities) is too naïve to sufficiently explore the multiple similarities. In this paper, based on Gene Ontology and pathway annotation, we introduce two novel target similarity metrics to address above issues. More importantly, we propose a more effective strategy via decision template to integrate multiple classifiers designed with multiple similarity metrics. In the scenarios that predict existing targets for new drugs and predict approved drugs for new protein targets, the results on the DTI benchmark datasets show that our target similarity metrics are able to enhance the predictive accuracies in two scenarios. And the elaborate fusion strategy of multiple classifiers has better predictive power than the naïve combination of multiple similarity metrics. Compared with other two state-of-the-art approaches on the four popular benchmark datasets of binary drug-target interactions, our method achieves the best results in terms of AUC and AUPR for predicting available targets for new drugs (S2), and predicting approved drugs for new protein targets (S3).These results demonstrate that our method can effectively predict the drug-target interactions. The software package can

Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances

PubMed Central

Xu, Shi; Olenyuk, Bogdan Z.; Okamoto, Curtis T.; Hamm-Alvarez, Sarah F.

2012-01-01

Targeting of drugs and their carrier systems by using receptor-mediated endocytotic pathways was in its nascent stages 25 years ago. In the intervening years, an explosion of knowledge focused on design and synthesis of nanoparticulate delivery systems as well as elucidation of the cellular complexity of what was previously-termed receptor-mediated endocytosis has now created a situation when it has become possible to design and test the feasibility of delivery of highly specific nanoparticle drug carriers to specific cells and tissue. This review outlines the mechanisms governing the major modes of receptor-mediated endocytosis used in drug delivery and highlights recent approaches using these as targets for in vivo drug delivery of nanoparticles. The review also discusses some of the inherent complexity associated with the simple shift from a ligand-drug conjugate versus a ligand-nanoparticle conjugate, in terms of ligand valency and its relationship to the mode of receptor-mediated internalization. PMID:23026636

Multiple pathways of crystal nucleation in an extremely supersaturated aqueous potassium dihydrogen phosphate (KDP) solution droplet

PubMed Central

Lee, Sooheyong; Wi, Haeng Sub; Jo, Wonhyuk; Cho, Yong Chan; Lee, Hyun Hwi; Jeong, Se-Young; Kim, Yong-Il; Lee, Geun Woo

2016-01-01

Solution studies have proposed that crystal nucleation can take more complex pathways than previously expected in classical nucleation theory, such as formation of prenucleation clusters or densified amorphous/liquid phases. These findings show that it is possible to separate fluctuations in the different order parameters governing crystal nucleation, that is, density and structure. However, a direct observation of the multipathways from aqueous solutions remains a great challenge because heterogeneous nucleation sites, such as container walls, can prevent these paths. Here, we demonstrate the existence of multiple pathways of nucleation in highly supersaturated aqueous KH2PO4 (KDP) solution using the combination of a containerless device (electrostatic levitation), and in situ micro-Raman and synchrotron X-ray scattering. Specifically, we find that, at an unprecedentedly deep level of supersaturation, a high-concentration KDP solution first transforms into a metastable crystal before reaching stability at room temperature. However, a low-concentration solution, with different local structures, directly transforms into the stable crystal phase. These apparent multiple pathways of crystallization depend on the degree of supersaturation. PMID:27791068

Multiple pathways of crystal nucleation in an extremely supersaturated aqueous potassium dihydrogen phosphate (KDP) solution droplet.

PubMed

Lee, Sooheyong; Wi, Haeng Sub; Jo, Wonhyuk; Cho, Yong Chan; Lee, Hyun Hwi; Jeong, Se-Young; Kim, Yong-Il; Lee, Geun Woo

2016-11-29

Solution studies have proposed that crystal nucleation can take more complex pathways than previously expected in classical nucleation theory, such as formation of prenucleation clusters or densified amorphous/liquid phases. These findings show that it is possible to separate fluctuations in the different order parameters governing crystal nucleation, that is, density and structure. However, a direct observation of the multipathways from aqueous solutions remains a great challenge because heterogeneous nucleation sites, such as container walls, can prevent these paths. Here, we demonstrate the existence of multiple pathways of nucleation in highly supersaturated aqueous KH 2 PO 4 (KDP) solution using the combination of a containerless device (electrostatic levitation), and in situ micro-Raman and synchrotron X-ray scattering. Specifically, we find that, at an unprecedentedly deep level of supersaturation, a high-concentration KDP solution first transforms into a metastable crystal before reaching stability at room temperature. However, a low-concentration solution, with different local structures, directly transforms into the stable crystal phase. These apparent multiple pathways of crystallization depend on the degree of supersaturation.

Automated multiple target detection and tracking in UAV videos

NASA Astrophysics Data System (ADS)

Mao, Hongwei; Yang, Chenhui; Abousleman, Glen P.; Si, Jennie

2010-04-01

In this paper, a novel system is presented to detect and track multiple targets in Unmanned Air Vehicles (UAV) video sequences. Since the output of the system is based on target motion, we first segment foreground moving areas from the background in each video frame using background subtraction. To stabilize the video, a multi-point-descriptor-based image registration method is performed where a projective model is employed to describe the global transformation between frames. For each detected foreground blob, an object model is used to describe its appearance and motion information. Rather than immediately classifying the detected objects as targets, we track them for a certain period of time and only those with qualified motion patterns are labeled as targets. In the subsequent tracking process, a Kalman filter is assigned to each tracked target to dynamically estimate its position in each frame. Blobs detected at a later time are used as observations to update the state of the tracked targets to which they are associated. The proposed overlap-rate-based data association method considers the splitting and merging of the observations, and therefore is able to maintain tracks more consistently. Experimental results demonstrate that the system performs well on real-world UAV video sequences. Moreover, careful consideration given to each component in the system has made the proposed system feasible for real-time applications.

First passage times for multiple particles with reversible target-binding kinetics

NASA Astrophysics Data System (ADS)

Grebenkov, Denis S.

2017-10-01

We investigate the first passage problem for multiple particles that diffuse towards a target, partially adsorb there, and then desorb after a finite exponentially distributed residence time. We search for the first time when m particles undergoing such reversible target-binding kinetics are found simultaneously on the target that may trigger an irreversible chemical reaction or a biophysical event. Even if the particles are independent, the finite residence time on the target yields an intricate temporal coupling between particles. We compute analytically the mean first passage time (MFPT) for two independent particles by mapping the original problem to higher-dimensional surface-mediated diffusion and solving the coupled partial differential equations. The respective effects of the adsorption and desorption rates on the MFPT are revealed and discussed.

The hippocampo-prefrontal pathway: a possible therapeutic target for negative and cognitive symptoms of schizophrenia

PubMed Central

Ghoshal, Ayan; Conn, P Jeffrey

2015-01-01

The hippocampo-prefrontal (H-PFC) pathway has been linked to cognitive and emotional disturbances in several psychiatric disorders including schizophrenia. Preclinical evidence from the NMDA receptor antagonism rodent model of schizophrenia shows severe pathology selective to the H-PFC pathway. It is speculated that there is an increased excitatory drive from the hippocampus to the prefrontal cortex due to dysfunctions in the H-PFC plasticity, which may serve as the basis for the behavioral consequences observed in this rodent model. Thus, the H-PFC pathway is currently emerging as a promising therapeutic target for the negative and cognitive symptom clusters of schizophrenia. Here, we have reviewed the physiological, pharmacological and functional characteristics of the H-PFC pathway and we propose that allosteric activation of glutamatergic and cholinergic neurotransmission can serve as a plausible therapeutic approach. PMID:25825588

Gene- and pathway-based association tests for multiple traits with GWAS summary statistics.

PubMed

Kwak, Il-Youp; Pan, Wei

2017-01-01

To identify novel genetic variants associated with complex traits and to shed new insights on underlying biology, in addition to the most popular single SNP-single trait association analysis, it would be useful to explore multiple correlated (intermediate) traits at the gene- or pathway-level by mining existing single GWAS or meta-analyzed GWAS data. For this purpose, we present an adaptive gene-based test and a pathway-based test for association analysis of multiple traits with GWAS summary statistics. The proposed tests are adaptive at both the SNP- and trait-levels; that is, they account for possibly varying association patterns (e.g. signal sparsity levels) across SNPs and traits, thus maintaining high power across a wide range of situations. Furthermore, the proposed methods are general: they can be applied to mixed types of traits, and to Z-statistics or P-values as summary statistics obtained from either a single GWAS or a meta-analysis of multiple GWAS. Our numerical studies with simulated and real data demonstrated the promising performance of the proposed methods. The methods are implemented in R package aSPU, freely and publicly available at: https://cran.r-project.org/web/packages/aSPU/ CONTACT: weip@biostat.umn.eduSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Therapeutic Potential of Targeting the Ghrelin Pathway.

PubMed

Colldén, Gustav; Tschöp, Matthias H; Müller, Timo D

2017-04-11

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems' metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.

Therapeutic Potential of Targeting the Ghrelin Pathway

PubMed Central

Colldén, Gustav; Tschöp, Matthias H.; Müller, Timo D.

2017-01-01

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome. PMID:28398233

Rabies virus envelope glycoprotein targets lentiviral vectors to the axonal retrograde pathway in motor neurons.

