Strategies that Target Leukocyte Traffic in IBD: Recent Developments

PubMed Central

Rivera-Nieves, Jesús

2015-01-01

Purpose of review We review the most recent developments regarding the targeting of molecules involved in the traffic of leukocytes for the treatment of IBD. Recent Findings We discuss the most important findings of one published phase II trial that targeted the β7 integrin (Etrolizumab), two phase II trials that targeted the α4β7 integrin ligand: Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1, PF-00547659), a phase II targeting the chemokine IP-10 (CXCL10) in Crohn’s and a phase II trial that targeted the sphingosine-1-phosphate receptor-1 (S1P1): ozanimod in patients with ulcerative colitis (UC). Summary Targeting molecules involved in leukocyte traffic has recently become an effective and safe strategy for the treatment of IBD. Novel approaches now not only target the integrins on the lymphocyte surface, but also its endothelial ligand: MAdCAM-1. As with vedolizumab, antibodies against MAdCAM-1 appear most effective in ulcerative colitis rather than in Crohn’s. Targeting chemokines or their receptors does not appear to have the same efficacy as those that target the most stable integrin:immunoglobulin superfamily interactions between the lymphocyte and endothelium. Preliminary results also suggest that the sphingosine-1-phosphate pathway might also be targeted therapeutically in IBD, no longer with parenterally administered antibodies but with orally administered small molecules. PMID:26398681

The impact of molecular targets in cancer drug development: major hurdles and future strategies.

PubMed

Hebar, Alexandra; Valent, Peter; Selzer, Edgar

2013-01-01

The last decades were characterized by enormous technological advances resulting in a better understanding of disease pathologies and improvement of treatment strategies. The development of targeted drugs, whose beginning can be traced back to Paul Ehrlich's theory of the 'magic bullet' approximately 100 years ago, is today widely appraised as a promising strategy to combat benign, as well as malignant, diseases. Over 40 years after US President Nixon declared the 'war on cancer', treatment outcome, especially of solid tumors in the advanced stages of disease, still lies far behind expectations. In this perspective article, the authors discuss the recent development of targeted cancer drugs and identify major hurdles. The authors further highlight future strategies that might improve and accelerate the drug-development process.

Novel therapeutic Strategies for Targeting Liver Cancer Stem Cells

PubMed Central

Oishi, Naoki; Wang, Xin Wei

2011-01-01

The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment. Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC. Here we provide a brief review of

Novel treatment strategies for brain tumors and metastases

PubMed Central

El-Habashy, Salma E.; Nazief, Alaa M.; Adkins, Chris E.; Wen, Ming Ming; El-Kamel, Amal H.; Hamdan, Ahmed M.; Hanafy, Amira S.; Terrell, Tori O.; Mohammad, Afroz S.; Lockman, Paul R.; Nounou, Mohamed Ismail

2015-01-01

This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application. PMID:24998288

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies.

PubMed

Mangraviti, Antonella; Gullotti, David; Tyler, Betty; Brem, Henry

2016-10-28

Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the impedance of the blood brain barrier (BBB), and the lack of therapeutic agents that can selectively target the intracranial tumor environment. To overcome such barriers, a number of chemotherapeutic agents and nucleic acid-based therapies are rapidly being synthesized and tested as new brain tumor-targeted delivery strategies. Novel carriers include liposomal and polymeric nanoparticles, wafers, microchips, microparticle-based nanoplatforms and cells-based vectors. Strong preclinical results suggest that these nanotechnologies are set to transform the therapeutic paradigm for brain tumor treatment. In addition to new tumoricidal agents, parallel work is also being conducted on the BBB front. Preclinical testing of chemical and physical modulation strategies is yielding improved intracranial concentrations. New diagnostic and therapeutic imaging techniques, such as high-intensity focused ultrasound and MRI-guided focused ultrasound, are being used to modulate the BBB in a more precise and non-invasive manner. This review details some of the tremendous advances that are being explored in current brain tumor targeted therapies, including local implant development, nanobiotechnology-based delivery strategies, and techniques of BBB manipulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases.

PubMed

Al-Bari, Md Abdul Alim

2017-02-01

Emerging viruses such as HIV, dengue, influenza A, SARS coronavirus, Ebola, and other viruses pose a significant threat to human health. Majority of these viruses are responsible for the outbreaks of pathogenic lethal infections. To date, there are no effective therapeutic strategies available for the prophylaxis and treatment of these infections. Chloroquine analogs have been used for decades as the primary and most successful drugs against malaria. Concomitant with the emergence of chloroquine-resistant Plasmodium strains and a subsequent decrease in the use as antimalarial drugs, other applications of the analogs have been investigated. Since the analogs have interesting biochemical properties, these drugs are found to be effective against a wide variety of viral infections. As antiviral action, the analogs have been shown to inhibit acidification of endosome during the events of replication and infection. Moreover, immunomodulatory effects of analogs have been beneficial to patients with severe inflammatory complications of several viral diseases. Interestingly, one of the successful targeting strategies is the inhibition of HIV replication by the analogs in vitro which are being tested in several clinical trials. This review focuses on the potentialities of chloroquine analogs for the treatment of endosomal low pH dependent emerging viral diseases.

Nanomedicine strategies for sustained, controlled, and targeted treatment of cancer stem cells of the digestive system.

PubMed

Xie, Fang-Yuan; Xu, Wei-Heng; Yin, Chuan; Zhang, Guo-Qing; Zhong, Yan-Qiang; Gao, Jie

2016-10-15

Cancer stem cells (CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability. They have been identified in a variety of tumors, including tumors of the digestive system. CSCs exhibit some unique characteristics, which are responsible for cancer metastasis and recurrence. Consequently, the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy. Several potential approaches to target CSCs of the digestive system have been explored, including targeting CSC surface markers and signaling pathways, inducing the differentiation of CSCs, altering the tumor microenvironment or niche, and inhibiting ATP-driven efflux transporters. However, conventional therapies may not successfully eradicate CSCs owing to various problems, including poor solubility, stability, rapid clearance, poor cellular uptake, and unacceptable cytotoxicity. Nanomedicine strategies, which include drug, gene, targeted, and combinational delivery, could solve these problems and significantly improve the therapeutic index. This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.

Nanomedicine strategies for sustained, controlled, and targeted treatment of cancer stem cells of the digestive system

PubMed Central

Xie, Fang-Yuan; Xu, Wei-Heng; Yin, Chuan; Zhang, Guo-Qing; Zhong, Yan-Qiang; Gao, Jie

2016-01-01

Cancer stem cells (CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability. They have been identified in a variety of tumors, including tumors of the digestive system. CSCs exhibit some unique characteristics, which are responsible for cancer metastasis and recurrence. Consequently, the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy. Several potential approaches to target CSCs of the digestive system have been explored, including targeting CSC surface markers and signaling pathways, inducing the differentiation of CSCs, altering the tumor microenvironment or niche, and inhibiting ATP-driven efflux transporters. However, conventional therapies may not successfully eradicate CSCs owing to various problems, including poor solubility, stability, rapid clearance, poor cellular uptake, and unacceptable cytotoxicity. Nanomedicine strategies, which include drug, gene, targeted, and combinational delivery, could solve these problems and significantly improve the therapeutic index. This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system. PMID:27795813

Targeted flock/herd and individual ruminant treatment approaches.

PubMed

Kenyon, F; Jackson, F

2012-05-04

In Europe, most nematodoses are subclinical involving morbid rather than mortal effects and control is largely achieved using anthelmintics. In cattle, the genera most associated with sub-optimal performance are Ostertagia and Cooperia whereas in sheep and goats, subclinical losses are most often caused by Teladorsagia and Trichostrongylus. In some regions, at certain times, other species such as Nematodirus and Haemonchus also cause disease in sheep and goats. Unfortunately, anthelmintic resistance has now become an issue for European small ruminant producers. One of the key aims of the EU-funded PARASOL project was to identify low input and sustainable approaches to control nematode parasites in ruminants using refugia-based strategies. Two approaches to optimise anthelmintic treatments in sheep and cattle were studied; targeted treatments (TT) - whole-group treatments optimised on the basis of a marker of infection e.g. faecal egg count (FEC), and targeted selected treatment (TST) - treatments given to identified individuals to provide epidemiological and/or production benefits. A number of indicators for TT and TST were assessed to define parasitological and production-system specific indicators for treatment that best suited the regions where the PARASOL studies were conducted. These included liveweight gain, production efficiency, FEC, body condition score and diarrhoea score in small ruminants, and pepsinogen levels and Ostertagia bulk milk tank ELISA in cattle. The PARASOL studies confirmed the value of monitoring FEC as a means of targeting whole-flock treatments in small ruminants. In cattle, bulk milk tank ELISA and serum pepsinogen assays could be used retrospectively to determine the levels of exposure and hence, in the next season to optimise anthelmintic usage. TST approaches in sheep and goats examined production efficiency and liveweight gain as indicators for treatment and confirmed the value of this approach in maintaining performance and

Cancer Nanotechnology: Recent Trends and Developments in Strategies for Targeting Cancer Cells to Improve Cancer Imaging and Treatment.

PubMed

Xu, Jingyao; Zhou, Xiaoling; Li, Yifei; Tian, Yudan

2017-01-01

Nanotechnology is a multidisciplinary field, which have the potential to cover applications in many subjects such as biology, chemistry and physics. The combined efforts of these subjects can lead to the successful engineering of nanodevices and nanovectors for targeted delivery and sensing/detection of cancer cells/tissues. The modulation of nanomaterials at surface and bulk level further adds value to this technology and develop strategies for early detection of precancerous and malignant cells from biological fluids. Furthermore, the novel nanotechnology-based imaging modalities have the prospects to offer non-invasive cancer imaging and treatment response study in real-time. This review covers the advantages of nanotechnology, which have been exploited for effective and targeted delivery of anti-cancer agents. Moreover, the initiatives taken by National Cancer Laboratory, USA to improve the clinical success of nanomedicines and nanovectors have also been comprehensively summarized. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Optimization of a Nanomedicine-based Pc 4-PDT Strategy for Targeted Treatment of EGFR-Overexpressing Cancers

PubMed Central

Master, Alyssa M.; Livingston, Megan; Oleinick, Nancy L.; Gupta, Anirban Sen

2012-01-01

The current clinical mainstays for cancer treatment, namely, surgical resection, chemotherapy and radiotherapy, can cause significant trauma, systemic toxicity, and functional/cosmetic debilitation of tissue, especially if repetitive treatment becomes necessary due to tumor recurrence. Hence there is significant clinical interest in alternate treatment strategies like photodynamic therapy (PDT) which can effectively and selectively eradicate tumors and can be safely repeated if needed. We have previously demonstrated that the second-generation photosensitizer Pc 4 can be formulated within polymeric micelles, and these micelles can be specifically targeted to EGFR-overexpressing cancer cells using GE11 peptide ligands, to enhance cell-specific Pc 4 delivery and internalization. In the current study, we report on the in vitro optimization of the EGFR-targeting, Pc 4 loading of the micellar nanoformulation, along with optimization of the corresponding photoirradiation conditions to maximize Pc 4 delivery, internalization and subsequent PDT-induced cytotoxicity in EGFR-overexpressing cells in vitro. In our studies, absorption and fluorescence spectroscopy were used to monitor the cell-specific uptake of the GE11-decorated Pc 4-loaded micelles and the cytotoxic singlet oxygen production from the micelle-encapsulated Pc 4, to determine the optimum ligand density and Pc 4 loading. It was found that the micelle formulations bearing 10 mole% of GE11-modified polymer component resulted in the highest cellular uptake in EGFR-overexpressing A431 cells within the shortest incubation periods. Also, the loading of ~50 μg Pc 4 per mg of polymer in these micellar formulations resulted in the highest levels of singlet oxygen production. When formulations bearing these optimized parameters were tested in vitro on A431 cells for PDT effect, a formulation dose containing 400 nM Pc 4 and photoirradiation duration of 400 seconds at a fluence of 200 mJ/cm2 yielded close to 100% cell

Space based lidar shot pattern targeting strategies for small targets such as streams

NASA Technical Reports Server (NTRS)

Spiers, Gary D.

2001-01-01

An analysis of the effectiveness of four different types of lidar shot distribution is conducted to determine which is best for concentrating shots in a given location. A simple preemptive targeting strategy is found to work as adequately as a more involved dynamic strategy for most target sizes considered.

Strategies that target leukocyte traffic in inflammatory bowel diseases: recent developments.

PubMed

Rivera-Nieves, Jesús

2015-11-01

We review the most recent developments regarding the targeting of molecules involved in the traffic of leukocytes for the treatment of inflammatory bowel diseases (IBD). We discuss the most important findings of one published phase II trial that targeted the β7 integrin (etrolizumab), two phase II trials that targeted the α4β7 integrin ligand: mucosal addressin cell adhesion molecule 1 (MAdCAM-1, PF-00547659), a phase II trial targeting the chemokine IP-10 (CXCL10) in Crohn's, and a phase II trial that targeted the sphingosine-1-phosphate receptor-1: ozanimod in patients with ulcerative colitis. Targeting molecules involved in leukocyte traffic has recently become an effective and well tolerated strategy for the treatment of IBD. Novel approaches now not only target the integrins on the lymphocyte surface, but also its endothelial ligand: MAdCAM-1. As with vedolizumab, antibodies against MAdCAM-1 appear most effective in ulcerative colitis rather than in Crohn's. Targeting chemokines or their receptors does not appear to have the same efficacy as those that target the most stable integrin: immunoglobulin superfamily interactions between the lymphocyte and endothelium. Preliminary results also suggest that the sphingosine-1-phosphate pathway might also be targeted therapeutically in IBD, no longer with parenterally administered antibodies but with orally administered small molecules.

A review of the ligands and related targeting strategies for active targeting of paclitaxel to tumours.

PubMed

Li, Juan; Wang, Fengshan; Sun, Deqing; Wang, Rongmei

2016-08-01

It has been 30 years since the discovery of the anti-tumour property of paclitaxel (PTX), which has been successfully applied in clinic for the treatment of carcinomas of the lungs, breast and ovarian. However, PTX is poorly soluble in water and has no targeting and selectivity to tumour tissue. Recent advances in active tumour targeting of PTX delivery vehicles have addressed some of the issues related to lack of solubility in water and non-specific toxicities associated with PTX. These PTX delivery vehicles are designed for active targeting to specific cancer cells by the addition of ligands for recognition by specific receptors/antigens on cancer cells. This article will focus on various ligands and related targeting strategies serving as potential tools for active targeting of PTX to tumour tissues, illustrating their use in different tumour models. This review also highlights the need of further studies on the discovery of receptors in different cells of specific organ and ligands with binding efficiency to these specific receptors.

An innovative pre-targeting strategy for tumor cell specific imaging and therapy

NASA Astrophysics Data System (ADS)

Qin, Si-Yong; Peng, Meng-Yun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Cheng, Si-Xue; Feng, Jun; Zhang, Xian-Zheng

2015-08-01

A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging

Multistage Targeting Strategy Using Magnetic Composite Nanoparticles for Synergism of Photothermal Therapy and Chemotherapy.

PubMed

Wang, Yi; Wei, Guoqing; Zhang, Xiaobin; Huang, Xuehui; Zhao, Jingya; Guo, Xing; Zhou, Shaobing

2018-03-01

Mitochondrial-targeting therapy is an emerging strategy for enhanced cancer treatment. In the present study, a multistage targeting strategy using doxorubicin-loaded magnetic composite nanoparticles is developed for enhanced efficacy of photothermal and chemical therapy. The nanoparticles with a core-shell-SS-shell architecture are composed of a core of Fe 3 O 4 colloidal nanocrystal clusters, an inner shell of polydopamine (PDA) functionalized with triphenylphosphonium (TPP), and an outer shell of methoxy poly(ethylene glycol) linked to the PDA by disulfide bonds. The magnetic core can increase the accumulation of nanoparticles at the tumor site for the first stage of tumor tissue targeting. After the nanoparticles enter the tumor cells, the second stage of mitochondrial targeting is realized as the mPEG shell is detached from the nanoparticles by redox responsiveness to expose the TPP. Using near-infrared light irradiation at the tumor site, a photothermal effect is generated from the PDA photosensitizer, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the loaded doxorubicin can rapidly enter the mitochondria and subsequently damage the mitochondrial DNA, resulting in cell apoptosis. Thus, the synergism of photothermal therapy and chemotherapy targeting the mitochondria significantly enhances the cancer treatment. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantitative proteomics in cardiovascular research: global and targeted strategies

PubMed Central

Shen, Xiaomeng; Young, Rebeccah; Canty, John M.; Qu, Jun

2014-01-01

Extensive technical advances in the past decade have substantially expanded quantitative proteomics in cardiovascular research. This has great promise for elucidating the mechanisms of cardiovascular diseases (CVD) and the discovery of cardiac biomarkers used for diagnosis and treatment evaluation. Global and targeted proteomics are the two major avenues of quantitative proteomics. While global approaches enable unbiased discovery of altered proteins via relative quantification at the proteome level, targeted techniques provide higher sensitivity and accuracy, and are capable of multiplexed absolute quantification in numerous clinical/biological samples. While promising, technical challenges need to be overcome to enable full utilization of these techniques in cardiovascular medicine. Here we discuss recent advances in quantitative proteomics and summarize applications in cardiovascular research with an emphasis on biomarker discovery and elucidating molecular mechanisms of disease. We propose the integration of global and targeted strategies as a high-throughput pipeline for cardiovascular proteomics. Targeted approaches enable rapid, extensive validation of biomarker candidates discovered by global proteomics. These approaches provide a promising alternative to immunoassays and other low-throughput means currently used for limited validation. PMID:24920501

Pharmacological and Physical Vessel Modulation Strategies to Improve EPR-mediated Drug Targeting to Tumors

PubMed Central

Ojha, Tarun; Pathak, Vertika; Shi, Yang; Hennink, Wim; Moonen, Chrit; Storm, Gert; Kiessling, Fabian; Lammers, Twan

2018-01-01

The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines. PMID:28697952

Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors.

PubMed

Ojha, Tarun; Pathak, Vertika; Shi, Yang; Hennink, Wim E; Moonen, Chrit T W; Storm, Gert; Kiessling, Fabian; Lammers, Twan

2017-09-15

The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Tumor-targeted inhibition by a novel strategy - mimoretrovirus expressing siRNA targeting the Pokemon gene.

PubMed

Tian, Zhiqiang; Wang, Huaizhi; Jia, Zhengcai; Shi, Jinglei; Tang, Jun; Mao, Liwei; Liu, Hongli; Deng, Yijing; He, Yangdong; Ruan, Zhihua; Li, Jintao; Wu, Yuzhang; Ni, Bing

2010-12-01

Pokemon gene has crucial but versatile functions in cell differentiation, proliferation and tumorigenesis. It is a master regulator of the ARF-HDM2-p53 and Rb-E2F pathways. The facts that the expression of Pokemon is essential for tumor formation and many kinds of tumors over-express the Pokemon gene make it an attractive target for therapeutic intervention for cancer treatment. In this study, we used an RNAi strategy to silence the Pokemon gene in a cervical cancer model. To address the issues involving tumor specific delivery and durable expression of siRNA, we applied the Arg-Gly-Asp (RGD) peptide ligand and polylysine (K(18)) fusion peptide to encapsulate a recombinant retrovirus plasmid expressing a siRNA targeting the Pokemon gene and produced the 'mimoretrovirus'. At charge ratio 2.0 of fusion peptide/plasmid, the mimoretrovirus formed stable and homogenous nanoparticles, and provided complete DNase I protection and complete gel retardation. This nanoparticle inhibited SiHa cell proliferation and invasion, while it promoted SiHa cell apoptosis. The binding of the nanoparticle to SiHa cells was mediated via the RGD-integrin α(v)β(3) interaction, as evidenced by the finding that unconjugated RGD peptide inhibited this binding significantly. This tumor-targeting mimoretrovirus exhibited excellent anti-tumor capacity in vivo in a nude mouse model. Moreover, the mimoretrovirus inhibited tumor growth with a much higher efficiency than recombinant retrovirus expressing siRNA or the K(18)/P4 nanoparticle lacking the RGD peptide. Results suggest that the RNAi/RGD-based mimoretrovirus developed in this study represents a novel anti-tumor strategy that may be applicable to most research involving cancer therapy and, thus, has promising potential as a cervical cancer treatment.

Mass Media Strategies Targeting High Sensation Seekers: What Works and Why

ERIC Educational Resources Information Center

Stephenson, Michael T.

2003-01-01

Objectives: To examine strategies for using the mass media effectively in drug prevention campaigns targeting high sensation seekers. Methods: Both experimental lab and field studies were used to develop a comprehensive audience segmentation strategy targeting high sensation seekers. Results: A 4-pronged targeting strategy employed in an…

Target marketing strategies for occupational therapy entrepreneurs.

PubMed

Kautzmann, L N; Kautzmann, F N; Navarro, F H

1989-01-01

Understanding marketing techniques is one of the skills needed by successful entre renews. Target marketing is an effective method for occupational therapy entrepreneurs to use in determining when and where to enter the marketplace. The two components of target marketing, market segmentation and the development of marketing mix strategies for each identified market segment, are described. The Profife of Attitudes Toward Health Care (PATH) method of psychographic market segmentation of health care consumers is presented. Occupational therapy marketing mix strategies for each PATH consumer group are delineated and compatible groupings of market segments are suggested.

Targeting microbial biofilms: current and prospective therapeutic strategies

PubMed Central

Koo, Hyun; Allan, Raymond N; Howlin, Robert P; Hall-Stoodley, Luanne; Stoodley, Paul

2017-01-01

Biofilm formation is a key virulence factor for a wide range of microorganisms that cause chronic infections. The multifactorial nature of biofilm development and drug tolerance imposes great challenges for the use of conventional antimicrobials, and indicates the need for multi-targeted or combinatorial therapies. In this review, we focus on current therapeutic strategies and those that are under development that target vital structural and functional traits of microbial biofilms and drug tolerance mechanisms, including the extracellular matrix and dormant cells. We emphasize strategies that are supported by in vivo or ex vivo studies, highlight emerging biofilm-targeting technologies, and provide a rationale for multi-targeted therapies that are aimed at disrupting the complex biofilm microenvironment. PMID:28944770

Proteolysis targeting peptide (PROTAP) strategy for protein ubiquitination and degradation.

PubMed

Zheng, Jing; Tan, Chunyan; Xue, Pengcheng; Cao, Jiakun; Liu, Feng; Tan, Ying; Jiang, Yuyang

2016-02-19

Ubiquitination proteasome pathway (UPP) is the most important and selective way to degrade proteins in vivo. Here, a novel proteolysis targeting peptide (PROTAP) strategy, composed of a target protein binding peptide, a linker and a ubiquitin E3 ligase recognition peptide, was designed to recruit both target protein and E3 ligase and then induce polyubiquitination and degradation of the target protein through UPP. In our study, the PROTAP strategy was proved to be a general method with high specificity using Bcl-xL protein as model target in vitro and in cells, which indicates that the strategy has great potential for in vivo application. Copyright © 2016 Elsevier Inc. All rights reserved.

An innovative pre-targeting strategy for tumor cell specific imaging and therapy.

PubMed

Qin, Si-Yong; Peng, Meng-Yun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Cheng, Si-Xue; Feng, Jun; Zhang, Xian-Zheng

2015-09-21

A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the "biotin-avidin" interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.

Targeting the host-pathogen interface for treatment of Staphylococcus aureus infection.

PubMed

Park, Bonggoo; Liu, George Y

2012-03-01

Recent emergence of methicillin-resistant Staphylococcus aureus both within and outside healthcare settings has accelerated the use of once reserved last line antibiotics such as vancomycin. With increased use of antibiotics, there has been a rapid rise in the rate of resistance development to the anti-MRSA drugs. As the antibiotic pipeline becomes strained, alternative strategies are being sought for future treatment of S. aureus. Here, we review several novel anti-staphylococcal strategies that, unlike conventional antibiotics, do not target essential gene products elaborated by the pathogen. The approaches seek instead to weaken the S. aureus defense by neutralizing its virulence factors or boosting host immunity. Other strategies target commensal bacteria that naturally colonize the human host to inhibit S. aureus colonization. Ultimately, the aim is to shift the balance between host defense and pathogen virulence in favor of inhibition of S. aureus pathogenic activities.

Targeted treatments for fragile X syndrome.

PubMed

Berry-Kravis, Elizabeth; Knox, Andrew; Hervey, Crystal

2011-09-01

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders.

Prodrug strategy for cancer cell-specific targeting: A recent overview.

PubMed

Zhang, Xian; Li, Xiang; You, Qidong; Zhang, Xiaojin

2017-10-20

The increasing development of targeted cancer therapy provides extensive possibilities in clinical trials, and numerous strategies have been explored. The prodrug is one of the most promising strategies in targeted cancer therapy to improve the selectivity and efficacy of cytotoxic compounds. Compared with normal tissues, cancer cells are characterized by unique aberrant markers, thus inactive prodrugs targeting these markers are excellent therapeutics to release active drugs, killing cancer cells without damaging normal tissues. In this review, we explore an integrated view of potential prodrugs applied in targeted cancer therapy based on aberrant cancer specific markers and some examples are provided for inspiring new ideas of prodrug strategy for cancer cell-specific targeting. Copyright © 2017. Published by Elsevier Masson SAS.

Voyager 1 Saturn targeting strategy

NASA Technical Reports Server (NTRS)

Cesarone, R. J.

1980-01-01

A trajectory targeting strategy for the Voyager 1 Saturn encounter has been designed to accomodate predicted uncertainties in Titan's ephemeris while maximizing spacecraft safety and science return. The encounter is characterized by a close Titan flyby 18 hours prior to Saturn periapse. Retargeting of the nominal trajectory to account for late updates in Titan's estimated position can disperse the ascending node location, which is nominally situated at a radius of low expected particle density in Saturn's ring plane. The strategy utilizes a floating Titan impact vector magnitude to minimize this dispersion. Encounter trajectory characteristics and optimal tradeoffs are presented.

Mutation testing for directing upfront targeted therapy and post-progression combination therapy strategies in lung adenocarcinoma

PubMed Central

Salgia, Ravi

2016-01-01

ABSTRACT Introduction: Advances in the biology of non-small-cell lung cancer, especially adenocarcinoma, reveal multiple molecular subtypes driving oncogenesis. Accordingly, individualized targeted therapeutics are based on mutational diagnostics. Areas covered: Advances in strategies and techniques for individualized treatment, particularly of adenocarcinoma, are described through literature review. Approved therapies are established for some molecular subsets, with new driver mutations emerging that represent increasing proportions of patients. Actionable mutations are de novo oncogenic drivers or acquired resistance mediators, and mutational profiling is important for directing therapy. Patients should be monitored for emerging actionable resistance mutations. Liquid biopsy and associated multiplex diagnostics will be important means to monitor patients during treatment. Expert commentary: Outcomes with targeted agents may be improved by integrating mutation screens during treatment to optimize subsequent therapy. In order for this to be translated into impactful patient benefit, appropriate platforms and strategies need to be optimized and then implemented universally. PMID:27139190

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

Bioinspired Gold Nanorod Functionalization Strategies for MUC1-Targeted Imaging and Photothermal Therapy

NASA Astrophysics Data System (ADS)

Zelasko-Leon, Daria Cecylia

The majority of cancers diagnosed in 2016 are epithelial in origin, constituting 85% of all new cases and predicted to account for 78% of all cancer deaths this year. Given these statistics, improving patient outcomes by providing personalized, multimodal, and minimally invasive medical interventions is critically needed. Mucin 1 (MUC1), a transmembrane glycoprotein, extends over 100 nm from cell membranes and is a key marker promoting epithelial carcinogenesis. Due to its antenna-like manifestation, MUC1 is a unique yet underexplored candidate for targeted cancer therapy, with overexpression in >64% of epithelial cancers. To overcome the limitations of existing treatment strategies for epithelial cancer, this dissertation describes a novel platform for nanomedicine, highlighting bioinspired modifications of gold nanorod (AuNR) surfaces for diagnostic cancer imaging and photothermal therapy. An ongoing challenge in the field of nanomedicine is the need for simple and effective strategies for simple surface modification of nanoparticles to facilitate targeting and enhance efficacy. Here, biofunctionalization of AuNRs was achieved with polydopamine (PD) and tannic acid (TA), polyphenolic compounds found in the marine mussel and throughout the plant kingdom that exhibit promiscuous interfacial binding properties. AuNR stabilization was achieved via PD or TA coatings followed by secondary modification with the serum protein, bovine serum albumin (BSA), or glycoprotein-mimetic polymers. The resultant constructs demonstrated good biocompatibility, enabled diagnostic imaging, and facilitated MUC1-specific photothermal treatment of breast and oral cancer cells. The in vivo performance of BSA and PD modified AuNRs was evaluated in two orthotopic animal models of breast cancer. Clinically relevant hyperthermia and high response rates with MUC1-targeted formulations were found, with significant enhancement of progression-free survival and several complete tumor regressions

Kawasaki Disease: Etiopathogenesis and Novel Treatment Strategies

PubMed Central

Agarwal, Shreya; Agrawal, Devendra K.

2017-01-01

Introduction Kawasaki disease is an acute febrile systemic vasculitis that predominantly occurs in children below five years of age. Its etiopathogenesis is still not clear, but it is thought to be a complex interplay of genetic factors, infections and immunity. Areas covered This review article discusses in detail Kawasaki disease, with particular emphasis on the recent updates on its pathogenesis and upcoming alternate treatment options. Though self-limiting in many cases, it can lead to severe complications like coronary artery aneurysms and thrombo-embolic occlusions, and hence requires early diagnosis and urgent attention to avoid them. Intravenous immunoglobulin (IVIG) with or without aspirin has remained the sole treatment option for these cases, but 10-15% cases develop resistance to this treatment. Expert Commentary There is a need to develop additional treatment strategies for children with Kawasaki disease. Targeting different steps of pathogenesis could provide us with alternate therapeutic options. PMID:27590181

In Search of New Therapeutic Targets in Obesity Treatment: Sirtuins

PubMed Central

Kurylowicz, Alina

2016-01-01

Most of the available non-invasive medical therapies for obesity are non-efficient in a long-term evaluation; therefore there is a constant need for new methods of treatment. Research on calorie restriction has led to the discovery of sirtuins (silent information regulators, SIRTs), enzymes regulating different cellular pathways that may constitute potential targets in the treatment of obesity. This review paper presents the role of SIRTs in the regulation of glucose and lipid metabolism as well as in the differentiation of adipocytes. How disturbances of SIRTs’ expression and activity may lead to the development of obesity and related complications is discussed. A special emphasis is placed on polymorphisms in genes encoding SIRTs and their possible association with susceptibility to obesity and metabolic complications, as well as on data regarding altered expression of SIRTs in human obesity. Finally, the therapeutic potential of SIRTs-targeted strategies in the treatment of obesity and related disorders is discussed. PMID:27104517

Obstacles to the implementation of the treat-to-target strategy for rheumatoid arthritis in clinical practice in Japan.

PubMed

Kaneko, Yuko; Koike, Takao; Oda, Hiromi; Yamamoto, Kazuhiko; Miyasaka, Nobuyuki; Harigai, Masayoshi; Yamanaka, Hisashi; Ishiguro, Naoki; Tanaka, Yoshiya; Takeuchi, Tsutomu

2015-01-01

To clarify the obstacles preventing the implementation of the treat-to-target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice. A total of 301 rheumatologists in Japan completed a questionnaire. In the first section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application. Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations. Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain.

Current diagnostics and treatment of fibrosarcoma –perspectives for future therapeutic targets and strategies

PubMed Central

Augsburger, Daniela; Nelson, Peter J.; Kalinski, Thomas; Udelnow, Andrej; Knösel, Thomas; Hofstetter, Monika; Qin, Ji Wei; Wang, Yan; Gupta, Arvid Sen; Bonifatius, Susanne; Li, Minglun; Bruns, Christiane J.; Zhao, Yue

2017-01-01

Adult-type fibrosarcoma is a rare and highly aggressive subtype of soft tissue sarcomas. Due to the existence of other spindle-cell shaped sarcomas, its diagnosis is always one of exclusion. The likelihood of misdiagnoses between similar tumour entities is high, and often leads to inappropriate tumour treatment. We summarize here the main features of fibrosarcoma. When fibrosarcoma is appropriately diagnosed, the patient`s overall prognosis is generally quite poor. Fibrosarcoma is characterized by its low sensitivity towards radio- and chemotherapy as well as by its high rate of tumour recurrences. Thus it is important to identify new methods to improve treatment of this tumour entity. We discuss some promising new directions in fibrosarcoma research, specifically focusing on more effective targeting of the tumour microenvironment. Communication between tumour cells and their surrounding stromal tissue play a crucial role in cancer progression, invasion, metastasis and chemosensitivity. The therapeutic potential of targeting the tumour microenvironment is addressed. PMID:29262667

Communication strategies to improve HIV treatment adherence.

PubMed

Rochon, Donna; Ross, Michael W; Looney, Carol; Nepal, Vishnu P; Price, Andrea J; Giordano, Thomas P

2011-01-01

Although antiretroviral therapy has increased the survival of HIV-positive patients, traditional approaches to improving medication adherence have failed consistently. Acknowledging the role of communication in health behavior, we conducted a qualitative study to learn about patients' HIV treatment adherence experiences and to identify which communication strategies might influence adherence. Findings indicate that five constructs--cultural beliefs/language, stigma, cues to action, self-efficacy, and mood state--are potentially modifiable by improved communication. Results will be used to create a direct marketing campaign targeted to HIV-infected patients. Copyright © Taylor & Francis Group, LLC

The concept of crosstalk-directed embryological target mining and its application to essential hypertension treatment failures.

PubMed

Sag, Alan Alper; Sal, Oguzhan; Kilic, Yagmur; Onal, Emine Meltem; Kanbay, Mehmet

2017-05-01

This review aims to introduce the novel concept of embryological target mining applied to interorgan crosstalk network genesis, and applies embryological target mining to multidrug-resistant essential hypertension (a prototype, complex, undertreated, multiorgan systemic syndrome) to uncover new treatment targets and critique why existing strategies fail. Briefly, interorgan crosstalk pathways represent the next frontier for target mining in molecular medicine. This is because stereotyped stepwise organogenesis presents a unique opportunity to infer interorgan crosstalk pathways that may be crucial to discovering novel treatment targets. Insights gained from this review will be applied to patient management in a clinician-directed fashion. ©2017 Wiley Periodicals, Inc.

Multiple polysaccharide-drug complex-loaded liposomes: A unique strategy in drug loading and cancer targeting.