PubMed

Hislop, James N; Islam, Tarin A; Eleftheriadou, Ioanna; Carpentier, David C J; Trabalza, Antonio; Parkinson, Michael; Schiavo, Giampietro; Mazarakis, Nicholas D

2014-06-06

Rabies pseudotyped lentiviral vectors have great potential in gene therapy, not least because of their ability to transduce neurons following their distal axonal application. However, very little is known about the molecular processes that underlie their retrograde transport and cell transduction. Using multiple labeling techniques and confocal microscopy, we demonstrated that pseudotyping with rabies virus envelope glycoprotein (RV-G) enabled the axonal retrograde transport of two distinct subtypes of lentiviral vector in motor neuron cultures. Analysis of this process revealed that these vectors trafficked through Rab5-positive endosomes and accumulated within a non-acidic Rab7 compartment. RV-G pseudotyped vectors were co-transported with both the tetanus neurotoxin-binding fragment and the membrane proteins thought to mediate rabies virus endocytosis (neural cell adhesion molecule, nicotinic acetylcholine receptor, and p75 neurotrophin receptor), thus demonstrating that pseudotyping with RV-G targets lentiviral vectors for transport along the same pathway exploited by several toxins and viruses. Using motor neurons cultured in compartmentalized chambers, we demonstrated that axonal retrograde transport of these vectors was rapid and efficient; however, it was not able to transduce the targeted neurons efficiently, suggesting that impairment in processes occurring after arrival of the viral vector in the soma is responsible for the low transduction efficiency seen in vivo, which suggests a novel area for improvement of gene therapy vectors. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Emerging science and therapies in non-small-cell lung cancer: targeting the MET pathway.

PubMed

Kris, Mark G; Arenberg, Douglas A; Herbst, Roy S; Riely, Gregory J

2014-11-01

During this enduring, learner-driven, interactive CME webseries, lung cancer specialists will address the science and targeted therapies for the MET pathway in non-small cell lung cancer. Over the past decade, research has evolved in the science of identifying targeted biological changes in DNA and individual cancer cells. Along with the advanced understanding of lung cancer mutations, has come the development of specific targeted therapies that improve patient outcomes. The first step in treating a patient with lung cancer is proper diagnosis and staging, applying to the principles of personalize medicine. Our current understanding of lung cancer is that of a collection of diseases individualized through specific mutations. This CME activity reviews the role of the pulmonologist and pathologist in proper tissue acquisition and analysis. This new era of personalized medicine and clinical research advances has changed the way clinicians evaluate and treat patients with lung cancer. The data on lung cancer cell mutations and newer targeted therapies have improved the progression free survival and quality of life of lung cancer patients. This CME activity is designed to present a practical overview of recent evidenced based data of MET targeted therapies for patients with lung cancer. As research continues to evolve, we continue to advance our understanding in the science of lung cancers involving the MET pathway. Evidenced based data supporting newer targeted therapeutics provides insight on applying treatment for optimal outcomes. This CME activity will focus on the individualized treatment strategies using practical decision making for patients with MET expression. This activity has been designed to meet the educational needs of medical oncologists, pathologists, radiation oncologists, surgeons, pulmonologists, internists, and other healthcare clinicians responsible for the care of patients with lung cancer. Online access:http://www.elseviercme.com/516/.

Labeled RFS-Based Track-Before-Detect for Multiple Maneuvering Targets in the Infrared Focal Plane Array.

PubMed

Li, Miao; Li, Jun; Zhou, Yiyu

2015-12-08

The problem of jointly detecting and tracking multiple targets from the raw observations of an infrared focal plane array is a challenging task, especially for the case with uncertain target dynamics. In this paper a multi-model labeled multi-Bernoulli (MM-LMB) track-before-detect method is proposed within the labeled random finite sets (RFS) framework. The proposed track-before-detect method consists of two parts-MM-LMB filter and MM-LMB smoother. For the MM-LMB filter, original LMB filter is applied to track-before-detect based on target and measurement models, and is integrated with the interacting multiple models (IMM) approach to accommodate the uncertainty of target dynamics. For the MM-LMB smoother, taking advantage of the track labels and posterior model transition probability, the single-model single-target smoother is extended to a multi-model multi-target smoother. A Sequential Monte Carlo approach is also presented to implement the proposed method. Simulation results show the proposed method can effectively achieve tracking continuity for multiple maneuvering targets. In addition, compared with the forward filtering alone, our method is more robust due to its combination of forward filtering and backward smoothing.

Labeled RFS-Based Track-Before-Detect for Multiple Maneuvering Targets in the Infrared Focal Plane Array

PubMed Central

Li, Miao; Li, Jun; Zhou, Yiyu

2015-01-01

The problem of jointly detecting and tracking multiple targets from the raw observations of an infrared focal plane array is a challenging task, especially for the case with uncertain target dynamics. In this paper a multi-model labeled multi-Bernoulli (MM-LMB) track-before-detect method is proposed within the labeled random finite sets (RFS) framework. The proposed track-before-detect method consists of two parts—MM-LMB filter and MM-LMB smoother. For the MM-LMB filter, original LMB filter is applied to track-before-detect based on target and measurement models, and is integrated with the interacting multiple models (IMM) approach to accommodate the uncertainty of target dynamics. For the MM-LMB smoother, taking advantage of the track labels and posterior model transition probability, the single-model single-target smoother is extended to a multi-model multi-target smoother. A Sequential Monte Carlo approach is also presented to implement the proposed method. Simulation results show the proposed method can effectively achieve tracking continuity for multiple maneuvering targets. In addition, compared with the forward filtering alone, our method is more robust due to its combination of forward filtering and backward smoothing. PMID:26670234

Target Deconvolution Efforts on Wnt Pathway Screen Reveal Dual Modulation of Oxidative Phosphorylation and SERCA2.

PubMed

Casás-Selves, Matias; Zhang, Andrew X; Dowling, James E; Hallén, Stefan; Kawatkar, Aarti; Pace, Nicholas J; Denz, Christopher R; Pontz, Timothy; Garahdaghi, Farzin; Cao, Qing; Sabirsh, Alan; Thakur, Kumar; O'Connell, Nichole; Hu, Jun; Cornella-Taracido, Iván; Weerapana, Eranthie; Zinda, Michael; Goodnow, Robert A; Castaldi, M Paola

2017-06-21

Wnt signaling is critical for development, cell proliferation and differentiation, and mutations in this pathway resulting in constitutive signaling have been implicated in various cancers. A pathway screen using a Wnt-dependent reporter identified a chemical series based on a 1,2,3-thiadiazole-5-carboxamide (TDZ) core with sub-micromolar potency. Herein we report a comprehensive mechanism-of-action deconvolution study toward identifying the efficacy target(s) and biological implication of this chemical series involving bottom-up quantitative chemoproteomics, cell biology, and biochemical methods. Through observing the effects of our probes on metabolism and performing confirmatory cellular and biochemical assays, we found that this chemical series inhibits ATP synthesis by uncoupling the mitochondrial potential. Affinity chemoproteomics experiments identified sarco(endo)plasmic reticulum Ca 2+ -dependent ATPase (SERCA2) as a binding partner of the TDZ series, and subsequent validation studies suggest that the TDZ series can act as ionophores through SERCA2 toward Wnt pathway inhibition. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis.

PubMed

Evans, Joanna C; Trujillo, Carolina; Wang, Zhe; Eoh, Hyungjin; Ehrt, Sabine; Schnappinger, Dirk; Boshoff, Helena I M; Rhee, Kyu Y; Barry, Clifton E; Mizrahi, Valerie

2016-12-09

Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro, whereas silencing of panB, panC, or coaE was bacteriostatic over the same time course. Silencing of coaBC was likewise bactericidal in vivo, whether initiated at infection or during either the acute or chronic stages of infection, confirming that CoaBC is required for M. tuberculosis to grow and persist in mice and arguing against significant CoaBC bypass via transport and assimilation of host-derived pantetheine in this animal model. These results provide convincing genetic validation of CoaBC as a new bactericidal drug target.

From the "little brain" gastrointestinal infection to the "big brain" neuroinflammation: a proposed fast axonal transport pathway involved in multiple sclerosis.

PubMed

Deretzi, Georgia; Kountouras, Jannis; Grigoriadis, Nikolaos; Zavos, Christos; Chatzigeorgiou, Stavros; Koutlas, Evangelos; Tsiptsios, Iakovos

2009-11-01

The human central nervous system (CNS) is targeted by different pathogens which, apart from pathogens' intranasal inoculation or trafficking into the brain through infected blood cells, may use a distinct pathway to bypass the blood-brain barrier by using the gastrointestinal tract (GIT) retrograde axonal transport through sensory or motor fibres. The recent findings regarding the enteric nervous system (often called the "little brain") similarities with CNS and GIT axonal transport of infections resulting in CNS neuroinflammation are mainly reviewed in this article. We herein propose that the GIT is the vulnerable area through which pathogens (such as Helicobacter pylori) may influence the brain and induce multiple sclerosis pathologies, mainly via the fast axonal transport by the afferent neurones connecting the GIT to brain.

Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells.

PubMed

Sherbenou, Daniel W; Aftab, Blake T; Su, Yang; Behrens, Christopher R; Wiita, Arun; Logan, Aaron C; Acosta-Alvear, Diego; Hann, Byron C; Walter, Peter; Shuman, Marc A; Wu, Xiaobo; Atkinson, John P; Wolf, Jeffrey L; Martin, Thomas G; Liu, Bin

2016-12-01

Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs). In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models. In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number. Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q.

Target-responsive DNA hydrogel mediated "stop-flow" microfluidic paper-based analytic device for rapid, portable and visual detection of multiple targets.

PubMed

Wei, Xiaofeng; Tian, Tian; Jia, Shasha; Zhu, Zhi; Ma, Yanli; Sun, Jianjun; Lin, Zhenyu; Yang, Chaoyong James

2015-04-21

A versatile point-of-care assay platform was developed for simultaneous detection of multiple targets based on a microfluidic paper-based analytic device (μPAD) using a target-responsive hydrogel to mediate fluidic flow and signal readout. An aptamer-cross-linked hydrogel was used as a target-responsive flow regulator in the μPAD. In the absence of a target, the hydrogel is formed in the flow channel, stopping the flow in the μPAD and preventing the colored indicator from traveling to the final observation spot, thus yielding a "signal off" readout. In contrast, in the presence of a target, no hydrogel is formed because of the preferential interaction of target and aptamer. This allows free fluidic flow in the μPAD, carrying the indicator to the observation spot and producing a "signal on" readout. The device is inexpensive to fabricate, easy to use, and disposable after detection. Testing results can be obtained within 6 min by the naked eye via a simple loading operation without the need for any auxiliary equipment. Multiple targets, including cocaine, adenosine, and Pb(2+), can be detected simultaneously, even in complex biological matrices such as urine. The reported method offers simple, low cost, rapid, user-friendly, point-of-care testing, which will be useful in many applications.

Finding pathways to national-scale land-sector sustainability.

PubMed

Gao, Lei; Bryan, Brett A

2017-04-12

The 17 Sustainable Development Goals (SDGs) and 169 targets under Agenda 2030 of the United Nations map a coherent global sustainability ambition at a level of detail general enough to garner consensus amongst nations. However, achieving the global agenda will depend heavily on successful national-scale implementation, which requires the development of effective science-driven targets tailored to specific national contexts and supported by strong national governance. Here we assess the feasibility of achieving multiple SDG targets at the national scale for the Australian land-sector. We scaled targets to three levels of ambition and two timeframes, then quantitatively explored the option space for target achievement under 648 plausible future environmental, socio-economic, technological and policy pathways using the Land-Use Trade-Offs (LUTO) integrated land systems model. We show that target achievement is very sensitive to global efforts to abate emissions, domestic land-use policy, productivity growth rate, and land-use change adoption behaviour and capacity constraints. Weaker target-setting ambition resulted in higher achievement but poorer sustainability outcomes. Accelerating land-use dynamics after 2030 changed the targets achieved by 2050, warranting a longer-term view and greater flexibility in sustainability implementation. Simultaneous achievement of multiple targets is rare owing to the complexity of sustainability target implementation and the pervasive trade-offs in resource-constrained land systems. Given that hard choices are needed, the land-sector must first address the essential food/fibre production, biodiversity and land degradation components of sustainability via specific policy pathways. It may also contribute to emissions abatement, water and energy targets by capitalizing on co-benefits. However, achieving targets relevant to the land-sector will also require substantial contributions from other sectors such as clean energy, food systems

Finding pathways to national-scale land-sector sustainability

NASA Astrophysics Data System (ADS)

Gao, Lei; Bryan, Brett A.

2017-04-01

The 17 Sustainable Development Goals (SDGs) and 169 targets under Agenda 2030 of the United Nations map a coherent global sustainability ambition at a level of detail general enough to garner consensus amongst nations. However, achieving the global agenda will depend heavily on successful national-scale implementation, which requires the development of effective science-driven targets tailored to specific national contexts and supported by strong national governance. Here we assess the feasibility of achieving multiple SDG targets at the national scale for the Australian land-sector. We scaled targets to three levels of ambition and two timeframes, then quantitatively explored the option space for target achievement under 648 plausible future environmental, socio-economic, technological and policy pathways using the Land-Use Trade-Offs (LUTO) integrated land systems model. We show that target achievement is very sensitive to global efforts to abate emissions, domestic land-use policy, productivity growth rate, and land-use change adoption behaviour and capacity constraints. Weaker target-setting ambition resulted in higher achievement but poorer sustainability outcomes. Accelerating land-use dynamics after 2030 changed the targets achieved by 2050, warranting a longer-term view and greater flexibility in sustainability implementation. Simultaneous achievement of multiple targets is rare owing to the complexity of sustainability target implementation and the pervasive trade-offs in resource-constrained land systems. Given that hard choices are needed, the land-sector must first address the essential food/fibre production, biodiversity and land degradation components of sustainability via specific policy pathways. It may also contribute to emissions abatement, water and energy targets by capitalizing on co-benefits. However, achieving targets relevant to the land-sector will also require substantial contributions from other sectors such as clean energy, food systems

In vitro C3 Deposition on Cryptococcus Capsule Occurs Via Multiple Complement Activation Pathways

PubMed Central

Mershon-Shier, Kileen L.; Vasuthasawat, Alex; Takahashi, Kazue; Morrison, Sherie L.; Beenhouwer, David O.

2011-01-01

Complement can be activated via three pathways: classical, alternative, and lectin. Cryptococcus gattii and C. neoformans are closely related fungal pathogens possessing a polysaccharide capsule composed mainly of glucuronoxylomannan (GXM), which serves as a site for complement activation and deposition of complement components. We determined C3 deposition on Cryptococcus spp. by flow cytometry and confocal microscopy after incubation with serum from C57BL/6J mice as well as mice deficient in complement components C4, C3, factor B, and mannose binding lectin (MBL). C. gattii and C. neoformans activate complement in EGTA-treated serum indicating that they can activate the alternative pathway. However, complement activation was seen with factor B−/− serum suggesting activation could also take place in the absence of a functional alternative pathway. Furthermore, we uncovered a role for C4 in the alternative pathway activation by Cryptococcus spp. We also identified an unexpected and complex role for MBL in complement activation by Cryptococcus spp. No complement activation occurred in the absence of MBL-A and -C proteins although activation took place when the lectin binding activity of MBL was disrupted by calcium chelation. In addition, alternative pathway activation by C. neoformans required both MBL-A and -C, while either MBL-A or -C was sufficient for alternative pathway activation by C. gattii. Thus, complement activation by Cryptococcus spp. can take place through multiple pathways and complement activation via the alternative pathway requires the presence of C4 and MBL proteins. PMID:21723612

Multiple sclerosis pathways: an innovative nursing role in disease management.

PubMed

Madonna, M G; Keating, M M

1999-12-01

Multiple sclerosis (MS), a chronic disease of the central nervous system, is characterized by a variable and unpredictable course. The most common pattern of the disease is the relapsing-remitting form in which clearly defined relapses (also called exacerbations) are followed by complete or incomplete recovery. Interferon beta-1b (Betaseron), a drug that affects the natural course of the disease, was developed for the treatment of relapsing-remitting MS. Multiple Sclerosis Pathways (MSP), a disease management program, was developed to provide comprehensive and personal support to MS patients taking interferon beta-1b and to serve as an information resource for all people with MS, their families, and healthcare professionals. The MSP program includes personal patient assistance, reimbursement services, a 24-hour nurse hotline, training program, educational resources, and injection supplies. The nurse hotline counselor (NHC) utilizes the nursing process in a unique telephone nursing practice in this program. The positive impact of education and support on adherence to therapy has been validated by training and nurse hotline data.

Targeting loss of the Hippo signaling pathway in NF2-deficient papillary kidney cancers

PubMed Central

Ricketts, Christopher J.; Wei, Darmood; Yang, Youfeng; Baranes, Sarah M.; Gibbs, Benjamin K.; Ohanjanian, Lernik; Spencer Krane, L.; Scroggins, Bradley T.; Keith Killian, J.; Wei, Ming-Hui; Kijima, Toshiki; Meltzer, Paul S.; Citrin, Deborah E.; Neckers, Len; Vocke, Cathy D.; Marston Linehan, W.

2018-01-01

Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15–20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of NF2 results in aberrant YAP1 activation. The Src family kinase member Yes also regulates YAP1 transcriptional activity. This study investigated the importance of YAP and Yes activity in three NF2-deficient PRCC cell lines. NF2-deficency correlated with increased expression of YAP1 transcriptional targets and siRNA-based knockdown of YAP1 and Yes1 downregulated this pathway and dramatically reduced cell viability. Dasatinib and saracatinib have potent inhibitory effects on Yes and treatment with either resulted in downregulation of YAP1 transcription targets, reduced cell viability, and G0-G1 cell cycle arrest. Xenograft models for NF2-deficient PRCC also demonstrated reduced tumor growth in response to dasatinib. Thus, inhibiting Yes and the subsequent transcriptional activity of YAP1 had a substantial anti-tumor cell effect both in vitro and in vivo and may provide a viable therapeutic approach for patients with NF2-deficient PRCC. PMID:29535838

Hippo-YAP signaling pathway: A new paradigm for cancer therapy.

PubMed

Ma, Yanlei; Yang, Yongzhi; Wang, Feng; Wei, Qing; Qin, Huanlong

2015-11-15

In the past decades, the Hippo signaling pathway has been delineated and shown to play multiple roles in the control of organ size in both Drosophila and mammals. In mammals, the Hippo pathway is a kinase cascade leading from Mst1/2 to YAP and its paralog TAZ. Several studies have demonstrated that YAP/TAZ is a candidate oncogene and that other members of the Hippo pathway are tumor suppressive genes. The dysregulation of the Hippo pathway has been observed in a variety of cancers. This review chronicles the recent progress in elucidating the function of Hippo signaling in tumorigenesis and provide a rich source of potential targets for cancer therapy. © 2014 UICC.

Therapeutic targeting of epithelial plasticity programs – Focus on the epithelial-mesenchymal transition

PubMed Central

Malek, Reem; Wang, Hailun; Taparra, Kekoa; Tran, Phuoc T.

2017-01-01

Mounting data points to epithelial plasticity programs such as the epithelial-mesenchymal transition (EMT) as clinically relevant therapeutic targets for the treatment of malignant tumors. In addition to the widely realized role of EMT in increasing cancer cell invasiveness during cancer metastasis, the EMT has also been implicated in allowing cancer cells to avoid tumor suppressor pathways during early tumorigenesis. In addition, data linking EMT to innate and acquired treatment resistance further points towards the desire to develop pharmacological therapies to target epithelial plasticity in cancer. In this review we organized our discussion on pathways and agents that can be used to target the EMT in cancer into three groups: (1) extracellular inducers of EMT; (2) the transcription factors that orchestrate the EMT transcriptome; and, (3) the downstream effectors of EMT. We highlight only briefly specific canonical pathways known to be involved in EMT such as the signal transduction pathways TGFβ, EFGR and Axl-Gas6. We emphasize in more detail pathways that are we believe are emerging novel pathways and therapeutic targets such as epigenetic therapies, glycosylation pathways and immunotherapy. The heterogeneity of tumors and the dynamic nature of epithelial plasticity in cancer cells make it likely that targeting only one EMT related process will be unsuccessful or only transiently successful. We suggest with greater understanding of epithelial plasticity regulation such as with the EMT, a more systematic targeting of multiple EMT regulatory networks will be the best path forward to improve cancer outcomes. PMID:28214899

Modeling of nitrous oxide production by autotrophic ammonia-oxidizing bacteria with multiple production pathways.