PubMed

Ruttala, Hima Bindu; Ramasamy, Thiruganesh; Gupta, Biki; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2017-10-01

In the present study, a unique strategy was developed to develop nanocarriers containing multiple therapeutics with controlled release characteristics. In this study, we demonstrated the synthesis of dextran sulfate-doxorubicin (DS-DOX) and alginate-cisplatin (AL-CIS) polymer-drug complexes to produce a transferrin ligand-conjugated liposome. The targeted nanoparticles (TL-DDAC) were nano-sized and spherical. The targeted liposome exhibited a specific receptor-mediated endocytic uptake in cancer cells. The enhanced cellular uptake of TL-DDAC resulted in a significantly better anticancer effect in resistant and sensitive breast cancer cells compared to that of the free drugs. Specifically, DOX and CIS at a molar ratio of 1:1 exhibited better therapeutic performance compared to that of other combinations. The combination of an anthracycline-based topoisomerase II inhibitor (DOX) and a platinum compound (CIS) resulted in significantly higher cell apoptosis (early and late) in both types of cancer cells. In conclusion, treatment with DS-DOX and AL-CIS based combination liposomes modified with transferrin (TL-DDAC) was an effective cancer treatment strategy. Further investigation in clinically relevant animal models is warranted to prove the therapeutic efficacy of this unique strategy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeted Treatment Options in Mastocytosis

PubMed Central

Vaes, Mélanie; Benghiat, Fleur Samantha; Hermine, Olivier

2017-01-01

Mastocytosis refers to a heterogeneous group of disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin (cutaneous mastocytosis when only in the skin, CM) or in various organs (systemic mastocytosis, SM). This leads to a wide variety of clinical manifestations resulting from excessive mediator release in CM and benign forms of SM (indolent SM, ISM) and from tissue mast cell infiltration causing multiorgan dysfunction and failure in more aggressive subtypes (aggressive SM, ASM, or mast cell leukemia). In addition, SM may be associated with hematological neoplasms (AHN). While treatment of ISM primarily aims at symptom management with anti-mediator therapies, cytoreductive and targeted therapies are needed to control the expansion of neoplastic mast cells in advanced forms of SM, in order to improve overall survival. Mast cell accumulation results from a gain-of-function mutation (mostly the D816V mutation) within the KIT tyrosine kinase domain expressed by mast cells and additional genetic and epigenetic mutations may further determine the features of the disease (ASM and AHN). Consequently, tyrosine kinase inhibitors and targeted therapies directed against the oncogenic signaling machinery downstream of KIT are attractive therapeutic approaches. A better understanding of the relative contribution of these genetic and epigenetic events to the molecular pathogenesis of mastocytosis is of particular interest for the development of targeted therapies and therefore to better choose patient subgroups that would best benefit from a given therapeutic strategy. PMID:28775983

Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages.

PubMed

Qian, Yuan; Qiao, Sha; Dai, Yanfeng; Xu, Guoqiang; Dai, Bolei; Lu, Lisen; Yu, Xiang; Luo, Qingming; Zhang, Zhihong

2017-09-26

Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancer immunotherapy. Targeted delivery of therapeutic drugs to the tumor-promoting M2-like TAMs is challenging. Here, we developed M2-like TAM dual-targeting nanoparticles (M2NPs), whose structure and function were controlled by α-peptide (a scavenger receptor B type 1 (SR-B1) targeting peptide) linked with M2pep (an M2 macrophage binding peptide). By loading anti-colony stimulating factor-1 receptor (anti-CSF-1R) small interfering RNA (siRNA) on the M2NPs, we developed a molecular-targeted immunotherapeutic approach to specifically block the survival signal of M2-like TAMs and deplete them from melanoma tumors. We confirmed the validity of SR-B1 for M2-like TAM targeting and demonstrated the synergistic effect of the two targeting units (α-peptide and M2pep) in the fusion peptide (α-M2pep). After being administered to tumor-bearing mice, M2NPs had higher affinity to M2-like TAMs than to tissue-resident macrophages in liver, spleen, and lung. Compared with control treatment groups, M2NP-based siRNA delivery resulted in a dramatic elimination of M2-like TAMs (52%), decreased tumor size (87%), and prolonged survival. Additionally, this molecular-targeted strategy inhibited immunosuppressive IL-10 and TGF-β production and increased immunostimulatory cytokines (IL-12 and IFN-γ) expression and CD8 + T cell infiltration (2.9-fold) in the tumor microenvironment. Moreover, the siRNA-carrying M2NPs down-regulated expression of the exhaustion markers (PD-1 and Tim-3) on the infiltrating CD8 + T cells and stimulated their IFN-γ secretion (6.2-fold), indicating the restoration of T cell immune function. Thus, the dual-targeting property of M2NPs combined with RNA interference provides a potential strategy of molecular-targeted cancer immunotherapy for clinical application.

Target discrimination strategies in optics detection

NASA Astrophysics Data System (ADS)

Sjöqvist, Lars; Allard, Lars; Henriksson, Markus; Jonsson, Per; Pettersson, Magnus

2013-10-01

Detection and localisation of optical assemblies used for weapon guidance or sniper rifle scopes has attracted interest for security and military applications. Typically a laser system is used to interrogate a scene of interest and the retro-reflected radiation is detected. Different system approaches for area coverage can be realised ranging from flood illumination to step-and-stare or continuous scanning schemes. Independently of the chosen approach target discrimination is a crucial issue, particularly if a complex scene such as in an urban environment and autonomous operation is considered. In this work target discrimination strategies in optics detection are discussed. Typical parameters affecting the reflected laser radiation from the target are the wavelength, polarisation properties, temporal effects and the range resolution. Knowledge about the target characteristics is important to predict the target discrimination capability. Two different systems were used to investigate polarisation properties and range resolution information from targets including e.g. road signs, optical reflexes, rifle sights and optical references. The experimental results and implications on target discrimination will be discussed. If autonomous operation is required target discrimination becomes critical in order to reduce the number of false alarms.

Targeting vacuolar H+-ATPases as a new strategy against cancer.

PubMed

Fais, Stefano; De Milito, Angelo; You, Haiyan; Qin, Wenxin

2007-11-15

Growing evidence suggests a key role of tumor acidic microenvironment in cancer development, progression, and metastasis. As a consequence, the need for compounds that specifically target the mechanism(s) responsible for the low pH of tumors is increasing. Among the key regulators of the tumor acidic microenvironment, vacuolar H(+)-ATPases (V-ATPases) play an important role. These proteins cover a number of functions in a variety of normal as well as tumor cells, in which they pump ions across the membranes. We discuss here some recent results showing that a molecular inhibition of V-ATPases by small interfering RNA in vivo as well as a pharmacologic inhibition through proton pump inhibitors led to tumor cytotoxicity and marked inhibition of human tumor growth in xenograft models. These results propose V-ATPases as a key target for new strategies in cancer treatment.

Green design "bioinspired disassembly-reassembly strategy" applied for improved tumor-targeted anticancer drug delivery.

PubMed

Wang, Ruoning; Gu, Xiaochen; Zhou, Jianping; Shen, Lingjia; Yin, Lifang; Hua, Peiying; Ding, Yang

2016-08-10

In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeting Tumor-Associated Macrophages as a Potential Strategy to Enhance the Response to Immune Checkpoint Inhibitors.

PubMed

Cassetta, Luca; Kitamura, Takanori

2018-01-01

Inhibition of immune checkpoint pathways in CD8 + T cell is a promising therapeutic strategy for the treatment of solid tumors that has shown significant anti-tumor effects and is now approved by the FDA to treat patients with melanoma and lung cancer. However the response to this therapy is limited to a certain fraction of patients and tumor types, for reasons still unknown. To ensure success of this treatment, CD8 + T cells, the main target of the checkpoint inhibitors, should exert full cytotoxicity against tumor cells. However recent studies show that tumor-associated macrophages (TAM) can impede this process by different mechanisms. In this mini-review we will summarize recent studies showing the effect of TAM targeting on immune checkpoint inhibitors efficacy. We will also discuss on the limitations of the current strategies as well on the future scientific challenges for the progress of the tumor immunology field.

Can Australia eliminate TB? Modelling immigration strategies for reaching MDG targets in a low-transmission setting.

PubMed

Denholm, Justin T; McBryde, Emma S

2014-02-01

The 2050 Millennium Development Goals (MDG) for tuberculosis (TB) aim for elimination of TB as a public health issue. We used a mathematical modelling approach to evaluate the feasibility of this target in a low-prevalence setting with immigration-related strategies directed at latent tuberculosis. We used a stochastic individual-based model to simulate tuberculosis disease among immigrants to Victoria, Australia; a representative low-transmission setting. A variety of screening and treatment approaches aimed at preventing reactivation of latent infection were applied to evaluate overall tuberculosis incidence reduction and rates of multidrug resistant disease. Without additional intervention, tuberculosis incidence was predicted to reach 34.5 cases/million by 2050. Strategies involving the introduction of an available screening/treatment combination reduced TB incidence to between 16.9-23.8 cases/million, and required screening of 136-427 new arrivals for each case of TB prevented. Limiting screening to higher incidence regions of origin was less effective but more efficient. Public health strategies targeting latent tuberculosis infection in immigrants may substantially reduce tuberculosis incidence in a low prevalence region. However, immigration-focused strategies cannot achieve the 2050 MDG and alternative or complementary approaches are required. © 2014 The Authors. ANZJPH © 2014 Public Health Association of Australia.

Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.

PubMed

Yoon, Hong Yeol; Shin, Min Lee; Shim, Man Kyu; Lee, Sangmin; Na, Jin Hee; Koo, Heebeom; Lee, Hyukjin; Kim, Jong-Ho; Lee, Kuen Yong; Kim, Kwangmeyung; Kwon, Ick Chan

2017-05-01

Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin α v β 3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

Photothermal Effect Enhanced Cascade-Targeting Strategy for Improved Pancreatic Cancer Therapy by Gold Nanoshell@Mesoporous Silica Nanorod.

PubMed

Zhao, Ruifang; Han, Xuexiang; Li, Yiye; Wang, Hai; Ji, Tianjiao; Zhao, Yuliang; Nie, Guangjun

2017-08-22

Pancreatic cancer, one of the leading causes of cancer-related mortality, is characterized by desmoplasia and hypovascular cancerous tissue, with a 5 year survival rate of <8%. To overcome the severe resistance of pancreatic cancer to conventional therapies, we synthesized gold nanoshell-coated rod-like mesoporous silica (GNRS) nanoparticles which integrated cascade tumor targeting (mediated by photothermal effect and molecular receptor binding) and photothermal treatment-enhanced gemcitabine chemotherapy, under mild near-infrared laser irradiation condition. GNRS significantly improved gemcitabine penetration and accumulation in tumor tissues, thus destroying the dense stroma barrier of pancreatic cancer and reinforcing chemosensitivity in mice. Our current findings strongly support the notion that further development of this integrated plasmonic photothermal strategy may represent a promising translational nanoformulation for effective treatment of pancreatic cancer with integral cascade tumor targeting strategy and enhanced drug delivery efficacy.

Emerging strategies for EphA2 receptor targeting for cancer therapeutics.

PubMed

Tandon, Manish; Vemula, Sai Vikram; Mittal, Suresh K

2011-01-01

High mortality rates with cancers warrant further development of earlier diagnostics and better treatment strategies. Membrane-bound erythropoietin-producing hepatocellular receptor tyrosine kinase class A2 (EphA2) is overexpressed in breast, prostate, urinary bladder, skin, lung, ovary and brain cancers. EphA2 overexpression in cancers, its signaling mechanisms and strategies to target its deregulation. High EphA2 expression in cancer cells is correlated with a poor prognosis associated with recurrence due to enhanced metastasis. Interaction of the EphA2 receptor with its ligand (e.g., ephrinA1) triggers events that are deregulated and implicated in carcinogenesis. EphrinA1-independent oncogenic activity and ephrinA1-dependent tumor suppressor roles for EphA2 are described. Molecular interactions of EphA2 with signaling proteins are associated with the modulation of cytoskeleton dynamics, cell adhesion, proliferation, differentiation and metastasis. The deregulated signaling by EphA2 and its involvement in oncogenesis provide multiple avenues for the rational design of intervention approaches. EphA2 has been tested as a drug target using multiple approaches such as agonist antibodies, RNA interference, immunotherapy, virus vector-mediated gene transfer, small-molecule inhibitors and nanoparticles. With over a decade of research, encouraging results with targeting of EphA2 expression in various pre-clinical cancer models necessitate further studies.

Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain

PubMed Central

Berta, Temugin; Qadri, Yawar; Tan, Ping-Heng; Ji, Ru-Rong

2018-01-01

Introduction Currently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. Areas covered The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons. These changes result in hypersensitivity and hyperexcitability of sensory neurons (peripheral sensitization) and are crucial for the onset and maintenance of chronic pain. We discuss the following new strategies to target DRGs and primary sensory neurons as a means of alleviating chronic pain and minimizing side effects: inhibition of sensory neuron-expressing ion channels such as TRPA1, TRPV1, and Nav1.7, selective blockade of C- and Aβ-afferent fibers, gene therapy, and implantation of bone marrow stem cells. Expert opinion These peripheral pharmacological treatments, as well as gene and cell therapies, aimed at DRG tissues and primary sensory neurons can offer better and safer treatments for inflammatory, neuropathic, cancer, and other chronic pain states. PMID:28480765

Nonrandom Intrafraction Target Motions and General Strategy for Correction of Spine Stereotactic Body Radiotherapy

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

Ma Lijun, E-mail: lijunma@radonc.ucsf.ed; Sahgal, Arjun; Hossain, Sabbir

2009-11-15

Purpose: To characterize nonrandom intrafraction target motions for spine stereotactic body radiotherapy and to develop a method of correction via image guidance. The dependence of target motions, as well as the effectiveness of the correction strategy for lesions of different locations within the spine, was analyzed. Methods and Materials: Intrafraction target motions for 64 targets in 64 patients treated with a total of 233 fractions were analyzed. Based on the target location, the cases were divided into three groups, i.e., cervical (n = 20 patients), thoracic (n = 20 patients), or lumbar-sacrum (n = 24 patients) lesions. For each case,more » time-lag autocorrelation analysis was performed for each degree of freedom of motion that included both translations (x, y, and z shifts) and rotations (roll, yaw, and pitch). A general correction strategy based on periodic interventions was derived to determine the time interval required between two adjacent interventions, to overcome the patient-specific target motions. Results: Nonrandom target motions were detected for 100% of cases regardless of target locations. Cervical spine targets were found to possess the highest incidence of nonrandom target motion compared with thoracic and lumbar-sacral lesions (p < 0.001). The average time needed to maintain the target motion to within 1 mm of translation or 1 deg. of rotational deviation was 5.5 min, 5.9 min, and 7.1 min for cervical, thoracic, and lumbar-sacrum locations, respectively (at 95% confidence level). Conclusions: A high incidence of nonrandom intrafraction target motions was found for spine stereotactic body radiotherapy treatments. Periodic interventions at approximately every 5 minutes or less were needed to overcome such motions.« less

Changing strategies for target therapy in gastric cancer.

PubMed

Lee, Suk-Young; Oh, Sang Cheul

2016-01-21

In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of targeted therapy. Firstly, many patients with metastatic gastric cancer who receive trastuzumab in combination with chemotherapeutic agents develop resistance to the targeted therapy. Secondly, many clinical trials testing novel molecular targeted agents with demonstrated efficacy in other malignancies have failed to show benefit in patients with metastatic gastric cancer, suggesting the importance of the selection of appropriate indications according to molecular characteristics in application of targeted agents. Herein, we review the molecular targeted agents currently approved and in use, and clinical trials in patients with metastatic gastric cancer, and demonstrate the limitations and future direction in treatment of advanced gastric cancer.

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

PubMed

Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

2017-12-27

The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

EGFR, HER2 and VEGF pathways: validated targets for cancer treatment.

PubMed

Press, Michael F; Lenz, Heinz-Josef

2007-01-01

Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody. On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.

[Strategies of treatment for febrile neutropenia].

PubMed

Terui, Yasuhito

2013-06-01

The guideline on febrile neutropenia(FN)was published by the Japanese Society of Medical Oncology(JSMO)in 2012. Based on this guideline, the treatment strategy for febrile neutropenia that is discussed in this paper includes empiric treatment strategies, methicillin-resistant Staphylococcus aureus antibiotics in the initial treatment, treatment for severe FN, treatment for outpatients, duration of FN treatment, treatment after recovery from fever associated with neutropenia, and empiric treatment with anti-fungal drugs in patients with prolonged FN.

Emerging strategies for EphA2 receptor targeting for cancer therapeutics

PubMed Central

Tandon, Manish; Vemula, Sai Vikram; Mittal, Suresh K.

2010-01-01

Importance of the field High mortality rates with cancers warrant further development of earlier diagnostics and better treatment strategies. Membrane-bound hepatocellular receptor tyrosine kinase class A2 (EphA2) is overexpressed in breast, prostate, urinary bladder, skin, lung, ovary and brain cancers. Areas covered in this review This review describes EphA2 overexpression in cancers, its signaling mechanisms and strategies to target its deregulation. What will the reader will gain High EphA2 expression in cancer cells is correlated to a poor prognosis associated with recurrence due to enhanced metastasis. Interaction of the EphA2 receptor with its ligand (e.g., EphrinA1) triggers events that are deregulated and implicated in carcinogenesis. Both EphrinA1-independent oncogenic activity and EphrinA1-dependent tumor suppressor roles for EphA2 are described. Molecular interactions of EphA2 with signaling proteins are associated with the modulation of cytoskeleton dynamics, cell adhesion, proliferation, differentiation and metastasis. The deregulated signaling by EphA2 and its involvement in oncogenesis provide multiple avenues for the rational design of intervention approaches. Take home message EphA2 has been tested as a drug target using multiple approaches such as agonist antibodies, RNA interference, immunotherapy, virus vectors-mediated gene transfer, small molecule inhibitors and nanoparticles. With over a decade of research, encouraging results with successful targeting of EphA2 expression in various pre-clinical cancer models necessitate further studies. PMID:21142802

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.

Is androgen receptor targeting an emerging treatment strategy for triple negative breast cancer?

PubMed

Anestis, Aristomenis; Karamouzis, Michalis V; Dalagiorgou, Georgia; Papavassiliou, Athanasios G

2015-06-01

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. The absence of expression and/or amplification of estrogen and progesterone receptor as well as ERBB-2 prevent the use of currently available endocrine options and/or ERBB-2-directed drugs and indicates chemotherapy as the main current therapy. TNBC represents approximately 15% of breast cancer cases with high index of heterogeneity. Here, we review the role of androgen receptor in breast carcinogenesis and its association with alterations in the expression pattern and functional roles of regulatory molecules and signal transduction pathways in TNBC. Additionally, based on the so far preclinical and clinical published data, we evaluate the perspectives for using and/or developing androgen receptor targeting strategies for specific TNBC subtypes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Strategies in treatment of suicidality: identification of common and treatment-specific interventions in empirically supported treatment manuals.

PubMed

Weinberg, Igor; Ronningstam, Elsa; Goldblatt, Mark J; Schechter, Mark; Wheelis, Joan; Maltsberger, John T

2010-06-01

Many reports of treatments for suicidal patients claim effectiveness in reducing suicidal behavior but fail to demonstrate which treatment interventions, or combinations thereof, diminish suicidality. In this study, treatment manuals for empirically supported psychological treatments for suicidal patients were examined to identify which interventions they had in common and which interventions were treatment-specific. Empirically supported treatments for suicidality were identified through a literature search of PsychLit and MEDLINE for the years 1970-2007, employing the following search strategy: [suicide OR parasuicide] AND [therapy OR psychotherapy OR treatment] AND [random OR randomized]. After identifying the reports on randomized controlled studies that tested effectiveness of different treatments, the reference list of each report was searched for further studies. Only reports published in English were included. To ensure that rated manuals actually correspond to the delivered and tested treatments, we included only treatment interventions with explicit adherence rating and scoring and with adequate adherence ratings in the published studies. Five manualized treatments demonstrating efficacy in reducing suicide risk were identified and were independently evaluated by raters using a list of treatment interventions. The common interventions included a clear treatment framework; a defined strategy for managing suicide crises; close attention to affect; an active, participatory therapist style; and use of exploratory and change-oriented interventions. Some treatments encouraged a multimodal approach and identification of suicidality as an explicit target behavior, and some concentrated on the patient-therapist relationship. Emphasis on interpretation and supportive interventions varied. Not all methods encouraged systematic support for therapists. This study identified candidate interventions for possible effectiveness in reducing suicidality. These interventions

A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles.

PubMed

Wang, Mingxin; You, Chaoqun; Gao, Zhiguo; Wu, Hongshuai; Sun, Baiwang; Zhu, Xiaoli; Chen, Renjie

2018-08-01

The functionalized nanoparticles have been widely studied and reported as carriers of drug transport recently. Furthermore, many groups have focused more on developing novel and efficient treatment methods, such as photodynamic therapy and photothermal therapy, since both therapies have shown inspiring potential in the application of antitumor. The mentioned treatments exhibited the superiority of cooperative manner and showed the ability to compensate for the adverse effects caused by conventional monotherapy in proposed strategies. In view of the above descriptions, we formulated a thermosensitive drug delivery system, which achieved the enhanced delivery of cisplatin and two photosensitizers (ICG and Ce6) by dual-targeting traction. Drawing on the thin film hydration method, cisplatin and photosensitizers were encapsulated inside nanoparticles. Meanwhile, the targeting peptide cRGD and targeting molecule folate can be modified on the surface of nanoparticles to realize the active identification of tumor cells. The measurements of dynamic light scattering showed that the prepared nanoparticles had an ideal dispersibility and uniform particle size of 102.6 nm. On the basis of the results observed from confocal laser scanning microscope, the modified nanoparticles were more efficient endocytosed by MCF-7 cells as a contrast to SGC-7901 cells. Photothermal conversion-triggered drug release and photo-therapies produced a significant apoptosis rate of 85.9% on MCF-7 cells. The distinguished results made it believed that the formulated delivery system had conducted great efforts and innovations for the realization of concise collaboration and provided a promising strategy for the treatment of breast cancer.

Evolving therapeutic strategies for Duchenne muscular dystrophy: targeting downstream events.

PubMed

Tidball, James G; Wehling-Henricks, Michelle

2004-12-01

Duchenne muscular dystrophy (DMD) is a progressive, lethal, muscle wasting disease that affects 1 of 3500 boys born worldwide. The disease results from mutation of the dystrophin gene that encodes a cytoskeletal protein associated with the muscle cell membrane. Although gene therapy will likely provide the cure for DMD, it remains on the distant horizon, emphasizing the need for more rapid development of palliative treatments that build on improved understanding of the complex pathology of dystrophin deficiency. In this review, we have focused on therapeutic strategies that target downstream events in the pathologic progression of DMD. Much of this work has been developed initially using the dystrophin-deficient mdx mouse to explore basic features of the pathophysiology of dystrophin deficiency and to test potential therapeutic interventions to slow, reverse, or compensate for functional losses that occur in muscular dystrophy. In some cases, the initial findings in the mdx model have led to clinical treatments for DMD boys that have produced improvements in muscle function and quality of life. Many of these investigations have concerned interventions that can affect protein balance in muscle, by inhibiting specific proteases implicated in the DMD pathology, or by providing anabolic factors or depleting catabolic factors that can contribute to muscle wasting. Other investigations have exploited the use of anti-inflammatory agents that can reduce the contribution of leukocytes to promoting secondary damage to dystrophic muscle. A third general strategy is designed to increase the regenerative capacity of dystrophic muscle and thereby help retain functional muscle mass. Each of these general approaches to slowing the pathology of dystrophin deficiency has yielded encouragement and suggests that targeting downstream events in dystrophinopathy can yield worthwhile, functional improvements in DMD.

Novel pharmacotherapeutic strategies for treatment of opioid-induced neonatal abstinence syndrome

PubMed Central

McLemore, Gabrielle L.; Lewis, Tamorah; Jones, Catherine H.; Gauda, Estelle B.

2014-01-01

Summary The non-medical use of prescription drugs, in general, and opioids, in particular, is a national epidemic, resulting in enormous addiction rates, healthcare expenditures, and overdose deaths. Prescription opioids are overly prescribed, illegally trafficked, and frequently abused, all of which have created a new opioid addiction pathway, adding to the number of opioid-dependent newborns requiring treatment for neonatal abstinence syndrome (NAS), and contributing to challenges in effective care in maternal and fetal/neonatal (M-F/N) medicine. The standard of care for illicit or prescription opioid dependence during pregnancy is opioid agonist (methadone or buprenorphine) substitution therapy, which are also frequently abused. The next generation of pharmacotherapies for the treatment of illicit or prescription opioid addiction in the M-F/N interactional dyad must take into consideration the interplay between genetic, epigenetic, and environmental factors. Addiction to illicit drugs during pregnancy presents unique challenges to effectively treat the mother, and the developing fetus and infant after delivery. New pharmacotherapies should be safe to the developing fetus, effective in treating the physical and psychological consequences of addiction in the mother, and reduce the incidence and severity of NAS in the infant after birth. More pharmacotherapeutic options should be available to the physician such that a more individualized rather than a one-drug/strategy-fits-all approach can be used. A myriad of new and exciting pharmacotherapeutic strategies for the treatment of opioid dependence and addiction are on the horizon. This review focuses on such three strategies: (i) pharmacotherapeutic targeting of the serotoninergic system; (ii) mixed opioid immunotherapeutics (vaccines); (iii) pharmacogenomics as a therapeutic strategy to insure personalized care. We review and discuss how these strategies may offer additional treatment modalities for the treatment

Strategies to improve treatment coverage in community-based public health programs: A systematic review of the literature.

PubMed

Deardorff, Katrina V; Rubin Means, Arianna; Ásbjörnsdóttir, Kristjana H; Walson, Judd

2018-02-01

Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare interventions to targeted populations at scale. However, these programs often fall short of established coverage targets. The purpose of this systematic review was to evaluate the impact of strategies used to increase treatment coverage in community-based public health campaigns. We systematically searched CAB Direct, Embase, and PubMed archives for studies utilizing specific interventions to increase coverage of community-based distribution of drugs, vaccines, or other public health services. We identified 5,637 articles, from which 79 full texts were evaluated according to pre-defined inclusion and exclusion criteria. Twenty-eight articles met inclusion criteria and data were abstracted regarding strategy-specific changes in coverage from these sources. Strategies used to increase coverage included community-directed treatment (n = 6, pooled percent change in coverage: +26.2%), distributor incentives (n = 2, +25.3%), distribution along kinship networks (n = 1, +24.5%), intensified information, education, and communication activities (n = 8, +21.6%), fixed-point delivery (n = 1, +21.4%), door-to-door delivery (n = 1, +14.0%), integrated service distribution (n = 9, +12.7%), conversion from school- to community-based delivery (n = 3, +11.9%), and management by a non-governmental organization (n = 1, +5.8%). Strategies that target improving community member ownership of distribution appear to have a large impact on increasing treatment coverage. However, all strategies used to increase coverage successfully did so. These results may be useful to National Ministries, programs, and implementing partners in optimizing treatment coverage in community-based public health programs.

Strategies to improve treatment coverage in community-based public health programs: A systematic review of the literature

PubMed Central

2018-01-01

Background Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare interventions to targeted populations at scale. However, these programs often fall short of established coverage targets. The purpose of this systematic review was to evaluate the impact of strategies used to increase treatment coverage in community-based public health campaigns. Methodology/ principal findings We systematically searched CAB Direct, Embase, and PubMed archives for studies utilizing specific interventions to increase coverage of community-based distribution of drugs, vaccines, or other public health services. We identified 5,637 articles, from which 79 full texts were evaluated according to pre-defined inclusion and exclusion criteria. Twenty-eight articles met inclusion criteria and data were abstracted regarding strategy-specific changes in coverage from these sources. Strategies used to increase coverage included community-directed treatment (n = 6, pooled percent change in coverage: +26.2%), distributor incentives (n = 2, +25.3%), distribution along kinship networks (n = 1, +24.5%), intensified information, education, and communication activities (n = 8, +21.6%), fixed-point delivery (n = 1, +21.4%), door-to-door delivery (n = 1, +14.0%), integrated service distribution (n = 9, +12.7%), conversion from school- to community-based delivery (n = 3, +11.9%), and management by a non-governmental organization (n = 1, +5.8%). Conclusions/significance Strategies that target improving community member ownership of distribution appear to have a large impact on increasing treatment coverage. However, all strategies used to increase coverage successfully did so. These results may be useful to National Ministries, programs, and implementing partners in optimizing treatment coverage in community-based public health programs. PMID:29420534

Cost-effectiveness of clinical remission by treat to target strategy in established rheumatoid arthritis: results of the CREATE registry.

PubMed

Cárdenas, M; de la Fuente, S; Castro-Villegas, M C; Romero-Gómez, M; Ruiz-Vílchez, D; Calvo-Gutiérrez, J; Escudero-Contreras, A; Del Prado, J R; Collantes-Estévez, E; Font, P

2016-12-01

To analyse the cost-effectiveness, in daily clinical practice, of the strategy of treating to the target of clinical remission (CR) in patients with established rheumatoid arthritis (RA), after 2 years of treatment with biological therapy. Adult patients with established RA were treated with biological therapy and followed up for 2 years by a multidisciplinary team responsible for their clinical management. Treatment effectiveness was evaluated by the DAS28 score. The direct costs incurred during this period were quantified from the perspective of the healthcare system. We calculated the cost-effectiveness of obtaining a DAS28 < 2.6, considered as CR. The study included 144 RA patients treated with biological therapies. After 2 years of treatment, 32.6% of patients achieved CR. The mean cost of achieving CR at 2 years was 79,681 ± 38,880 euros. The strategy of treatment to the target of CR is considered the most effective, but in actual clinical practice in patients with established RA, it has a high cost.

[Current Status of Targeted Treatment in Breast Cancer].

PubMed

Seiffert, Katharina; Schmalfeldt, Barbara; Müller, Volkmar

2017-11-01

Within the last years, significant improvements have been achieved in breast cancer treatment, particularly with the development of targeted therapies. Major progress has been made in identifying the drivers malignant growth in oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of the cyclin-dependent kinases CDK4 and CDK6 like palbociclib and inhibitors of mTOR substantially improve progression-free survival. For patients with HER2-positive disease the addition of Pertuzumab to Trastuzumab in combination with chemotherapy has been a significant improvement in anti-HER2 therapy in early as well as metastatic breast cancer. Evidence-based further line therapy options in the metastatic setting include T-DM1 and in later lines Lapatinib. For triple negative disease the angiogenesis inhibitor Bevacizumab is approved, which increases progression free survival. Immune checkpoint inhibitors, PARP-inhibitors or anti-androgens represent promising strategies, all of which are currently being evaluated in clinical trials. The development of predictive biomarkers to guide targeted therapies is still the subject of research. © Georg Thieme Verlag KG Stuttgart · New York.

Advances in targeting strategies for nanoparticles in cancer imaging and therapy.

PubMed

Yhee, Ji Young; Lee, Sangmin; Kim, Kwangmeyung

2014-11-21

In the last decade, nanoparticles have offered great advances in diagnostic imaging and targeted drug delivery. In particular, nanoparticles have provided remarkable progress in cancer imaging and therapy based on materials science and biochemical engineering technology. Researchers constantly attempted to develop the nanoparticles which can deliver drugs more specifically to cancer cells, and these efforts brought the advances in the targeting strategy of nanoparticles. This minireview will discuss the progress in targeting strategies for nanoparticles focused on the recent innovative work for nanomedicine.

[Oligometastasized colorectal cancer-modern treatment strategies].

PubMed

Binnebösel, M; Lambertz, A; Dejong, K; Neumann, U P

2018-06-05

The prognosis of colorectal cancer in UICC stage IV has been improved in the last decades by improvements in interdisciplinary treatment. Treatment strategies for oligometastasized colorectal cancer are developing more and more into an individualized treatment. An overview of the current literature of modern treatment concepts in oligometastasized colorectal cancer UICC stage IV is given. Surgery still has the supreme mandate in resectable colorectal liver metastases, as neoadjuvant and adjuvant treatment strategies to not provide any benefits for these patients. In marginal or non-resectable stages systemic treatment is superior in these patients depending on the prognostic parameters. Also in curative settings local treatment options should be considered as a reasonable additive tool. An interesting treatment approach for isolated liver metastases and non-resectable colorectal cancer is liver transplantation. Irrespective of new developments in treatment strategies for metastasized colorectal cancer, resection of colorectal liver metastases remains the gold standard whenever possible.

IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

PubMed Central

Wei, Wei; Lewis, Michael T.

2015-01-01

Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

Novel Strategies on Personalized Medicine for Breast Cancer Treatment: An Update.

PubMed

Chan, Carmen W H; Law, Bernard M H; So, Winnie K W; Chow, Ka Ming; Waye, Mary M Y

2017-11-15

Breast cancer is the most common cancer type among women worldwide. With breast cancer patients and survivors being reported to experience a repertoire of symptoms that are detrimental to their quality of life, the development of breast cancer treatment strategies that are effective with minimal side effects is therefore required. Personalized medicine, the treatment process that is tailored to the individual needs of each patient, is recently gaining increasing attention for its prospect in the development of effective cancer treatment regimens. Indeed, recent studies have identified a number of genes and molecules that may be used as biomarkers for predicting drug response and severity of common cancer-associated symptoms. These would provide useful clues not only for the determination of the optimal drug choice/dosage to be used in personalized treatment, but also for the identification of gene or molecular targets for the development of novel symptom management strategies, which ultimately would lead to the development of more personalized therapies for effective cancer treatment. In this article, recent studies that would provide potential new options for personalized therapies for breast cancer patients and survivors are reviewed. We suggest novel strategies, including the optimization of drug choice/dosage and the identification of genetic changes that are associated with cancer symptom occurrence and severity, which may help in enhancing the effectiveness and acceptability of the currently available cancer therapies.

Strategies for systemic radiotherapy of micrometastases using antibody-targeted 131I.

PubMed

Wheldon, T E; O'Donoghue, J A; Hilditch, T E; Barrett, A

1988-02-01

A simple analysis is developed to evaluate the likely effectiveness of treatment of micrometastases by antibody-targeted 131I. Account is taken of the low levels of tumour uptake of antibody-conjugated 131I presently achievable and of the "energy wastage" in targeting microscopic tumours with a radionuclide whose disintegration energy is widely dissipated. The analysis shows that only modest doses can be delivered to micrometastases when total body dose is restricted to levels which allow recovery of bone marrow. Much higher doses could be delivered to micrometastases when bone marrow rescue is used. A rationale is presented for targeted systemic radiotherapy used in combination with external beam total body irradiation (TBI) and bone marrow rescue. This has some practical advantages. The effect of the targeted component is to impose a biological non-uniformity on the total body dose distribution with regions of high tumour cell density receiving higher doses. Where targeting results in high doses to particular normal organs (e.g. liver, kidney) the total dose to these organs could be kept within tolerable limits by appropriate shielding of the external beam radiation component of the treatment. Greater levels of tumour cell kill should be achievable by the combination regime without any increase in normal tissue damage over that inflicted by conventional TBI. The predicted superiority of the combination regime is especially marked for tumours just below the threshold for detectability (e.g. approximately 1 mm-1 cm diameter). This approach has the advantage that targeted radiotherapy provides only a proportion of the total body dose, most of which is given by a familiar technique. The proportion of dose given by the targeted component could be increased as experience is gained. The predicted superiority of the combination strategy should be experimentally testable using laboratory animals. Clinical applications should be cautiously approached, with due regard to

Non-target screening to trace ozonation transformation products in a wastewater treatment train including different post-treatments.

PubMed

Schollée, Jennifer E; Bourgin, Marc; von Gunten, Urs; McArdell, Christa S; Hollender, Juliane

2018-05-25

WWTP and revealed 11 relevant trends. OTP removal was compared among the five post-treatments and 54-83% of the non-target features that appeared after ozonation were removed, with the two GAC filters performing the best. Overall, these data analysis strategies for non-target screening provide a useful tool to understand the behavior of unknown features during ozonation and post-treatment and to prioritize certain non-targets for further identification. Copyright © 2018 Elsevier Ltd. All rights reserved.

Drug-targeting strategies in cancer therapy.

PubMed

Huang, P S; Oliff, A

2001-02-01

Genetic changes in cell-cycle, apoptotic, and survival pathways cause tumorigenesis, leading to significant phenotypic changes in transformed cells. These changes in the tumor environment - elevated expression of surface proteases, increased angiogenesis and glucuronidase activity - can be taken advantage of to improve the therapeutic index of existing cancer therapies. Targeting cytotoxics to tumor cells by enzymatic activation is a promising strategy for improving chemotherapeutics.

Cellulose degradation: a therapeutic strategy in the improved treatment of Acanthamoeba infections.