PubMed

Ni, Bing-Jie; Peng, Lai; Law, Yingyu; Guo, Jianhua; Yuan, Zhiguo

2014-04-01

Autotrophic ammonia oxidizing bacteria (AOB) have been recognized as a major contributor to N2O production in wastewater treatment systems. However, so far N2O models have been proposed based on a single N2O production pathway by AOB, and there is still a lack of effective approach for the integration of these models. In this work, an integrated mathematical model that considers multiple production pathways is developed to describe N2O production by AOB. The pathways considered include the nitrifier denitrification pathway (N2O as the final product of AOB denitrification with NO2(-) as the terminal electron acceptor) and the hydroxylamine (NH2OH) pathway (N2O as a byproduct of incomplete oxidation of NH2OH to NO2(-)). In this model, the oxidation and reduction processes are modeled separately, with intracellular electron carriers introduced to link the two types of processes. The model is calibrated and validated using experimental data obtained with two independent nitrifying cultures. The model satisfactorily describes the N2O data from both systems. The model also predicts shifts of the dominating pathway at various dissolved oxygen (DO) and nitrite levels, consistent with previous hypotheses. This unified model is expected to enhance our ability to predict N2O production by AOB in wastewater treatment systems under varying operational conditions.

A Small RNA-Catalytic Argonaute Pathway Tunes Germline Transcript Levels to Ensure Embryonic Divisions

PubMed Central

Gerson-Gurwitz, Adina; Wang, Shaohe; Sathe, Shashank; Green, Rebecca; Yeo, Gene W.; Oegema, Karen; Desai, Arshad

2016-01-01

SUMMARY Multiple division cycles without growth are a characteristic feature of early embryogenesis. The female germline loads proteins and RNAs into oocytes to support these divisions, which lack many quality control mechanisms operating in somatic cells undergoing growth. Here we describe a small RNA-Argonaute pathway that ensures early embryonic divisions in C. elegans by employing catalytic slicing activity to broadly tune, instead of silence, germline gene expression. Misregulation of one target, a kinesin-13 microtubule depolymerase, underlies a major phenotype associated with pathway loss. Tuning of target transcript levels is guided by density of homologous small RNAs, whose generation must ultimately be related to target sequence. Thus, the tuning action of a small RNA-catalytic Argonaute pathway generates oocytes capable of supporting embryogenesis. We speculate that the specialized nature of germline chromatin led to emergence of small RNA-catalytic Argonaute pathways in the female germline as a post-transcriptional control layer to optimize oocyte composition. PMID:27020753

Molecular pathways: targeting p21-activated kinase 1 signaling in cancer--opportunities, challenges, and limitations.

PubMed

Eswaran, Jeyanthy; Li, Da-Qiang; Shah, Anil; Kumar, Rakesh

2012-07-15

The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a variety of new functions for this kinase in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely upregulated in several human cancers, such as hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. Structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibility to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize recent findings about the PAK1 molecular pathways in human cancer and discuss the current status of PAK1-targeted anticancer therapies.

Distinct MicroRNA Expression Profile and Targeted Biological Pathways in Functional Myeloid-derived Suppressor Cells Induced by Δ9-Tetrahydrocannabinol in Vivo

PubMed Central

Hegde, Venkatesh L.; Tomar, Sunil; Jackson, Austin; Rao, Roshni; Yang, Xiaoming; Singh, Udai P.; Singh, Narendra P.; Nagarkatti, Prakash S.; Nagarkatti, Mitzi

2013-01-01

Δ9-Tetrahydrocannabinol (THC), the major bioactive component of marijuana, has been shown to induce functional myeloid-derived suppressor cells (MDSCs) in vivo. Here, we studied the involvement of microRNA (miRNA) in this process. CD11b+Gr-1+ MDSCs were purified from peritoneal exudates of mice administered with THC and used for genome-wide miRNA profiling. Expression of CD31 and Ki-67 confirmed that the THC-MDSCs were immature and proliferating. THC-induced MDSCs exhibited distinct miRNA expression signature relative to various myeloid cells and BM precursors. We identified 13 differentially expressed (>2-fold) miRNA in THC-MDSCs relative to control BM precursors. In silico target prediction for these miRNA and pathway analysis using multiple bioinformatics tools revealed significant overrepresentation of Gene Ontology clusters within hematopoiesis, myeloid cell differentiation, and regulation categories. Insulin-like growth factor 1 signaling involved in cell growth and proliferation, and myeloid differentiation pathways were among the most significantly enriched canonical pathways. Among the differentially expressed, miRNA-690 was highly overexpressed in THC-MDSCs (∼16-fold). Transcription factor CCAAT/enhancer-binding protein α (C/EBPα) was identified as a potential functional target of miR-690. Supporting this, C/EBPα expression was attenuated in THC-MDSCs as compared with BM precursors and exhibited an inverse relation with miR-690. miR-690 knockdown using peptide nucleic acid-antagomiR was able to unblock and significantly increase C/EBPα expression establishing the functional link. Further, CD11b+Ly6G+Ly6C+ and CD11b+Ly6G−Ly6C+ purified subtypes showed high levels of miR-690 with attenuated C/EBPα expression. Moreover, EL-4 tumor-elicited MDSCs showed increased miR-690 expression. In conclusion, miRNA are significantly altered during the generation of functional MDSC from BM. Select miRNA such as miR-690 targeting genes involved in myeloid

JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer.

PubMed

Shien, Kazuhiko; Papadimitrakopoulou, Vassiliki A; Ruder, Dennis; Behrens, Carmen; Shen, Li; Kalhor, Neda; Song, Juhee; Lee, J Jack; Wang, Jing; Tang, Ximing; Herbst, Roy S; Toyooka, Shinichi; Girard, Luc; Minna, John D; Kurie, Jonathan M; Wistuba, Ignacio I; Izzo, Julie G

2017-10-01

Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6-cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234-45. ©2017 AACR . ©2017 American Association for Cancer Research.

Integrated analysis of microRNAs, transcription factors and target genes expression discloses a specific molecular architecture of hyperdiploid multiple myeloma

PubMed Central

Caracciolo, Daniele; Agnelli, Luca; Neri, Antonino; Walker, Brian A.; Morgan, Gareth J.; Cannataro, Mario

2015-01-01

Multiple Myeloma (MM) is a malignancy characterized by the hyperdiploid (HD-MM) and the non-hyperdiploid (nHD-MM) subtypes. To shed light within the molecular architecture of these subtypes, we used a novel integromics approach. By annotated MM patient mRNA/microRNA (miRNA) datasets, we investigated mRNAs and miRNAs profiles with relation to changes in transcriptional regulators expression. We found that HD-MM displays specific gene and miRNA expression profiles, involving the Signal Transducer and Activator of Transcription (STAT)3 pathway as well as the Transforming Growth Factor–beta (TGFβ) and the transcription regulator Nuclear Protein-1 (NUPR1). Our data define specific molecular features of HD-MM that may translate in the identification of novel relevant druggable targets. PMID:26056083

Coupling nutrient sensing to metabolic homoeostasis: the role of the mammalian target of rapamycin complex 1 pathway.

PubMed

André, Caroline; Cota, Daniela

2012-11-01

The mammalian target of rapamycin complex 1 (mTORC1) pathway is known to couple different environmental cues to the regulation of several energy-demanding functions within the cell, spanning from protein translation to mitochondrial activity. As a result, at the organism level, mTORC1 activity affects energy balance and general metabolic homoeostasis by modulating both the activity of neuronal populations that play key roles in the control of food intake and body weight, as well as by determining storage and use of fuel substrates in peripheral tissues. This review focuses on recent advances made in understanding the role of the mTORC1 pathway in the regulation of energy balance. More particularly, it aims at providing an overview of the status of knowledge regarding the mechanisms underlying the ability of certain amino acids, glucose and fatty acids, to affect mTORC1 activity and in turn illustrates how the mTORC1 pathway couples nutrient sensing to the hypothalamic regulation of the organisms' energy homoeostasis and to the control of intracellular metabolic processes, such as glucose uptake, protein and lipid biosynthesis. The evidence reviewed pinpoints the mTORC1 pathway as an integrator of the actions of nutrients on metabolic health and provides insight into the relevance of this intracellular pathway as a potential target for the therapy of metabolic diseases such as obesity and type-2 diabetes.

Active Debris Removal of Multiple Priority Targets

NASA Astrophysics Data System (ADS)

Braun, Vitali; Flegel, Sven Kevin; Vörsmann, Peter; Wiedemann, Carsten; Gelhaus, Johannes; Moeckel, Marek; Kebschull, Christopher

2012-07-01

Today's space debris environment shows major concentrations of objects within distinct orbital regions for nearly all size regimes. The most critical region is found at orbital altitudes near 800 kilometers with high declinations. Within this region many satellites are operated in so called sun-synchronous orbits (SSO). Among those, there are Earth observation, communication and weather satellites. Due to the orbital geometry, head-on encounters with relative velocities of about 15 km/s are most probable and would thus result in highly energetic collisions, which are often referred to as catastrophic collisions, leading to the complete fragmentation of the participating objects. So called feedback collisions can then be triggered by the newly generated fragments, thus leading to a further population increase in the affected orbital region. This effect is known as the Kessler syndrome. Current studies show that catastrophic collisions are not a major problem today, but will become the main process for debris generation within the SSO region in the near future, even without any future launches. In order to avoid this effect, objects with a major impact on collisional cascading have to be actively removed from the critical region after their end of life. Not having the capability to perform an end-of-life maneuver in order to transfer to a graveyard orbit or to de-orbit, many satellites and rocket bodies would have to be de-orbited within a dedicated mission. In such a mission, a service satellite would perform a de-orbit maneuver, after having docked to a specific target. In this paper several systems, e.g. chemical and electrical engines are analysed with the main focus on removing multiple targets within one single mission. The service satellite has to undock from the previously de-orbited target in order to start the rendezvous and docking phase for a subsequent target. The targets are chosen from a previously defined priority list in order to enhance the mission

Multiple Drug Transport Pathways through Human P-Glycoprotein.