PubMed

Lakhundi, Sahreena; Siddiqui, Ruqaiyyah; Khan, Naveed Ahmed

2015-01-14

Acanthamoeba is an opportunistic free-living amoeba that can cause blinding keratitis and fatal brain infection. Early diagnosis, followed by aggressive treatment is a pre-requisite in the successful treatment but even then the prognosis remains poor. A major drawback during the course of treatment is the ability of the amoeba to enclose itself within a shell (a process known as encystment), making it resistant to chemotherapeutic agents. As the cyst wall is partly made of cellulose, thus cellulose degradation offers a potential therapeutic strategy in the effective targeting of trophozoite encased within the cyst walls. Here, we present a comprehensive report on the structure of cellulose and cellulases, as well as known cellulose degradation mechanisms with an eye to target the Acanthamoeba cyst wall. The disruption of the cyst wall will make amoeba (concealed within) susceptible to chemotherapeutic agents, and at the very least inhibition of the excystment process will impede infection recurrence, as we bring these promising drug targets into focus so that they can be explored to their fullest.

Using Chemical Reaction Kinetics to Predict Optimal Antibiotic Treatment Strategies.

PubMed

Abel Zur Wiesch, Pia; Clarelli, Fabrizio; Cohen, Ted

2017-01-01

Identifying optimal dosing of antibiotics has proven challenging-some antibiotics are most effective when they are administered periodically at high doses, while others work best when minimizing concentration fluctuations. Mechanistic explanations for why antibiotics differ in their optimal dosing are lacking, limiting our ability to predict optimal therapy and leading to long and costly experiments. We use mathematical models that describe both bacterial growth and intracellular antibiotic-target binding to investigate the effects of fluctuating antibiotic concentrations on individual bacterial cells and bacterial populations. We show that physicochemical parameters, e.g. the rate of drug transmembrane diffusion and the antibiotic-target complex half-life are sufficient to explain which treatment strategy is most effective. If the drug-target complex dissociates rapidly, the antibiotic must be kept constantly at a concentration that prevents bacterial replication. If antibiotics cross bacterial cell envelopes slowly to reach their target, there is a delay in the onset of action that may be reduced by increasing initial antibiotic concentration. Finally, slow drug-target dissociation and slow diffusion out of cells act to prolong antibiotic effects, thereby allowing for less frequent dosing. Our model can be used as a tool in the rational design of treatment for bacterial infections. It is easily adaptable to other biological systems, e.g. HIV, malaria and cancer, where the effects of physiological fluctuations of drug concentration are also poorly understood.

Using Chemical Reaction Kinetics to Predict Optimal Antibiotic Treatment Strategies

PubMed Central

Abel zur Wiesch, Pia; Cohen, Ted

2017-01-01

Identifying optimal dosing of antibiotics has proven challenging—some antibiotics are most effective when they are administered periodically at high doses, while others work best when minimizing concentration fluctuations. Mechanistic explanations for why antibiotics differ in their optimal dosing are lacking, limiting our ability to predict optimal therapy and leading to long and costly experiments. We use mathematical models that describe both bacterial growth and intracellular antibiotic-target binding to investigate the effects of fluctuating antibiotic concentrations on individual bacterial cells and bacterial populations. We show that physicochemical parameters, e.g. the rate of drug transmembrane diffusion and the antibiotic-target complex half-life are sufficient to explain which treatment strategy is most effective. If the drug-target complex dissociates rapidly, the antibiotic must be kept constantly at a concentration that prevents bacterial replication. If antibiotics cross bacterial cell envelopes slowly to reach their target, there is a delay in the onset of action that may be reduced by increasing initial antibiotic concentration. Finally, slow drug-target dissociation and slow diffusion out of cells act to prolong antibiotic effects, thereby allowing for less frequent dosing. Our model can be used as a tool in the rational design of treatment for bacterial infections. It is easily adaptable to other biological systems, e.g. HIV, malaria and cancer, where the effects of physiological fluctuations of drug concentration are also poorly understood. PMID:28060813

Improved targeted immunization strategies based on two rounds of selection

NASA Astrophysics Data System (ADS)

Xia, Ling-Ling; Song, Yu-Rong; Li, Chan-Chan; Jiang, Guo-Ping

2018-04-01

In the case of high degree targeted immunization where the number of vaccine is limited, when more than one node associated with the same degree meets the requirement of high degree centrality, how can we choose a certain number of nodes from those nodes, so that the number of immunized nodes will not exceed the limit? In this paper, we introduce a new idea derived from the selection process of second-round exam to solve this problem and then propose three improved targeted immunization strategies. In these proposed strategies, the immunized nodes are selected through two rounds of selection, where we increase the quotas of first-round selection according the evaluation criterion of degree centrality and then consider another characteristic parameter of node, such as node's clustering coefficient, betweenness and closeness, to help choose targeted nodes in the second-round selection. To validate the effectiveness of the proposed strategies, we compare them with the degree immunizations including the high degree targeted and the high degree adaptive immunizations using two metrics: the size of the largest connected component of immunized network and the number of infected nodes. Simulation results demonstrate that the proposed strategies based on two rounds of sorting are effective for heterogeneous networks and their immunization effects are better than that of the degree immunizations.

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson's Disease.

PubMed

Curry, Daniel W; Stutz, Bernardo; Andrews, Zane B; Elsworth, John D

2018-03-26

Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5'-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g., metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD.

Anti-tumour strategies aiming to target tumour-associated macrophages

PubMed Central

Tang, Xiaoqiang; Mo, Chunfen; Wang, Yongsheng; Wei, Dandan; Xiao, Hengyi

2013-01-01

Tumour-associated macrophages (TAMs) represent a predominant population of inflammatory cells that present in solid tumours. TAMs are mostly characterized as alternatively activated M2-like macrophages and are known to orchestrate nearly all stages of tumour progression. Experimental investigations indicate that TAMs contribute to drug-resistance and radio-protective effects, and clinical evidence shows that an elevated number of TAMs and their M2 profile are correlated with therapy failure and poor prognosis in cancer patients. Recently, many studies on TAM-targeted strategies have made significant progress and some pilot works have achieved encouraging results. Among these, connections between some anti-tumour drugs and their influence on TAMs have been suggested. In this review, we will summarize recent advances in TAM-targeted strategies for tumour therapy. Based on the proposed mechanisms, those strategies are grouped into four categories: (i) inhibiting macrophage recruitment; (ii) suppressing TAM survival; (iii) enhancing M1-like tumoricidal activity of TAMs; (iv) blocking M2-like tumour-promoting activity of TAMs. It is desired that further attention be drawn to this research field and more effort be made to promote TAM-targeted tumour therapy. PMID:23113570

The drug efflux pump Pgp1 in pro-inflammatory lymphocytes is a target for novel treatment strategies in COPD.

PubMed

Hodge, Greg; Holmes, Mark; Jersmann, Hubertus; Reynolds, Paul N; Hodge, Sandra

2013-06-03

Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro-inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids. Pgp1, granzyme B, IFNγ and TNFα expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (± cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry. There was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNγ, TNFα and granzyme B in COPD patients compared with controls (e.g. %IFNγ/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all). Treatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity.

CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)

PubMed Central

Debnath, Anjan; Calvet, Claudia M.; Aksenov, Alexander; Abagyan, Ruben; Nes, W. David; McKerrow, James H.

2017-01-01

Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered “rare” (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug ‘repurposing’—a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially ‘druggable’ target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM. PMID:29284029

A cost-controlling treatment strategy of adding liraglutide to insulin in type 2 diabetes.

PubMed

de Wit, H M; Vervoort, G M M; de Galan, B E; Tack, C J

2017-09-01

Addition of the GLP-1 receptor agonist liraglutide to insulin can reverse insulin-associated weight gain, improve HbA1c and decrease the need for insulin, but is expensive. From a cost perspective, such treatment should be discontinued when it is clear that treatment targets will not be achieved. Our aim was to find the best cost-controlling treatment strategy: the shortest possible trial period needed to discriminate successfully treated patients from those failing to achieve predefined targets of treatment success. We used data from the 'Effect of Liraglutide on insulin-associated wEight GAiN in patients with Type 2 diabetes' (ELEGANT) trial, comparing additional liraglutide (n = 47) and standard insulin therapy (n = 24) during 26 weeks, to calculate the costs associated with different trial periods. Treatment success after 26 weeks was defined by having achieved ≥ 2 of the following: ≥ 4% weight loss, HbA1c ≤ 53 mmol/mol (7%), and/or discontinuation of insulin. The additional direct costs of adding liraglutide for 26 weeks were € 699 per patient, or € 137 per 1 kg weight loss, compared with standard therapy. The best cost-controlling treatment strategy (identifying 21 of 23 responders, treating four non-responders) was to continue treatment in patients showing ≥ 3% weight loss or ≥ 60% decrease in insulin dose at 8 weeks, with a total cost of € 246 for this t rial period, saving € 453 in case of early discontinuation. An 8-week trial period of adding liraglutide to insulin in patients with insulin-associated weight gain is an effective cost-controlling treatment strategy if the liraglutide is discontinued in patients not showing an early response regarding weight loss or insulin reduction.

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

PubMed Central

Chavez-Gonzalez, Antonieta; Bakhshinejad, Babak; Pakravan, Katayoon

2018-01-01

Background Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are characterized by high self-renewal and multi-lineage differentiation capacities. CSCs are thought to play indispensable roles in the initiation, progression and metastasis of many types of cancer. Leukemias are thought to be initiated and maintained by a specific sub-type of CSC, the leukemia stem cell (LSC). An important feature of LSCs is their resistance to standard therapy, which may lead to relapse. Increasing efforts are aimed at developing novel therapeutic strategies that selectively target LSCs, while sparing their normal counterparts and, thus, minimizing adverse treatment-associated side-effects. These LSC targeting therapies aim to eradicate LSCs through affecting mechanisms that control their survival, self-renewal, differentiation, proliferation and cell cycle progression. Some LSC targeting therapies have already been proven successful in pre-clinical studies and they are now being tested in clinical studies, mainly in combination with conventional treatment regimens. Conclusions A growing body of evidence indicates that the selective targeting of LSCs represents a promising approach to improve disease outcome. Beyond doubt, the CSC hypothesis has added a new dimension to the area of anticancer research, thereby paving the way for shaping a new trend in cancer therapy. PMID:27678246

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

Personalized Antidepressant Selection and Pathway to Novel Treatments: Clinical Utility of Targeting Inflammation

PubMed Central

Jha, Manish K.; Trivedi, Madhukar H.

2018-01-01

Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP)-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments. PMID:29329256

Drug Target Interference in Immunogenicity Assays: Recommendations and Mitigation Strategies.

PubMed

Zhong, Zhandong Don; Clements-Egan, Adrienne; Gorovits, Boris; Maia, Mauricio; Sumner, Giane; Theobald, Valerie; Wu, Yuling; Rajadhyaksha, Manoj

2017-11-01

Sensitive and specific methodology is required for the detection and characterization of anti-drug antibodies (ADAs). High-quality ADA data enables the evaluation of potential impact of ADAs on the drug pharmacokinetic profile, patient safety, and efficacious response to the drug. Immunogenicity assessments are typically initiated at early stages in preclinical studies and continue throughout the drug development program. One of the potential bioanalytical challenges encountered with ADA testing is the need to identify and mitigate the interference mediated by the presence of soluble drug target. A drug target, when present at sufficiently high circulating concentrations, can potentially interfere with the performance of ADA and neutralizing antibody (NAb) assays, leading to either false-positive or, in some cases, false-negative ADA and NAb assay results. This publication describes various mechanisms of assay interference by soluble drug target, as well as strategies to recognize and mitigate such target interference. Pertinent examples are presented to illustrate the impact of target interference on ADA and NAb assays as well as several mitigation strategies, including the use of anti-target antibodies, soluble versions of the receptors, target-binding proteins, lectins, and solid-phase removal of targets. Furthermore, recommendations for detection and mitigation of such interference in different formats of ADA and NAb assays are provided.

Endothelium as a Potential Target for Treatment of Abdominal Aortic Aneurysm

PubMed Central

Sun, Jingyuan; Deng, Hongping; Zhou, Zhen

2018-01-01

Abdominal aortic aneurysm (AAA) was previously ascribed to weaken defective medial arterial/adventitial layers, for example, smooth muscle/fibroblast cells. Therefore, besides surgical repair, medications targeting the medial layer to strengthen the aortic wall are the most feasible treatment strategy for AAA. However, so far, it is unclear whether such drugs have any beneficial effect on AAA prognosis, rate of aneurysm growth, rupture, or survival. Notably, clinical studies have shown that AAA is highly associated with endothelial dysfunction in the aged population. Additionally, animal models of endothelial dysfunction and endothelial nitric oxide synthase (eNOS) uncoupling had a very high rate of AAA formation, indicating there is crucial involvement of the endothelium and a possible pharmacological solution targeting the endothelium in AAA treatment. Endothelial cells have been found to trigger vascular wall remodeling by releasing proteases, or recruiting macrophages along with other neutrophils, into the medial layer. Moreover, inflammation and oxidative stress of the arterial wall were induced by endothelial dysfunction. Interestingly, there is a paradoxical differential correlation between diabetes and aneurysm formation in retinal capillaries and the aorta. Deciphering the significance of such a difference may explain current unsuccessful AAA medications and offer a solution to this treatment challenge. It is now believed that AAA and atherosclerosis are two separate but related diseases, based on their different clinical patterns which have further complicated the puzzle. Therefore, a thorough investigation of the interaction between endothelium and medial/adventitial layer may provide us a better understanding and new perspective on AAA formation, especially after taking into account the importance of endothelium in the development of AAA. Moreover, a novel medication strategy replacing the currently used, but suboptimal treatments for AAA, could be

Planning schistosomiasis control: investigation of alternative sampling strategies for Schistosoma mansoni to target mass drug administration of praziquantel in East Africa.

PubMed

Sturrock, Hugh J W; Gething, Pete W; Ashton, Ruth A; Kolaczinski, Jan H; Kabatereine, Narcis B; Brooker, Simon

2011-09-01

In schistosomiasis control, there is a need to geographically target treatment to populations at high risk of morbidity. This paper evaluates alternative sampling strategies for surveys of Schistosoma mansoni to target mass drug administration in Kenya and Ethiopia. Two main designs are considered: lot quality assurance sampling (LQAS) of children from all schools; and a geostatistical design that samples a subset of schools and uses semi-variogram analysis and spatial interpolation to predict prevalence in the remaining unsurveyed schools. Computerized simulations are used to investigate the performance of sampling strategies in correctly classifying schools according to treatment needs and their cost-effectiveness in identifying high prevalence schools. LQAS performs better than geostatistical sampling in correctly classifying schools, but at a cost with a higher cost per high prevalence school correctly classified. It is suggested that the optimal surveying strategy for S. mansoni needs to take into account the goals of the control programme and the financial and drug resources available.

Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies

PubMed Central

Foo, Jasmine; Michor, Franziska

2009-01-01

The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administration strategies so that the risk of resistance is minimized. In this paper, we investigate optimal drug dosing schedules to prevent, or at least delay, the emergence of resistance. We design and analyze a stochastic mathematical model describing the evolutionary dynamics of a tumor cell population during therapy. We consider drug resistance emerging due to a single (epi)genetic alteration and calculate the probability of resistance arising during specific dosing strategies. We then optimize treatment protocols such that the risk of resistance is minimal while considering drug toxicity and side effects as constraints. Our methodology can be used to identify optimum drug administration schedules to avoid resistance conferred by one (epi)genetic alteration for any cancer and treatment type. PMID:19893626

Translating Empirically Supported Strategies into Accessible Interventions: The Potential Utility of Exercise for the Treatment of Panic Disorder

ERIC Educational Resources Information Center

Smits, Jasper A. J.; Powers, Mark B.; Berry, Angela C.; Otto, Michael W.

2007-01-01

Many patients suffering from panic disorder do not receive adequate care. Advances in the conceptualization and treatment of panic disorder encourage innovative strategies for targeting core fears (fears of anxiety sensations) that underlie this disorder. In this article, we discuss the use of exercise as a potential strategy for therapeutic…

Target Acquired: Progress and Promise of Targeted Therapeutics in the Treatment of Prostate Cancer.

PubMed

Stuchbery, Ryan; Kurganovs, Natalie J; McCoy, Patrick J; Nelson, Colleen C; Hayes, Vanessa M; Corcoran, Niall M; Hovens, Christopher M

2015-01-01

Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient's disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.

CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia.

PubMed

Cramer, Paula; von Tresckow, Julia; Bahlo, Jasmin; Engelke, Anja; Langerbeins, Petra; Fink, Anna-Maria; Fischer, Kirsten; Wendtner, Clemens-Martin; Kreuzer, Karl-Anton; Stilgenbauer, Stephan; Böttcher, Sebastian; Eichhorst, Barbara; Hallek, Michael

2018-03-01

Four Phase II trials (clinical trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity. This strategy represents a new era of chronic lymphocytic leukemia therapy where chemotherapy is increasingly replaced by targeted agents and treatment duration is tailored to the patient's individual tumor load and response.

Newer antiatherosclerosis treatment strategies.

PubMed

Aggarwal, Amitesh; Singh, Safal

2011-01-01

Atherosclerosis has been a target of much clinical and molecular research. As a result of this extensive research, it is amply clear that atherogenesis is a multifactorial process involving an interplay of metabolic, immune and inflammatory mechanisms. Antiatherosclerotic strategies are today aiming for a multipronged approach targeting each arm of this multifactorial process. The newer agents under development can be divided into three broad categories: anti-inflammatory agents, modulators of intermediary metabolism and antiatherosclerosis vaccines. Potential targets for anti-inflammatory agents include inhibition of conversion of low-density lipoprotein (LDL) to oxidised LDL, blocking or downregulation of cell adhesion molecules, chemokine modulation and macrophage receptor blockade. Beyond inhibition of plaque formation, efforts are also ongoing to develop agents which stabilise the plaque by increasing its fibrous content and inhibiting its disruption. So far as research in the sphere of intermediary metabolism is concerned, the focus is now primarily on raising high-density lipoprotein and promoting reverse cholesterol transport; potential targets include cholesteryl ester transfer protein, liver X-receptor, lecithin cholesterol acyltransferase and high-density lipoprotein mimetics. Acyl-coenzymeA: cholesterol acyltransferase is another enzyme whose selective and differential inhibition is under active investigation. The concept of immunisation against a non-communicable disease such as atherosclerosis is still in its nascent stages. However, with increasing evidence to suggest the role of antigen-specific T-cell-mediated immunity in atherogenesis, this approach is potentially promising. Possible antigens under evaluation include oxidised LDL and its subparticles, heat-shock proteins and cholesteryl ester transfer protein. With cardiovascular disease being the single leading cause of death worldwide, the development of a safe and successful antiatherosclerosis

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

PubMed

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

2018-06-20

Well-balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in haematopoietic cells are SHP-1 and SHP-2. SHP-1, 2 promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP is another inhibitory phosphatase that is specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and SHIP deficiency results in myeloproliferation and B-cell lymphoma in mice. The validation of SHP-1, 2 and SHIP as oncology targets has generated interest in the development of inhibitors as potential therapeutic agents for cancers; however, SHP-1, 2 and SHIP have proven to be an extremely difficult target for drug discovery, primarily due to the highly conserved and positively charged nature of their PTP active site, and many PTP inhibitors lack either appro-priate selectivity or membrane permeability. To overcome these caveats, novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and amongst them; some are already in clinical development which are discussed in this review. © 2018 S. Karger AG, Basel.

SU-F-T-212: A Comparison of Treatment Strategies for Intracranial Stereotactic Radiosurgery

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

Lamberton, T; Slater, J; Wroe, A

2016-06-15

Purpose: Stereotactic radiosurgery is an effective and noninvasive treatment for intracranial lesions that uses highly focused radiation beams in a single treatment fraction. The purpose of this study is to investigate the dosimetric differences between the treatment brain metastasis with a proton beam vs. intensity modulated radiation therapy (IMRT). Methods: Ten separate brain metastasis targets where chosen and treatment plans were created for each, using three different strategies: custom proton beam shaping devices, standardized proton beam shaping devices, and IMRT. Each plan was required to satisfy set parameters for providing adequate coverage and minimizing risk to adjacent tissues. The effectivenessmore » of each plan was calculated by comparing the homogeneity index, conformity index, and V12 for each target using a paired one tailed T-test (α=0.05). Specific comparison of the conformity indices was also made using a subcategory containing targets with volume>1cc. Results: There was no significant difference between the homogeneity indices of the three plans (p>0.05), showing that each plan has the capability of adequately covering the targets. There was a statistically significant difference (p<0.01) between the conformity indices of the custom and the standard proton plan, as with the custom proton and IMRT (p<0.01), with custom proton showing stronger conformity to the target in both cases. There was also a statistical difference between the V12 of all three plans (Custom v. Standardized: p=0.02, Custom v. IMRT: p<0.01, Standardized v. IMRT: p<0.01) with custom proton supplying the lowest dose to surrounding tissues. For large targets (volume>1cc) there was no statistical difference between the proton plans and the IMRT treatment for the conformity index. Conclusion: A custom proton plan is the recommended treatment explored in this study as it is the most reliable way of effectively treating the target while sparing the maximum amount of normal

Sensory-Targeted Ankle Rehabilitation Strategies for Chronic Ankle Instability.

PubMed

McKeon, Patrick O; Wikstrom, Erik A

2016-05-01

Deficient sensory input from damaged ankle ligament receptors is thought to contribute to sensorimotor deficits in those with chronic ankle instability (CAI). Targeting other viable sensory receptors may then enhance sensorimotor control in these patients. The purpose of this randomized controlled trial was to evaluate the effects of 2 wk of sensory-targeted ankle rehabilitation strategies (STARS) on patient- and clinician-oriented outcomes in those with CAI. Eighty patients with self-reported CAI participated. All patients completed patient-oriented questionnaires capturing self-reported function as well as the weight-bearing lunge test and an eyes-closed single-limb balance test. After baseline testing, patients were randomly allocated to four STARS groups: joint mobilization, plantar massage, triceps surae stretching, or control. Each patient in the intervention groups received six 5-min treatments of their respective STARS over 2 wk. All subjects were reassessed on patient- and clinician-oriented measures immediately after the intervention and completed a 1-month follow-up that consisted of patient-oriented measures. Change scores of the three STARS groups were compared with the control using independent t-tests and Hedges' g effect sizes with 95% confidence intervals. The joint mobilization group had the greatest weight-bearing lunge test improvement. Plantar massage had the most meaningful single-limb balance improvement. All STARS groups improved patient-oriented outcomes with joint mobilization having the most meaningful effect immediately after the intervention and plantar massage at the 1-month follow-up. Each STARS treatment offers unique contributions to the patient- and clinician-oriented rehabilitation outcomes of those with CAI. Both joint mobilization and plantar massage appear to demonstrate the greatest potential to improve sensorimotor function in those with CAI.

Stakeholder analysis and mapping as targeted communication strategy.

PubMed

Shirey, Maria R

2012-09-01

This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advancing organizational change, content includes evidence-based projects, tools, and resources that mobilize and sustain organizational change initiatives. In this article, the author highlights the importance of stakeholder theory and discusses how to apply the theory to conduct a stakeholder analysis. This article also provides an explanation of how to use related stakeholder mapping techniques with targeted communication strategies.

Targeting CD4+ T cells for the treatment of sarcoidosis: a promising strategy?

PubMed Central

Celada, Lindsay J; Drake, Wonder P

2017-01-01

Sarcoidois is an inflammatory disease of unknown origin characterized by the abnormal accumulation of noncaseating granulomas at sites of disease activity in multiple organs throughout the body with a predilection for the lungs. Because the exact trigger that leads to disease activity is still under investigation, current treatment options are contingent on the organ or organs affected. Corticosteroids are the therapy of choice, but antimalarials and TNF-α antagonists are also commonly prescribed. Recent findings provide evidence for the use of CD20 B-cell-depleting therapy as an alternative method of choice. However, because sarcoidosis is predominantly a T-helper cell-driven disorder, an overwhelming amount of compelling evidence exists for the use of CD4+ T-cell targeted therapy. PMID:25572480

Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases.

PubMed

Pisani, L; Catto, M; Leonetti, F; Nicolotti, O; Stefanachi, A; Campagna, F; Carotti, A

2011-01-01

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

Inflammation and Immune Regulation as Potential Drug Targets in Antidepressant Treatment

PubMed Central

Schmidt, Frank M.; Kirkby, Kenneth C.; Lichtblau, Nicole

2016-01-01

Growing evidence supports a mutual relationship between inflammation and major depression. A variety of mechanisms are outlined, indicating how inflammation may be involved in the pathogenesis, course and treatment of major depression. In particular, this review addresses 1) inflammatory cytokines as markers of depression and potential predictors of treatment response, 2) findings that cytokines interact with antidepressants and non-pharmacological antidepressive therapies, such as electroconvulsive therapy, deep brain stimulation and physical activity, 3) the influence of cytokines on the cytochrome (CYP) p450-system and drug efflux transporters, and 4) how cascades of inflammation might serve as antidepressant drug targets. A number of clinical trials have focused on agents with immunmodulatory properties in the treatment of depression, of which this review covers nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, ketamine, polyunsaturated fatty acids, statins and curcumin. A perspective is also provided on possible future immune targets for antidepressant therapy, such as toll-like receptor-inhibitors, glycogen synthase kinase-3 inhibitors, oleanolic acid analogs and minocycline. Concluding from the available data, markers of inflammation may become relevant factors for more personalised planning and prediction of response of antidepressant treatment strategies. Agents with anti-inflammatory properties have the potential to serve as clinically relevant antidepressants. Further studies are required to better define and identify subgroups of patients responsive to inflammatory agents as well as to define optimal time points for treatment onset and duration. PMID:26769225

Targeted Treatment of Yaws With Household Contact Tracing: How Much Do We Miss?

PubMed Central

Dyson, Louise; Marks, Michael; Crook, Oliver M; Sokana, Oliver; Solomon, Anthony W; Bishop, Alex; Mabey, David C W; Hollingsworth, T Déirdre

2018-01-01

Abstract Yaws is a disabling bacterial infection found primarily in warm and humid tropical areas. The World Health Organization strategy mandates an initial round of total community treatment (TCT) with single-dose azithromycin followed either by further TCT or active case-finding and treatment of cases and their contacts (the Morges strategy). We sought to investigate the effectiveness of the Morges strategy. We employed a stochastic household model to study the transmission of infection using data collected from a pre-TCT survey conducted in the Solomon Islands. We used this model to assess the proportion of asymptomatic infections that occurred in households without active cases. This analysis indicated that targeted treatment of cases and their household contacts would miss a large fraction of asymptomatic infections (65%–100%). This fraction was actually higher at lower prevalences. Even assuming that all active cases and their households were successfully treated, our analysis demonstrated that at all prevalences present in the data set, up to 90% of (active and asymptomatic) infections would not be treated under household-based contact tracing. Mapping was undertaken as part of the study “Epidemiology of Yaws in the Solomon Islands and the Impact of a Trachoma Control Programme,” in September–October 2013. PMID:29140407

Evaluation of target coverage and margins adequacy during CyberKnife Lung Optimized Treatment.

PubMed

Ricotti, Rosalinda; Seregni, Matteo; Ciardo, Delia; Vigorito, Sabrina; Rondi, Elena; Piperno, Gaia; Ferrari, Annamaria; Zerella, Maria Alessia; Arculeo, Simona; Francia, Claudia Maria; Sibio, Daniela; Cattani, Federica; De Marinis, Filippo; Spaggiari, Lorenzo; Orecchia, Roberto; Riboldi, Marco; Baroni, Guido; Jereczek-Fossa, Barbara Alicja

2018-04-01

Evaluation of target coverage and verification of safety margins, in motion management strategies implemented by Lung Optimized Treatment (LOT) module in CyberKnife system. Three fiducial-less motion management strategies provided by LOT can be selected according to tumor visibility in the X ray images acquired during treatment. In 2-view modality the tumor is visible in both X ray images and full motion tracking is performed. In 1-view modality the tumor is visible in a single X ray image, therefore, motion tracking is combined with an internal target volume (ITV)-based margin expansion. In 0-view modality the lesion is not visible, consequently the treatment relies entirely on an ITV-based approach. Data from 30 patients treated in 2-view modality were selected providing information on the three-dimensional tumor motion in correspondence to each X ray image. Treatments in 1-view and 0-view modalities were simulated by processing log files and planning volumes. Planning target volume (PTV) margins were defined according to the tracking modality: end-exhale clinical target volume (CTV) + 3 mm in 2-view and ITV + 5 mm in 0-view. In the 1-view scenario, the ITV encompasses only tumor motion along the non-visible direction. Then, non-uniform ITV to PTV margins were applied: 3 mm and 5 mm in the visible and non-visible direction, respectively. We defined the coverage of each voxel of the CTV as the percentage of X ray images where such voxel was included in the PTV. In 2-view modality coverage was calculated as the intersection between the CTV centred on the imaged target position and the PTV centred on the predicted target position, as recorded in log files. In 1-view modality, coverage was calculated as the intersection between the CTV centred on the imaged target position and the PTV centred on the projected predictor data. In 0-view modality coverage was calculated as the intersection between the CTV centred on the imaged target position and the non

Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer.

PubMed

Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin

2017-08-10

One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metabolism in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metabolism in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

The key role of extinction learning in anxiety disorders: behavioral strategies to enhance exposure-based treatments.

PubMed

Pittig, Andre; van den Berg, Linda; Vervliet, Bram

2016-01-01

Extinction learning is a major mechanism for fear reduction by means of exposure. Current research targets innovative strategies to enhance fear extinction and thereby optimize exposure-based treatments for anxiety disorders. This selective review updates novel behavioral strategies that may provide cutting-edge clinical implications. Recent studies provide further support for two types of enhancement strategies. Procedural enhancement strategies implemented during extinction training translate to how exposure exercises may be conducted to optimize fear extinction. These strategies mostly focus on a maximized violation of dysfunctional threat expectancies and on reducing context and stimulus specificity of extinction learning. Flanking enhancement strategies target periods before and after extinction training and inform optimal preparation and post-processing of exposure exercises. These flanking strategies focus on the enhancement of learning in general, memory (re-)consolidation, and memory retrieval. Behavioral strategies to enhance fear extinction may provide powerful clinical applications to further maximize the efficacy of exposure-based interventions. However, future replications, mechanistic examinations, and translational studies are warranted to verify long-term effects and naturalistic utility. Future directions also comprise the interplay of optimized fear extinction with (avoidance) behavior and motivational antecedents of exposure.

Network pharmacology-based strategy for predicting active ingredients and potential targets of Yangxinshi tablet for treating heart failure.

PubMed

Chen, Langdong; Cao, Yan; Zhang, Hai; Lv, Diya; Zhao, Yahong; Liu, Yanjun; Ye, Guan; Chai, Yifeng

2018-01-31

Yangxinshi tablet (YXST) is an effective treatment for heart failure and myocardial infarction; it consists of 13 herbal medicines formulated according to traditional Chinese Medicine (TCM) practices. It has been used for the treatment of cardiovascular disease for many years in China. In this study, a network pharmacology-based strategy was used to elucidate the mechanism of action of YXST for the treatment of heart failure. Cardiovascular disease-related protein target and compound databases were constructed for YXST. A molecular docking platform was used to predict the protein targets of YXST. The affinity between proteins and ingredients was determined using surface plasmon resonance (SPR) assays. The action modes between targets and representative ingredients were calculated using Glide docking, and the related pathways were predicted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A protein target database containing 924 proteins was constructed; 179 compounds in YXST were identified, and 48 compounds with high relevance to the proteins were defined as representative ingredients. Thirty-four protein targets of the 48 representative ingredients were analyzed and classified into two categories: immune and cardiovascular systems. The SPR assay and molecular docking partly validated the interplay between protein targets and representative ingredients. Moreover, 28 pathways related to heart failure were identified, which provided directions for further research on YXST. This study demonstrated that the cardiovascular protective effect of YXST mainly involved the immune and cardiovascular systems. Through the research strategy based on network pharmacology, we analysis the complex system of YXST and found 48 representative compounds, 34 proteins and 28 related pathways of YXST, which could help us understand the underlying mechanism of YSXT's anti-heart failure effect. The network-based investigation could help researchers simplify the complex

Behavioral side effects of pediatric acute lymphoblastic leukemia treatment: the role of parenting strategies.

PubMed

Williams, Lauren K; Lamb, Karen E; McCarthy, Maria C

2014-11-01

Behavioral and emotional difficulties are a recognised side effect of childhood acute lymphoblastic leukemia (ALL) treatment. Modifiable factors, such as parenting strategies, may be an appropriate target for interventions to assist families with managing their child's behavior, potentially leading to improved psychosocial and clinical outcomes. This study examined whether parenting strategies are associated with child behavioral and emotional problems in a pediatric oncology context, with the aim of establishing whether parenting is a potential modifiable target for psychosocial intervention. Participants included 73 parents of children aged 2-6 years who were either (i) in the maintenance phase of treatment for ALL at the Royal Children's Hospital Children's Cancer Centre, Melbourne (N = 43), or (ii) had no major medical history (healthy control group) (N = 30). Participants completed psychometrically validated questionnaires that assessed parenting strategies and child emotional and behavioral problems. Results revealed that the ALL group parents reported higher lax parenting and more spoiling and bribing of their child than the healthy control group. Results from regression models indicated that, after controlling for the significant contribution of illness status and child age on child emotional and behavioral difficulties, parental laxness and parental overprotection were significantly associated with child emotional and behavioral difficulties. Supporting parents to minimise sub-optimal parenting strategies, particularly lax parenting, may offer a fruitful avenue for future research directed toward modifiable factors associated with managing child emotional and behavioral problems in a pediatric oncology context. © 2014 Wiley Periodicals, Inc.

cGMP signaling as a target for the prevention and treatment of breast cancer.

PubMed

Windham, Perrin F; Tinsley, Heather N

2015-04-01

One in eight women in the United States will be diagnosed with invasive breast cancer in her lifetime. Advances in therapeutic strategies, diagnosis, and improved awareness have resulted in a significant reduction in breast cancer related mortality. However, there is a continued need for more effective and less toxic drugs for both the prevention and the treatment of breast cancer in order to see a continued decline in the morbidity and mortality associated with this disease. Recent studies suggest that the cGMP signaling pathway may be aberrantly regulated in breast cancer. As such, this pathway may serve as a source of novel targets for future breast cancer drug discovery efforts. This review provides an overview of cGMP signaling in normal physiology and in breast cancer as well as current strategies being investigated for targeting this pathway in breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells

PubMed Central

Zhao, Yunqi; Duan, Shaofeng; Zeng, Xing; Liu, Chunjing; Davies, Neal M.; Li, Benyi; Forrest, M. Laird

2013-01-01

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment. PMID:22494444

Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics.

PubMed

Selbo, Pål Kristian; Bostad, Monica; Olsen, Cathrine Elisabeth; Edwards, Victoria Tudor; Høgset, Anders; Weyergang, Anette; Berg, Kristian

2015-08-01

Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs. The present review outlines our recent study on photochemical internalisation (PCI) using the clinically relevant photosensitiser TPCS2a/Amphinex® as a rational, non-invasive strategy for the light-controlled endosomal escape of CSC-targeting drugs. PCI is an intracellular drug delivery method based on light-induced ROS-generation and a subsequent membrane-disruption of endocytic vesicles, leading to cytosolic release of the entrapped drugs of interest. In different proof-of-concept studies we have demonstrated that PCI of CSC-directed immunotoxins targeting CD133, CD44, CSPG4 and EpCAM is a highly specific and effective strategy for killing cancer cells and CSCs. CSCs overexpressing CD133 are PDT-resistant; however, this is circumvented by PCI of CD133-targeting immunotoxins. In view of the fact that TPCS2a is not a substrate of the efflux pumps ABCG2 and P-glycoprotein (ABCB1), the PCI-method is a promising anti-CSC therapeutic strategy. Due to a laser-controlled exposure, PCI of CSC-targeting drugs will be confined exclusively to the tumour tissue, suggesting that this drug delivery method has the potential to spare distant normal stem cells.

Strategies of targeting oral drug delivery systems to the colon and their potential use for the treatment of colorectal cancer.

PubMed

Krishnaiah, Yellela S R; Khan, Mansoor A

2012-01-01

Colorectal cancer (CRC) is the third most common cause of cancer-related death in both men and women. Often, surgical intervention remains the choice in treating CRC. Traditional dosage forms used for treating CRC deliver drug to wanted as well as unwanted sites of drug action resulting in several adverse side effects. Targeted oral drug delivery systems are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific delivery of a drug to colon increases its concentration at the target site, and thus requires a lower dose with reduced incidence of side effects. The major obstacle to be overcome for successful targeting of drug to colon through oral route is that drug absorption/degradation must be avoided in stomach and small intestine before the dosage form reaches colon. The review includes discussion of physiological factors that must be considered when targeting drugs directly to colorectal region, an outline on drugs used for treatment and prevention of CRC, and a brief description of various types of colon-targeted oral drug delivery systems. The focus is on the assessment of various formulation approaches being investigated for oral colon-specific delivery of drugs used in the treatment and prevention of CRC.

Engaging Foster Parents in Treatment: A Randomized Trial of Supplementing Trauma-focused Cognitive Behavioral Therapy with Evidence-based Engagement Strategies

PubMed Central

Pullmann, Michael D.; Berliner, Lucy; Koschmann, Elizabeth; McKay, Mary; Deblinger, Esther

2014-01-01

The goal of this study was to examine the impact of supplementing Trauma-focused Cognitive Behavioral Therapy (TF-CBT; Cohen, Mannarino, & Deblinger, 2006) with evidence-based engagement strategies on foster parent and foster youth engagement in treatment, given challenges engaging foster parents in treatment. A randomized controlled trial of TF-CBT standard delivery compared to TF-CBT plus evidence-based engagement strategies was conducted with 47 children and adolescents in foster care and one of their foster parents. Attendence, engagement, and clinical outcomes were assessed 1 month into treatment, end of treatment, and 3 months post-treatment. Youth and foster parents who received TF-CBT plus evidence-based engagement strategies were more likely to be retained in treatment through four sessions and were less likely to drop out of treatment prematurely. The engagement strategies did not appear to have an effect on the number of cancelled or no-show sessions or on treatment satisfaction. Clinical outcomes did not differ by study condition, but exploratory analyses suggest that youth had significant improvements with treatment. Strategies that specifically target engagement may hold promise for increasing access to evidence-based practices and for increasing likelihood of treatment completion. PMID:24791605

Cognitive Function as a Trans-Diagnostic Treatment Target in Stimulant Use Disorders

PubMed Central

Sofuoglu, Mehmet; DeVito, Elise E.; Waters, Andrew J.; Carroll, Kathleen M.

2016-01-01

control and include cholinesterase inhibitors (e.g., galantamine, rivastigmine) and monoamine transporter inhibitors (e.g., modafinil, methylphenidate). Cognitive behavioral therapy and cognitive rehabilitation also enhance executive control, while cognitive bias modification targets impairments associated with automatic processes. Cognitive enhancements to improve treatment outcomes is a novel and promising strategy, but its clinical value for the treatment of stimulant use disorder, with or without other psychiatric comorbidities, remains to be determined in future studies. PMID:26828702

Molecules that target nucleophosmin for cancer treatment: an update

PubMed Central

Di Matteo, Adele; Franceschini, Mimma; Chiarella, Sara; Rocchio, Serena; Travaglini-Allocatelli, Carlo; Federici, Luca

2016-01-01

Nucleophosmin is a highly and ubiquitously expressed protein, mainly localized in nucleoli but able to shuttle between nucleus and cytoplasm. Nucleophosmin plays crucial roles in ribosome maturation and export, centrosome duplication, cell cycle progression, histone assembly and response to a variety of stress stimuli. Much interest in this protein has arisen in the past ten years, since the discovery of heterozygous mutations in the terminal exon of the NPM1 gene, which are the most frequent genetic alteration in acute myeloid leukemia. Nucleophosmin is also frequently overexpressed in solid tumours and, in many cases, its overexpression correlates with mitotic index and metastatization. Therefore it is considered as a promising target for the treatment of both haematologic and solid malignancies. NPM1 targeting molecules may suppress different functions of the protein, interfere with its subcellular localization, with its oligomerization properties or drive its degradation. In the recent years, several such molecules have been described and here we review what is currently known about them, their interaction with nucleophosmin and the mechanistic basis of their toxicity. Collectively, these molecules exemplify a number of different strategies that can be adopted to target nucleophosmin and we summarize them at the end of the review. PMID:27058426

Polymeric nanoparticles for targeted treatment in oncology: current insights

PubMed Central

Prabhu, Rashmi H; Patravale, Vandana B; Joshi, Medha D

2015-01-01

Chemotherapy, a major strategy for cancer treatment, lacks the specificity to localize the cancer therapeutics in the tumor site, thereby affecting normal healthy tissues and advocating toxic adverse effects. Nanotechnological intervention has greatly revolutionized the therapy of cancer by surmounting the current limitations in conventional chemotherapy, which include undesirable biodistribution, cancer cell drug resistance, and severe systemic side effects. Nanoparticles (NPs) achieve preferential accumulation in the tumor site by virtue of their passive and ligand-based targeting mechanisms. Polymer-based nanomedicine, an arena that entails the use of polymeric NPs, polymer micelles, dendrimers, polymersomes, polyplexes, polymer–lipid hybrid systems, and polymer–drug/protein conjugates for improvement in efficacy of cancer therapeutics, has been widely explored. The broad scope for chemically modifying the polymer into desired construct makes it a versatile delivery system. Several polymer-based therapeutic NPs have been approved for clinical use. This review provides an insight into the advances in polymer-based targeted nanocarriers with focus on therapeutic aspects in the field of oncology. PMID:25678788

Osteoclast-targeting small molecules for the treatment of neoplastic bone metastases.

PubMed

Kawatani, Makoto; Osada, Hiroyuki

2009-11-01

Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical/biological approach for identifying osteoclast-targeting small molecular inhibitors.

Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma.

PubMed

Van Goethem, Alan; Yigit, Nurten; Moreno-Smith, Myrthala; Vasudevan, Sanjeev A; Barbieri, Eveline; Speleman, Frank; Shohet, Jason; Vandesompele, Jo; Van Maerken, Tom

2017-08-22

Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway.

PubMed

Tremblay-LeMay, Rosemarie; Rastgoo, Nasrin; Chang, Hong

2018-03-27

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.

Comparison of provider and plan-based targeting strategies for disease management.

PubMed

Annis, Ann M; Holtrop, Jodi Summers; Tao, Min; Chang, Hsiu-Ching; Luo, Zhehui

2015-05-01

We aimed to describe and contrast the targeting methods and engagement outcomes for health plan-delivered disease management with those of a provider-delivered care management program. Health plan epidemiologists partnered with university health services researchers to conduct a quasi-experimental, mixed-methods study of a 2-year pilot. We used semi-structured interviews to assess the characteristics of program-targeting strategies, and calculated target and engagement rates from clinical encounter data. Five physician organizations (POs) with 51 participating practices implemented care management. Health plan member lists were sent monthly to the practices to accept patients, and then the practices sent back data reports regarding targeting and engagement in care management. Among patients accepted by the POs, we compared those who were targeted and engaged by POs with those who met health plan targeting criteria. The health plan's targeting process combined claims algorithms and employer group preferences to identify candidates for disease management; on the other hand, several different factors influenced PO practices' targeting approaches, including clinical and personal knowledge of the patients, health assessment information, and availability of disease-relevant programs. Practices targeted a higher percentage of patients for care management than the health plan (38% vs 16%), where only 7% of these patients met the targeting criteria of both. Practices engaged a higher percentage of their targeted patients than the health plan (50% vs 13%). The health plan's claims-driven targeting approach and the clinically based strategies of practices both provide advantages; an optimal model may be to combine the strengths of each approach to maximize benefits in care management.

Particle therapy of moving targets—the strategies for tumour motion monitoring and moving targets irradiation

PubMed Central

2016-01-01

Particle therapy of moving targets is still a great challenge. The motion of organs situated in the thorax and abdomen strongly affects the precision of proton and carbon ion radiotherapy. The motion is responsible for not only the dislocation of the tumour but also the alterations in the internal density along the beam path, which influence the range of particle beams. Furthermore, in case of pencil beam scanning, there is an interference between the target movement and dynamic beam delivery. This review presents the strategies for tumour motion monitoring and moving target irradiation in the context of hadron therapy. Methods enabling the direct determination of tumour position (fluoroscopic imaging of implanted radio-opaque fiducial markers, electromagnetic detection of inserted transponders and ultrasonic tumour localization systems) are presented. Attention is also drawn to the techniques which use external surrogate motion for an indirect estimation of target displacement during irradiation. The role of respiratory-correlated CT [four-dimensional CT (4DCT)] in the determination of motion pattern prior to the particle treatment is also considered. An essential part of the article is the review of the main approaches to moving target irradiation in hadron therapy: gating, rescanning (repainting), gated rescanning and tumour tracking. The advantages, drawbacks and development trends of these methods are discussed. The new accelerators, called “cyclinacs”, are presented, because their application to particle therapy will allow making a breakthrough in the 4D spot scanning treatment of moving organs. PMID:27376637

Wellness at work. Boost wellness center participation with target marketing strategies.

PubMed

DeMoranville, C W; Schoenbachler, D D; Przytulski, J

1998-01-01

By using target marketing strategies, corporate wellness programs can increase employee participation rates and tailor activities to meet employee needs. The authors examined this issue through a research survey that segmented a university's staff and employee population into three wellness program groups: High Participators, Moderate Participators, and Low Participators. Participators' views on the following issues were analyzed: health management programs, exercise programs, wellness center use inhibitors, wellness center use incentives, wellness center communications, and willingness to pay for the wellness center. The results identified unique lifestyle characteristics for each group that can help make target marketing strategies effective.

78 FR 14121 - Notice of Availability of Funds and Solicitation for Grant Applications for Strategies Targeting...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-04

... Solicitation for Grant Applications for Strategies Targeting Characteristics Common to Female Ex-Offenders... will be targeted to females, but must also be open to eligible male ex-offenders. Strategies Targeting Characteristics Common to Female Ex-Offenders grants [[Page 14122

Dosimetric evaluation of three adaptive strategies for prostate cancer treatment including pelvic lymph nodes irradiation

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

Cantin, Audrey; Gingras, Luc; Archambault, Louis, E-mail: louis.archambault@phy.ulaval.ca

Purpose: The movements of the prostate relative to the pelvic lymph nodes during intensity-modulated radiation therapy treatment can limit margin reduction and affect the protection of the organs at risk (OAR). In this study, the authors performed an analysis of three adaptive treatment strategies that combine information from both bony and gold marker registrations. The robustness of those treatments against the interfraction prostate movements was evaluated. Methods: A retrospective study was conducted on five prostate cancer patients with 7–13 daily cone-beam CTs (CBCTs). The clinical target volumes (CTVs) consisting of pelvic lymph nodes, prostate, and seminal vesicles as well asmore » the OARs were delineated on each CBCT and the initial CT. Three adaptive strategies were analyzed. Two of these methods relied on a two-step patient positioning at each fraction. First step: a bony registration was used to deliver the nodal CTV prescription. Second step: a gold marker registration was then used either to (1) complete the dose delivered to the prostate (complement); (2) or give almost the entire prescription to the prostate with a weak dose gradient between the targets to compensate for possible motions (gradient). The third method (COR) used a pool of precalculated plans based on images acquired at previous treatment fractions. At each new fraction, a plan is selected from that pool based on the daily position of prostate center-of-mass. The dosimetric comparison was conducted and results are presented with and without the systematic shift in the prostate position on the CT planning. The adaptive strategies were compared to the current clinical standard where all fractions are treated with the initial nonadaptive plan. Results: The minimum daily prostate D{sub 95%} is improved by 2%, 9%, and 6% for the complement, the gradient, and the COR approaches, respectively, compared to the nonadaptive method. The average nodal CTV D{sub 95%} remains constant across

Dosimetric evaluation of three adaptive strategies for prostate cancer treatment including pelvic lymph nodes irradiation.

PubMed

Cantin, Audrey; Gingras, Luc; Lachance, Bernard; Foster, William; Goudreault, Julie; Archambault, Louis

2015-12-01

The movements of the prostate relative to the pelvic lymph nodes during intensity-modulated radiation therapy treatment can limit margin reduction and affect the protection of the organs at risk (OAR). In this study, the authors performed an analysis of three adaptive treatment strategies that combine information from both bony and gold marker registrations. The robustness of those treatments against the interfraction prostate movements was evaluated. A retrospective study was conducted on five prostate cancer patients with 7-13 daily cone-beam CTs (CBCTs). The clinical target volumes (CTVs) consisting of pelvic lymph nodes, prostate, and seminal vesicles as well as the OARs were delineated on each CBCT and the initial CT. Three adaptive strategies were analyzed. Two of these methods relied on a two-step patient positioning at each fraction. First step: a bony registration was used to deliver the nodal CTV prescription. Second step: a gold marker registration was then used either to (1) complete the dose delivered to the prostate (complement); (2) or give almost the entire prescription to the prostate with a weak dose gradient between the targets to compensate for possible motions (gradient). The third method (COR) used a pool of precalculated plans based on images acquired at previous treatment fractions. At each new fraction, a plan is selected from that pool based on the daily position of prostate center-of-mass. The dosimetric comparison was conducted and results are presented with and without the systematic shift in the prostate position on the CT planning. The adaptive strategies were compared to the current clinical standard where all fractions are treated with the initial nonadaptive plan. The minimum daily prostate D95% is improved by 2%, 9%, and 6% for the complement, the gradient, and the COR approaches, respectively, compared to the nonadaptive method. The average nodal CTV D95% remains constant across the strategies, except for the gradient approach

The n-by-T Target Discharge Strategy for Inpatient Units.

PubMed

Parikh, Pratik J; Ballester, Nicholas; Ramsey, Kylie; Kong, Nan; Pook, Nancy

2017-07-01

Ineffective inpatient discharge planning often causes discharge delays and upstream boarding. While an optimal discharge strategy that works across all units at a hospital is likely difficult to identify and implement, a strategy that provides a reasonable target to the discharge team appears feasible. We used observational and retrospective data from an inpatient trauma unit at a Level 2 trauma center in the Midwest US. Our proposed novel n-by-T strategy-discharge n patients by the Tth hour-was evaluated using a validated simulation model. Outcome measures included 2 measures: time-based (mean discharge completion and upstream boarding times) and capacity-based (increase in annual inpatient and upstream bed hours). Data from the pilot implementation of a 2-by-12 strategy at the unit was obtained and analyzed. The model suggested that the 1-by-T and 2-by-T strategies could advance the mean completion times by over 1.38 and 2.72 h, respectively (for 10 AM ≤ T ≤ noon, occupancy rate = 85%); the corresponding mean boarding time reductions were nearly 11% and 15%. These strategies could increase the availability of annual inpatient and upstream bed hours by at least 2,469 and 500, respectively. At 100% occupancy rate, the hospital-favored 2-by-12 strategy reduced the mean boarding time by 26.1%. A pilot implementation of the 2-by-12 strategy at the unit corroborated with the model findings: a 1.98-h advancement in completion times (P<0.0001) and a 14.5% reduction in boarding times (P = 0.027). Target discharge strategies, such as the n-by-T, can help substantially reduce discharge lateness and upstream boarding, especially during high unit occupancy. To sustain implementation, necessary commitment from the unit staff and physicians is vital, and may require some training.

Engaging foster parents in treatment: a randomized trial of supplementing trauma-focused cognitive behavioral therapy with evidence-based engagement strategies.

PubMed

Dorsey, Shannon; Pullmann, Michael D; Berliner, Lucy; Koschmann, Elizabeth; McKay, Mary; Deblinger, Esther

2014-09-01

The goal of this study was to examine the impact of supplementing Trauma-focused Cognitive Behavioral Therapy (TF-CBT; Cohen et al., 2006) with evidence-based engagement strategies on foster parent and foster youth engagement in treatment, given challenges engaging foster parents in treatment. A randomized controlled trial of TF-CBT standard delivery compared to TF-CBT plus evidence-based engagement strategies was conducted with 47 children and adolescents in foster care and one of their foster parents. Attendance, engagement, and clinical outcomes were assessed 1 month into treatment, end of treatment, and 3 months post-treatment. Youth and foster parents who received TF-CBT plus evidence-based engagement strategies were more likely to be retained in treatment through four sessions and were less likely to drop out of treatment prematurely. The engagement strategies did not appear to have an effect on the number of canceled or no-show sessions or on treatment satisfaction. Clinical outcomes did not differ by study condition, but exploratory analyses suggest that youth had significant improvements with treatment. Strategies that specifically target engagement may hold promise for increasing access to evidence-based treatments and for increasing likelihood of treatment completion. Copyright © 2014 Elsevier Ltd. All rights reserved.

Targeting human breast cancer cells by an oncolytic adenovirus using microRNA-targeting strategy.

PubMed

Shayestehpour, Mohammad; Moghim, Sharareh; Salimi, Vahid; Jalilvand, Somayeh; Yavarian, Jila; Romani, Bizhan; Mokhtari-Azad, Talat

2017-08-15

MicroRNA-targeting strategy is a promising approach that enables oncolytic viruses to replicate in tumor cells but not in normal cells. In this study, we targeted adenoviral replication toward breast cancer cells by inserting ten complementary binding sites for miR-145-5p downstream of E1A gene. In addition, we evaluated the effect of increasing miR-145 binding sites on inhibition of virus replication. Ad5-control and adenoviruses carrying five or ten copies of miR145-5p target sites (Ad5-5miR145T, Ad5-10miR145T) were generated and inoculated into MDA-MB-453, BT-20, MCF-7 breast cancer cell lines and human mammary epithelial cells (HMEpC). Titer of Ad5-10miR145T in HMEpC was significantly lower than Ad5-control titer. Difference between the titer of these two viruses at 12, 24, 36, and 48h after infection was 1.25, 2.96, 3.06, and 3.77 log TCID 50 . No significant difference was observed between the titer of both adenoviruses in MDA-MB-453, BT-20 and MCF-7 cells. The infectious titer of adenovirus containing 10 miR-145 binding sites in HMEpC cells at 24, 36, and 48h post-infection was 1.7, 2.08, and 4-fold, respectively, lower than the titer of adenovirus carrying 5 miR-145 targets. Our results suggest that miR-145-targeting strategy provides selectivity for adenovirus replication in breast cancer cells. Increasing the number of miRNA binding sites within the adenoviral genome confers more selectivity for viral replication in cancer cells. Copyright © 2017. Published by Elsevier B.V.

Inverse targeting —An effective immunization strategy

NASA Astrophysics Data System (ADS)

Schneider, C. M.; Mihaljev, T.; Herrmann, H. J.

2012-05-01

We propose a new method to immunize populations or computer networks against epidemics which is more efficient than any continuous immunization method considered before. The novelty of our method resides in the way of determining the immunization targets. First we identify those individuals or computers that contribute the least to the disease spreading measured through their contribution to the size of the largest connected cluster in the social or a computer network. The immunization process follows the list of identified individuals or computers in inverse order, immunizing first those which are most relevant for the epidemic spreading. We have applied our immunization strategy to several model networks and two real networks, the Internet and the collaboration network of high-energy physicists. We find that our new immunization strategy is in the case of model networks up to 14%, and for real networks up to 33% more efficient than immunizing dynamically the most connected nodes in a network. Our strategy is also numerically efficient and can therefore be applied to large systems.

A method for evaluating cognitively informed micro-targeted campaign strategies: An agent-based model proof of principle

PubMed Central

Pilditch, Toby D.

2018-01-01

In political campaigns, perceived candidate credibility influences the persuasiveness of messages. In campaigns aiming to influence people’s beliefs, micro-targeted campaigns (MTCs) that target specific voters using their psychological profile have become increasingly prevalent. It remains open how effective MTCs are, notably in comparison to population-targeted campaign strategies. Using an agent-based model, the paper applies recent insights from cognitive models of persuasion, extending them to the societal level in a novel framework for exploring political campaigning. The paper provides an initial treatment of the complex dynamics of population level political campaigning in a psychologically informed manner. Model simulations show that MTCs can take advantage of the psychology of the electorate by targeting voters favourable disposed towards the candidate. Relative to broad campaigning, MTCs allow for efficient and adaptive management of complex campaigns. Findings show that disliked MTC candidates can beat liked population-targeting candidates, pointing to societal questions concerning campaign regulations. PMID:29634722

A method for evaluating cognitively informed micro-targeted campaign strategies: An agent-based model proof of principle.

PubMed

Madsen, Jens Koed; Pilditch, Toby D

2018-01-01

In political campaigns, perceived candidate credibility influences the persuasiveness of messages. In campaigns aiming to influence people's beliefs, micro-targeted campaigns (MTCs) that target specific voters using their psychological profile have become increasingly prevalent. It remains open how effective MTCs are, notably in comparison to population-targeted campaign strategies. Using an agent-based model, the paper applies recent insights from cognitive models of persuasion, extending them to the societal level in a novel framework for exploring political campaigning. The paper provides an initial treatment of the complex dynamics of population level political campaigning in a psychologically informed manner. Model simulations show that MTCs can take advantage of the psychology of the electorate by targeting voters favourable disposed towards the candidate. Relative to broad campaigning, MTCs allow for efficient and adaptive management of complex campaigns. Findings show that disliked MTC candidates can beat liked population-targeting candidates, pointing to societal questions concerning campaign regulations.

Advances in Risk Classification and Treatment Strategies for Neuroblastoma

PubMed Central

Pinto, Navin R.; Applebaum, Mark A.; Volchenboum, Samuel L.; Matthay, Katherine K.; London, Wendy B.; Ambros, Peter F.; Nakagawara, Akira; Berthold, Frank; Schleiermacher, Gudrun; Park, Julie R.; Valteau-Couanet, Dominique; Pearson, Andrew D.J.

2015-01-01

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations. PMID:26304901

Advances in Risk Classification and Treatment Strategies for Neuroblastoma.

PubMed

Pinto, Navin R; Applebaum, Mark A; Volchenboum, Samuel L; Matthay, Katherine K; London, Wendy B; Ambros, Peter F; Nakagawara, Akira; Berthold, Frank; Schleiermacher, Gudrun; Park, Julie R; Valteau-Couanet, Dominique; Pearson, Andrew D J; Cohn, Susan L

2015-09-20

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations. © 2015 by American Society of Clinical Oncology.

Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy.

PubMed

Zhu, Bo; Tang, Liming; Chen, Shuyang; Yin, Chengqian; Peng, Shiguang; Li, Xin; Liu, Tongzheng; Liu, Wei; Han, Changpeng; Stawski, Lukasz; Xu, Zhi-Xiang; Zhou, Guangbiao; Chen, Xiang; Gao, Xiumei; Goding, Colin R; Xu, Nan; Cui, Rutao; Cao, Peng

2018-05-22

Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8 + and CD4 + T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.

Oesophageal cancer treatment: studies, strategies and facts.

PubMed

Wobst, A; Audisio, R A; Colleoni, M; Geraghty, J G

1998-09-01

Esophageal cancer is among the ten most frequent cancers in the world. Once diagnosis is established prognosis is poor with five-year survival rates below 10%. Over the last few years, the evidence--base for treatment of oesophageal cancer has changed with the publication of several important articles in this field. This article reviews these and other relevant publications with focus on current evidence which holds potential for an improvement in survival in oesophageal cancer patients. Prevention and early detection represent the mainstay in the ongoing struggle to improve prognosis, which is most stringently linked to tumor stage. Other efforts have been dedicated to optimise surgical treatment, radiotherapy and chemotherapy and to discover the most efficient combinations of these treatment modalities. Strong but not unanimous evidence in favour of a multimodality approach with chemoradiotherapy followed by surgery has accumulated in recent years, and confirmatory trials are presently ongoing. A pathological complete response to chemoradiotherapy has been identified to significantly enhance survival. Among the strategies to achieve higher response rates, variations in the administration of the most commonly used drugs rather than higher drug and radiation dosages seem promising. Occult lymphatic spread has been recognized as a major source of recurrence and has been successfully targeted by three field surgical dissection and extended field radiotherapy. In search of the optimal treatment for patients with oesophageal cancer, a variety of different tracks are being pursued. This review outlines and analyses current treatment approaches and investigates how recent advances may impact on patient management.

Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment.

PubMed

Kintzing, James R; Filsinger Interrante, Maria V; Cochran, Jennifer R

2016-12-01

Protein-based therapeutics have been revolutionizing the oncology space since they first appeared in the clinic two decades ago. Unlike traditional small-molecule chemotherapeutics, protein biologics promote active targeting of cancer cells by binding to cell-surface receptors and other markers specifically associated with or overexpressed on tumors versus healthy tissue. While the first approved cancer biologics were monoclonal antibodies, the burgeoning field of protein engineering is spawning research on an expanded range of protein formats and modifications that allow tuning of properties such as target-binding affinity, serum half-life, stability, and immunogenicity. In this review we highlight some of these strategies and provide examples of modified and engineered proteins under development as preclinical and clinical-stage drug candidates for the treatment of cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Management of rheumatoid arthritis in clinical practice using treat-to-target strategy: Where do we stand in the multi-ethnic Malaysia population?

PubMed

Tan, Bee Eng; Lim, Ai Lee; Kan, Sow Lai; Lim, Chong Hong; Ng, Ying Fun; Tng, Serene Li Ching; Hassin, Nur Syakirah; Chandran, Losshenee; Hamid, Norshahida Abdul; Lee, Yvonne Yin Leng

2017-06-01

To evaluate the achievement of treat-to-target (T2T) strategy in rheumatoid arthritis (RA) and identify factors associated with failed treatment target in a public rheumatology center. A cross-sectional study was conducted from June 2015 to February 2016. RA patients with disease duration greater than 2 years and under T2T for over a year were invited to the study. Demographic, clinical data, disease activity score of 28 joints (DAS28), and clinical disease activity index (CDAI) were collected in a single routine clinic visit. Treatment target was defined as DAS28 <3.2 or CDAI ≤10. Retrospective chart review was performed to determine reasons of failed treatment target. A total of 371 patients were recruited and 87.1% were female. Mean age and duration of RA were 53.5 years (SD 10.3) and 9.1 years (SD 6.6), respectively. Ethnic distribution was 49% Chinese, 27% Malay, and 24% Indian. T2T was achieved in 81.7% of the cohort. Non-Chinese ethnicity, positive rheumatoid factor, and treatment with three disease modifying anti-rheumatic drugs (DMARDs) were associated with failed treatment target. After controlling for covariates, Malay ethnicity (OR 2.96; 95% CI 1.47-5.96) and treatment with three DMARDs (OR 2.14; 95% CI 1.06-4.35) were associated with failed treatment target. There was no association between age, gender, duration of RA, BMI, smoking status, anti-citrulinated cyclic peptide, and achievement of T2T. The most common reasons of failed treatment target were inability to escalate DMARDs due to side effects (18.8%), lack of biologics fund (15.6%), and persistent disease despite optimum treatment (14.1%). T2T was successfully implemented. Malay patients need aggressive treatment adaptation to achieve optimal outcome.

Point target detection utilizing super-resolution strategy for infrared scanning oversampling system

NASA Astrophysics Data System (ADS)

Wang, Longguang; Lin, Zaiping; Deng, Xinpu; An, Wei

2017-11-01

To improve the resolution of remote sensing infrared images, infrared scanning oversampling system is employed with information amount quadrupled, which contributes to the target detection. Generally the image data from double-line detector of infrared scanning oversampling system is shuffled to a whole oversampled image to be post-processed, whereas the aliasing between neighboring pixels leads to image degradation with a great impact on target detection. This paper formulates a point target detection method utilizing super-resolution (SR) strategy concerning infrared scanning oversampling system, with an accelerated SR strategy proposed to realize fast de-aliasing of the oversampled image and an adaptive MRF-based regularization designed to achieve the preserving and aggregation of target energy. Extensive experiments demonstrate the superior detection performance, robustness and efficiency of the proposed method compared with other state-of-the-art approaches.

Strategies for targeting primate neural circuits with viral vectors

PubMed Central

El-Shamayleh, Yasmine; Ni, Amy M.

2016-01-01

Understanding how the brain works requires understanding how different types of neurons contribute to circuit function and organism behavior. Progress on this front has been accelerated by optogenetics and chemogenetics, which provide an unprecedented level of control over distinct neuronal types in small animals. In primates, however, targeting specific types of neurons with these tools remains challenging. In this review, we discuss existing and emerging strategies for directing genetic manipulations to targeted neurons in the adult primate central nervous system. We review the literature on viral vectors for gene delivery to neurons, focusing on adeno-associated viral vectors and lentiviral vectors, their tropism for different cell types, and prospects for new variants with improved efficacy and selectivity. We discuss two projection targeting approaches for probing neural circuits: anterograde projection targeting and retrograde transport of viral vectors. We conclude with an analysis of cell type-specific promoters and other nucleotide sequences that can be used in viral vectors to target neuronal types at the transcriptional level. PMID:27052579

Clinical evaluation of 4D PET motion compensation strategies for treatment verification in ion beam therapy

NASA Astrophysics Data System (ADS)

Gianoli, Chiara; Kurz, Christopher; Riboldi, Marco; Bauer, Julia; Fontana, Giulia; Baroni, Guido; Debus, Jürgen; Parodi, Katia

2016-06-01

A clinical trial named PROMETHEUS is currently ongoing for inoperable hepatocellular carcinoma (HCC) at the Heidelberg Ion Beam Therapy Center (HIT, Germany). In this framework, 4D PET-CT datasets are acquired shortly after the therapeutic treatment to compare the irradiation induced PET image with a Monte Carlo PET prediction resulting from the simulation of treatment delivery. The extremely low count statistics of this measured PET image represents a major limitation of this technique, especially in presence of target motion. The purpose of the study is to investigate two different 4D PET motion compensation strategies towards the recovery of the whole count statistics for improved image quality of the 4D PET-CT datasets for PET-based treatment verification. The well-known 4D-MLEM reconstruction algorithm, embedding the motion compensation in the reconstruction process of 4D PET sinograms, was compared to a recently proposed pre-reconstruction motion compensation strategy, which operates in sinogram domain by applying the motion compensation to the 4D PET sinograms. With reference to phantom and patient datasets, advantages and drawbacks of the two 4D PET motion compensation strategies were identified. The 4D-MLEM algorithm was strongly affected by inverse inconsistency of the motion model but demonstrated the capability to mitigate the noise-break-up effects. Conversely, the pre-reconstruction warping showed less sensitivity to inverse inconsistency but also more noise in the reconstructed images. The comparison was performed by relying on quantification of PET activity and ion range difference, typically yielding similar results. The study demonstrated that treatment verification of moving targets could be accomplished by relying on the whole count statistics image quality, as obtained from the application of 4D PET motion compensation strategies. In particular, the pre-reconstruction warping was shown to represent a promising choice when combined with intra

New advances in targeted gastric cancer treatment.

PubMed

Lazăr, Daniela Cornelia; Tăban, Sorina; Cornianu, Marioara; Faur, Alexandra; Goldiş, Adrian

2016-08-14

Despite a decrease in incidence over past decades, gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours.

New advances in targeted gastric cancer treatment

PubMed Central

Lazăr, Daniela Cornelia; Tăban, Sorina; Cornianu, Marioara; Faur, Alexandra; Goldiş, Adrian

2016-01-01

Despite a decrease in incidence over past decades, gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours. PMID:27570417

[Improvement in zinc nutrition due to zinc transporter-targeting strategy].

PubMed

Kambe, Taiho

2016-07-01

Adequate intake of zinc from the daily diet is indispensable to maintain health. However, the dietary zinc content often fails to fulfill the recommended daily intake, leading to zinc deficiency and also increases the risk of developing chronic diseases, particularly in elderly individuals. Therefore, increased attention is required to overcome zinc deficiency and it is important to improve zinc nutrition in daily life. In the small intestine, the zinc transporter, ZIP4, functions as a component that is essential for zinc absorption. In this manuscript, we present a brief overview regarding zinc deficiency. Moreover, we review a novel strategy, called "ZIP4-targeting", which has the potential to enable efficient zinc absorption from the diet. ZIP4-targeting strategy is possibly a major step in preventing zinc deficiency and improving human health.

Modeling of the clinical and economic impact of a risk-sharing agreement supporting a treat-to-target strategy in the management of patients with rheumatoid arthritis in France.

PubMed

Fagnani, Francis; Pham, Thao; Claudepierre, Pascal; Berenbaum, Francis; De Chalus, Thibault; Saadoun, Carine; Joubert, Jean-Michel; Fautrel, Bruno

2016-08-01

To evaluate the cost-effectiveness of a Treat-to-Target strategy with certolizumab pegol in patients with rheumatoid arthritis in the context of a pay-for-performance agreement in which medication costs are refunded in case of discontinuation during the first 3 months of treatment. The Treat-to-Target strategy consisted of a systematic switch to second-line tumor necrosis factor (TNF)α inhibitor in case of an unmet ACR50 response at 3 months compared to current routine clinical practice. A reference cohort treated first-line with certolizumab pegol according to current practice without systematic switching was considered as the comparator. A decision-tree model was constructed to estimate clinical outcome (health assessment questionnaire-disability index or HAQ-DI score), time spent in ACR50 response (ACR 50), and direct costs of treatment over a 2-year period. HAQ scores were derived from American College of Rheumatology 50 (ACR50) responses. All TNFα inhibitors were assumed to have equivalent efficacy and tolerability. Costs were estimated at 2013 French retail prices (date of the pay-for-performance agreement). The mean duration of an ACR50 response was 1.23 years in the Treat-to-Target strategy certolizumab pegol cohort vs 0.98 years in the reference cohort, resulting in a mean gain in HAQ at 24 months of 0.117. The Treat-to-Target strategy with a mix of TNFα inhibitors as second-line therapy was more expensive than the reference strategy in absolute terms, but this difference was entirely offset by the pay-for-performance agreement. The Treat-to-Target strategy was, thus, cost-neutral over a 2-year period after the payback of CZP cost for patients not achieving the target at 3 months. In the context of a pay-for-performance agreement, the management of patients with rheumatoid arthritis using a Treat-to-Target strategy with certolizumab pegol in first line is dominant compared to standard use of this drug in the French setting in 2013.

Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment.

PubMed

Saadeh, Claire E

2005-04-01

Oral mucositis is a frequently encountered and potentially severe complication associated with administration of chemotherapy and radiotherapy. Although many pharmacologic interventions have been used for the prevention and treatment of oral mucositis, there is not one universally accepted strategy for its management. Most preventive and treatment strategies are based on limited, often anecdotal, clinical data. Basic oral hygiene and comprehensive patient education are important components of care for any patient with cancer at risk for development of oral mucositis. Nonpharmacologic approaches for the prevention of oral mucositis include oral cryotherapy for patients receiving chemotherapy with bolus 5-fluorouracil, and low-level laser therapy for patients undergoing hematopoietic stem cell transplantation. Chlorhexidine, amifostine, hematologic growth factors, pentoxifylline, glutamine, and several other agents have all been investigated for prevention of oral mucositis. Results have been conflicting, inconclusive, or of limited benefit. Treatment of established mucositis remains a challenge and focuses on a palliative management approach. Topical anesthetics, mixtures (also called cocktails), and mucosal coating agents have been used despite the lack of experimental evidence supporting their efficacy. Investigational agents are targeting the specific mechanisms of mucosal injury; among the most promising of these is recombinant human keratinocyte growth factor.

Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models.

PubMed

Ciamporcero, Eric; Miles, Kiersten Marie; Adelaiye, Remi; Ramakrishnan, Swathi; Shen, Li; Ku, ShengYu; Pizzimenti, Stefania; Sennino, Barbara; Barrera, Giuseppina; Pili, Roberto

2015-01-01

Alternative pathways to the VEGF, such as hepatocyte growth factor or HGF/c-met, are emerging as key players in tumor angiogenesis and resistance to anti-VEGF therapies. The aim of this study was to assess the effects of a combination strategy targeting the VEGF and c-met pathways in clear cell renal cell carcinoma (ccRCC) models. Male SCID mice (8/group) were implanted with 786-O tumor pieces and treated with either a selective VEGF receptor tyrosine kinase inhibitor, axitinib (36 mg/kg, 2×/day); a c-met inhibitor, crizotinib (25 mg/kg, 1×/day); or combination. We further tested this drug combination in a human ccRCC patient-derived xenograft, RP-R-01, in both VEGF-targeted therapy-sensitive and -resistant models. To evaluate the resistant phenotype, we established an RP-R-01 sunitinib-resistant model by continuous sunitinib treatment (60 mg/kg, 1×/day) of RP-R-01-bearing mice. Treatment with single-agent crizotinib reduced tumor vascularization but failed to inhibit tumor growth in either model, despite also a significant increase of c-met expression and phosphorylation in the sunitinib-resistant tumors. In contrast, axitinib treatment was effective in inhibiting angiogenesis and tumor growth in both models, with its antitumor effect significantly increased by the combined treatment with crizotinib, independently from c-met expression. Combination treatment also induced prolonged survival and significant tumor growth inhibition in the 786-O human RCC model. Overall, our results support the rationale for the clinical testing of combined VEGF and HGF/c-met pathway blockade in the treatment of ccRCC, both in first- and second-line setting. ©2014 American Association for Cancer Research.

TARGETED TREATMENTS IN AUTISM AND FRAGILE X SYNDROME

PubMed Central

Gürkan, C. Kağan; Hagerman, Randi J.

2012-01-01

Autism is a neurodevelopmental disorder consisting of a constellation of symptoms that sometimes occur as part of a complex disorder characterized by impairments in social interaction, communication and behavioral domains. It is a highly disabling disorder and there is a need for treatment targeting the core symptoms. Although autism is accepted as highly heritable, there is no genetic cure at this time. Autism is shown to be linked to several genes and is a feature of some complex genetic disorders, including fragile X syndrome (FXS), fragile X premutation involvement, tuberous sclerosis and Rett syndrome. The term autism spectrum disorders (ASDs) covers autism, Asperger syndrome and pervasive developmental disorders (PDD-NOS) and the etiologies are heterogeneous. In recent years, targeted treatments have been developed for several disorders that have a known specific genetic cause leading to autism. Since there are significant molecular and neurobiological overlaps among disorders, targeted treatments developed for a specific disorder may be helpful in ASD of unknown etiology. Examples of this are two drug classes developed to treat FXS, Arbaclofen, a GABAB agonist, and mGluR5 antagonists, and both may be helpful in autism without FXS. The mGluR5 antagonists are also likely to have a benefit in the aging problems of fragile X premutation carriers, the fragile X –associated tremor ataxia syndrome (FXTAS) and the Parkinsonism that can occur in aging patients with fragile X syndrome. Targeted treatments in FXS which has a well known genetic etiology may lead to new targeted treatments in autism. PMID:23162607

"Real-life" treatment of chronic pain: Targets and goals.

PubMed

Ablin, Jacob N; Buskila, Dan

2015-02-01

Treating chronic pain is a complex challenge. While textbooks and medical education classically categorize pain as originating from peripheral (nociceptive), neuropathic, or centralized origins, in real life each and every patient may present a combination of various pain sources, types, and mechanisms. Moreover, individual patients may evolve and develop differing types of pain throughout their clinical follow-up, further emphasizing the necessity to maintain clinical diligence during the evaluation and follow-up of these patients. Rational treatment of patients suffering from chronic pain must attempt at deconstructing complex pain cases, identifying variegate pain generators, and targeting them with appropriate interventions, while incorporating both pharmacological and non-pharmacological strategies, rather than focusing on the total pain level, which represents an integral of all pain types. Failing to recognize the coexistence of different types of pain in an individual patient and escalating medications only on the basis of total pain intensity are liable to lead to both ineffective control of pain and increased untoward effects. In the current review, we outline strategies for deconstructing complex pain and therapeutic suggestions. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rett syndrome treatment in mouse models: searching for effective targets and strategies.

PubMed

Ricceri, Laura; De Filippis, Bianca; Laviola, Giovanni

2013-05-01

Rett syndrome (RTT) is a pervasive developmental disorder, primarily affecting girls with a prevalence of 1 in every 10,000 births; it represents the second most common cause of intellectual disability in females. Mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) have been identified as clear etiological factors in more than 90% of classical RTT cases. Whereas the mechanisms leading to the severe, progressive and specific neurological dysfunctions when this gene is mutated still remain to be elucidated, a series of different mouse models have been generated, bearing different Mecp2 mutation. Neurobehavioural analysis in these mouse lines have been carried out and phenotyping analysis can be now utilised to preclinically evaluate the effects of potential RTT treatments. This review summarizes the different results achieved in this research field taking into account different key targets identified to ameliorate RTT phenotype in mouse models, including those not directly downstream of MeCP2 and those limited to the early phases of postnatal development. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Telepsychiatrists' Medication Treatment Strategies in the Children's Attention-Deficit/Hyperactivity Disorder Telemental Health Treatment Study

PubMed Central

Tse, Yuet Juhn; Fesinmeyer, Megan D.; Garcia, Jessica; Myers, Kathleen

2016-01-01

Abstract Objective: The purpose of this study was to examine the prescribing strategies that telepsychiatrists used to provide pharmacologic treatment in the Children's Attention-Deficit/Hyperactivity Disorder (ADHD) Telemental Health Treatment Study (CATTS). Methods: CATTS was a randomized controlled trial that demonstrated the superiority of a telehealth service delivery model for the treatment of ADHD with combined pharmacotherapy and behavior training (n=111), compared with management in primary care augmented with a telepsychiatry consultation (n=112). A diagnosis of ADHD was established with the Computerized Diagnostic Interview Schedule for Children (CDISC), and comorbidity for oppositional defiant disorder (ODD) and anxiety disorders (AD) was established using the CDISC and the Child Behavior Checklist. Telepsychiatrists used the Texas Children's Medication Algorithm Project (TCMAP) for ADHD to guide pharmacotherapy and the treat-to-target model to encourage their assertive medication management to a predetermined goal of 50% reduction in ADHD-related symptoms. We assessed whether telepsychiatrists' decision making about making medication changes was associated with baseline ADHD symptom severity, comorbidity, and attainment of the treat-to-target goal. Results: Telepsychiatrists showed high fidelity (91%) to their chosen algorithms in medication management. At the end of the trial, the CATTS intervention showed 46.0% attainment of the treat-to-target goal compared with 13.6% for the augmented primary care condition, and significantly greater attainment of the goal by comorbidity status for the ADHD with one and ADHD with two comorbidities groups. Telepsychiatrists' were more likely to decide to make medication adjustments for youth with higher baseline ADHD severity and the presence of disorders comorbid with ADHD. Multiple mixed methods regression analyses controlling for baseline ADHD severity and comorbidity status indicated that the telepsychiatrists

Performance and strategy comparisons of human listeners and logistic regression in discriminating underwater targets.

PubMed

Yang, Lixue; Chen, Kean

2015-11-01

To improve the design of underwater target recognition systems based on auditory perception, this study compared human listeners with automatic classifiers. Performances measures and strategies in three discrimination experiments, including discriminations between man-made and natural targets, between ships and submarines, and among three types of ships, were used. In the experiments, the subjects were asked to assign a score to each sound based on how confident they were about the category to which it belonged, and logistic regression, which represents linear discriminative models, also completed three similar tasks by utilizing many auditory features. The results indicated that the performances of logistic regression improved as the ratio between inter- and intra-class differences became larger, whereas the performances of the human subjects were limited by their unfamiliarity with the targets. Logistic regression performed better than the human subjects in all tasks but the discrimination between man-made and natural targets, and the strategies employed by excellent human subjects were similar to that of logistic regression. Logistic regression and several human subjects demonstrated similar performances when discriminating man-made and natural targets, but in this case, their strategies were not similar. An appropriate fusion of their strategies led to further improvement in recognition accuracy.

Surface Functionalization and Targeting Strategies of Liposomes in Solid Tumor Therapy: A Review

PubMed Central

Riaz, Muhammad Kashif; Riaz, Muhammad Adil; Zhang, Xue; Lin, Congcong; Wong, Ka Hong; Chen, Xiaoyu; Lu, Aiping

2018-01-01

Surface functionalization of liposomes can play a key role in overcoming the current limitations of nanocarriers to treat solid tumors, i.e., biological barriers and physiological factors. The phospholipid vesicles (liposomes) containing anticancer agents produce fewer side effects than non-liposomal anticancer formulations, and can effectively target the solid tumors. This article reviews information about the strategies for targeting of liposomes to solid tumors along with the possible targets in cancer cells, i.e., extracellular and intracellular targets and targets in tumor microenvironment or vasculature. Targeting ligands for functionalization of liposomes with relevant surface engineering techniques have been described. Stimuli strategies for enhanced delivery of anticancer agents at requisite location using stimuli-responsive functionalized liposomes have been discussed. Recent approaches for enhanced delivery of anticancer agents at tumor site with relevant surface functionalization techniques have been reviewed. Finally, current challenges of functionalized liposomes and future perspective of smart functionalized liposomes have been discussed. PMID:29315231

The blood-brain barrier as a target in traumatic brain injury treatment.

PubMed

Thal, Serge C; Neuhaus, Winfried

2014-11-01

Traumatic brain injury (TBI) is one of the most frequent causes of death in the young population. Several clinical trials have unsuccessfully focused on direct neuroprotective therapies. Recently immunotherapeutic strategies shifted into focus of translational research in acute CNS diseases. Cross-talk between activated microglia and blood-brain barrier (BBB) could initiate opening of the BBB and subsequent recruitment of systemic immune cells and mediators into the brain. Stabilization of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage and acute neurodegeneration. This review provides an overview on the pathophysiology of TBI and brain edema formation including definitions and classification of TBI, current clinical treatment strategies, as well as current understanding on the underlying cellular processes. A summary of in vivo and in vitro models to study different aspects of TBI is presented. Three mechanisms proposed for stabilization of the BBB, myosin light chain kinases, glucocorticoid receptors and peroxisome proliferator-activated receptors are reviewed for their influence on barrier-integrity and outcome after TBI. In conclusion, the BBB is recommended as a promising target for the treatment of traumatic brain injury, and it is suggested that a combination of BBB stabilization and neuroprotectants may improve therapeutic success. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents.

PubMed

Ma, Brigette B Y; Bristow, Robert G; Kim, John; Siu, Lillian L

2003-07-15

Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity. This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors. Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity. Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration.

PubMed

Lin, Tai-Chi; Hung, Kuo-Hsuan; Peng, Chi-Hsien; Liu, Jorn-Hon; Woung, Lin-Chung; Tsai, Ching-Yao; Chen, Shih-Jen; Chen, Yan-Ting; Hsu, Chih-Chien

2015-11-01

Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF) and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration. Copyright © 2015. Published by Elsevier Taiwan.

Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model

PubMed Central

Lineweaver, Charles H.; Davies, Paul C.W.; Vincent, Mark D.

2014-01-01

In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. PMID:25043755

Treatment strategy based on targeting P-glycoprotein on peripheral lymphocytes in patients with systemic autoimmune disease.

PubMed

Tsujimura, Shizuyo; Tanaka, Yoshiya

2012-02-01

Although corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) are widely used in the treatment of various systemic autoimmune diseases such as systemic lupus erythematosus (SLE), we often experience patients with systemic autoimmune diseases who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, is known to play a pivotal role in the acquisition of drug resistance to chemotherapy in malignancy. However, the relevance of MDR-1 and P-gp to resting and activated lymphocytes, which are the major target in the treatment of systemic autoimmune diseases, remains unclear. Studies from our laboratories found surface expression of P-gp on peripheral lymphocytes in patients with SLE and a significant correlation between the expression level and disease activity. Such expression is induced not only by genotoxic stresses but also by various stimuli including cytokines, resulting in active efflux of drugs from the cytoplasm of lymphocytes, resulting in drug-resistance and high disease activity. However, the use of both P-gp antagonists (e.g., cyclosporine) and inhibition of P-gp synthesis with intensive immunosuppressive therapy successfully reduces the efflux of corticosteroids from lymphocytes in vitro, suggesting that P-gp antagonists and P-gp synthesis inhibitors could be used to overcome drug-resistance in vivo and improve outcome. In conclusion, lymphocytes activated by various stimuli in patients with highly active disease apparently acquire MDR-1-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. The expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable target to combat drug resistance in patients with active systemic autoimmune diseases.

Targeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy.

PubMed

Li, Lin; Di, Xingsheng; Wu, Mingrui; Sun, Zhisu; Zhong, Lu; Wang, Yongjun; Fu, Qiang; Kan, Qiming; Sun, Jin; He, Zhonggui

2017-04-01

Designing active targeting nanocarriers with increased cellular accumulation of chemotherapeutic agents is a promising strategy in cancer therapy. Herein, we report a novel active targeting strategy based on the large amino acid transporter 1 (LAT1) overexpressed in a variety of cancers. Glutamate was conjugated to polyoxyethylene stearate as a targeting ligand to achieve LAT1-targeting PLGA nanoparticles. The targeting efficiency of nanoparticles was investigated in HeLa and MCF-7 cells. Significant increase in cellular uptake and cytotoxicity was observed in LAT1-targeting nanoparticles compared to the unmodified ones. More interestingly, the internalized LAT1 together with targeting nanoparticles could recycle back to the cell membrane within 3 h, guaranteeing sufficient transporters on cell membrane for continuous cellular uptake. The LAT1 targeting nanoparticles exhibited better tumor accumulation and antitumor effects. These results suggested that the overexpressed LAT1 on cancer cells holds a great potential to be a high-efficiency target for the rational design of active-targeting nanosystems. Copyright © 2016 Elsevier Inc. All rights reserved.

Fragile X Syndrome and Targeted Treatment Trials

PubMed Central

Lauterborn, Julie; Au, Jacky; Berry-Kravis, Elizabeth

2014-01-01

Work in recent years has revealed an abundance of possible new treatment targets for fragile X syndrome (FXS). The use of animal models, including the fragile X knockout mouse which manifests a phenotype very similar to FXS in humans, has resulted in great strides in this direction of research. The lack of Fragile X Mental Retardation Protein (FMRP) in FXS causes dysregulation and usually overexpression of a number of its target genes, which can cause imbalances of neurotransmission and deficits in synaptic plasticity. The use of metabotropic glutamate receptor (mGluR) blockers and gamma amino-butyric acid (GABA) agonists have been shown to be efficacious in reversing cellular and behavioral phenotypes, and restoring proper brain connectivity in the mouse and fly models. Proposed new pharmacological treatments and educational interventions are discussed in this chapter. In combination, these various targeted treatments show promising preliminary results in mitigating or even reversing the neurobiological abnormalities caused by loss of FMRP, with possible translational applications to other neurodevelopmental disorders including autism. PMID:22009360

Fragile X syndrome and targeted treatment trials.

PubMed

Hagerman, Randi; Lauterborn, Julie; Au, Jacky; Berry-Kravis, Elizabeth

2012-01-01

Work in recent years has revealed an abundance of possible new treatment targets for fragile X syndrome (FXS). The use of animal models, including the fragile X knockout mouse which manifests a phenotype very similar to FXS in humans, has resulted in great strides in this direction of research. The lack of Fragile X Mental Retardation Protein (FMRP) in FXS causes dysregulation and usually overexpression of a number of its target genes, which can cause imbalances of neurotransmission and deficits in synaptic plasticity. The use of metabotropic glutamate receptor (mGluR) blockers and gamma amino-butyric acid (GABA) agonists have been shown to be efficacious in reversing cellular and behavioral phenotypes, and restoring proper brain connectivity in the mouse and fly models. Proposed new pharmacological treatments and educational interventions are discussed in this chapter. In combination, these various targeted treatments show promising preliminary results in mitigating or even reversing the neurobiological abnormalities caused by loss of FMRP, with possible translational applications to other neurodevelopmental disorders including autism.

Targeting of glycine site on NMDA receptor as a possible new strategy for autism treatment.

PubMed

Ghanizadeh, Ahmad

2011-05-01

The exact pathophysiology of the neurodevelopment disorder of autism is not clear and there is not any curative approach for it. There is only one FDA-approved medication for its management. Therefore, providing of novel treatments is highly required. The hypofunction of GABAergic system and glutamate toxicity are generally believed to have a causal role for autism. The antagonist of the N-methyl-D-aspartic acid (NMDA) glutamate receptor improves autism. Glycine is required for the activation of NMDA receptor. The antagonist of glycine site decreases NMDA receptor conductance. It is hypothesis that glycine site antagonists can be tested as a new strategy for the management of autism.

STAT3 targeting by polyphenols: Novel therapeutic strategy for melanoma.

PubMed

Momtaz, Saeideh; Niaz, Kamal; Maqbool, Faheem; Abdollahi, Mohammad; Rastrelli, Luca; Nabavi, Seyed Mohammad

2017-05-06

Melanoma or malignant melanocytes appear with the low incidence rate, but very high mortality rate worldwide. Epidemiological studies suggest that polyphenolic compounds contribute for prevention or treatment of several cancers particularly melanoma. Such findings motivate to dig out novel therapeutic strategies against melanoma, including research toward the development of new chemotherapeutic and biologic agents that can target the tumor cells by different mechanisms. Recently, it has been found that signal transducer and activator of transcription 3 (STAT3) is activated in many cancer cases surprisingly. Different evidences supply the aspect that STAT3 activation plays a vital role in the metastasis, including proliferation of cells, survival, invasion, migration, and angiogenesis. This significant feature plays a vital role in various cellular processes, such as cell proliferation and survival. Here, we reviewed the mechanisms of the STAT3 pathway regulation and their role in promoting melanoma. Also, we have evaluated the emerging data on polyphenols (PPs) specifically their contribution in melanoma therapies with an emphasis on their regulatory/inhibitory actions in relation to STAT3 pathway and current progress in the development of phytochemical therapeutic techniques. An understanding of targeting STAT3 by PPs brings an opportunity to melanoma therapy. © 2016 BioFactors, 43(3):347-370, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

Emerging immunotherapy and strategies directly targeting B cells for the treatment of diffuse large B-cell lymphoma.

PubMed

Witkowska, Magdalena; Smolewski, Piotr

2015-01-01

During the last decade, significant prolonged survival in diffusive large B-cell lymphoma (DLBCL) has been observed. The efficacy of initial treatment improved mostly due to addition of a chimeric anti-CD20 monoclonal antibody (rituximab) to standard chemotherapeutic regimens. Moreover, accurate understanding of DLBCL pathogenesis and remarkable progress in gene expression profiling have led to the development of a variety of tumor-specific regimens. Novel agents target directly the pathways involved in signal transduction, lead to apoptosis and cancer cells differentiation. In this article, we mainly focus on new treatment options, such as monoclonal antibodies, tyrosine kinase inhibitors and immunomodulatory drugs, currently investigated in aggressive B-cell lymphoma with particular attention to DLBCL type.

Treatment Strategies for Hypopigmentation in the Context of Burn Hypertrophic Scars

PubMed Central

Carney, Bonnie C.; McKesey, Jacqueline P.; Rosenthal, Dean S.

2018-01-01

Dyspigmentation in burn scars can contribute to the development of psychosocial complications after injury and can be detrimental to social reintegration and quality of life for burn survivors. Although treatments for skin lightening to treat hyperpigmentation have been well reviewed in the literature, skin-darkening strategies to treat hypopigmentation have not. The following potential treatment options in the context of burn hypertrophic scar will be discussed: use of the melanocyte-keratinocyte transplantation procedure, use of ectopic synthetic analogues of alpha-melanocyte stimulating hormone to initiate melanogenesis, and use of FK506 to induce melanogenesis. A proposed future direction of research in laser-assisted drug delivery of inducers of local melanin production, with the hope of developing a targeted, effective approach to dyspigmentation in hypertrophic scar is also discussed. PMID:29464168

Neurotransmitter-based strategies for the treatment of cognitive dysfunction in Down syndrome.

PubMed

Das, Devsmita; Phillips, Cristy; Hsieh, Wayne; Sumanth, Krithika; Dang, Van; Salehi, Ahmad

2014-10-03

Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimer's disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important roles in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration. Published by Elsevier Inc.

Strategies to target non-T-cell HIV reservoirs.

PubMed

Sacha, Jonah B; Ndhlovu, Lishomwa C

2016-07-01

A central question for the HIV cure field is to determine new ways to target clinically relevant, latently and actively replicating HIV-infected cells beyond resting memory CD4 T cells, particularly in anatomical areas of low drug penetrability. HIV eradication strategies being positioned for targeting HIV for extinction in the CD4 T-cell compartment may also show promise in non-CD4 T-cells reservoirs. Furthermore, several exciting novel therapeutic approaches specifically focused on HIV clearance from non-CD4 T-cell populations are being developed. Although reservoir validity in these non-CD4 T cells continues to remain debated, this review will highlight recent advances and make an argument as to their clinical relevancy as we progress towards an HIV cure.

Predictive and preventive strategies to advance the treatments of cardiovascular and cerebrovascular diseases: the Ukrainian context

PubMed Central

2012-01-01

Despite great efforts in treatments of cardiovascular diseases, the field requires innovative strategies because of high rates of morbidity, mortality and disability, indicating evident deficits in predictive vascular diagnosis and individualized treatment approaches. Talking about the vascular system, currently, physicians are not provided with integrated medical approaches to diagnose and treat vascular diseases. Only an individual global approach to the analysis of all segments in the vascular system of a patient allows finding the optimal way for vascular disease treatment. As for the existing methodology, there is a dominance of static methods such as X-ray contrast angiography and magnetic resonance imaging in angiomode. Taking into account the world experience, this article deals with innovative strategies, aiming at predictive diagnosis in vascular system, personalization of the biomedical treatment approaches, and targeted prevention of individual patient cohorts. Clinical examples illustrate the advances in corresponding healthcare sectors. Recommendations are provided to promote the field. PMID:23083430

Novel Therapeutic Target for the Treatment of Lupus

DTIC Science & Technology

2014-09-01

AWARD NUMBER: W81XWH-12-1-0205 TITLE: Novel Therapeutic Target for the Treatment of Lupus PRINCIPAL INVESTIGATOR: Lisa Laury-Kleintop...SUBTITLE 5a. CONTRACT NUMBER Novel Therapeutic Target for the Treatment of Lupus 5b. GRANT NUMBER W81XWH-12-1-0205 5c. PROGRAM ELEMENT NUMBER 6...Systemic lupus erythematosus, autoantibodies. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 7 19a. NAME OF

Construction and applications of exon-trapping gene-targeting vectors with a novel strategy for negative selection.

PubMed

Saito, Shinta; Ura, Kiyoe; Kodama, Miho; Adachi, Noritaka

2015-06-30

Targeted gene modification by homologous recombination provides a powerful tool for studying gene function in cells and animals. In higher eukaryotes, non-homologous integration of targeting vectors occurs several orders of magnitude more frequently than does targeted integration, making the gene-targeting technology highly inefficient. For this reason, negative-selection strategies have been employed to reduce the number of drug-resistant clones associated with non-homologous vector integration, particularly when artificial nucleases to introduce a DNA break at the target site are unavailable or undesirable. As such, an exon-trap strategy using a promoterless drug-resistance marker gene provides an effective way to counterselect non-homologous integrants. However, constructing exon-trapping targeting vectors has been a time-consuming and complicated process. By virtue of highly efficient att-mediated recombination, we successfully developed a simple and rapid method to construct plasmid-based vectors that allow for exon-trapping gene targeting. These exon-trap vectors were useful in obtaining correctly targeted clones in mouse embryonic stem cells and human HT1080 cells. Most importantly, with the use of a conditionally cytotoxic gene, we further developed a novel strategy for negative selection, thereby enhancing the efficiency of counterselection for non-homologous integration of exon-trap vectors. Our methods will greatly facilitate exon-trapping gene-targeting technologies in mammalian cells, particularly when combined with the novel negative selection strategy.

[Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies].

PubMed

Bachelot, Thomas; Le Rhun, Emilie; Labidi-Gally, Intidar; Heudel, Pierre; Gilabert, Marine; Bonneterre, Jacques; Pierga, Jean-Yves; Gonçalves, Anthony

2013-01-01

Prevalence of brain metastases is increasing in breast cancer. Brain metastases represent a poor-prognosis disease for which local treatments continue to play a major role. In spite of the presence of a physiological blood-brain barrier limiting their activity, some systemic treatments may display a significant antitumor activity at the central nervous system level. In HER2-positive metastatic breast cancer with brain metastases not previously treated with whole brain radiotherapy, capecitabine and lapatinib combination obtains a volumetric reponse in two thirds of patients (LANDSCAPE study). If confirmed, these results could modify in selected patients the layout of therapeutic strategies. Promoting novel targeted approaches and innovative therapeutic combinations is a critical need to improve survival of breast cancer patients with brain metastases.

Nonspecific Organelle-Targeting Strategy with Core-Shell Nanoparticles of Varied Lipid Components/Ratios.

PubMed

Zhang, Lu; Sun, Jiashu; Wang, Yilian; Wang, Jiancheng; Shi, Xinghua; Hu, Guoqing

2016-07-19

We report a nonspecific organelle-targeting strategy through one-step microfluidic fabrication and screening of a library of surface charge- and lipid components/ratios-varied lipid shell-polymer core nanoparticles. Different from the common strategy relying on the use of organelle-targeted moieties conjugated onto the surface of nanoparticles, here, we program the distribution of hybrid nanoparticles in lysosomes or mitochondria by tuning the lipid components/ratios in shell. Hybrid nanoparticles with 60% 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 20% 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) can intracellularly target mitochondria in both in vitro and in vivo models. While replacing DOPE with the same amount of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the nanoparticles do not show mitochondrial targeting, indicating an incremental effect of cationic and fusogenic lipids on lysosomal escape which is further studied by molecular dynamics simulations. This work unveils the lipid-regulated subcellular distribution of hybrid nanoparticles in which target moieties and complex synthetic steps are avoided.

Treatment of 9L gliosarcoma in rats by ferrociphenol-loaded lipid nanocapsules based on a passive targeting strategy via the EPR effect.

PubMed

Huynh, Ngoc Trinh; Morille, Marie; Bejaud, Jerome; Legras, Pierre; Vessieres, Anne; Jaouen, Gerard; Benoit, Jean-Pierre; Passirani, Catherine

2011-12-01

To study a passive targeting strategy, via the enhanced permeability and retention effect following systemic administration of lipid nanocapsules (LNCs) loaded with ferrociphenol, FcdiOH. Long chains of polyethylene glycol (DSPE-mPEG2000) were incorporated onto the surface of LNCs by post-insertion technique. Stealth properties of LNCs were investigated by in vitro complement consumption and macrophage uptake, and in vivo pharmacokinetics in healthy rats. Antitumour effect of FcdiOH-loaded LNCs was evaluated in subcutaneous and intracranial 9L gliosarcoma rat models. LNCs and DSPE-mPEG2000-LNCs presented low complement activation and weak macrophage uptake. DSPE-mPEG2000-LNCs exhibited prolonged half-life and extended area under the curve in healthy rats. In a subcutaneous gliosarcoma model, a single intravenous injection of FcdiOH-LNCs (400 μL, 2.4 mg/rat) considerably inhibited tumour growth when compared to the control. DSPE-mPEG2000-FcdiOH-LNCs exhibited a strong antitumour effect by nearly eradicating the tumour by the end of the study. In intracranial gliosarcoma model, treatment with DSPE-mPEG2000-FcdiOH-LNCs and FcdiOH-LNCs statistically improved median survival time (28 and 27.5 days, respectively) compared to the control (25 days). These results demonstrate the interesting perspectives for the systemic treatment of glioma thanks to bio-organometallic chemotherapy via lipid nanocapsules.

A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology

PubMed Central

Durrant, Jacob D.; Amaro, Rommie E.; Xie, Lei; Urbaniak, Michael D.; Ferguson, Michael A. J.; Haapalainen, Antti; Chen, Zhijun; Di Guilmi, Anne Marie; Wunder, Frank; Bourne, Philip E.; McCammon, J. Andrew

2010-01-01

Conventional drug design embraces the “one gene, one drug, one disease” philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology. PMID:20098496

A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology.

PubMed

Durrant, Jacob D; Amaro, Rommie E; Xie, Lei; Urbaniak, Michael D; Ferguson, Michael A J; Haapalainen, Antti; Chen, Zhijun; Di Guilmi, Anne Marie; Wunder, Frank; Bourne, Philip E; McCammon, J Andrew

2010-01-22

Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology.

Strategies for target identification of antimicrobial natural products.

PubMed

Farha, Maya A; Brown, Eric D

2016-05-04

Covering: 2000 to 2015Despite a pervasive decline in natural product research at many pharmaceutical companies over the last two decades, natural products have undeniably been a prolific and unsurpassed source for new lead antibacterial compounds. Due to their inherent complexity, natural extracts face several hurdles in high-throughout discovery programs, including target identification. Target identification and validation is a crucial process for advancing hits through the discovery pipeline, but has remained a major bottleneck. In the case of natural products, extremely low yields and limited compound supply further impede the process. Here, we review the wealth of target identification strategies that have been proposed and implemented for the characterization of novel antibacterials. Traditionally, these have included genomic and biochemical-based approaches, which, in recent years, have been improved with modern-day technology and better honed for natural product discovery. Further, we discuss the more recent innovative approaches for uncovering the target of new antibacterial natural products, which have resulted from modern advances in chemical biology tools. Finally, we present unique screening platforms implemented to streamline the process of target identification. The different innovative methods to respond to the challenge of characterizing the mode of action for antibacterial natural products have cumulatively built useful frameworks that may advocate a renovated interest in natural product drug discovery programs.

Dual peptide conjugation strategy for improved cellular uptake and mitochondria targeting.

PubMed

Lin, Ran; Zhang, Pengcheng; Cheetham, Andrew G; Walston, Jeremy; Abadir, Peter; Cui, Honggang

2015-01-21

Mitochondria are critical regulators of cellular function and survival. Delivery of therapeutic and diagnostic agents into mitochondria is a challenging task in modern pharmacology because the molecule to be delivered needs to first overcome the cell membrane barrier and then be able to actively target the intracellular organelle. Current strategy of conjugating either a cell penetrating peptide (CPP) or a subcellular targeting sequence to the molecule of interest only has limited success. We report here a dual peptide conjugation strategy to achieve effective delivery of a non-membrane-penetrating dye 5-carboxyfluorescein (5-FAM) into mitochondria through the incorporation of both a mitochondrial targeting sequence (MTS) and a CPP into one conjugated molecule. Notably, circular dichroism studies reveal that the combined use of α-helix and PPII-like secondary structures has an unexpected, synergistic contribution to the internalization of the conjugate. Our results suggest that although the use of positively charged MTS peptide allows for improved targeting of mitochondria, with MTS alone it showed poor cellular uptake. With further covalent linkage of the MTS-5-FAM conjugate to a CPP sequence (R8), the dually conjugated molecule was found to show both improved cellular uptake and effective mitochondria targeting. We believe these results offer important insight into the rational design of peptide conjugates for intracellular delivery.

MTTE: an innovative strategy for the evaluation of targeted/exome enrichment efficiency

PubMed Central

Klonowska, Katarzyna; Handschuh, Luiza; Swiercz, Aleksandra; Figlerowicz, Marek; Kozlowski, Piotr

2016-01-01

Although currently available strategies for the preparation of exome-enriched libraries are well established, a final validation of the libraries in terms of exome enrichment efficiency prior to the sequencing step is of considerable importance. Here, we present a strategy for the evaluation of exome enrichment, i.e., the Multipoint Test for Targeted-enrichment Efficiency (MTTE), PCR-based approach utilizing multiplex ligation-dependent probe amplification with capillary electrophoresis separation. We used MTTE for the analysis of subsequent steps of the Illumina TruSeq Exome Enrichment procedure. The calculated values of enrichment-associated parameters (i.e., relative enrichment, relative clearance, overall clearance, and fold enrichment) and the comparison of MTTE results with the actual enrichment revealed the high reliability of our assay. Additionally, the MTTE assay enabled the determination of the sequence-associated features that may confer bias in the enrichment of different targets. Importantly, the MTTE is low cost method that can be easily adapted to the region of interest important for a particular project. Thus, the MTTE strategy is attractive for post-capture validation in a variety of targeted/exome enrichment NGS projects. PMID:27572310

MTTE: an innovative strategy for the evaluation of targeted/exome enrichment efficiency.

PubMed

Klonowska, Katarzyna; Handschuh, Luiza; Swiercz, Aleksandra; Figlerowicz, Marek; Kozlowski, Piotr

2016-10-11

Although currently available strategies for the preparation of exome-enriched libraries are well established, a final validation of the libraries in terms of exome enrichment efficiency prior to the sequencing step is of considerable importance. Here, we present a strategy for the evaluation of exome enrichment, i.e., the Multipoint Test for Targeted-enrichment Efficiency (MTTE), PCR-based approach utilizing multiplex ligation-dependent probe amplification with capillary electrophoresis separation. We used MTTE for the analysis of subsequent steps of the Illumina TruSeq Exome Enrichment procedure. The calculated values of enrichment-associated parameters (i.e., relative enrichment, relative clearance, overall clearance, and fold enrichment) and the comparison of MTTE results with the actual enrichment revealed the high reliability of our assay. Additionally, the MTTE assay enabled the determination of the sequence-associated features that may confer bias in the enrichment of different targets. Importantly, the MTTE is low cost method that can be easily adapted to the region of interest important for a particular project. Thus, the MTTE strategy is attractive for post-capture validation in a variety of targeted/exome enrichment NGS projects.

Targeted therapies for the treatment of leukemia.

PubMed

Stull, Dawn Marie

2003-05-01

To review novel targeted therapies for the treatment of leukemia. Professional journals, books, and government publications. Nonspecific cytotoxic chemotherapeutic agents provide marginal therapeutic benefit and significant toxicity when used in the treatment of leukemia. There is a tremendous need for new therapies with increased efficacy and decreased adverse effects. Advances in molecular science, genetics, and immunology, along with improved laboratory technology, have led to the discovery of unique targets integral to the growth and proliferation of malignant cells which are providing the foundation for the development of a new generation of antitumor agents. Nurses must be prepared to educate patients, administer novel therapies, and manage side effects.

Feasibility of reaching world health organization targets for hepatitis C and the cost-effectiveness of alternative strategies.

PubMed

Wisløff, T; White, R; Dalgard, O; Amundsen, E J; Meijerink, H; Kløvstad, H

2018-04-06

New drugs for treating hepatitis C have considerably increased the probability of being cured. Treatment uptake, however, is still low. The objectives of this study were to analyse the impact of initiatives that may increase the proportion of infected people on treatment and interventions aimed at reducing the incidence of new infection among people who inject drugs. A compartmental model for Norway was used to simulate hepatitis C and related complications. We analysed 2 different screening initiatives aimed to increase the proportion of infected people on treatment. Interventions aiming at reducing the hepatitis C incidence analysed were opioid substitution therapy (OST), a clean needle and syringe programme and a combination of both. The most cost-effective strategy for increasing hepatitis C treatment uptake was screening by general practitioners while simultaneously allowing for all infected people to be treated. We estimated that this intervention reduces the incidence of hepatitis C by 2030 by 63% compared with the current incidence. The 2 harm reduction strategies both reduced the incidence of hepatitis C by about 70%. Combining an increase in the current clean needles and syringe programme with OST was clearly the most cost-effective option. This strategy would reduce the incidence of hepatitis C by 80% compared with the current incidence by 2030. Thus, interventions to reduce the burden and spread of hepatitis C are cost-effective. Reaching the WHO target of a 90% reduction in hepatitis C incidence by 2030 may be difficult without combining different initiatives. © 2018 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.