PubMed

McCormick, James W; Vogel, Pia D; Wise, John G

2015-07-21

P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.

Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy.

PubMed

Kong, Delin; Zhao, Yicheng; Men, Tong; Teng, Chun-Bo

2015-02-01

Cell behaviors, including proliferation, differentiation and apoptosis, are intricately controlled during organ development and tissue regeneration. In the past 9 years, the Hippo signaling pathway has been delineated to play critical roles in organ size control, tissue regeneration and tumorigenesis through regulating cell behaviors. In mammals, the core modules of the Hippo signaling pathway include the MST1/2-LATS1/2 kinase cascade and the transcriptional co-activators YAP/TAZ. The activity of YAP/TAZ is suppressed by cytoplasmic retention due to phosphorylation in the canonical MST1/2-LATS1/2 kinase cascade-dependent manner or the non-canonical MST1/2- and/or LATS1/2-independent manner. Hippo signaling pathway, which can be activated or inactivated by cell polarity, contact inhibition, mechanical stretch and extracellular factors, has been demonstrated to be involved in development and tumorigenesis of liver and pancreas. In addition, we have summarized several small molecules currently available that can target Hippo-YAP pathway for potential treatment of hepatic and pancreatic cancers, providing clues for other YAP initiated cancers therapy as well.

Impaired neurosteroid synthesis in multiple sclerosis

PubMed Central

Noorbakhsh, Farshid; Ellestad, Kristofor K.; Maingat, Ferdinand; Warren, Kenneth G.; Han, May H.; Steinman, Lawrence; Baker, Glen B.

2011-01-01

High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcription–polymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to

The mammalian target of rapamycin signaling pathway regulates myocyte enhancer factor-2C phosphorylation levels through integrin-linked kinase in goat skeletal muscle satellite cells.

PubMed

Wu, Haiqing; Ren, Yu; Pan, Wei; Dong, Zhenguo; Cang, Ming; Liu, Dongjun

2015-11-01

Mammalian target of rapamycin (mTOR) signaling pathway plays a key role in muscle development and is involved in multiple intracellular signaling pathways. Myocyte enhancer factor-2 (MEF2) regulates muscle cell proliferation and differentiation. However, how the mTOR signaling pathway regulates MEF2 activity remains unclear. We isolated goat skeletal muscle satellite cells (gSSCs) as model cells to explore mTOR signaling pathway regulation of MEF2C. We inhibited mTOR activity in gSSCs with PP242 and found that MEF2C phosphorylation was decreased and that muscle creatine kinase (MCK) expression was suppressed. Subsequently, we detected integrin-linked kinase (ILK) using MEF2C coimmunoprecipitation; ILK and MEF2C were colocalized in the gSSCs. We found that inhibiting mTOR activity increased ILK phosphorylation levels and that inhibiting ILK activity with Cpd 22 and knocking down ILK with small interfering RNA increased MEF2C phosphorylation and MCK expression. In the presence of Cpd 22, mTOR activity inhibition did not affect MEF2C phosphorylation. Moreover, ILK dephosphorylated MEF2C in vitro. These results suggest that the mTOR signaling pathway regulates MEF2C positively and regulates ILK negatively and that ILK regulates MEF2C negatively. It appears that the mTOR signaling pathway regulates MEF2C through ILK, further regulating the expression of muscle-related genes in gSSCs. © 2015 International Federation for Cell Biology.

Beyond Monoamines-Novel Targets for Treatment-Resistant Depression: A Comprehensive Review

PubMed Central

Rosenblat, Christian; McIntyre, Roger S.; Alves, Gilberto S.; Fountoulakis, Konstantinos N.; Carvalho, André F.

2015-01-01

Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown. PMID:26467412

Molecular pathway activation - new type of biomarkers for tumor morphology and personalized selection of target drugs.

PubMed

Buzdin, Anton; Sorokin, Maxim; Garazha, Andrew; Sekacheva, Marina; Kim, Ella; Zhukov, Nikolay; Wang, Ye; Li, Xinmin; Kar, Souvik; Hartmann, Christian; Samii, Amir; Giese, Alf; Borisov, Nicolas

2018-06-20

Anticancer target drugs (ATDs) specifically bind and inhibit molecular targets that play important roles in cancer development and progression, being deeply implicated in intracellular signaling pathways. To date, hundreds of different ATDs were approved for clinical use in the different countries. Compared to previous chemotherapy treatments, ATDs often demonstrate reduced side effects and increased efficiency, but also have higher costs. However, the efficiency of ATDs for the advanced stage tumors is still insufficient. Different ATDs have different mechanisms of action and are effective in different cohorts of patients. Personalized approaches are therefore needed to select the best ATD candidates for the individual patients. In this review, we focus on a new generation of biomarkers - molecular pathway activation - and on their applications for predicting individual tumor response to ATDs. The success in high throughput gene expression profiling and emergence of novel bioinformatic tools reinforced quick development of pathway related field of molecular biomedicine. The ability to quantitatively measure degree of a pathway activation using gene expression data has revolutionized this field and made the corresponding analysis quick, robust and inexpensive. This success was further enhanced by using machine learning algorithms for selection of the best biomarkers. We review here the current progress in translating these studies to clinical oncology and patient-oriented adjustment of cancer therapy. Copyright © 2018. Published by Elsevier Ltd.

Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder.

PubMed

Bellivier, Frank; Geoffroy, Pierre-Alexis; Etain, Bruno; Scott, Jan

2015-06-01

Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs. This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression. We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with 'omics' approaches are crucial steps for new drug development.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans.

PubMed

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans

PubMed Central

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma. PMID:24149939

Multiplicity distributions of shower particles and target fragments in 84 Kr 36-emulsion interactions at 1 GeV per nucleon

NASA Astrophysics Data System (ADS)

Singh, M. K.; Soma, A. K.; Pathak, Ramji; Singh, V.

2014-03-01

This article focuses on multiplicity distributions of shower particles and target fragments for interaction of 84 Kr 36 with NIKFI BR-2 nuclear emulsion target at kinetic energy of 1 GeV per nucleon. Experimental multiplicity distributions of shower particles, grey particles, black particles and heavily ionization particles are well described by multi-component Erlang distribution of multi-source thermal model. We have observed a linear correlation in multiplicities for the above mentioned particles or fragments. Further experimental studies have shown a saturation phenomenon in shower particle multiplicity with the increase of target fragment multiplicity.

A Mouse Polyomavirus-encoded microRNA Targets the Cellular Apoptosis Pathway through Smad2 Inhibition

PubMed Central

Sung, Chang Kyoo; Yim, Hyungshin; Andrews, Erik; Benjamin, Thomas L.

2014-01-01

Some viruses and most eukaryotic cells have microRNAs that regulate the expression of many genes. Although many viral miRNAs have been identified, only a few have been included in in vivo functional studies. Here we show that a Py-encoded miRNA downregulates the expression of the pro-apoptotic factor Smad2, resulting in the suppression of the apoptosis pathway. To study the Py miRNA in an in vivo context, a miRNA-deficient mutant virus was created on the background of the LID virus strain which establishes a rapid and lethal infection in newborn mice. Apoptosis analysis on kidney tissues indicates that the pro-apoptotic pathway is targeted in the infected host as well. Suppression of apoptosis through targeting of Smad2 by the Py miRNA is expected to synergize with anti-apoptotic effects previously attributed to the polyoma tumor antigens in support of virus replication in the natural host. PMID:25146733

Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways

PubMed Central

Ovadje, Pamela; Ammar, Saleem; Guerrero, Jose-Antonio; Arnason, John Thor; Pandey, Siyaram

2016-01-01

Dandelion extracts have been studied extensively in recent years for its anti-depressant and anti-inflammatory activity. Recent work from our lab, with in-vitro systems, shows the anti-cancer potential of an aqueous dandelion root extract (DRE) in several cancer cell models, with no toxicity to non-cancer cells. In this study, we examined the cancer cell-killing effectiveness of an aqueous DRE in colon cancer cell models. Aqueous DRE induced programmed cell death (PCD) selectively in > 95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment. The anti-cancer efficacy of this extract was confirmed in in-vivo studies, as the oral administration of DRE retarded the growth of human colon xenograft models by more than 90%. We found the activation of multiple death pathways in cancer cells by DRE treatment, as revealed by gene expression analyses showing the expression of genes implicated in programmed cell death. Phytochemical analyses of the extract showed complex multi-component composition of the DRE, including some known bioactive phytochemicals such as α-amyrin, β-amyrin, lupeol and taraxasterol. This suggested that this natural extract could engage and effectively target multiple vulnerabilities of cancer cells. Therefore, DRE could be a non-toxic and effective anti-cancer alternative, instrumental for reducing the occurrence of cancer cells drug-resistance. PMID:27564258

Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors.

PubMed

Starostina, Natalia G; Kipreos, Edward T

2012-01-01

The mammalian CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors (CKIs) comprises three proteins--p21(Cip1/WAF1), p27(Kip1), and p57(Kip2)--that bind and inhibit cyclin-CDK complexes, which are key regulators of the cell cycle. CIP/KIP CKIs have additional independent functions in regulating transcription, apoptosis and actin cytoskeletal dynamics. These divergent functions are performed in distinct cellular compartments and contribute to the seemingly contradictory observation that the CKIs can both suppress and promote cancer. Multiple ubiquitin ligases (E3s) direct the proteasome-mediated degradation of p21, p27 and p57. This review analyzes recent data highlighting our current understanding of how distinct E3 pathways regulate subpopulations of the CKIs to control their diverse functions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Multi-target QSPR modeling for simultaneous prediction of multiple gas-phase kinetic rate constants of diverse chemicals

NASA Astrophysics Data System (ADS)

Basant, Nikita; Gupta, Shikha

2018-03-01

The reactions of molecular ozone (O3), hydroxyl (•OH) and nitrate (NO3) radicals are among the major pathways of removal of volatile organic compounds (VOCs) in the atmospheric environment. The gas-phase kinetic rate constants (kO3, kOH, kNO3) are thus, important in assessing the ultimate fate and exposure risk of atmospheric VOCs. Experimental data for rate constants are not available for many emerging VOCs and the computational methods reported so far address a single target modeling only. In this study, we have developed a multi-target (mt) QSPR model for simultaneous prediction of multiple kinetic rate constants (kO3, kOH, kNO3) of diverse organic chemicals considering an experimental data set of VOCs for which values of all the three rate constants are available. The mt-QSPR model identified and used five descriptors related to the molecular size, degree of saturation and electron density in a molecule, which were mechanistically interpretable. These descriptors successfully predicted three rate constants simultaneously. The model yielded high correlations (R2 = 0.874-0.924) between the experimental and simultaneously predicted endpoint rate constant (kO3, kOH, kNO3) values in test arrays for all the three systems. The model also passed all the stringent statistical validation tests for external predictivity. The proposed multi-target QSPR model can be successfully used for predicting reactivity of new VOCs simultaneously for their exposure risk assessment.