Development of practice and consensus-based strategies including a treat-to-target approach for the management of moderate and severe juvenile dermatomyositis in Germany and Austria.

PubMed

Hinze, Claas H; Oommen, Prasad T; Dressler, Frank; Urban, Andreas; Weller-Heinemann, Frank; Speth, Fabian; Lainka, Elke; Brunner, Jürgen; Fesq, Heike; Foell, Dirk; Müller-Felber, Wolfgang; Neudorf, Ulrich; Rietschel, Christoph; Schwarz, Tobias; Schara, Ulrike; Haas, Johannes-Peter

2018-06-25

Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM. The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements. Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease. Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

PubMed

Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

2016-12-01

Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

Maladaptive repetitive thought as a transdiagnostic phenomenon and treatment target: An integrative review.

PubMed

Kaplan, Deanna M; Palitsky, Roman; Carey, Angela L; Crane, Tracy E; Havens, Cody M; Medrano, Michael R; Reznik, Samantha J; Sbarra, David A; O'Connor, Mary-Frances

2018-07-01

Maladaptive repetitive thought (RT), the frequent and repetitive revisiting of thoughts or internal experiences, is associated with a range of psychopathological processes and disorders. We present a synthesis of prior research on maladaptive RT and develop a framework for elucidating and distinguishing between five forms of maladaptive RT. In addition to the previously studied maladaptive RT (worry, rumination, and obsession), this framework is used to identify two additional forms of maladaptive RT (yearning and interoceptive RT). We then present a review of extant psychotherapy intervention research targeting maladaptive RT, focusing both on specific empirically based treatment strategies, and also constructs within treatments that impact maladaptive RT. The paper concludes with recommendations for future basic and intervention research on maladaptive RT and related psychopathologies. © 2018 Wiley Periodicals, Inc.

The long-term outcomes of four alternative treatment strategies for primary open-angle glaucoma.

PubMed

van Gestel, Aukje; Webers, Carroll A; Severens, Johan L; Beckers, Henny J; Jansonius, Nomdo M; Hendrikse, Fred; Schouten, Jan S

2012-02-01

To evaluate the long-term effects and costs of four treatment strategies for primary open-angle glaucoma compared to usual care. Cost-effectiveness analyses with a lifelong horizon were made from a societal perspective. Data were generated with a patient-level model based on discrete event simulation. The model structure and parameter estimates were based on literature, particularly clinical studies on the natural course of glaucoma and the effect of treatment. We simulated heterogeneous cohorts of 3000 patients and explored the impact of uncertainty with sensitivity analyses. The incremental cost-effectiveness ratio (ICER) of initial treatment with a prostaglandin analogue compared with a β-blocker was €12.931 per quality-adjusted life year (QALY) gained. A low initial target pressure (15 mmHg) resulted in 0.115 QALYs gained and €1550 saved compared to a gradual decrease from 21 to 15 mmHg upon progression. Visual field (VF) measurements every 6 rather than 12 months lead to health gains at increased costs (ICER €173,486 per QALY gained), whereas measurements every 24 months lead to health losses at reduced costs (ICER €21,516 per QALY lost). All treatment strategies were dominant over 'withholding treatment'. From a cost-effectiveness point of view, it seems advantageous to aim for a low intraocular pressure in all glaucoma patients. The feasibility of this strategy should therefore be investigated. Additionally, the cost-effectiveness outcomes of initiating monotherapy with a prostaglandin analogue and reducing the frequency of VF testing may be acceptable. © 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.

Drug discovery strategies to outer membrane targets in Gram-negative pathogens.

PubMed

Brown, Dean G

2016-12-15

This review will cover selected recent examples of drug discovery strategies which target the outer membrane (OM) of Gram-negative bacteria either by disruption of outer membrane function or by inhibition of essential gene products necessary for outer membrane assembly. Significant advances in pathway elucidation, structural biology and molecular inhibitor designs have created new opportunities for drug discovery within this target-class space. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fortification of foods with vitamin D in India: strategies targeted at children.

PubMed

G, Ritu; Gupta, Ajay

2015-01-01

Vitamin D deficiency is endemic in India, despite abundant sunshine, due to several socioeconomic and cultural constraints. Fortification of staple foods with vitamin D is a viable population-based strategy for the general population in India. These strategies are discussed in the review article entitled, "Fortification of Foods With Vitamin D in India" [1]. The quantity of foods consumed by children is much smaller compared to adults. Therefore, children need energy-dense and micronutrient-dense foods to meet their daily nutritional requirements. Targeted food fortification programs are needed to meet the special needs of children. This review explores potential strategies that could be used for fortification of foods with vitamin D for children in India. Sattu has the potential to be a valuable vehicle for vitamin D fortification in India. The salient characteristics and merits of sattu as an ideal food to be fortified with micronutrients, especially vitamin D, are reviewed here. Key teaching points: • Fortification of foods with vitamin D, specifically targeted towards the nutritional requirements of infants and children, is a viable strategy in the Indian scenario. •Government programs targeting the nutritional needs of children in India, especially via midday meal programs in schools, should incorporate indigenous ready-to-eat foods fortified with micronutrients including vitamin D. These foods would need to have longer shelf life, require minimal preparation, and have economic and technological feasibility. • Sattu, a protein rich Indian fast food, comprised of roasted flour made from cereals and legumes, has immense potential to serve as an economically and technologically feasible fortification vehicle for vitamin D fortification strategies.

Estimation of dynamic treatment strategies for maintenance therapy of children with acute lymphoblastic leukaemia: an application of history-adjusted marginal structural models.

PubMed

Rosthøj, S; Keiding, N; Schmiegelow, K

2012-02-28

Childhood acute lymphoblastic leukaemia is treated with long-term intensive chemotherapy. During the latter part of the treatment, the maintenance therapy, the patients receive oral doses of two cytostatics. The doses are tailored to blood counts measured on a weekly basis, and the treatment is therefore highly dynamic. In 1992-1996, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) conducted a randomised study (NOPHO-ALL-92) to investigate the effect of a new and more sophisticated dynamic treatment strategy. Unexpectedly, the new strategy worsened the outcome for the girls, whereas there were no treatment differences for the boys. There are as yet no general guidelines for optimising the treatment. On basis of the data from this study, our goal is to formulate an alternative dosing strategy. We use recently developed methods proposed by van der Laan et al. to obtain statistical models that may be used in the guidance of how the physicians should assign the doses to the patients to obtain the target of the treatment. We present a possible strategy and discuss the reliability of this strategy. The implementation is complicated, and we touch upon the limitations of the methods in relation to the formulation of alternative dosing strategies for the maintenance therapy. Copyright © 2011 John Wiley & Sons, Ltd.

Therapeutic gene targeting approaches for the treatment of dyslipidemias and atherosclerosis.

PubMed

Mäkinen, Petri I; Ylä-Herttuala, Seppo

2013-04-01

Despite improved therapies, cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Therefore, new therapeutic approaches are still needed. In the gene therapy field, RNA interference (RNAi) and regulation of microRNAs (miRNAs) have gained a lot of attention in addition to traditional overexpression based strategies. Here, recent findings in therapeutic gene silencing and modulation of small RNA expression related to atherogenesis and dyslipidemia are summarized. Novel gene therapy approaches for the treatment of hyperlipidemia have been addressed. Antisense oligonucleotide and RNAi-based therapies against apolipoprotein B100 and proprotein convertase subtilisin/kexin type 9 have shown already efficacy in preclinical and clinical trials. In addition, several miRNAs dysregulated in atherosclerotic lesions and regulating cholesterol homeostasis have been found, which may represent novel targets for future therapies. New therapies for lowering lipid levels are now being tested in clinical trials, and both antisense oligonucleotide and RNAi-based therapies have shown promising results in lowering cholesterol levels. However, the modulation of inflammatory component in atherosclerosis by gene therapy and targeting of the effects to plaques are still difficult challenges.

Marine natural products for multi-targeted cancer treatment: A future insight.

PubMed

Kumar, Maushmi S; Adki, Kaveri M

2018-05-30

Cancer is world's second largest alarming disease, which involves abnormal cell growth and have potential to spread to other parts of the body. Most of the available anticancer drugs are designed to act on specific targets by altering the activity of involved transporters and genes. As cancer cells exhibit complex cellular machinery, the regeneration of cancer tissues and chemo resistance towards the therapy has been the main obstacle in cancer treatment. This fact encourages the researchers to explore the multitargeted use of existing medicines to overcome the shortcomings of chemotherapy for alternative and safer treatment strategies. Recent developments in genomics-proteomics and an understanding of the molecular pharmacology of cancer have also challenged researchers to come up with target-based drugs. The literature supports the evidence of natural compounds exhibiting antioxidant, antimitotic, anti-inflammatory, antibiotic as well as anticancer activity. In this review, we have selected marine sponges as a prolific source of bioactive compounds which can be explored for their possible use in cancer and have tried to link their role in cancer pathway. To prove this, we revisited the literature for the selection of cancer genes for the multitargeted use of existing drugs and natural products. We used Cytoscape network analysis and Search tool for retrieval of interacting genes/ proteins (STRING) to study the possible interactions to show the links between the antioxidants, antibiotics, anti-inflammatory and antimitotic agents and their targets for their possible use in cancer. We included total 78 pathways, their genes and natural compounds from the above four pharmacological classes used in cancer treatment for multitargeted approach. Based on the Cytoscape network analysis results, we shortlist 22 genes based on their average shortest path length connecting one node to all other nodes in a network. These selected genes are CDKN2A, FH, VHL, STK11, SUFU, RB1

Macrophage Repolarization with Targeted Alginate Nanoparticles Containing IL-10 Plasmid DNA for the Treatment of Experimental Arthritis

PubMed Central

Jain, Shardool; Tran, Thanh-Huyen; Amiji, Mansoor

2015-01-01

In this study, we have shown for the first time the effectiveness of a non-viral gene transfection strategy to re-polarize macrophages from M1 to M2 functional sub-type for the treatment of rheumatoid arthritis (RA). An anti-inflammatory (IL-10) cytokine encoding plasmid DNA was successfully encapsulated into non-condensing alginate based nanoparticles and the surface of the nano-carriers was modified with tuftsin peptide to achieve active macrophage targeting. Enhanced localization of tuftsin-modified alginate nanoparticles was observed in the inflamed paws of arthritic rats upon intraperitoneal administration. Importantly, targeted nanoparticle treatment was successful in reprogramming macrophage phenotype balance as ~66% of total synovial macrophages from arthritic rats treated with the IL-10 plasmid DNA loaded tuftsin/alginate nanoparticles were in the M2 state compared to ~9% of macrophages in the M2 state from untreated arthritic rats. Treatment significantly reduced systemic and joint tissue pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression and prevented the progression of inflammation and joint damage as revealed by magnetic resonance imaging and histology. Treatment enabled animals to retain their mobility throughout the course of study, whereas untreated animals suffered from impaired mobility. Overall, this study demonstrates that targeted alginate nanoparticles loaded with IL-10 plasmid DNA can efficiently re-polarize macrophages from an M1 to an M2 state, offering a novel treatment paradigm for treatment of chronic inflammatory diseases. PMID:26004232

[Therapeutic strategies targeting brain tumor stem cells].

PubMed

Toda, Masahiro

2009-07-01

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

Recent Advances in Targeted Therapy for Glioma.

PubMed

Lin, Lin; Cai, Jinquan; Jiang, Chuanlu

2017-01-01

Gliomas are the most common primary malignant brain tumors, which have a universally fatal outcome. Current standard treatment for glioma patients is surgical removal followed by radiotherapy and adjuvant chemotherapy. Due to therapeutic resistance and tumor recurrence, efforts are ongoing to identify the molecules that are fundamental to regulate the tumor progression and provide additional methods for individual treatment of glioma patients. By studying the initiation and maintenance of glioma, studies focused on the targets of tyrosine kinase receptors including EGFR, PDGFR and other crucial signal pathways such as PI3K/AKT and RAS/RAF/MAPK pathway. Furthermore, recent advances in targeting immunotherapy and stem cell therapy also brought numerous strategies to glioma treatment. This article reviewed the researches focused on the advanced strategies of various target therapies for improving the glioma treatment efficacy, and discussed the challenges and future directions for glioma therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

Maneuver Analysis and Targeting Strategy for the Stardust Re-Entry Capsule

NASA Technical Reports Server (NTRS)

Helfrich, Cliff; Bhat, Ramachand S.; Kangas, Julie A.; Wilson, Roby S.; Wong, Mau C.; Potts, Christopher L.; Williams, Kenneth E.

2006-01-01

The Stardust Sample Return Capsule (SRC) returned to Earth on January 15, 2006 after seven years of collecting interstellar and comet particles over three heliocentric revolutions, as shown in Figure 1. The SRC was carried on board the Stardust spacecraft, as shown in Figure 2. Because the spacecraft was built with unbalanced thrusters, turns and attitude control maintenance resulted in undesirable delta-v being imparted to the trajectory. As a result, a carefully planned maneuver strategy was devised to accurately target the Stardust capsule to the Utah Test and Training Range (UTTR). This paper provides an overview of the Stardust spacecraft and mission and describes the maneuver strategy that was employed to achieve the stringent targeting requirements for landing in Utah. In addition, an overview of Stardust maneuver analysis tools and techniques will also be presented.

Treatment-resistant Schizophrenia: Evidence-based Strategies

PubMed Central

Englisch, Susanne; Zink, Mathias

2012-01-01

Treatment-resistant symptoms complicate the clinical course of schizophrenia, and a large proportion of patients do not reach functional recovery. In consequence, polypharmacy is frequently used in treatment-refractory cases, addressing psychotic positive, negative and cognitive symptoms, treatment-emergent side effects caused by antipsychotics and comorbid depressive or obsessive-compulsive symptoms. To a large extent, such strategies are not covered by pharmacological guidelines which strongly suggest antipsychotic monotherapy. Add-on strategies comprise combinations of several antipsychotic agents and augmentations with mood stabilizers; moreover, antidepressants and experimental substances are applied. Based on the accumulated evidence of clinical trials and meta-analyses, combinations of clozapine with certain second-generation antipsychotic agents and the augmentation of antipsychotics with antidepressants seem recommendable, while the augmentation with mood stabilizers cannot be considered superior to placebo. Forthcoming investigations will have to focus on innovative pharmacological agents, the clinical spectrum of cognitive deficits and the implementation of cognitive behavioral therapy. PMID:22654380

Osteogenesis imperfecta in childhood: treatment strategies.

PubMed

Engelbert, R H; Pruijs, H E; Beemer, F A; Helders, P J

1998-12-01

Osteogenesis imperfecta (OI) is a skeletal disorder of remarkable clinical variability characterized by bone fragility, osteopenia, variable degrees of short stature, and progressive skeletal deformities. Additional clinical manifestations such as blue sclerae, dentinogenesis imperfecta, joint laxity, and maturity onset deafness are described in the literature. OI occurs in about 1 in 20,000 births and is caused by quantitative and qualitative defects in the synthesis of collagen I. Depending on the severity of the disease, a large impact on motor development, range of joint motion, muscle strength, and functional ability may occur. Treatment strategies should primarily focus on the improvement of functional ability and the adoption of compensatory strategies, rather than merely improving range of joint motion and muscle strength. Surgical treatment of the extremities may be indicated to stabilize the long bones to optimize functional ability and walking capacity. Surgical treatment of the spine may be indicated in patients with progressive spinal deformity and in those with symptomatic basilar impression.

Therapeutic strategy with artificially-designed i-lncRNA targeting multiple oncogenic microRNAs exhibits effective antitumor activity in diffuse large B-cell lymphoma.

PubMed

Su, Yinghan; Sun, Bin; Lin, Xuejing; Zhao, Xinying; Ji, Weidan; He, Miaoxia; Qian, Haihua; Song, Xianmin; Yang, Jianmin; Wang, Jianmin; Chen, Jie

2016-08-02

In diffuse large B-cell lymphoma (DLBCL), many oncogenic microRNAs (OncomiRs) are highly expressed to promote disease development and progression by inhibiting the expression and function of certain tumor suppressor genes, and these OncomiRs comprise a promising new class of molecular targets for the treatment of DLBCL. However, most current therapeutic studies have focused on a single miRNA, with limited treatment outcomes. In this study, we generated tandem sequences of 10 copies of the complementary binding sequences to 13 OncomiRs and synthesized an interfering long non-coding RNA (i-lncRNA). The highly-expressed i-lncRNA in DLBCL cells would compete with the corresponding mRNAs of OncomiR target genes for binding OncomiRs, thereby effectively consuming a large amount of OncomiRs and protecting many tumor suppressor genes. The in vitro experiments confirmed that the i-lncRNA expression significantly inhibited cell proliferation, induced cell cycle arrest and apoptosis in DLBCL cell lines, mainly through upregulating the expression of PTEN, p27kip1, TIMP3, RECK and downregulating the expression of p38/MAPK, survivin, CDK4, c-myc. In the established SUDHL-4 xenografts in nude mice, the treatment strategy involving adenovirus-mediated i-lncRNA expression significantly inhibited the growth of DLBCL xenografts. Therefore, this treatment would specifically target the carcinogenic effects of many OncomiRs that are usually expressed in DLBCL and not in normal cells, such a strategy could improve anti-tumor efficacy and safety and may be a good prospect for clinical applications.

Understanding resistance to EGFR inhibitors—impact on future treatment strategies

PubMed Central

Wheeler, Deric L.; Dunn, Emily F.; Harari, Paul M.

2010-01-01

EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR biology, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer. PMID:20551942

The application of positron emission tomography/computed tomography in radiation treatment planning: effect on gross target volume definition and treatment management.

PubMed

Iğdem, S; Alço, G; Ercan, T; Unalan, B; Kara, B; Geceer, G; Akman, C; Zengin, F O; Atilla, S; Okkan, S

2010-04-01

To analyse the effect of the use of molecular imaging on gross target volume (GTV) definition and treatment management. Fifty patients with various solid tumours who underwent positron emission tomography (PET)/computed tomography (CT) simulation for radiotherapy planning from 2006 to 2008 were enrolled in this study. First, F-18 fluorodeoxyglucose (FDG)-PET and CT scans of the treatment site in the treatment position and then a whole body scan were carried out with a dedicated PET/CT scanner and fused thereafter. FDG-avid primary tumour and lymph nodes were included into the GTV. A multidisciplinary team defined the target volume, and contouring was carried out by a radiation oncologist using visual methods. To compare the PET/CT-based volumes with CT-based volumes, contours were drawn on CT-only data with the help of site-specific radiologists who were blind to the PET/CT results after a median time of 7 months. In general, our PET/CT volumes were larger than our CT-based volumes. This difference was significant in patients with head and neck cancers. Major changes (> or =25%) in GTV delineation were observed in 44% of patients. In 16% of cases, PET/CT detected incidental second primaries and metastatic disease, changing the treatment strategy from curative to palliative. Integrating functional imaging with FDG-PET/CT into the radiotherapy planning process resulted in major changes in a significant proportion of our patients. An interdisciplinary approach between imaging and radiation oncology departments is essential in defining the target volumes. Copyright 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Understanding L2 French Teaching Strategies in a Non-Target Language Classroom Context

ERIC Educational Resources Information Center

Sun, Peijian; Yuan, Rui; Teng, Lin

2015-01-01

This research explored the congruence and disparity between teachers' and students' attitudes towards French as a second language (L2) teaching strategies in a non-target language classroom context in the USA. The findings suggest students' and teachers' attitudes towards the direct and indirect teaching strategies were generally consistent, but…

Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies.

PubMed

Rudomanova, Valeria; Blaxall, Burns C

2017-08-01

The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gβγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gβγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gβγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gβγ-GRK2 interactions. Further, we explore the potential of GPCR-Gβγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies. Copyright © 2017 Elsevier B.V. All rights reserved.

Targeting Hsp90-Cdc37: A Promising Therapeutic Strategy by Inhibiting Hsp90 Chaperone Function.

PubMed

Wang, Lei; Li, Li; Gu, Kai; Xu, Xiao-Li; Sun, Yuan; You, Qi-Dong

2017-01-01

The Hsp90 chaperone protein regulates the folding, maturation and stability of a wide variety of oncoproteins. In recent years, many Hsp90 inhibitors have entered into the clinical trials while all of them target ATPase showing similar binding capacity and kinds of side-effects so that none have reached to the market. During the regulation progress, numerous protein- protein interactions (PPI) such as Hsp90 and client proteins or cochaperones are involved. With the Hsp90-cochaperones PPI networks being more and more clear, many cancerous proteins have been reported to be tightly correlated to Hsp90-cochaperones PPI. Among them, Hsp90-Cdc37 PPI has been widely reported to associate with numerous protein kinases, making it a novel target for the treatment of cancers. In this paper, we briefly review the strategies and modulators targeting Hsp90-Cdc37 complex including direct and indirect regulation mechanism. Through these discussions we expect to present inspirations for new insights into an alternative way to inhibit Hsp90 chaperone function. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Tumor target amplification: Implications for nano drug delivery systems.

PubMed

Seidi, Khaled; Neubauer, Heidi A; Moriggl, Richard; Jahanban-Esfahlan, Rana; Javaheri, Tahereh

2018-04-10

Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting. Copyright © 2018 Elsevier B.V. All rights reserved.

PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer.

PubMed

Rogers, Oliver C; Anthony, Lizamma; Rosen, D Marc; Brennen, W Nathaniel; Denmeade, Samuel R

2018-04-27

Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death in American men. While localized therapy is highly curative, treatments for metastatic prostate cancer are largely palliative. Thus, new innovative therapies are needed to target metastatic tumors. Prostate-Specific Antigen (PSA) is a chymotrypsin-like protease with a unique substrate specificity that is secreted by both normal and malignant prostate epithelial cells. Previous studies demonstrated the presence of high levels (μM-mM) of enzymatically active PSA is present in the extracellular fluid of the prostate cancer microenvironment. Because of this, PSA is an attractive target for a protease activated pro-toxin therapeutic strategy. Because prostate cancers typically grow very slowly, a strategy employing a proliferation-independent cytotoxic payload is preferred. Recently, it was shown that the human protease Granzyme B (GZMB), at low micromolar concentrations in the extracellular space, can cleave an array of extracellular matrix (ECM) proteins thus perturbing cell growth, signaling, motility, and integrity. It is also well established that other human proteases such as trypsin can induce similar effects. Because both enzymes require N-terminal proteolytic activation, we propose to convert these proteins into PSA-activated cytotoxins. In this study, we examine the enzymatic and cell targeting parameters of these PSA-activated cytotoxic serine proteases. These pro-enzymes were activated robustly by PSA and induced ECM damage that led to the death of prostate cancer cells in vitro thus supporting the potential use of this strategy as means to target metastatic prostate cancers.

PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer

PubMed Central

Rogers, Oliver C.; Anthony, Lizamma; Rosen, D. Marc; Brennen, W. Nathaniel; Denmeade, Samuel R.

2018-01-01

Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death in American men. While localized therapy is highly curative, treatments for metastatic prostate cancer are largely palliative. Thus, new innovative therapies are needed to target metastatic tumors. Prostate-Specific Antigen (PSA) is a chymotrypsin-like protease with a unique substrate specificity that is secreted by both normal and malignant prostate epithelial cells. Previous studies demonstrated the presence of high levels (μM-mM) of enzymatically active PSA is present in the extracellular fluid of the prostate cancer microenvironment. Because of this, PSA is an attractive target for a protease activated pro-toxin therapeutic strategy. Because prostate cancers typically grow very slowly, a strategy employing a proliferation-independent cytotoxic payload is preferred. Recently, it was shown that the human protease Granzyme B (GZMB), at low micromolar concentrations in the extracellular space, can cleave an array of extracellular matrix (ECM) proteins thus perturbing cell growth, signaling, motility, and integrity. It is also well established that other human proteases such as trypsin can induce similar effects. Because both enzymes require N-terminal proteolytic activation, we propose to convert these proteins into PSA-activated cytotoxins. In this study, we examine the enzymatic and cell targeting parameters of these PSA-activated cytotoxic serine proteases. These pro-enzymes were activated robustly by PSA and induced ECM damage that led to the death of prostate cancer cells in vitro thus supporting the potential use of this strategy as means to target metastatic prostate cancers. PMID:29854290

Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy.

PubMed

Ständer, Sonja; Siepmann, Dorothee; Herrgott, Ilka; Sunderkötter, Cord; Luger, Thomas A

2010-06-04

Chronic pruritus is a global clinical problem with a high impact on the quality of life and lack of specific therapies. It is an excruciating and frequent symptom of e.g. uncurable renal, liver and skin diseases which often does not respond to conventional treatment with e.g. antihistamines. Therefore antipruritic therapies which target physiological mechanisms of pruritus need to be developed. Substance P (SP) is a major mediator of pruritus. As it binds to the neurokinin receptor 1 (NKR1), we evaluated if the application of a NKR1 antagonist would significantly decrease chronic pruritus. Twenty hitherto untreatable patients with chronic pruritus (12 female, 8 male; mean age, 66.7 years) were treated with the NKR1 antagonist aprepitant 80 mg for one week. 16 of 20 patients (80%) experienced a considerable reduction of itch intensity, as assessed by the visual analog scale (VAS, range 0 to 10). Considering all patients, the mean value of pruritus intensity was significantly reduced from 8.4 VAS points (SD +/-1.7) before treatment to 4.9 VAS points (SD +/-3.2) (p<0.001, CI 1.913-5.187). Patients with dermatological diseases (e.g. atopic diathesis, prurigo nodularis) had the best profit from the treatment. Side-effects were mild (nausea, vertigo, and drowsiness) and only occurred in three patients. The high response rate in patients with therapy refractory pruritus suggests that the NKR1 antagonist aprepitant may indeed exhibit antipruritic effects and may present a novel, effective treatment strategy based on pathophysiology of chronic pruritus. The results are promising enough to warrant confirming the efficacy of NKR1 antagonists in a randomized, controlled clinical trial.

Molecular targeted therapy for the treatment of gastric cancer.

PubMed

Xu, Wenting; Yang, Zhen; Lu, Nonghua

2016-01-04

Despite the global decline in the incidence and mortality of gastric cancer, it remains one of the most common malignant tumors of the digestive system. Although surgical resection is the preferred treatment for gastric cancer, chemotherapy is the preferred treatment for recurrent and advanced gastric cancer patients who are not candidates for reoperation. The short overall survival and lack of a standard chemotherapy regimen make it important to identify novel treatment modalities for gastric cancer. Within the field of tumor biology, molecular targeted therapy has attracted substantial attention to improve the specificity of anti-cancer efficacy and significantly reduce non-selective resistance and toxicity. Multiple clinical studies have confirmed that molecular targeted therapy acts on various mechanisms of gastric cancer, such as the regulation of epidermal growth factor, angiogenesis, immuno-checkpoint blockade, the cell cycle, cell apoptosis, key enzymes, c-Met, mTOR signaling and insulin-like growth factor receptors, to exert a stronger anti-tumor effect. An in-depth understanding of the mechanisms that underlie molecular targeted therapies will provide new insights into gastric cancer treatment.

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

PubMed Central

2015-01-01

Abstract Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686–729. PMID:25546574

In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC

PubMed Central

Heavey, Susan; Cuffe, Sinead; Finn, Stephen; Young, Vincent; Ryan, Ronan; Nicholson, Siobhan; Leonard, Niamh; McVeigh, Niall; Barr, Martin; O'Byrne, Kenneth; Gately, Kathy

2016-01-01

Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach. Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression. The effects of GDC-0941 (a pan PI3K inhibitor), GDC-0980 (a dual PI3K/mTOR inhibitor) and GDC-0973 (a MEK inhibitor) alone and in combination were assessed in 3 NSCLC cell lines. PIK3CA was mutated in 5.17% of NSCLC patients. GDC-0941 and GDC-0980 treatment induced anti-proliferative and pro-apoptotic responses across all NSCLC cell lines, while GDC-0973 treatment induced only anti-proliferative responses. GDC-0980 and GDC-0973 combined treatment led to significant increases in apoptosis and synergistic reductions in proliferation across the panel of cell lines. This study found that the PI3K/MEK co-targeted inhibition strategy is synergistic in all 3 molecular subtypes of NSCLC investigated. Consequently, we would advocate clinical trials for NSCLC patients combining GDC-0980 and GDC-0973, each of which are separately under clinical investigation currently. PMID:27765909

In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC.

PubMed

Heavey, Susan; Cuffe, Sinead; Finn, Stephen; Young, Vincent; Ryan, Ronan; Nicholson, Siobhan; Leonard, Niamh; McVeigh, Niall; Barr, Martin; O'Byrne, Kenneth; Gately, Kathy

2016-11-29

Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression. The effects of GDC-0941 (a pan PI3K inhibitor), GDC-0980 (a dual PI3K/mTOR inhibitor) and GDC-0973 (a MEK inhibitor) alone and in combination were assessed in 3 NSCLC cell lines.PIK3CA was mutated in 5.17% of NSCLC patients. GDC-0941 and GDC-0980 treatment induced anti-proliferative and pro-apoptotic responses across all NSCLC cell lines, while GDC-0973 treatment induced only anti-proliferative responses. GDC-0980 and GDC-0973 combined treatment led to significant increases in apoptosis and synergistic reductions in proliferation across the panel of cell lines.This study found that the PI3K/MEK co-targeted inhibition strategy is synergistic in all 3 molecular subtypes of NSCLC investigated. Consequently, we would advocate clinical trials for NSCLC patients combining GDC-0980 and GDC-0973, each of which are separately under clinical investigation currently.

Treatment Strategy for Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

PubMed

Nakamura, Shotaro; Matsumoto, Takayuki

2015-09-01

Recent trends and current knowledge on the diagnosis and treatment strategy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma are reviewed. Helicobacter pylori infection plays the causative role in the pathogenesis, and H pylori eradication is the first-line treatment of this disease, which leads to complete remission in 60% to 90% of cases. A Japanese multicenter study confirmed that the long-term outcome of gastric MALT lymphoma after H pylori eradication is excellent. Treatment strategies for patients not responding to H pylori eradication including "watch and wait" strategy, radiotherapy, chemotherapy, rituximab immunotherapy, and combination of these should be tailored in consideration of the disease extent in each patient. Copyright © 2015 Elsevier Inc. All rights reserved.

Targeting International Terrorism with the Law of Armed Conflict: An Alternative Strategy

DTIC Science & Technology

1991-02-11

AD-A236 582 D TIC III IBII IH IH JUNI 1. 1991. (Unclassified Paper) NAVAL WAR COLLEGE Newport, R.I. TARGETING INTERNATIONAL TERRORISM WITH THE LAW OF...11. TITLE OWN11110 Secrty Ceu4ifction) TARGETING INTERNATIONAL TERRORISM WITH THE LAW OF ARMED CONFLICT: AN ALTERNATIVE STRATEGY (1.) 12, PERSONAL...lawegieforcoperatiosb re forcdaigwt nes.nItiofurther rorimmendgfral rbetos msesnt ofte thkede easuc-tresa en ocnrotadrsodttate-sponsored terrorism . Ti a

Stepping through treatment: reflections on an adaptive treatment strategy among methamphetamine users with depression.

PubMed

Kay-Lambkin, Frances J; Baker, Amanda L; McKetin, Rebecca; Lee, Nicole

2010-09-01

Stepped-care has been recommended in the alcohol and other drug field and adopted in a number of service settings, but few research projects have examined this approach. This article aims to describe a pilot trial of stepped-care methods in the treatment of methamphetamine use and depression comorbidity. An adaptive treatment strategy was developed based on recommendations for stepped-care among methamphetamine users, and incorporating cognitive behaviour therapy/motivational intervention for methamphetamine use and depression. The adaptive treatment strategy was compared with a fixed treatment, comprising an extended integrated cognitive behaviour therapy/motivational intervention treatment. Eighteen participants across two study sites were involved in the trial, and were current users of methamphetamines (at least once weekly) exhibiting at least moderate symptoms of depression (score of 17 or greater on the Beck Depression Inventory II). Treatment delivered via the adaptive treatment (stepped-care) model was associated with improvement in depression and methamphetamine use, however, was not associated with more efficient delivery of psychological treatment to this population relative to the comparison treatment. This pilot trial attests to the potential for adaptive treatment strategies to increase the evidence base for stepped-care approaches within the alcohol and other drug field. However, in order for stepped-care treatment in this trial to be delivered efficiently, specific training in the delivery and philosophy of the model is required.

A look at treatment strategies for relapsed multiple myeloma.

PubMed

Cetani, Giusy; Boccadoro, Mario; Oliva, Stefania

2018-05-16

Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials. Of note, new drugs, such as carfilzomib, ixazomib, pomalidomide, daratumumab and elotuzumab, alone or in combinations in doublet or triplet regimens, have greatly increased the treatment armamentarium against myeloma. Expert Commentary: Impressive results have been obtained with new drugs in relapsed patients. Besides number of prior therapies and previous response, other factors play a crucial role in the selection of therapy. Re-challenge with previous drugs can be adopted if previous responses lasted at least 6 months and therapy had induced low toxicity. Patients' risk status can further help to appropriately select therapy at relapse, and clinical trials will allow physicians to use newer targeted therapies and immune-therapies, thus delaying palliative approaches to later relapse stages.

Interventions That Target Criminogenic Needs for Justice-Involved Persons With Serious Mental Illnesses: A Targeted Service Delivery Approach.

PubMed

Wilson, Amy Blank; Farkas, Kathleen; Bonfine, Natalie; Duda-Banwar, Janelle

2018-05-01

This research describes the development of a targeted service delivery approach that tailors the delivery of interventions that target criminogenic needs to the specific learning and treatment needs of justice-involved people with serious mental illnesses (SMIs). This targeted service delivery approach includes five service delivery strategies: repetition and summarizing, amplification, active coaching, low-demand practice, and maximizing participation. Examples of how to apply each strategy in session are provided, as well as recommendations on when to use each strategy during the delivery of interventions that target criminogenic needs. This targeted service delivery approach makes an important contribution to the development of interventions for justice-involved people with SMI by increasing the chances that people with SMI can participate fully in and benefit from these interventions that target criminogenic needs. These developments come at a critical time in the field as the next generation of services for justice-involved people with SMI are being developed.

Systematic Assessment of Strategies for Lung-targeted Delivery of MicroRNA Mimics

PubMed Central

Schlosser, Kenny; Taha, Mohamad; Stewart, Duncan J.