Propolis Augments Apoptosis Induced by Butyrate via Targeting Cell Survival Pathways

PubMed Central

Drago, Eric; Bordonaro, Michael; Lee, Seon; Atamna, Wafa; Lazarova, Darina L.

2013-01-01

Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC), and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling) may produce high levels of programmed death in CC cells. Here we report the combined effect of butyrate, an apoptosis inducer that is produced through fermentation of fiber in the colon, and propolis, a honeybee product, on CC cells. We established that propolis increases the apoptosis of CC cells exposed to butyrate through suppression of cell survival pathways such as the AKT signaling. The programmed death of CC cells by combined exposure to butyrate and propolis is further augmented by inhibition of the JNK signaling pathway. Analyses on the contribution of the downstream targets of JNK signaling, c-JUN and JAK/STAT, to the apoptosis of butyrate/propolis-treated CC cells ascertained that JAK/STAT signaling has an anti-apoptotic role; whereas, the role of cJUN might be dependent upon regulatory cell factors. Thus, our studies ascertained that propolis augments apoptosis of butyrate-sensitive CC cells and re-sensitizes butyrate-resistant CC cells to apoptosis by suppressing AKT signaling and downregulating the JAK/STAT pathway. Future in vivo studies should evaluate the CC-preventive potential of a dietary supplement that produces high levels of colonic butyrate, propolis, and diet-derived JAK/STAT inhibitors. PMID:24023824

Multiple pathways of commodity crop expansion in tropical forest landscapes

NASA Astrophysics Data System (ADS)

Meyfroidt, Patrick; Carlson, Kimberly M.; Fagan, Matthew E.; Gutiérrez-Vélez, Victor H.; Macedo, Marcia N.; Curran, Lisa M.; DeFries, Ruth S.; Dyer, George A.; Gibbs, Holly K.; Lambin, Eric F.; Morton, Douglas C.; Robiglio, Valentina

2014-07-01

Commodity crop expansion, for both global and domestic urban markets, follows multiple land change pathways entailing direct and indirect deforestation, and results in various social and environmental impacts. Here we compare six published case studies of rapid commodity crop expansion within forested tropical regions. Across cases, between 1.7% and 89.5% of new commodity cropland was sourced from forestlands. Four main factors controlled pathways of commodity crop expansion: (i) the availability of suitable forestland, which is determined by forest area, agroecological or accessibility constraints, and land use policies, (ii) economic and technical characteristics of agricultural systems, (iii) differences in constraints and strategies between small-scale and large-scale actors, and (iv) variable costs and benefits of forest clearing. When remaining forests were unsuitable for agriculture and/or policies restricted forest encroachment, a larger share of commodity crop expansion occurred by conversion of existing agricultural lands, and land use displacement was smaller. Expansion strategies of large-scale actors emerge from context-specific balances between the search for suitable lands; transaction costs or conflicts associated with expanding into forests or other state-owned lands versus smallholder lands; net benefits of forest clearing; and greater access to infrastructure in already-cleared lands. We propose five hypotheses to be tested in further studies: (i) land availability mediates expansion pathways and the likelihood that land use is displaced to distant, rather than to local places; (ii) use of already-cleared lands is favored when commodity crops require access to infrastructure; (iii) in proportion to total agricultural expansion, large-scale actors generate more clearing of mature forests than smallholders; (iv) property rights and land tenure security influence the actors participating in commodity crop expansion, the form of land use displacement

MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis

PubMed Central

Qiu, Jing-Xin; Kim, Edward J.; Yu, Ai-Ming

2016-01-01

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Better understanding of pancreatic cancer biology may help identify new oncotargets towards more effective therapies. This study investigated the mechanistic actions of microRNA-1291 (miR-1291) in the suppression of pancreatic tumorigenesis. Our data showed that miR-1291 was downregulated in a set of clinical pancreatic carcinoma specimens and human pancreatic cancer cell lines. Restoration of miR-1291 expression inhibited pancreatic cancer cell proliferation, which was associated with cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 sharply suppressed the tumorigenicity of PANC-1 cells in mouse models. A proteomic profiling study revealed 32 proteins altered over 2-fold in miR-1291-expressing PANC-1 cells that could be assembled into multiple critical pathways for cancer. Among them anterior gradient 2 (AGR2) was reduced to the greatest degree. Through computational and experimental studies we further identified that forkhead box protein A2 (FOXA2), a transcription factor governing AGR2 expression, was a direct target of miR-1291. These results connect miR-1291 to the FOXA2-AGR2 regulatory pathway in the suppression of pancreatic cancer cell proliferation and tumorigenesis, providing new insight into the development of miRNA-based therapy to combat pancreatic cancer. PMID:27322206

Anticancer molecules targeting fibroblast growth factor receptors.

PubMed

Liang, Guang; Liu, Zhiguo; Wu, Jianzhang; Cai, Yuepiao; Li, Xiaokun

2012-10-01

The fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases: FGFR1-4. Upon ligand binding, FGFRs activate an array of downstream signaling pathways, such as the mitogen activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K)/Akt pathways. These FGFR cascades play crucial roles in tumor cell proliferation, angiogenesis, migration, and survival. The combination of knockdown studies and pharmaceutical inhibition in preclinical models demonstrates that FGFRs are attractive targets for therapeutic intervention in cancer. Multiple FGFR inhibitors with various structural skeletons have been designed, synthesized, and evaluated. Reviews on FGFRs have recently focused on FGFR signaling, pathophysiology, and functions in cancer or other diseases. In this article, we review recent advances in structure-activity relationships (SAR) of FGFR inhibitors, as well as the FGFR-targeting drug design strategies currently employed in targeting deregulated FGFRs by antibodies and small molecule inhibitors. Copyright © 2012 Elsevier Ltd. All rights reserved.

Context matters: the structure of task goals affects accuracy in multiple-target visual search.

PubMed

Clark, Kait; Cain, Matthew S; Adcock, R Alison; Mitroff, Stephen R

2014-05-01

Career visual searchers such as radiologists and airport security screeners strive to conduct accurate visual searches, but despite extensive training, errors still occur. A key difference between searches in radiology and airport security is the structure of the search task: Radiologists typically scan a certain number of medical images (fixed objective), and airport security screeners typically search X-rays for a specified time period (fixed duration). Might these structural differences affect accuracy? We compared performance on a search task administered either under constraints that approximated radiology or airport security. Some displays contained more than one target because the presence of multiple targets is an established source of errors for career searchers, and accuracy for additional targets tends to be especially sensitive to contextual conditions. Results indicate that participants searching within the fixed objective framework produced more multiple-target search errors; thus, adopting a fixed duration framework could improve accuracy for career searchers. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

MIR506 induces autophagy-related cell death in pancreatic cancer cells by targeting the STAT3 pathway.

PubMed

Sun, Longhao; Hu, Limei; Cogdell, David; Lu, Li; Gao, Chao; Tian, Weijun; Zhang, Zhixiang; Kang, Ya'an; Fleming, Jason B; Zhang, Wei

2017-04-03

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and lethal cancer. The role of autophagy in the pathobiology of PDAC is intricate, with opposing functions manifested in different cellular contexts. MIR506 functions as a tumor suppressor in many cancer types through the regulation of multiple pathways. In this study, we hypothesized that MIR506 exerted a tumor suppression function in PDAC by inducing autophagy-related cell death. Our results provided evidence that downregulation of MIR506 expression was associated with disease progression in human PDAC. MIR506 triggered autophagic flux in PDAC cells, which led to autophagy-related cell death through direct targeting of the STAT3 (signal transducer and activator of transcription 3)-BCL2-BECN1 axis. Silencing and inhibiting STAT3 recapitulated the effects of MIR506, whereas forced expression of STAT3 abrogated the effects of MIR506. We propose that the apoptosis-inhibitory protein BCL2, which also inhibits induction of autophagy by blocking BECN1, was inhibited by MIR506 through targeting STAT3, thus augmenting BECN1 and promoting autophagy-related cell death. Silencing BECN1 and overexpression of BCL2 abrogated the effects of MIR506. These findings expand the known mechanisms of MIR506-mediated tumor suppression to activation of autophagy-related cell death and suggest a strategy for using MIR506 as an anti-STAT3 approach to PDAC treatment.

TBK1-targeted suppression of TRIF-dependent signaling pathway of Toll-like receptors by 6-shogaol, an active component of ginger.