2018-01-01

There is considerable interest in the use of synthetic miRNA mimics (or inhibitors) as potential therapeutic agents in pulmonary vascular disease; however, the optimal delivery method to achieve high efficiency, selective lung targeting has not been determined. Here, we sought to investigate the relative merits of different lung-targeted strategies for delivering miRNA mimics in rats. Methods: Tissue levels of a synthetic miRNA mimic, cel-miR-39-3p (0.5 nmol in 50 µL invivofectamine/PBS vehicle) were compared in male rats (n=3 rats/method) after delivery by commonly used lung-targeting strategies including intratracheal liquid instillation (IT-L), intratracheal aerosolization with (IT-AV) or without ventilator assistance (IT-A), intranasal liquid instillation (IN-L) and intranasal aerosolization (IN-A). Intravenous (IV; via jugular vein), intraperitoneal (IP) and subcutaneous (SC) delivery served as controls. Relative levels of cel-miR-39 were quantified by RT-qPCR. Results: At 2 h post delivery, IT-L showed the highest lung mimic level, which was significantly higher than levels achieved by all other methods (from ~10- to 10,000-fold, p<0.05). Mimic levels remained detectable in the lung 24 h after delivery, but were 10- to 100-fold lower. The intrapulmonary distribution of cel-miR-39 was comparable when delivered as either a liquid or aerosol, with evidence of mimic distribution to both the left and right lung lobes and penetration to distal regions. All lung-targeted strategies showed lung-selective mimic uptake, with mimic levels 10- to 100-fold lower in heart and 100- to 10,000-fold lower in liver, kidney and spleen. In contrast, IV, SC and IP routes showed comparable or higher mimic levels in non-pulmonary tissues. Conclusions: miRNA uptake in the lungs differed markedly by up to 4 orders of magnitude, demonstrating that the choice of delivery strategy could have a significant impact on potential therapeutic outcomes in preclinical investigations of mi

Near-Nash targeting strategies for heterogeneous teams of autonomous combat vehicles

NASA Astrophysics Data System (ADS)

Galati, David G.; Simaan, Marwan A.

2008-04-01

Military strategists are currently seeking methodologies to control large numbers of autonomous assets. Automated planners based upon the Nash equilibrium concept in non-zero sum games are one option. Because such planners inherently consider possible adversarial actions, assets are able to adapt to, and to some extent predict, potential enemy actions. However, these planners must function properly both in cases in which a pure Nash strategy does not exist and in scenarios possessing multiple Nash equilibria. Another issue that needs to be overcome is the scalability of the Nash equilibrium. That is, as the dimensionality of the problem increases, the Nash strategies become unfeasible to compute using traditional methodologies. In this paper we introduce the concept of near-Nash strategies as a mechanism to overcome these difficulties. We then illustrate this concept by deriving the near-Nash strategies and using these strategies as the basis for an intelligent battle plan for heterogeneous teams of autonomous combat air vehicles in the Multi-Team Dynamic Weapon Target Assignment model.

Theranostic gas-generating nanoparticles for targeted ultrasound imaging and treatment of neuroblastoma.

PubMed

Lee, Jangwook; Min, Hyun-Su; You, Dong Gil; Kim, Kwangmeyung; Kwon, Ick Chan; Rhim, Taiyoun; Lee, Kuen Yong

2016-02-10

The development of safe and efficient diagnostic/therapeutic agents for treating cancer in clinics remains challenging due to the potential toxicity of conventional agents. Although the annual incidence of neuroblastoma is not that high, the disease mainly occurs in children, a population vulnerable to toxic contrast agents and therapeutics. We demonstrate here that cancer-targeting, gas-generating polymeric nanoparticles are useful as a theranostic tool for ultrasound (US) imaging and treating neuroblastoma. We encapsulated calcium carbonate using poly(d,l-lactide-co-glycolide) and created gas-generating polymer nanoparticles (GNPs). These nanoparticles release carbon dioxide bubbles under acidic conditions and enhance US signals. When GNPs are modified using rabies virus glycoprotein (RVG) peptide, a targeting moiety to neuroblastoma, RVG-GNPs effectively accumulate at the tumor site and substantially enhance US signals in a tumor-bearing mouse model. Intravenous administration of RVG-GNPs also reduces tumor growth in the mouse model without the use of conventional therapeutic agents. This approach to developing theranostic agents with disease-targeting ability may provide useful strategy for the detection and treatment of cancers, allowing safe and efficient clinical applications with fewer side effects than may occur with conventional agents. Copyright © 2015 Elsevier B.V. All rights reserved.

Modelling outcomes of complex treatment strategies following a clinical guideline for treatment decisions in patients with rheumatoid arthritis.

PubMed

Tran-Duy, An; Boonen, Annelies; Kievit, Wietske; van Riel, Piet L C M; van de Laar, Mart A F J; Severens, Johan L

2014-10-01

Management of rheumatoid arthritis (RA) is characterised by a sequence of disease-modifying antirheumatic drugs (DMARDs) and biological response modifiers (BRMs). In most of the Western countries, the drug sequences are determined based on disease activity and treatment history of the patients. A model for realistic patient outcomes should reflect the treatment pathways relevant for patients with specific characteristics. This study aimed at developing a model that could simulate long-term patient outcomes and cost effectiveness of treatment strategies with and without inclusion of BRMs following a clinical guideline for treatment decisions. Discrete event simulation taking into account patient characteristics and treatment history was used for model development. Treatment effect on disease activity, costs, health utilities and times to events were estimated using Dutch observational studies. Long-term progression of physical functioning was quantified using a linear mixed-effects model. Costs and health utilities were estimated using two-part models. The treatment strategy recommended by the Dutch Society for Rheumatology where both DMARDs and BRMs were available (Strategy 2) was compared with the treatment strategy without BRMs (Strategy 1). Ten thousand theoretical patients were tracked individually until death. In the probabilistic sensitivity analysis, Monte Carlo simulations were performed with 1,000 sets of parameters sampled from appropriate probability distributions. The simulated changes over time in disease activity and physical functioning were plausible. The incremental cost per quality-adjusted life-year gained of Strategy 2 compared with Strategy 1 was 124,011. At a willingness-to-pay threshold higher than 119,167, Strategy 2 dominated Strategy 1 in terms of cost effectiveness but the probability that the Strategy 2 is cost effective never exceeded 0.87. It is possible to model the outcomes of complex treatment strategies based on a

Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?

PubMed

Minucci, S; Nervi, C; Lo Coco, F; Pelicci, P G

2001-05-28

Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

Active radar guides missile to its target: receptor-based targeted treatment of hepatocellular carcinoma by nanoparticulate systems.

PubMed

Yan, Jing-Jun; Liao, Jia-Zhi; Lin, Ju-Sheng; He, Xing-Xing

2015-01-01

Patients with hepatocellular carcinoma (HCC) usually present at advanced stages and do not benefit from surgical resection, so drug therapy should deserve a prominent place in unresectable HCC treatment. But chemotherapy agents, such as doxorubicin, cisplatin, and paclitaxel, frequently encounter important problems such as low specificity and non-selective biodistribution. Recently, the development of nanotechnology led to significant breakthroughs to overcome these problems. Decorating the surfaces of nanoparticulate-based drug carriers with homing devices has demonstrated its potential in concentrating chemotherapy agents specifically to HCC cells. In this paper, we reviewed the current status of active targeting strategies for nanoparticulate systems based on various receptors such as asialoglycoprotein receptor, transferrin receptor, epidermal growth factor receptor, folate receptor, integrin, and CD44, which are abundantly expressed on the surfaces of hepatocytes or liver cancer cells. Furthermore, we pointed out their merits and defects and provided theoretical references for further research.

Factors that influence treatment strategies in advanced colorectal cancer.

PubMed

Nesbitt, C; Glendinning, R J; Byrne, C; Poston, G J

2007-12-01

This review focuses on the factors that now influence our treatment strategies designed to increase the pool of patients with colorectal liver metastases for whom curative treatment may be possible. These strategies include improved preoperative staging techniques, new standards for surgical resection, novel surgical strategies, the application of modern systemic chemotherapy in a neoadjuvant setting, an emerging role for ablative therapies and an emphasis on the collaborative, a reappraisal of staging advanced disease, multidisciplinary management, and defining the role of the patient in managing their disease. It is now clear that an aggressive multi-disciplinary approach to the management of this problem will lead to nearly one third of these patients being considered for treatment that even if not achieving complete cure, offers significant long-term survival.

Shivering Treatments for Targeted Temperature Management: A Review

PubMed Central

Jain, Akash; Gray, Maria; Slisz, Stephanie; Haymore, Joseph; Badjatia, Neeraj; Kulstad, Erik

2018-01-01

ABSTRACT Background: Shivering is common during targeted temperature management, and control of shivering can be challenging if clinicians are not familiar with the available options and recommended approaches. Purpose: The purpose of this review was to summarize the most relevant literature regarding various treatments available for control of shivering and suggest a recommended approach based on latest data. Methods: The electronic databases PubMed/MEDLINE and Google Scholar were used to identify studies for the literature review using the following keywords alone or in combination: “shivering treatment,” “therapeutic hypothermia,” “core temperature modulation devices,” and “targeted temperature management.” Results: Nonpharmacologic methods were found to have a very low adverse effect profile and ease of use but some limitations in complete control of shivering. Pharmacologic methods can effectively control shivering, but some have adverse effects, such that risks and benefits to the patient have to be balanced. Conclusion: An approach is provided which suggests that treatment for shivering control in targeted temperature management should be initiated before the onset of therapeutic hypothermia or prior to any attempt at lowering patient core temperature, with medications including acetaminophen, buspirone, and magnesium sulfate, ideally with the addition of skin counterwarming. After that, shivering intervention should be determined with the help of a shivering scale, and stepwise escalation can be implemented that balances shivering treatment with sedation, aiming to provide the most shivering reduction with the least sedating medications and reserving paralytics for the last line of treatment. PMID:29278601

Strategies for treatment of dystonia.

PubMed

Dressler, Dirk; Altenmueller, Eckart; Bhidayasiri, Roongroj; Bohlega, Saeed; Chana, Pedro; Chung, Tae Mo; Frucht, Steven; Garcia-Ruiz, Pedro J; Kaelin, Alain; Kaji, Ryuji; Kanovsky, Petr; Laskawi, Rainer; Micheli, Federico; Orlova, Olga; Relja, Maja; Rosales, Raymond; Slawek, Jaroslaw; Timerbaeva, Sofia; Warner, Thomas T; Saberi, Fereshte Adib

2016-03-01

Treatment of dystonias is generally symptomatic. To produce sufficient therapy effects, therefore, frequently a multimodal and interdisciplinary therapeutic approach becomes necessary, combining botulinum toxin therapy, deep brain stimulation, oral antidystonic drugs, adjuvant drugs and rehabilitation therapy including physiotherapy, occupational therapy, re-training, speech therapy, psychotherapy and sociotherapy. This review presents the recommendations of the IAB-Interdisciplinary Working Group for Movement Disorders Special Task Force on Interdisciplinary Treatment of Dystonia. It reviews the different therapeutic modalities and outlines a strategy to adapt them to the dystonia localisation and severity of the individual patient. Hints to emerging and future therapies will be given.

Treatment Targets in Inflammatory Bowel Disease: Current Status in Daily Practice.

PubMed

Römkens, Tessa E H; Gijsbers, Kim; Kievit, Wietske; Hoentjen, Frank; Drenth, Joost P H

2016-12-01

Recently, treatment goals in inflammatory bowel disease (IBD) in clinical trials have shifted from mainly symptom-based to more mucosa-driven. Real world data on treatment priorities are lacking. We aimed to investigate the current practice and most commonly used definitions of IBD treatment targets among Dutch gastroenterologists. Dutch gastroenterologists were asked to participate in a computer-based nation-wide survey. We asked questions on demographics, opinion and current practice regarding IBD treatment targets. Twenty-four percent (134/556) of the respondents completed the survey. For both Crohn's disease (CD) (47.3%, 61/129) and ulcerative colitis (UC)(45%, 58/129) the main treatment goal was to achieve and maintain deep remission, defined as clinical, biochemical and endoscopic remission. Seventy-six percent of the participants use mucosal healing (MH) as a potential treatment target for IBD, whereas 22.6% use histological remission. There is no single definition for MH in IBD. The majority use Mayo score ≤ 1 in UC (52%) and 'macroscopic normal mucosa' in CD (66%). More stringent and mucosa-driven treatment targets as 'deep remission' and 'mucosal healing' have found traction in clinical practice. The most commonly used definition for MH in routine practice is endoscopic MAYO score

Individualised treatment targets in patients with type-2 diabetes and hypertension.

PubMed

Schmieder, Roland E; Tschöpe, Diethelm; Koch, Cornelia; Ouarrak, Taoufik; Gitt, Anselm K

2018-01-22

Patients with type-2 diabetes mellitus (T2DM) are at high risk of cardiovascular events, accentuated in the presence of hypertension. At present, it is unclear to what extent the guidelines for the management of T2DM, advocating reduction in HbA1c levels to below target levels, are being adhered to in clinical practice. DIALOGUE was a prospective, observational, non-interventional registry performed across multiple centres in Germany. Patients aged 18 years or older who had T2DM and hypertension for whom the treating physician considered blood glucose lowering medication as inadequate and/or not safe/tolerable and chose to add a further oral drug or switch drug treatment were included. Patients were assigned a treatment target HbA1c value (≤ 6.5% [strict]; > 6.5 to ≤ 7.0% [intermediate]; > 7.0 to ≤ 7.5% [lenient]). 8568 patients with T2DM and hypertension were enrolled. 6691 (78.1%) had 12-month follow-up. Patients who were assigned a strict HbA1c treatment target (n = 2644) were younger, had shorter diabetes duration, and less comorbidity in comparison to those with intermediate (n = 2912) or lenient targets (n = 1135). Only 53.1% of patients achieved their HbA1c treatment target (46.2% [strict], 56.8% [intermediate], 59.4% [lenient]). There was little sign of treatment intensification for patients that had not achieved their HbA1c target. Achievement of treatment targets was poor, leaving many patients with sub-optimal blood glucose levels. The apparent reluctance of physicians to intensify antidiabetic drug therapy is alarming, especially considering the evidence pointing to an association of hyperglycaemia and microvascular complications in patients with T2DM.

Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization - A minimally invasive cancer stem cell-targeting strategy.

PubMed

Bostad, Monica; Olsen, Cathrine Elisabeth; Peng, Qian; Berg, Kristian; Høgset, Anders; Selbo, Pål Kristian

2015-05-28

The cancer stem cell (CSC) marker CD133 is an attractive target to improve antitumor therapy. We have used photochemical internalization (PCI) for the endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin (PCIAC133-saporin). PCI employs an endocytic vesicle-localizing photosensitizer, which generates reactive oxygen species upon light-activation causing a rupture of the vesicle membranes and endosomal escape of entrapped drugs. Here we show that AC133-saporin co-localizes with the PCI-photosensitizer TPCS2a, which upon light exposure induces cytosolic release of AC133-saporin. PCI of picomolar levels of AC133-saporin in colorectal adenocarcinoma WiDr cells blocked cell proliferation and induced 100% inhibition of cell viability and colony forming ability at the highest light doses, whereas no cytotoxicity was obtained in the absence of light. Efficient PCI-based CD133-targeting was in addition demonstrated in the stem-cell-like, triple negative breast cancer cell line MDA-MB-231 and in the aggressive malignant melanoma cell line FEMX-1, whereas no enhanced targeting was obtained in the CD133-negative breast cancer cell line MCF-7. PCIAC133-saporin induced mainly necrosis and a minimal apoptotic response based on assessing cleavage of caspase-3 and PARP, and the TUNEL assay. PCIAC133-saporin resulted in S phase arrest and reduced LC3-II conversion compared to control treatments. Notably, co-treatment with Bafilomycin A1 and PCIAC133-saporin blocked LC3-II conversion, indicating a termination of the autophagic flux in WiDr cells. For the first time, we demonstrate laser-controlled targeting of CD133 in vivo. After only one systemic injection of AC133-saporin and TPCS2a, a strong anti-tumor response was observed after PCIAC133-saporin. The present PCI-based endosomal escape technology represents a minimally invasive strategy for spatio-temporal, light-controlled targeting of CD133+ cells in localized primary tumors or metastasis. Copyright © 2015

Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization.

PubMed

Wang, Sheng; Huang, Peng; Chen, Xiaoyuan

2016-09-01

Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Kallikrein-related peptidase 7 is a potential target for the treatment of pancreatic cancer

PubMed Central

Zheng, Jun; Zhang, Ding; Liu, Wei; Zheng, Wei Hong; Li, Xiao Song; Yao, Ru Cheng; Wang, Fangyu; Liu, Sen; Tan, Xiao

2018-01-01

Pancreatic cancer is one of the deadliest cancers with very poor prognosis, and the five-year survival rate of the patients is less than 5% after diagnosis. Kallikrein-related peptidases (KLKs) belong to a serine protease family with 15 members that play important roles in cellular physiological behavior and diseases. The high expression level of KLK7 in pancreatic cancer tissues is considered to be a marker for the poor prognosis of this disease. In this work, we set out to investigate whether KLK7 could be a target for the treatment of pancreatic cancer. Short hairpin RNAs (shRNAs) were designed and constructed in lentivirus to knock down KLK7 in pancreatic cancer cell line PANC-1, and the real time cellular analysis (RTCA) was used to evaluate cell proliferation, migration and invasion abilities. Small molecules inhibiting KLK7 were discovered by computer-aided drug screening and used to inhibit PANC-1 cells. Our results confirmed that KLK7 is significantly up-regulated in pancreatic cancer tissue, and knocking down or inhibiting KLK7 efficiently inhibited the proliferation, migration and invasion of pancreatic cancer cells. This study suggested that KLK7 could be a potential chemotherapy target for treatment of pancreatic cancer, which would provide us a novel strategy for the treatment of this disease. PMID:29560118

Targeting Super-Enhancers for Disease Treatment and Diagnosis.

PubMed

Shin, Ha Youn

2018-05-10

The transcriptional regulation of genes determines the fate of animal cell differentiation and subsequent organ development. With the recent progress in genome-wide technologies, the genomic landscapes of enhancers have been broadly explored in mammalian genomes, which led to the discovery of novel specific subsets of enhancers, termed superenhancers. Super-enhancers are large clusters of enhancers covering the long region of regulatory DNA and are densely occupied by transcription factors, active histone marks, and co-activators. Accumulating evidence points to the critical role that super-enhancers play in cell type-specific development and differentiation, as well as in the development of various diseases. Here, I provide a comprehensive description of the optimal approach for identifying functional units of superenhancers and their unique chromatin features in normal development and in diseases, including cancers. I also review the recent updated knowledge on novel approaches of targeting super-enhancers for the treatment of specific diseases, such as small-molecule inhibitors and potential gene therapy. This review will provide perspectives on using superenhancers as biomarkers to develop novel disease diagnostic tools and establish new directions in clinical therapeutic strategies.

Drug delivery strategies for Alzheimer's disease treatment.

PubMed

Di Stefano, Antonio; Iannitelli, Antonio; Laserra, Sara; Sozio, Piera

2011-05-01

Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence. In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems. The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.

An Energy-Efficient Target-Tracking Strategy for Mobile Sensor Networks.

PubMed

Mahboubi, Hamid; Masoudimansour, Walid; Aghdam, Amir G; Sayrafian-Pour, Kamran

2017-02-01

In this paper, an energy-efficient strategy is proposed for tracking a moving target in an environment with obstacles, using a network of mobile sensors. Typically, the most dominant sources of energy consumption in a mobile sensor network are sensing, communication, and movement. The proposed algorithm first divides the field into a grid of sufficiently small cells. The grid is then represented by a graph whose edges are properly weighted to reflect the energy consumption of sensors. The proposed technique searches for near-optimal locations for the sensors in different time instants to route information from the target to destination, using a shortest path algorithm. Simulations confirm the efficacy of the proposed algorithm.

Identifying Molecular Targets for PTSD Treatment Using Single Prolonged Stress

DTIC Science & Technology

2015-10-01

1 AWARD NUMBER: W81XWH-13-1-0377 TITLE: Identifying Molecular Targets For PTSD Treatment Using Single Prolonged Stress PRINCIPAL...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0377 Identifying Molecular Targets For PTSD Treatment Using Single Prolonged Stress 5b. GRANT...brain GR and β-AR expression alters glutamatergic and GABAergic function in neural circuits that mediate SPS-induced deficits in extinction retention

Feature extraction and selection strategies for automated target recognition

NASA Astrophysics Data System (ADS)

Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

2010-04-01

Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory regionof- interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

Targeted intervention strategies to optimise diversion of BMW in the Dublin, Ireland region

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

Purcell, M., E-mail: mary.purcell@cit.ie; Centre for Water Resources Research, School of Architecture, Landscape and Civil Engineering, University College Dublin, Newstead, Belfield, Dublin 4; Magette, W.L.

Highlights: > Previous research indicates that targeted strategies designed for specific areas should lead to improved diversion. > Survey responses and GIS model predictions from previous research were the basis for goal setting. > Then logic modelling and behavioural research were employed to develop site-specific management intervention strategies. > Waste management initiatives can be tailored to specific needs of areas rather than one size fits all means currently used. - Abstract: Urgent transformation is required in Ireland to divert biodegradable municipal waste (BMW) from landfill and prevent increases in overall waste generation. When BMW is optimally managed, it becomes amore » resource with value instead of an unwanted by-product requiring disposal. An analysis of survey responses from commercial and residential sectors for the Dublin region in previous research by the authors proved that attitudes towards and behaviour regarding municipal solid waste is spatially variable. This finding indicates that targeted intervention strategies designed for specific geographic areas should lead to improved diversion rates of BMW from landfill, a requirement of the Landfill Directive 1999/31/EC. In the research described in this paper, survey responses and GIS model predictions from previous research were the basis for goal setting, after which logic modelling and behavioural research were employed to develop site-specific waste management intervention strategies. The main strategies devised include (a) roll out of the Brown Bin (Organics) Collection and Community Workshops in Dun Laoghaire Rathdown, (b) initiation of a Community Composting Project in Dublin City (c) implementation of a Waste Promotion and Motivation Scheme in South Dublin (d) development and distribution of a Waste Booklet to promote waste reduction activities in Fingal (e) region wide distribution of a Waste Booklet to the commercial sector and (f) Greening Irish Pubs Initiative. Each of these

Development In Drug Targeting And Delivery In Cervical Cancer.

PubMed

Aggarwal, Urvashi; Goyal, Amit Kumar; Rath, Goutam

2017-10-09

Cervical cancer is the second most common cancer in women. Standard treatment options available for cervical cancer including chemotherapy, surgery and radiation therapy associated with their own side effects and toxicities. Tumor-targeted delivery of anticancer drugs is perhaps one of the most appropriate strategies to achieve optimal outcomes from treatment and improve quality of life. Recently nanocarriers based drug delivery systems owing to their unique properties have been extensively investigated for anticancer drug delivery. In addition to that addressing the anatomical significance of cervical cancer, various local drug delivery strategies for the cancer treatment are introduced like: gels, nanoparticles, polymeric films, rods and wafers, lipid based nanocarrier. Localized drug delivery systems allows passive drug targeting results in high drug concentration at the target site. Further they can be tailor made to achieve both sustained and controlled release behavior, substantially improving therapeutic outcomes and minimizing side effects. This review summarizes the meaningful advances in drug delivery strategies to treat cervical cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Maximizing cost-effectiveness by adjusting treatment strategy according to glaucoma severity

PubMed Central

Guedes, Ricardo Augusto Paletta; Guedes, Vanessa Maria Paletta; Gomes, Carlos Eduardo de Mello; Chaoubah, Alfredo

2016-01-01

Abstract Background: The aim of this study is to determine the most cost-effective strategy for the treatment of primary open-angle glaucoma (POAG) in Brazil, from the payer's perspective (Brazilian Public Health System) in the setting of the Glaucoma Referral Centers. Methods: Study design was a cost-effectiveness analysis of different treatment strategies for POAG. We developed 3 Markov models (one for each glaucoma stage: early, moderate and advanced), using a hypothetical cohort of POAG patients, from the perspective of the Brazilian Public Health System (SUS) and a horizon of the average life expectancy of the Brazilian population. Different strategies were tested according to disease severity. For early glaucoma, we compared observation, laser and medications. For moderate glaucoma, medications, laser and surgery. For advanced glaucoma, medications and surgery. Main outcome measures were ICER (incremental cost-effectiveness ratio), medical direct costs and QALY (quality-adjusted life year). Results: In early glaucoma, both laser and medical treatment were cost-effective (ICERs of initial laser and initial medical treatment over observation only, were R$ 2,811.39/QALY and R$ 3,450.47/QALY). Compared to observation strategy, the two alternatives have provided significant gains in quality of life. In moderate glaucoma population, medical treatment presented the highest costs among treatment strategies. Both laser and surgery were highly cost-effective in this group. For advanced glaucoma, both tested strategies were cost-effective. Starting age had a great impact on results in all studied groups. Initiating glaucoma therapy using laser or surgery were more cost-effective, the younger the patient. Conclusion: All tested treatment strategies for glaucoma provided real gains in quality of life and were cost-effective. However, according to the disease severity, not all strategies provided the same cost-effectiveness profile. Based on our findings, there should be a

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.

Synergistic tumor microenvironment targeting and blood-brain barrier penetration via a pH-responsive dual-ligand strategy for enhanced breast cancer and brain metastasis therapy.

PubMed

Li, Man; Shi, Kairong; Tang, Xian; Wei, Jiaojie; Cun, Xingli; Long, Yang; Zhang, Zhirong; He, Qin

2018-05-22

Cancer associated fibroblasts (CAFs) which shape the tumor microenvironment (TME) and the presence of blood brain barrier (BBB) remain great challenges in targeting breast cancer and its brain metastasis. Herein, we reported a strategy using PTX-loaded liposome co-modified with acid-cleavable folic acid (FA) and BBB transmigrating cell penetrating peptide dNP2 peptide (cFd-Lip/PTX) for enhanced delivery to orthotopic breast cancer and its brain metastasis. Compared with single ligand or non-cleavable Fd modified liposomes, cFd-Lip exhibited synergistic TME targeting and BBB transmigration. Moreover, upon arrival at the TME, the acid-cleavable cFd-Lip/PTX showed sensitive cleavage of FA, which reduced the hindrance effect and maximized the function of both FA and dNP2 peptide. Consequently, efficient targeting of folate receptor (FR)-positive tumor cells and FR-negative CAFs was achieved, leading to enhanced anti-tumor activity. This strategy provides a feasible approach to the cascade targeting of TME and BBB transmigration in orthotopic and metastatic cancer treatment. Copyright © 2018. Published by Elsevier Inc.

Management of juvenile idiopathic arthritis: hitting the target.

PubMed

Hinze, Claas; Gohar, Faekah; Foell, Dirk

2015-05-01

The treatment of juvenile idiopathic arthritis (JIA) is evolving. The growing number of effective drugs has led to successful treatment and prevention of long-term sequelae in most patients. Although patients with JIA frequently achieve lasting clinical remission, sustained remission off medication is still elusive for most. Treatment approaches vary substantially among paediatric rheumatologists owing to the inherent heterogeneity of JIA and, until recently, to the lack of accepted and well-evidenced guidelines. Furthermore, many pertinent questions related to patient management remain unanswered, in particular regarding treatment targets, and selection, intensity and sequence of initiation or withdrawal of therapy. Existing JIA guidelines and recommendations do not specify treat-to-target or tight control strategies, in contrast to adult rheumatology in which these approaches have been successful. The concepts of window of opportunity (early treatment to improve long-term outcomes) and immunological remission (abrogation of subclinical disease activity) are also fundamental when defining treatment methodologies. This Review explores the application of these concepts to JIA and their possible contribution to the development of future clinical guidelines or consensus treatment protocols. The article also discusses how diverse forms of standardized, guideline-led care and personalized treatment can be combined into a targeted, patient-centred approach to optimize management strategies for patients with JIA.

Targeting Key Transporters in Tumor Glycolysis as a Novel Anticancer Strategy.

PubMed

Shi, Yunli; Liu, Shengnan; Ahmad, Shabir; Gao, Qingzhi

2018-05-22

Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity. Inhibition of glucose uptake or glycolysis may effectively kill hypoxic cancer cells. Facilitative drug uptake via active transportation provides the potential opportunity to circumvent the drug resistance in chemotherapy. GLUTs as the hallmarks and biotargets of cancer metabolism enable the design and development of novel targeted theranostic agents. In this updated review, we examine the current scenario of the GLUTs as strategic targets in cancer and the unique concepts for discovery and development of GLUTs-targeted anticancer agents. We highlight the recent progresses on structural biology and underlying mechanism studies of GLUTs, with a brief introduction to the computational approaches in GLUT-mediated drug transport and tumor targeting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hantavirus Gc induces long-term immune protection via LAMP-targeting DNA vaccine strategy.

PubMed

Jiang, Dong-Bo; Zhang, Jin-Peng; Cheng, Lin-Feng; Zhang, Guan-Wen; Li, Yun; Li, Zi-Chao; Lu, Zhen-Hua; Zhang, Zi-Xin; Lu, Yu-Chen; Zheng, Lian-He; Zhang, Fang-Lin; Yang, Kun

2018-02-01

Hemorrhagic fever with renal syndrome (HFRS) occurs widely throughout Eurasia. Unfortunately, there is no effective treatment, and prophylaxis remains the best option against the major pathogenic agent, hantaan virus (HTNV), which is an Old World hantavirus. However, the absence of cellular immune responses and immunological memory hampers acceptance of the current inactivated HFRS vaccine. Previous studies revealed that a lysosome-associated membrane protein 1 (LAMP1)-targeting strategy involving a DNA vaccine based on the HTNV glycoprotein Gn successfully conferred long-term immunity, and indicated that further research on Gc, another HTNV antigen, was warranted. Plasmids encoding Gc and lysosome-targeted Gc, designated pVAX-Gc and pVAX-LAMP/Gc, respectively, were constructed. Proteins of interest were identified by fluorescence microscopy following cell line transfection. Five groups of 20 female BALB/c mice were subjected to the following inoculations: inactivated HTNV vaccine, pVAX-LAMP/Gc, pVAX-Gc, and, as the negative controls, pVAX-LAMP or the blank vector pVAX1. Humoral and cellular immunity were assessed by enzyme-linked immunosorbent assays (ELISAs) and 15-mer peptide enzyme-linked immunospot (ELISpot) epitope mapping assays. Repeated immunization with pVAX-LAMP/Gc enhanced adaptive immune responses, as demonstrated by the specific and neutralizing antibody titers and increased IFN-γ production. The inactivated vaccine induced a comparable humoral reaction, but the negative controls only elicited insignificant responses. Using a mouse model of HTNV challenge, the in vivo protection conferred by the inactivated vaccine and Gc-based constructs (with/without LAMP recombination) was confirmed. Evidence of pan-epitope reactions highlighted the long-term cellular response to the LAMP-targeting strategy, and histological observations indicated the safety of the LAMP-targeting vaccines. The long-term protective immune responses induced by pVAX-LAMP/Gc may be

Targeting the VEGF pathway: antiangiogenic strategies in the treatment of non-small cell lung cancer.

PubMed

Aita, Marianna; Fasola, Gianpiero; Defferrari, Carlotta; Brianti, Annalisa; Bello, Maria Giovanna Dal; Follador, Alessandro; Sinaccio, Graziella; Pronzato, Paolo; Grossi, Francesco

2008-12-01

The management of advanced non-small cell lung cancer (NSCLC) has evolved considerably in recent years, due to a progressive understanding of tumour biology and the identification of promising molecular targets. Several agents have been developed so far inhibiting vascular endothelial growth factor (VEGF) - a key protein in tumour neoangiogenesis, growth and dissemination - or its receptor signalling system. The finding in study E4599 of a survival benefit for carboplatin-paclitaxel plus bevacizumab - a humanised anti-VEGF monoclonal antibody - over chemotherapy (CT) alone led the U.S. Food and Drug Administration (FDA) to approve the novel combination for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. In a randomised phase III trial presented at the American Society of Clinical Oncology (ASCO) 2007 Annual Meeting, patients receiving cisplatin-gemcitabine plus bevacizumab experienced a significantly longer progression-free survival (PFS) compared to the standard arm. Based on these data, the European Medicines Agency (EMEA) has granted marketing authorisation for bevacizumab in addition to any platinum-based CT for first-line treatment of advanced NSCLC other than predominantly squamous histology. Aim of this report is to provide an overview on bevacizumab in NSCLC, with special emphasis on clinical results presented at ASCO last meeting. Multitargeted tyrosine kinase inhibitors (TKIs), sharing a focus on both the angiogenesis process and additional cell-surface receptors, and VEGF Trap, a novel fusion protein with markedly higher affinity for VEGF than bevacizumab, will be briefly discussed as well.

Targeted therapies in the treatment of urothelial cancers.

PubMed

Aragon-Ching, Jeanny B; Trump, Donald L

2017-07-01

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

Treatment Strategies for Intracranial Mirror Aneurysms.

PubMed

Wang, Wen-Xin; Xue, Zhe; Li, Lin; Wu, Chen; Zhang, Yan-Yang; Lou, Xin; Ma, Lin; Sun, Zheng-Hui

2017-04-01

Intracranial mirror aneurysms are clinically rare and uncommonly reported in the literature. Therefore, the present study evaluated a series of mirror aneurysm cases with respect to the clinical features of the patients and the treatment strategies that were used. This study retrospectively reviewed and systematically analyzed the clinical features, imaging data, treatment methods, and treatment outcomes of 68 cases of mirror aneurysms (a total of 70 pairs) in patients who were admitted to our department between November 2007 and May 2016. The patient population included 24 male and 44 female patients, with a mean age of 52 years. The mirror aneurysms were primarily located in posterior communicating artery and middle cerebral artery and 65 of the aneurysms were large or giant (≧10 mm). Of the 68 patients, 28 were treated by the clipping or embolization of all aneurysms in one stage, 16 were treated in 2 stages, 16 were treated by treating part of the aneurysms, and 8 were observed. The modified Rankin Scale scores of the 60 patients that were treated indicated that 52 had a good recovery (modified Rankin Scale score ≦2; 86.7%), and 1 patient died. Treatment strategies for mirror aneurysms should be determined individually according to the location, size, and morphology of the aneurysm, as well as the clinical manifestations of each patient. Furthermore, the responsible ruptured aneurysm should be given treatment priority, whereas the contralateral unruptured aneurysm should be observed or treated in either 1 or 2 stages. Copyright © 2017 Elsevier Inc. All rights reserved.

Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells

PubMed Central

Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

2015-01-01

The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC. PMID:26517679

Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

PubMed

Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

2015-11-24

The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.

Individualized Nonadaptive and Online-Adaptive Intensity-Modulated Radiotherapy Treatment Strategies for Cervical Cancer Patients Based on Pretreatment Acquired Variable Bladder Filling Computed Tomography Scans

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

Bondar, M.L., E-mail: m.bondar@erasmusmc.nl; Hoogeman, M.S.; Mens, J.W.

2012-08-01

Purpose: To design and evaluate individualized nonadaptive and online-adaptive strategies based on a pretreatment established motion model for the highly deformable target volume in cervical cancer patients. Methods and Materials: For 14 patients, nine to ten variable bladder filling computed tomography (CT) scans were acquired at pretreatment and after 40 Gy. Individualized model-based internal target volumes (mbITVs) accounting for the cervix and uterus motion due to bladder volume changes were generated by using a motion-model constructed from two pretreatment CT scans (full and empty bladder). Two individualized strategies were designed: a nonadaptive strategy, using an mbITV accounting for the full-rangemore » of bladder volume changes throughout the treatment; and an online-adaptive strategy, using mbITVs of bladder volume subranges to construct a library of plans. The latter adapts the treatment online by selecting the plan-of-the-day from the library based on the measured bladder volume. The individualized strategies were evaluated by the seven to eight CT scans not used for mbITVs construction, and compared with a population-based approach. Geometric uniform margins around planning cervix-uterus and mbITVs were determined to ensure adequate coverage. For each strategy, the percentage of the cervix-uterus, bladder, and rectum volumes inside the planning target volume (PTV), and the clinical target volume (CTV)-to-PTV volume (volume difference between PTV and CTV) were calculated. Results: The margin for the population-based approach was 38 mm and for the individualized strategies was 7 to 10 mm. Compared with the population-based approach, the individualized nonadaptive strategy decreased the CTV-to-PTV volume by 48% {+-} 6% and the percentage of bladder and rectum inside the PTV by 5% to 45% and 26% to 74% (p < 0.001), respectively. Replacing the individualized nonadaptive strategy by an online-adaptive, two-plan library further decreased the percentage

Postgenomic strategies in antibacterial drug discovery.