PubMed

Park, Se-Jeong; Lee, Mi-Young; Son, Bu-Soon; Youn, Hyung-Sun

2009-07-01

Toll-like receptors (TLRs) are primary sensors that detect a wide variety of microbial components involving induction of innate immune responses. After recognition of microbial components, TLRs trigger the activation of myeloid differential factor 88 (MyD88) and Toll-interleukin-1 (IL-1) receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream signaling pathways. 6-Shoagol, an active ingredient of ginger, inhibits the MyD88-dependent signaling pathway by inhibiting inhibitor-kappaB kinase activity. Inhibitor-kappaB kinase is a key kinase in nuclear factor kappaB (NF-kappaB) activation. However, it is not known whether 6-shogaol inhibits the TRIF-dependent signaling pathway. Our goal was to identify the molecular target of 6-shogaol in the TRIF-dependent pathway of TLRs. 6-Shogaol inhibited the activation of interferon-regulatory factor 3 (IRF3) induced by lipopolysaccharide (LPS) and by polyriboinosinic polyribocytidylic acid (poly[I:C]), overexpression of TRIF, TANK-binding kinase1 (TBK1), and IRF3. Furthermore, 6-shogaol inhibited TBK1 activity in vitro. Together, these results suggest that 6-shogaol inhibits the TRIF-dependent signaling pathway of TLRs by targeting TBK1, and, they imply that 6-shogaol can modulate TLR-derived immune/inflammatory target gene expression induced by microbial infection.

Engineering metabolic pathways in plants by multigene transformation.

PubMed

Zorrilla-López, Uxue; Masip, Gemma; Arjó, Gemma; Bai, Chao; Banakar, Raviraj; Bassie, Ludovic; Berman, Judit; Farré, Gemma; Miralpeix, Bruna; Pérez-Massot, Eduard; Sabalza, Maite; Sanahuja, Georgina; Vamvaka, Evangelia; Twyman, Richard M; Christou, Paul; Zhu, Changfu; Capell, Teresa

2013-01-01

Metabolic engineering in plants can be used to increase the abundance of specific valuable metabolites, but single-point interventions generally do not improve the yields of target metabolites unless that product is immediately downstream of the intervention point and there is a plentiful supply of precursors. In many cases, an intervention is necessary at an early bottleneck, sometimes the first committed step in the pathway, but is often only successful in shifting the bottleneck downstream, sometimes also causing the accumulation of an undesirable metabolic intermediate. Occasionally it has been possible to induce multiple genes in a pathway by controlling the expression of a key regulator, such as a transcription factor, but this strategy is only possible if such master regulators exist and can be identified. A more robust approach is the simultaneous expression of multiple genes in the pathway, preferably representing every critical enzymatic step, therefore removing all bottlenecks and ensuring completely unrestricted metabolic flux. This approach requires the transfer of multiple enzyme-encoding genes to the recipient plant, which is achieved most efficiently if all genes are transferred at the same time. Here we review the state of the art in multigene transformation as applied to metabolic engineering in plants, highlighting some of the most significant recent advances in the field.

An integrative system biology approach to unravel potential drug candidates for multiple age related disorders.

PubMed

Srivastava, Isha; Khurana, Pooja; Yadav, Mohini; Hasija, Yasha

2017-12-01

Aging, though an inevitable part of life, is becoming a worldwide social and economic problem. Healthy aging is usually marked by low probability of age related disorders. Good therapeutic approaches are still in need to cure age related disorders. Occurrence of more than one ARD in an individual, expresses the need of discovery of such target proteins, which can affect multiple ARDs. Advanced scientific and medical research technologies throughout last three decades have arrived to the point where lots of key molecular determinants affect human disorders can be examined thoroughly. In this study, we designed and executed an approach to prioritize drugs that may target multiple age related disorders. Our methodology, focused on the analysis of biological pathways and protein protein interaction networks that may contribute to the pharmacology of age related disorders, included various steps such as retrieval and analysis of data, protein-protein interaction network analysis, and statistical and comparative analysis of topological coefficients, pathway, and functional enrichment analysis, and identification of drug-target proteins. We assume that the identified molecular determinants may be prioritized for further screening as novel drug targets to cure multiple ARDs. Based on the analysis, an online tool named as 'ARDnet' has been developed to construct and demonstrate ARD interactions at the level of PPI, ARDs and ARDs protein interaction, ARDs pathway interaction and drug-target interaction. The tool is freely made available at http://genomeinformatics.dtu.ac.in/ARDNet/Index.html. Copyright © 2017 Elsevier B.V. All rights reserved.

miR-206 Inhibits Stemness and Metastasis of Breast Cancer by Targeting MKL1/IL11 Pathway.

PubMed

Samaeekia, Ravand; Adorno-Cruz, Valery; Bockhorn, Jessica; Chang, Ya-Fang; Huang, Simo; Prat, Aleix; Ha, Nahun; Kibria, Golam; Huo, Dezheng; Zheng, Hui; Dalton, Rachel; Wang, Yuhao; Moskalenko, Grigoriy Y; Liu, Huiping

2017-02-15

Purpose: Effective targeting of cancer stem cells is necessary and important for eradicating cancer and reducing metastasis-related mortality. Understanding of cancer stemness-related signaling pathways at the molecular level will help control cancer and stop metastasis in the clinic. Experimental Design: By analyzing miRNA profiles and functions in cancer development, we aimed to identify regulators of breast tumor stemness and metastasis in human xenograft models in vivo and examined their effects on self-renewal and invasion of breast cancer cells in vitro To discover the direct targets and essential signaling pathways responsible for miRNA functions in breast cancer progression, we performed microarray analysis and target gene prediction in combination with functional studies on candidate genes (overexpression rescues and pheno-copying knockdowns). Results: In this study, we report that hsa-miR-206 suppresses breast tumor stemness and metastasis by inhibiting both self-renewal and invasion. We identified that among the candidate targets, twinfilin ( TWF1 ) rescues the miR-206 phenotype in invasion by enhancing the actin cytoskeleton dynamics and the activity of the mesenchymal lineage transcription factors, megakaryoblastic leukemia (translocation) 1 (MKL1), and serum response factor (SRF). MKL1 and SRF were further demonstrated to promote the expression of IL11 , which is essential for miR-206's function in inhibiting both invasion and stemness of breast cancer. Conclusions: The identification of the miR-206/TWF1/MKL1-SRF/IL11 signaling pathway sheds lights on the understanding of breast cancer initiation and progression, unveils new therapeutic targets, and facilitates innovative drug development to control cancer and block metastasis. Clin Cancer Res; 23(4); 1091-103. ©2016 AACR . ©2016 American Association for Cancer Research.

The Pentose Phosphate Pathway as a Potential Target for Cancer Therapy

PubMed Central

Cho, Eunae Sandra; Cha, Yong Hoon; Kim, Hyun Sil; Kim, Nam Hee; Yook, Jong In

2018-01-01

During cancer progression, cancer cells are repeatedly exposed to metabolic stress conditions in a resource-limited environment which they must escape. Increasing evidence indicates the importance of nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis in the survival of cancer cells under metabolic stress conditions, such as metabolic resource limitation and therapeutic intervention. NADPH is essential for scavenging of reactive oxygen species (ROS) mainly derived from oxidative phosphorylation required for ATP generation. Thus, metabolic reprogramming of NADPH homeostasis is an important step in cancer progression as well as in combinational therapeutic approaches. In mammalian, the pentose phosphate pathway (PPP) and one-carbon metabolism are major sources of NADPH production. In this review, we focus on the importance of glucose flux control towards PPP regulated by oncogenic pathways and the potential therein for metabolic targeting as a cancer therapy. We also summarize the role of Snail (Snai1), an important regulator of the epithelial mesenchymal transition (EMT), in controlling glucose flux towards PPP and thus potentiating cancer cell survival under oxidative and metabolic stress. PMID:29212304

Neural Representation of a Target Auditory Memory in a Cortico-Basal Ganglia Pathway

PubMed Central

Bottjer, Sarah W.

2013-01-01

Vocal learning in songbirds, like speech acquisition in humans, entails a period of sensorimotor integration during which vocalizations are evaluated via auditory feedback and progressively refined to achieve an imitation of memorized vocal sounds. This process requires the brain to compare feedback of current vocal behavior to a memory of target vocal sounds. We report the discovery of two distinct populations of neurons in a cortico-basal ganglia circuit of juvenile songbirds (zebra finches, Taeniopygia guttata) during vocal learning: (1) one in which neurons are selectively tuned to memorized sounds and (2) another in which neurons are selectively tuned to self-produced vocalizations. These results suggest that neurons tuned to learned vocal sounds encode a memory of those target sounds, whereas neurons tuned to self-produced vocalizations encode a representation of current vocal sounds. The presence of neurons tuned to memorized sounds is limited to early stages of sensorimotor integration: after learning, the incidence of neurons encoding memorized vocal sounds was greatly diminished. In contrast to this circuit, neurons known to drive vocal behavior through a parallel cortico-basal ganglia pathway show little selective tuning until late in learning. One interpretation of these data is that representations of current and target vocal sounds in the shell circuit are used to compare ongoing patterns of vocal feedback to memorized sounds, whereas the parallel core circuit has a motor-related role in learning. Such a functional subdivision is similar to mammalian cortico-basal ganglia pathways in which associative-limbic circuits mediate goal-directed responses, whereas sensorimotor circuits support motor aspects of learning. PMID:24005299

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

PubMed Central

Tang, Yujie; Gholamin, Sharareh; Schubert, Simone; Willardson, Minde I.; Lee, Alex; Bandopadhayay, Pratiti; Bergthold, Guillame; Masoud, Sabran; Nguyen, Brian; Vue, Nujsaubnusi; Balansay, Brianna; Yu, Furong; Oh, Sekyung; Woo, Pamelyn; Chen, Spenser; Ponnuswami, Anitha; Monje, Michelle; Atwood, Scott X.; Whitson, Ramon J.; Mitra, Siddhartha; Cheshier, Samuel H.; Qi, Jun; Beroukhim, Rameen; Tang, Jean Y.; Wechsler-Reya, Rob; Oro, Anthony E.; Link, Brian A.; Bradner, James E.; Cho, Yoon-Jae

2014-01-01

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. PMID:24973920

Chemical genomics: characterizing target pathways for bioactive compounds using the endomembrane trafficking network.

PubMed

Rodriguez-Furlán, Cecilia; Hicks, Glenn R; Norambuena, Lorena

2014-01-01

The plant endomembrane trafficking system is a highly complex set of processes. This complexity presents a challenge for its study. Classical plant genetics often struggles with loss-of-function lethality and gene redundancy. Chemical genomics allows overcoming many of these issues by using small molecules of natural or synthetic origin to inhibit specific trafficking proteins thereby affecting the processes in a tunable and reversible manner. Bioactive chemicals identified by high-throughput phenotype screens must be characterized in detail starting with understanding of the specific trafficking pathways affected. Here, we describe approaches to characterize bioactive compounds that perturb vesicle trafficking. This should equip researchers with practical knowledge on how to identify endomembrane-specific trafficking pathways that may be perturbed by specific compounds and will help to eventually identify molecular targets for these small molecules.

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

PubMed Central

Ferraldeschi, R; Welti, J; Luo, J; Attard, G; de Bono, JS

2015-01-01

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. PMID:24837363

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.

PubMed

Kamata, Shigeyuki; Kishimoto, Takashi; Kobayashi, Soichi; Miyazaki, Masaru; Ishikura, Hiroshi

2007-07-01

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.

Ibrutinib targets microRNA-21 in multiple myeloma cells by inhibiting NF-κB and STAT3.

PubMed

Ma, Jing; Gong, Wei; Liu, Su; Li, Qian; Guo, Mengzheng; Wang, Jinhan; Wang, Suying; Chen, Naiyao; Wang, Yafei; Liu, Qiang; Zhao, Hui

2018-01-01

The oncogenic microRNA-21 contributes to the pathogenesis of multiple myeloma. Ibrutinib (also referred to as PCI-32765), an inhibitor of Bruton's tyrosine kinase, while its effects on multiple myeloma have not been well described. Here, we show that microRNA-21 is an oncogenic marker closely linked with progression of multiple myeloma. Moreover, ibrutinib attenuates microRNA-21 expression in multiple myeloma cells by inhibiting nuclear factor-κB and signal transducer and activator of transcription 3 signaling pathways. Taken together, our results suggest that ibrutinib is a promising potential treatment for multiple myeloma. Further investigation of mechanisms of ibrutinib function in multiple myeloma will be necessary to evaluate its use as a novel multiple myeloma treatment.

Method for distinguishing multiple targets using time-reversal acoustics

DOEpatents

Berryman, James G.

2004-06-29

A method for distinguishing multiple targets using time-reversal acoustics. Time-reversal acoustics uses an iterative process to determine the optimum signal for locating a strongly reflecting target in a cluttered environment. An acoustic array sends a signal into a medium, and then receives the returned/reflected signal. This returned/reflected signal is then time-reversed and sent back into the medium again, and again, until the signal being sent and received is no longer changing. At that point, the array has isolated the largest eigenvalue/eigenvector combination and has effectively determined the location of a single target in the medium (the one that is most strongly reflecting). After the largest eigenvalue/eigenvector combination has been determined, to determine the location of other targets, instead of sending back the same signals, the method sends back these time reversed signals, but half of them will also be reversed in sign. There are various possibilities for choosing which half to do sign reversal. The most obvious choice is to reverse every other one in a linear array, or as in a checkerboard pattern in 2D. Then, a new send/receive, send-time reversed/receive iteration can proceed. Often, the first iteration in this sequence will be close to the desired signal from a second target. In some cases, orthogonalization procedures must be implemented to assure the returned signals are in fact orthogonal to the first eigenvector found.

Proteome-wide prediction of targets for aspirin: new insight into the molecular mechanism of aspirin

PubMed Central

Dai, Shao-Xing; Li, Wen-Xing

2016-01-01

Besides its anti-inflammatory, analgesic and anti-pyretic properties, aspirin is used for the prevention of cardiovascular disease and various types of cancer. The multiple activities of aspirin likely involve several molecular targets and pathways rather than a single target. Therefore, systematic identification of these targets of aspirin can help us understand the underlying mechanisms of the activities. In this study, we identified 23 putative targets of aspirin in the human proteome by using binding pocket similarity detecting tool combination with molecular docking, free energy calculation and pathway analysis. These targets have diverse folds and are derived from different protein family. However, they have similar aspirin-binding pockets. The binding free energy with aspirin for newly identified targets is comparable to that for the primary targets. Pathway analysis revealed that the targets were enriched in several pathways such as vascular endothelial growth factor (VEGF) signaling, Fc epsilon RI signaling and arachidonic acid metabolism, which are strongly involved in inflammation, cardiovascular disease and cancer. Therefore, the predicted target profile of aspirin suggests a new explanation for the disease prevention ability of aspirin. Our findings provide a new insight of aspirin and its efficacy of disease prevention in a systematic and global view. PMID:26989626

Proteome-wide prediction of targets for aspirin: new insight into the molecular mechanism of aspirin.

PubMed

Dai, Shao-Xing; Li, Wen-Xing; Li, Gong-Hua; Huang, Jing-Fei

2016-01-01

Besides its anti-inflammatory, analgesic and anti-pyretic properties, aspirin is used for the prevention of cardiovascular disease and various types of cancer. The multiple activities of aspirin likely involve several molecular targets and pathways rather than a single target. Therefore, systematic identification of these targets of aspirin can help us understand the underlying mechanisms of the activities. In this study, we identified 23 putative targets of aspirin in the human proteome by using binding pocket similarity detecting tool combination with molecular docking, free energy calculation and pathway analysis. These targets have diverse folds and are derived from different protein family. However, they have similar aspirin-binding pockets. The binding free energy with aspirin for newly identified targets is comparable to that for the primary targets. Pathway analysis revealed that the targets were enriched in several pathways such as vascular endothelial growth factor (VEGF) signaling, Fc epsilon RI signaling and arachidonic acid metabolism, which are strongly involved in inflammation, cardiovascular disease and cancer. Therefore, the predicted target profile of aspirin suggests a new explanation for the disease prevention ability of aspirin. Our findings provide a new insight of aspirin and its efficacy of disease prevention in a systematic and global view.

Nanoparticles that Communicate In Vivo to Amplify Tumour Targeting

PubMed Central

von Maltzahn, Geoffrey; Park, Ji-Ho; Lin, Kevin Y.; Singh, Neetu; Schwöppe, Christian; Mesters, Rolf; Berdel, Wolfgang E.; Ruoslahti, Erkki; Sailor, Michael J.; Bhatia, Sangeeta N.

2012-01-01

Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability for communication to improve targeting in biological systems, such inflammatory cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of ‘Signalling’ modules (nanoparticles or engineered proteins) that target tumours and then locally active the coagulation cascade to broadcast tumour location to clot-targeted ‘Receiving’ nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed from multiple types of Signalling and Receiving modules, can transmit information via multiple molecular pathways in coagulation, can operate autonomously, and can target over 40-fold higher doses of chemotherapeutics to tumours than non-communicating controls. PMID:21685903

Nanoparticles that communicate in vivo to amplify tumour targeting

NASA Astrophysics Data System (ADS)

von Maltzahn, Geoffrey; Park, Ji-Ho; Lin, Kevin Y.; Singh, Neetu; Schwöppe, Christian; Mesters, Rolf; Berdel, Wolfgang E.; Ruoslahti, Erkki; Sailor, Michael J.; Bhatia, Sangeeta N.

2011-07-01

Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability of communication to improve targeting in biological systems, such as inflammatory-cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of ‘signalling’ modules (nanoparticles or engineered proteins) that target tumours and then locally activate the coagulation cascade to broadcast tumour location to clot-targeted ‘receiving’ nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed of multiple types of signalling and receiving modules, can transmit information through multiple molecular pathways in coagulation, can operate autonomously and can target over 40 times higher doses of chemotherapeutics to tumours than non-communicating controls.

Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells.

PubMed

Ali, Dalia; Abuelreich, Sarah; Alkeraishan, Nora; Shwish, Najla Bin; Hamam, Rimi; Kassem, Moustapha; Alfayez, Musaad; Aldahmash, Abdullah; Alajez, Nehad M

2018-02-28

Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profiling during adipocyte differentiation of human bone marrow stromal (mesenchymal) stem cells (hMSCs) and identified 2,589 up-regulated and 2,583 down-regulated mRNA transcripts. Pathway analysis on the up-regulated gene list untraveled enrichment in multiple signaling pathways including insulin receptor signaling, focal Adhesion, metapathway biotransformation, a number of metabolic pathways e.g. selenium metabolism, Benzo(a)pyrene metabolism, fatty acid, triacylglycerol, ketone body metabolism, tryptophan metabolism, and catalytic cycle of mammalian flavin-containing monooxygenase (FMOs). On the other hand, pathway analysis on the down-regulated genes revealed significant enrichment in pathways related to cell cycle regulation. Based on these data, we assessed the effect of pharmacological inhibition of FAK signaling using PF-573228, PF-562271, and InsR/IGF-1R using NVP-AEW541 and GSK-1904529A on adipocyte differentiation. hMSCs exposed to FAK or IGF-1R/InsR inhibitors exhibited fewer adipocyte formation (27-58% inhibition, P <0005). Concordantly, the expression of adipocyte-specific genes AP2, AdipoQ, and CEBPα was significantly reduced. On the other hand, we did not detect significant effects on cell viability as a result of FAK or IGF-1R/InsR inhibition. Our data identified FAK and insulin signaling as important intracellular signaling pathways relevant to bone marrow adipogenesis. © 2018 The Author(s).

Targeting key proximal drivers of type 2 inflammation in disease.

PubMed

Gandhi, Namita A; Bennett, Brandy L; Graham, Neil M H; Pirozzi, Gianluca; Stahl, Neil; Yancopoulos, George D

2016-01-01

Systemic type 2 inflammation encompassing T helper 2 (TH2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the TH2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines - interleukin-4 (IL-4), IL-5 and IL-13 - represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL-4, IL-5 or IL-13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an 'allergic' phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL-4 and IL-13 has shown significant clinical activity in diseases that are often co-morbid with asthma - atopic dermatitis and chronic sinusitis with nasal polyps - supporting the hypothesis that targeting a central 'driver pathway' could benefit multiple allergic diseases.