PubMed

Brötz-Oesterhelt, Heike; Sass, Peter

2010-10-01

During the last decade the field of antibacterial drug discovery has changed in many aspects including bacterial organisms of primary interest, discovery strategies applied and pharmaceutical companies involved. Target-based high-throughput screening had been disappointingly unsuccessful for antibiotic research. Understanding of this lack of success has increased substantially and the lessons learned refer to characteristics of targets, screening libraries and screening strategies. The 'genomics' approach was replaced by a diverse array of discovery strategies, for example, searching for new natural product leads among previously abandoned compounds or new microbial sources, screening for synthetic inhibitors by targeted approaches including structure-based design and analyses of focused libraries and designing resistance-breaking properties into antibiotics of established classes. Furthermore, alternative treatment options are being pursued including anti-virulence strategies and immunotherapeutic approaches. This article summarizes the lessons learned from the genomics era and describes discovery strategies resulting from that knowledge.

Nanomedicines based drug delivery systems for anti-cancer targeting and treatment.

PubMed

Jain, Vikas; Jain, Shikha; Mahajan, S C

2015-01-01

Cancer is defined as an uncontrolled growth of abnormal cells. Current treatment strategies for cancer include combination of radiation, chemotherapy and surgery. The long-term use of conventional drug delivery systems for cancer chemotherapy leads to fatal damage of normal proliferate cells and this is particularly used for the management of solid tumors, where utmost tumor cells are not invaded quickly. A targeted drug delivery system (TDDS) is a system, which releases the drug at a preselected biosite in a controlled manner. Nanotechnology based delivery systems are making a significant impact on cancer treatment and the polymers play key role in the development of nanopraticlulate carriers for cancer therapy. Some important technological advantages of nanotherapeutic drug delivery systems (NDDS) include prolonged half-life, improved bio-distribution, increased circulation time of the drug, controlled and sustained release of the drug, versatility of route of administration, increased intercellular concentration of drug and many more. This review covers the current research on polymer based anticancer agents, the rationale for development of these polymer therapeutical systems and discusses the benefits and challenges of cancer nanomedicines including polymer-drug conjugates, micelles, dendrimers, immunoconjugates, liposomes, nanoparticles.

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

PubMed Central

Nör, Jacques Eduardo

2018-01-01

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

What the patient wants: Addressing patients' treatment targets in an integrative group psychotherapy programme.

PubMed

Kealy, David; Joyce, Anthony S; Weber, Rainer; Ehrenthal, Johannes C; Ogrodniczuk, John S

2018-02-13

Limited empirical attention has been devoted to individualized treatment objectives in intensive group therapy for personality dysfunction. This study investigated patients' ratings of distress associated with individual therapy goals - referred to as target object severity - in an intensive Evening Treatment Programme for patients with personality dysfunction. Change in target objective severity was examined in a sample of 81 patients who completed treatment in an intensive, integrative group therapy programme. Correlation and regression analyses were used to examine associations between change in target object severity and patients' pre-treatment diagnosis, symptom distress, and treatment outcome expectancy, and between change in target objective severity and patients' ratings of group therapy process (group climate, therapeutic alliance, group cohesion). The relationship between change in target objective severity and longer-range life satisfaction was also examined in a subsample of patients who rated life satisfaction at follow-up. While change in target objective severity was not significantly related to pre-treatment variables, significant associations were found with several aspects of group therapy process. Patients' experience of a highly engaged group climate was uniquely associated with improvement in target object severity. Such improvement was significantly related to longer-term life satisfaction after controlling for general symptom change. The working atmosphere in group therapy contributes to patients' progress regarding individual treatment targets, and such progress is an important factor in later satisfaction. Attention to individualized treatment targets deserves further clinical and research attention in the context of integrative group therapy for personality dysfunction. This study found that patients attending an integrative group treatment programme for personality dysfunction experienced significant improvement in severity of distress

Feature Extraction and Selection Strategies for Automated Target Recognition

NASA Technical Reports Server (NTRS)

Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

2010-01-01

Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory region of-interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

Viability of the Happy Factor™ targeted selective treatment approach on several sheep farms in Scotland.

PubMed

McBean, David; Nath, Mintu; Lambe, Nicola; Morgan-Davies, Claire; Kenyon, Fiona

2016-03-15

The aim of this study was to examine the use of Happy Factor™ weight based targeted selective treatment (TST) on several commercial farms in Scotland in combination with findings from a long term trial on a research farm to assess the potential for TST use in varying farming operations as an alternative to the current regimen of whole flock treatment. Lambs on each farm were regularly weighed and climatic conditions and pasture availability measured for inclusion into the Happy Factor™ model to calculate weight targets. Half of the lambs were allocated to TST treatment and any failing to reach the weight target was treated with the anthelmintic of choice on that farm, while the remaining half of each flock was treated with anthelmintic as per normal practice on that farm (routine treatment, RT). The research farm (farm 1) hosted a long term trial using four anthelmintic treatment regimes over 6 years, and data from two regimes are presented here, alongside findings from three further farms: two commercial enterprises (farms 2 and 3) and a research farm operating as a commercial analogue with two breeds (farms 4a and 4b). The effect of TST strategy on lamb productivity and the number of anthelmintic treatments was investigated. There was no evidence (p>0.300) that mean bodyweight or growth rate was different between TST and RT groups on any of the farms and 95% confidence intervals of TST and RT groups generally suggested that TST had negligible unfavourable effects on the average growth of lambs for most of the farms. Growth rates ranged from 97.39 to 189.16g/day reflecting the varied nature of the farms. All commercial farms used significantly less (1.34 RT versus 1.14 TST treatments per animal, p<0.05) anthelmintic in lambs following TST, with a reduction from 1, 1, 1.03 and 1.14 to 0.77, 0.57, 0.82 and 0.81 in the number of treatments per animal for farms 2, 3, 4a and 4b respectively. This study suggests that TST is a viable means of controlling parasitic

siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery.

PubMed

Gomes, Maria João; Martins, Susana; Sarmento, Bruno

2015-05-01

As the population ages, brain pathologies such as neurodegenerative diseases and brain cancer increase their incidence, being the need to find successful treatments of upmost importance. Drug delivery to the central nervous system (CNS) is required in order to reach diseases causes and treat them. However, biological barriers, mainly blood-brain barrier (BBB), are the key obstacles that prevent the effectiveness of possible treatments due to their ability to strongly limit the perfusion of compounds into the brain. Over the past decades, new approaches towards overcoming BBB and its efflux transporters had been proposed. One of these approaches here reviewed is through small interfering RNA (siRNA), which is capable to specifically target one gene and silence it in a post-transcriptional way. There are different possible functional proteins at the BBB, as the ones responsible for transport or just for its tightness, which could be a siRNA target. As important as the effective silence is the way to delivery siRNA to its anatomical site of action. This is where nanotechnology-based systems may help, by protecting siRNA circulation and providing cell/tissue-targeting and intracellular siRNA delivery. After an initial overview on incidence of brain diseases and basic features of the CNS, BBB and its efflux pumps, this review focuses on recent strategies to reach brain based on siRNA, and how to specifically target these approaches in order to treat brain diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Cognitive and neuropsychiatric impairments in Alzheimer's disease: current treatment strategies.

PubMed

Borisovskaya, Anna; Pascualy, Marcella; Borson, Soo

2014-09-01

This update on Alzheimer's disease (AD) discusses treatment strategies for cognitive and neuropsychiatric symptoms (such as agitation, psychosis, anxiety, and depression) common in this illness, emphasizing in particular nonpharmacologic strategies such as cognitive interventions, physical exercise, and psychotherapy. We provide an overview of cognitive enhancers and their combination strategies and medications commonly used for treatment of neuropsychiatric symptoms in AD. Finally, we give recommendations for providing support to caregivers and suggest how to identify caregiver/patient pairs most in need of intensive dementia care services.

[Diagnostics and treatment strategies for multiple trauma patients].

PubMed

Pfeifer, R; Pape, H-C

2016-02-01

Severe trauma is still one of the leading causes of death worldwide. The initial treatment and diagnostics are of immense importance in polytraumatized patients. The initial approach mainly focuses on the advanced trauma life support (ATLS) concept. This includes the identification of life-threatening conditions and application of life-saving interventions. Depending on the physiological condition of the patient, the surgical treatment strategies of early total care (ETC) or damage control orthopedics (DCO) can be chosen. Appropriate surgical management can reduce the incidence of associated delayed systemic complications. This review summarizes the most commonly used definitions of polytrauma (including the Berlin polytrauma definition) and classification systems of severely injured patients. Moreover, the recently introduced treatment strategy of the safe definitive surgery concept for severely injured patients is also discussed in this article.

Targeting mitochondrial respiration as a therapeutic strategy for cervical cancer.

PubMed

Tian, Shenglan; Chen, Heng; Tan, Wei

2018-05-23

Targeting mitochondrial respiration has been documented as an effective therapeutic strategy in cancer. However, the impact of mitochondrial respiration inhibition on cervical cancer cells are not well elucidated. Using a panel of cervical cancer cell lines, we show that an existing drug atovaquone is active against the cervical cancer cells with high profiling of mitochondrial biogenesis. Atovaquone inhibited proliferation and induced apoptosis with varying efficacy among cervical cancer cell lines regardless of HPV infection, cellular origin and their sensitivity to paclitaxel. We further demonstrated that atovaquone acts on cervical cancer cells via inhibiting mitochondrial respiration. In particular, atovaquone specifically inhibited mitochondrial complex III but not I, II or IV activity, leading to respiration inhibition and energy crisis. Importantly, we found that the different sensitivity of cervical cancer cell lines to atovaquone were due to their differential level of mitochondrial biogenesis and dependency to mitochondrial respiration. In addition, we demonstrated that the in vitro observations were translatable to in vivo cervical cancer xenograft mouse model. Our findings suggest that the mitochondrial biogenesis varies among patients with cervical cancer. Our work also suggests that atovaquone is a useful addition to cervical cancer treatment, particularly to those with high dependency on mitochondrial respiration. Copyright © 2018 Elsevier Inc. All rights reserved.

Immunotherapeutic strategies targeting Natural killer T cell responses in cancer

PubMed Central

Shissler, Susannah C.; Bollino, Dominique R.; Tiper, Irina V.; Bates, Joshua; Derakhshandeh, Roshanak; Webb, Tonya J.

2017-01-01

Natural killer T (NKT) cells are a unique subset of lymphocytes that bridge the innate and adaptive immune system. NKT cells possess a classic αβ T-cell receptor (TCR) that is able to recognize self and foreign glycolipid antigens presented by the nonclassical class I major histocompatibility complex (MHC) molecule, CD1d. Type I NKT cells (referred to as invariant NKT cells) express a semi-invariant Vα14Jα18 TCR in mice and Vα24Jα18 TCR in humans. Type II NKT cells are CD1d-restricted T cells that express a more diverse set of TCR α chains. The two types of NKT cells often exert opposing effects especially in tumor immunity, where Type II cells generally suppress tumor immunity while Type I NKT cells can enhance antitumor immune responses. In this review, we focus on the role of NKT cells in cancer. We discuss their effector and suppressive functions, as well as describe preclinical and clinical studies utilizing therapeutic strategies focused on harnessing their potent anti-tumor effector functions, and conclude with a discussion on potential next steps for the utilization of NKT cell targeted therapies for the treatment of cancer. PMID:27393665

Integrative biology approach identifies cytokine targeting strategies for psoriasis.

PubMed

Perera, Gayathri K; Ainali, Chrysanthi; Semenova, Ekaterina; Hundhausen, Christian; Barinaga, Guillermo; Kassen, Deepika; Williams, Andrew E; Mirza, Muddassar M; Balazs, Mercedesz; Wang, Xiaoting; Rodriguez, Robert Sanchez; Alendar, Andrej; Barker, Jonathan; Tsoka, Sophia; Ouyang, Wenjun; Nestle, Frank O

2014-02-12

Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease has been revolutionized by targeting inflammatory cytokines as key drivers of disease pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the clinic. We developed an integrative biology approach combining human disease transcriptome data sets with clinically relevant in vivo models in an attempt to bridge this translational gap. We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts produced marked inflammatory skin changes resembling human psoriasis. Injection of anti-IL-22 monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis integrating both the IL-22 and anti-IL-22 cytokine transcriptomes and mapping them onto a psoriasis disease gene coexpression network identified key cytokine-dependent hub genes. Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis. Using in silico integration of human data sets and biological models, we were able to identify a new target in the treatment of psoriasis.

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking

PubMed Central

Conniot, João; Silva, Joana M.; Fernandes, Joana G.; Silva, Liana C.; Gaspar, Rogério; Brocchini, Steve; Florindo, Helena F.; Barata, Teresa S.

2014-01-01

Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking

NASA Astrophysics Data System (ADS)

Conniot, João; Silva, Joana; Fernandes, Joana; Silva, Liana; Gaspar, Rogério; Brocchini, Steve; Florindo, Helena; Barata, Teresa

2014-11-01

Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options.

Modulating the tumor microenvironment with RNA interference as a cancer treatment strategy.

PubMed

Zins, Karin; Sioud, Mouldy; Aharinejad, Seyedhossein; Lucas, Trevor; Abraham, Dietmar

2015-01-01

The tumor microenvironment is composed of accessory cells and immune cells in addition to extracellular matrix (ECM) components. The stromal compartment interacts with cancer cells in a complex crosstalk to support tumor development. Growth factors and cytokines produced by stromal cells support the growth of tumor cells and promote interaction with the vasculature to enhance tumor progression and invasion. The activation of autocrine and paracrine oncogenic signaling pathways by growth factors, cytokines, and proteases derived from both tumor cells and the stromal compartment is thought to play a major role in assisting tumor cells during metastasis. Consequently, targeting tumor-stroma interactions by RNA interference (RNAi)-based approaches is a promising strategy in the search for novel treatment modalities in human cancer. Recent advances in packaging technology including the use of polymers, peptides, liposomes, and nanoparticles to deliver small interfering RNAs (siRNAs) into target cells may overcome limitations associated with potential RNAi-based therapeutics. Newly developed nonviral gene delivery approaches have shown improved anticancer efficacy suggesting that RNAi-based therapeutics provide novel opportunities to elicit significant gene silencing and induce regression of tumor growth. This chapter summarizes our current understanding of the tumor microenvironment and highlights some potential targets for therapeutic intervention with RNAi-based cancer therapeutics.

PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma

PubMed Central

Brenner, J. Chad; Feng, Felix Y.; Han, Sumin; Patel, Sonam; Goyal, Siddharth V.; Bou-Maroun, Laura M.; Liu, Meilan; Lonigro, Robert; Prensner, John R.; Tomlins, Scott A.; Chinnaiyan, Arul M.

2012-01-01

Ewing's sarcoma family tumors (ESFTs) are aggressive malignancies which frequently harbor characteristic EWS-FLI1 or EWS-ERG genomic fusions. Here we report that these fusion products interact with the DNA damage response protein and transcriptional co-regulator PARP-1. ESFT cells, primary tumor xenografts and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1-driven mouse xenograft model of ESFT. Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines. Notably, EWS-FLI1 fusion genes acted in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI-mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition. Together, our findings offer a strong preclinical rationale to target the EWS-FLI1: PARP1 intersection as a therapeutic strategy to improve the treatment of Ewing's sarcoma family tumors. PMID:22287547

Development of a targeted transgenesis strategy in highly differentiated cells: a powerful tool for functional genomic analysis.

PubMed

Puttini, Stefania; Ouvrard-Pascaud, Antoine; Palais, Gael; Beggah, Ahmed T; Gascard, Philippe; Cohen-Tannoudji, Michel; Babinet, Charles; Blot-Chabaud, Marcel; Jaisser, Frederic

2005-03-16

Functional genomic analysis is a challenging step in the so-called post-genomic field. Identification of potential targets using large-scale gene expression analysis requires functional validation to identify those that are physiologically relevant. Genetically modified cell models are often used for this purpose allowing up- or down-expression of selected targets in a well-defined and if possible highly differentiated cell type. However, the generation of such models remains time-consuming and expensive. In order to alleviate this step, we developed a strategy aimed at the rapid and efficient generation of genetically modified cell lines with conditional, inducible expression of various target genes. Efficient knock-in of various constructs, called targeted transgenesis, in a locus selected for its permissibility to the tet inducible system, was obtained through the stimulation of site-specific homologous recombination by the meganuclease I-SceI. Our results demonstrate that targeted transgenesis in a reference inducible locus greatly facilitated the functional analysis of the selected recombinant cells. The efficient screening strategy we have designed makes possible automation of the transfection and selection steps. Furthermore, this strategy could be applied to a variety of highly differentiated cells.

Recent Progress in Therapeutic Treatments and Screening Strategies for the Prevention and Treatment of HPV-Associated Head and Neck Cancer

PubMed Central

Whang, Sonia N.; Filippova, Maria; Duerksen-Hughes, Penelope

2015-01-01

The rise in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has elicited significant interest in the role of high-risk HPV in tumorigenesis. Because patients with HPV-positive HNSCC have better prognoses than do their HPV-negative counterparts, current therapeutic strategies for HPV+ HNSCC are increasingly considered to be overly aggressive, highlighting a need for customized treatment guidelines for this cohort. Additional issues include the unmet need for a reliable screening strategy for HNSCC, as well as the ongoing assessment of the efficacy of prophylactic vaccines for the prevention of HPV infections in the head and neck regions. This review also outlines a number of emerging prospects for therapeutic vaccines, as well as for targeted, molecular-based therapies for HPV-associated head and neck cancers. Overall, the future for developing novel and effective therapeutic agents for HPV-associated head and neck tumors is promising; continued progress is critical in order to meet the challenges posed by the growing epidemic. PMID:26393639

Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity.

PubMed

Kaur, Shamsherjit; Singh, Satinderpal; Chahal, Karan Singh; Prakash, Atish

2014-11-01

Organophosphates (OP) are highly toxic compounds that cause cholinergic neuronal excitotoxicity and dysfunction by irreversible inhibition of acetylcholinesterase, resulting in delayed brain damage. This delayed secondary neuronal destruction, which arises primarily in the cholinergic areas of the brain that contain dense accumulations of cholinergic neurons and the majority of cholinergic projection, could be largely responsible for persistent profound neuropsychiatric and neurological impairments such as memory, cognitive, mental, emotional, motor, and sensory deficits in the victims of OP poisoning. The therapeutic strategies for reducing neuronal brain damage must adopt a multifunctional approach to the various steps of brain deterioration: (i) standard treatment with atropine and related anticholinergic compounds; (ii) anti-excitotoxic therapies to prevent cerebral edema, blockage of calcium influx, inhibition of apoptosis, and allow for the control of seizure; (iii) neuroprotection by aid of antioxidants and N-methyl-d-aspartate (NMDA) antagonists (multifunctional drug therapy), to inhibit/limit the secondary neuronal damage; and (iv) therapies targeting chronic neuropsychiatric and neurological symptoms. These neuroprotective strategies may prevent secondary neuronal damage in both early and late stages of OP poisoning, and thus may be a beneficial approach to treating the neuropsychological and neuronal impairments resulting from OP toxicity.

Targeted Screening Strategies to Detect Trypanosoma cruzi Infection in Children

PubMed Central

Levy, Michael Z.; Kawai, Vivian; Bowman, Natalie M.; Waller, Lance A.; Cabrera, Lilia; Pinedo-Cancino, Viviana V.; Seitz, Amy E.; Steurer, Frank J.; Cornejo del Carpio, Juan G.; Cordova-Benzaquen, Eleazar; Maguire, James H.; Gilman, Robert H.; Bern, Caryn

2007-01-01

Background Millions of people are infected with Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. Anti-trypanosomal drug therapy can cure infected individuals, but treatment efficacy is highest early in infection. Vector control campaigns disrupt transmission of T. cruzi, but without timely diagnosis, children infected prior to vector control often miss the window of opportunity for effective chemotherapy. Methods and Findings We performed a serological survey in children 2–18 years old living in a peri-urban community of Arequipa, Peru, and linked the results to entomologic, spatial and census data gathered during a vector control campaign. 23 of 433 (5.3% [95% CI 3.4–7.9]) children were confirmed seropositive for T. cruzi infection by two methods. Spatial analysis revealed that households with infected children were very tightly clustered within looser clusters of households with parasite-infected vectors. Bayesian hierarchical mixed models, which controlled for clustering of infection, showed that a child's risk of being seropositive increased by 20% per year of age and 4% per vector captured within the child's house. Receiver operator characteristic (ROC) plots of best-fit models suggest that more than 83% of infected children could be identified while testing only 22% of eligible children. Conclusions We found evidence of spatially-focal vector-borne T. cruzi transmission in peri-urban Arequipa. Ongoing vector control campaigns, in addition to preventing further parasite transmission, facilitate the collection of data essential to identifying children at high risk of T. cruzi infection. Targeted screening strategies could make integration of diagnosis and treatment of children into Chagas disease control programs feasible in lower-resource settings. PMID:18160979

Recent advances in molecular biology and treatment strategies for intracranial germ cell tumors.

PubMed

Huang, Xiang; Zhang, Rong; Mao, Ying; Zhou, Liang-Fu; Zhang, Chao

2016-08-01

Intracranial germ cell tumors (IGCTs) are a group of rare pediatric brain tumors which include various subtypes. The current understanding of the etiology of the tumors and their optimal management strategies remain controversial. The data on IGCTs were collected from articles published in the past 20 years, and the origin and etiology of IGCTs at molecular level as well as the relative roles of varied treatment strategies in different prognosis groups according to Matsutani's classification were reviewed. Recent cellular and molecular evidence suggests that IGCTs may arise from the transformation of endogenous brain cells; and findings in the molecular characterization of IGCTs suggest roles of CCND2, RB1, and PRDM14 in the pathogenesis of IGCTs and identify the KIT/RAS and AKT1/mTOR pathways as potential therapeutic targets in future. According to Matsutani's classification of IGCTs, the good prognosis group includes both germinomas and mature teratomas. For germinomas, both radiation alone and reduced-dose radiotherapy in combination with adjuvant chemotherapy are effective, while complete surgical excision is recommended for mature teratomas. In the intermediate prognosis group, immature teratoma has been successfully treated with gamma knife surgery. However, for intermediate prognosis IGCTs other than immature teratomas, gross total resection with adjuvant chemotherapy and radiotherapy or gamma knife surgery may be necessary to achieve cure. In the poor prognosis group, survival outcomes are unsatisfactory, and complete surgical resection combined with more intensive chemotherapy and radiotherapy remains the best available treatment option at this time. IGCTs should be strictly classified according to their pathological categories before administering pathology-specific treatments. Although open microsurgical excision is the traditional surgical strategy for IGCTs, recent publications also support the role of endoscopic surgical options for pineal region

Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2014-11-01

Award Number: W81XWH-11-2-0011 TITLE: Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury PRINCIPAL INVESTIGATOR...Oct 2014 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...fluid percussion, traumatic brain injury, blood brain barrier, neuroinflammation, neurological dysfunction, endocannabinoids , microglia and 16

Four-Week Strategy-Based Training to Enhance Prospective Memory in Older Adults: Targeting Intention Retention Is More Beneficial than Targeting Intention Formation.

PubMed

Ihle, Andreas; Albiński, Rafal; Gurynowicz, Kamila; Kliegel, Matthias

2018-01-01

So far, training of prospective memory (PM) focused on very short instances (single sessions) and targeted the intention-formation phase only. We aimed to compare the effectiveness of 2 different 4-week strategy-based PM training types, namely imagery training (targeting the encoding of the PM intention in the intention-formation phase) versus rehearsal training (targeting the maintenance of the PM intention in the intention-retention phase) in older adults. We used a 4-week training protocol (8 sessions in total, 2 sessions per week). From the 44 participants, 21 were randomly assigned to the imagery training (vividly imagining a mental picture to memorize the connection between the PM cue words and related actions during intention formation) and 23 to the rehearsal training (rehearsing the PM cue words during intention retention). The criterion PM task was assessed before and after the training. Comparing the effectiveness of both training types, we found a significant time by training type interaction on PM accuracy in terms of PM cue detection, F(1, 42) = 6.07, p = 0.018, η2p = 0.13. Subsequent analyses revealed that the rehearsal training was more effective in enhancing PM accuracy in terms of PM cue detection than the imagery training. Strategy-based PM training in older adults targeting the maintenance of the PM intention in the intention-retention phase may be more effective in enhancing PM accuracy in terms of PM cue detection than the strategy targeting the encoding of the PM intention in the intention-formation phase. This suggests that for successful prospective remembering, older adults may need more support to keep the PM cues active in memory while working on the ongoing task than to initially encode the PM intention. © 2018 S. Karger AG, Basel.

Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance.

PubMed

Hegazy, Ahmed M; Yamada, Daisuke; Kobayashi, Masahiko; Kohno, Susumu; Ueno, Masaya; Ali, Mohamed A E; Ohta, Kumiko; Tadokoro, Yuko; Ino, Yasushi; Todo, Tomoki; Soga, Tomoyoshi; Takahashi, Chiaki; Hirao, Atsushi

2016-10-07

Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it is still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption of this energy balance efficiently suppresses aggressive malignant gliomas driven by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. In a mouse glioma model, mTORC1 hyperactivation induced by conditional Tsc1 deletion increased numbers of glioma-initiating cells (GICs) in vitro and in vivo Metabolic analysis revealed that mTORC1 hyperactivation enhanced mitochondrial biogenesis, as evidenced by elevations in oxygen consumption rate and ATP production. Inhibition of mitochondrial ATP synthetase was more effective in repressing sphere formation by Tsc1-deficient glioma cells than that by Tsc1-competent glioma cells, indicating a crucial function for mitochondrial bioenergetic capacity in GIC expansion. To translate this observation into the development of novel therapeutics targeting malignant gliomas, we screened drug libraries for small molecule compounds showing greater efficacy in inhibiting the proliferation/survival of Tsc1-deficient cells compared with controls. We identified several compounds able to preferentially inhibit mitochondrial activity, dramatically reducing ATP levels and blocking glioma sphere formation. In human patient-derived glioma cells, nigericin, which reportedly suppresses cancer stem cell properties, induced AMPK phosphorylation that was associated with mTORC1 inactivation and induction of autophagy and led to a marked decrease in sphere formation with loss of GIC marker expression. Furthermore, malignant characteristics of human glioma cells were markedly suppressed by nigericin treatment in vivo Thus, targeting mTORC1-driven processes, particularly those involved in maintaining a cancer cell's energy balance, may be an effective therapeutic strategy for glioma patients. © 2016 by The American

Heat-Treatment-Responsive Proteins in Different Developmental Stages of Tomato Pollen Detected by Targeted Mass Accuracy Precursor Alignment (tMAPA).

PubMed

Chaturvedi, Palak; Doerfler, Hannes; Jegadeesan, Sridharan; Ghatak, Arindam; Pressman, Etan; Castillejo, Maria Angeles; Wienkoop, Stefanie; Egelhofer, Volker; Firon, Nurit; Weckwerth, Wolfram

2015-11-06

Recently, we have developed a quantitative shotgun proteomics strategy called mass accuracy precursor alignment (MAPA). The MAPA algorithm uses high mass accuracy to bin mass-to-charge (m/z) ratios of precursor ions from LC-MS analyses, determines their intensities, and extracts a quantitative sample versus m/z ratio data alignment matrix from a multitude of samples. Here, we introduce a novel feature of this algorithm that allows the extraction and alignment of proteotypic peptide precursor ions or any other target peptide from complex shotgun proteomics data for accurate quantification of unique proteins. This strategy circumvents the problem of confusing the quantification of proteins due to indistinguishable protein isoforms by a typical shotgun proteomics approach. We applied this strategy to a comparison of control and heat-treated tomato pollen grains at two developmental stages, post-meiotic and mature. Pollen is a temperature-sensitive tissue involved in the reproductive cycle of plants and plays a major role in fruit setting and yield. By LC-MS-based shotgun proteomics, we identified more than 2000 proteins in total for all different tissues. By applying the targeted MAPA data-processing strategy, 51 unique proteins were identified as heat-treatment-responsive protein candidates. The potential function of the identified candidates in a specific developmental stage is discussed.

Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer.

PubMed

Koustas, Evangelos; Karamouzis, Michalis V; Mihailidou, Chrysovalantou; Schizas, Dimitrios; Papavassiliou, Athanasios G

2017-06-28

The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR MoAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways. Recent data also suggest that acquired-resistance to anti-EGFR MoAbs is accompanied by inhibition of EGFR internalization, ubiqutinization, degradation and prolonged downregulation. It is well established that autophagy, a self-cannibalization process, is considered to be associated with resistance to the anti-EGFR MoAbs therapy. Additionally, autophagy induced by anti-EGFR MoAbs acts as a protective response in cancer cells. Thus, inhibition of autophagy after treatment with EGFR MoAbs can result in autophagic cell death. A combination therapy comprising of anti-EGFR MoAbs and autophagy inhibitors would represent a multi-pronged approach that could be evolved into an active therapeutic strategy in mCRC patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Using cost-effectiveness analysis to evaluate targeting strategies: the case of vitamin A supplementation.

PubMed

Loevinsohn, B P; Sutter, R W; Costales, M O

1997-03-01

Given the demonstrated efficacy of vitamin A supplements in reducing childhood mortality, health officials now have to decide whether it would be efficient to target the supplements to high risk children. Decisions about targeting are complex because they depend on a number of factors; the degree of clustering of preventable deaths, the cost of the intervention, the side-effects of the intervention, the cost of identifying the high risk group, and the accuracy of the 'diagnosis' of risk. A cost-effectiveness analysis was used in the Philippines to examine whether vitamin A supplements should be given universally to all children 6-59 months, targeted broadly to children suffering from mild, moderate, or severe malnutrition, or targeted narrowly to pre-schoolers with moderate and severe malnutrition. The first year average cost of the universal approach was US$67.21 per death averted compared to $144.12 and $257.20 for the broad and narrow targeting approaches respectively. When subjected to sensitivity analysis the conclusion about the most cost-effective strategy was robust to changes in underlying assumptions such as the efficacy of supplements, clustering of deaths, and toxicity. Targeting vitamin A supplements to high risk children is not an efficient use of resources. Based on the results of this cost-effectiveness analysis and a consideration of alternate strategies, it is apparent that vitamin A, like immunization, should be provided to all pre-schoolers in the developing world. Issues about targeting public health interventions can usefully be addressed by cost-effectiveness analysis.

Strategies for targeting tetraspanin proteins: potential therapeutic applications in microbial infections.

PubMed

Hassuna, Noha; Monk, Peter N; Moseley, Gregory W; Partridge, Lynda J

2009-01-01

The identification of novel targets and strategies for therapy of microbial infections is an area of intensive research due to the failure of conventional vaccines or antibiotics to combat both newly emerging diseases (e.g. viruses such as severe acute respiratory syndrome (SARS) and new influenza strains, and antibiotic-resistant bacteria) and entrenched, pandemic diseases exemplified by HIV. One clear approach to this problem is to target processes of the host organism rather than the microbe. Recent data have indicated that members of the tetraspanin superfamily, proteins with a widespread distribution in eukaryotic organisms and 33 members in humans, may provide such an approach. Tetraspanins traverse the membrane four times, but are distinguished from other four-pass membrane proteins by the presence of conserved charged residues in the transmembrane domains and a defining 'signature' motif in the larger of the two extracellular domains (the EC2). They characteristically form promiscuous associations with one another and with other membrane proteins and lipids to generate a specialized type of microdomain: the tetraspanin-enriched microdomain (TEM). TEMs are integral to the main role of tetraspanins as 'molecular organizers' involved in functions such as membrane trafficking, cell-cell fusion, motility, and signaling. Increasing evidence demonstrates that tetraspanins are used by intracellular pathogens as a means of entering and replicating within human cells. Although previous investigations focused mainly on viruses such as hepatitis C and HIV, it is now becoming clear that other microbes associate with tetraspanins, using TEMs as a 'gateway' to infection. In this article we review the properties and functions of tetraspanins/TEMs that are relevant to infective processes and discuss the accumulating evidence that shows how different pathogens exploit these properties in infection and in the pathogenesis of disease. We then investigate the novel and exciting

Nanomedicine as a potential approach to empower the new strategies for the treatment of preeclampsia.

PubMed

Valero, Lucie; Alhareth, Khair; Gil, Sophie; Lecarpentier, Edouard; Tsatsaris, Vassilis; Mignet, Nathalie; Fournier, Thierry; Andrieux, Karine

2018-01-31

Preeclampsia is a serious pregnancy disorder characterized by the onset of high blood pressure and proteinuria. Although the understanding of the disease is increasing, it remains without treatment, other than the delivery of the baby and the placenta. This review sets out to discuss some new developments and strategies in the treatment of preeclampsia. We briefly review the current knowledge on the preeclamptic pathophysiology. We then examine the recent trends in preeclampsia treatment and, in particular, the tracks of potential therapeutic targets. Finally, we focus on the possibilities nanocarriers could offer in the management of preeclampsia. Indeed, nanocarriers could help to prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. Tendencies are then drawn from the available studies on the optimal characteristics of a nanocarrier to deliver drugs to the placenta. Copyright © 2018 Elsevier Ltd. All rights reserved.

New strategies for local treatment of vaginal infections.

PubMed

Palmeira-de-Oliveira, Rita; Palmeira-de-Oliveira, Ana; Martinez-de-Oliveira, José

2015-09-15

Vaginal infections are extremely prevalent, particularly among women of reproductive age. Although they do not result in high mortality rates, these infections are associated with high levels of anxiety and reduction of quality of life. In most cases, topical treatment of vaginal infections has been shown to be at least as effective as oral treatment, resulting in higher local drug concentrations, with fewer drug interactions and adverse effects. Furthermore, the emergence of microbial resistance to chemotherapeutics and the difficulties in managing infection recurrences sustain the need for more effective local treatments. However, conventional dosage forms have been associated with low retention in the vagina and discomfort. Formulation strategies such as the development of bioadhesive, thermogelling systems and microtechnological or nanotechnological approaches have been proposed to improve delivery of traditional drugs, and other treatment modalities such as new drugs, plant extracts, and probiotics are being studied. This article reviews the recent strategies studied to improve the treatment and prevention of the commonest vaginal infections-namely, vaginal bacteriosis, aerobic vaginitis, vulvovaginal candidosis, and trichomoniasis-through the intravaginal route. Copyright © 2015 Elsevier B.V. All rights reserved.

WE-DE-201-01: BEST IN PHYSICS (THERAPY): A Fast Multi-Target Inverse Treatment Planning Strategy Optimizing Dosimetric Measures for High-Dose-Rate (HDR) Brachytherapy

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

Guthier, C; University Medical Center Mannheim, Mannheim; Harvard Medical School, Boston, MA

Purpose: Inverse treatment planning (ITP) for interstitial HDR brachytherapy of gynecologic cancers seeks to maximize coverage of the clinical target volumes (tumor and vagina) while respecting dose-volume-histogram related dosimetric measures (DMs) for organs at risk (OARs). Commercially available ITP tools do not support DM-based planning because it is computationally too expensive to solve. In this study we present a novel approach that allows fast ITP for gynecologic cancers based on DMs for the first time. Methods: This novel strategy is an optimization model based on a smooth DM-based objective function. The smooth approximation is achieved by utilizing a logistic functionmore » for the evaluation of DMs. The resulting nonconvex and constrained optimization problem is then optimized with a BFGS algorithm. The model was evaluated using the implant geometry extracted from 20 patient treatment plans under an IRB-approved retrospective study. For each plan, the final DMs were evaluated and compared to the original clinical plans. The CTVs were the contoured tumor volume and the contoured surface of the vagina. Statistical significance was evaluated with a one-sided paired Wilcoxon signed-rank test. Results: As did the clinical plans, all generated plans fulfilled the defined DMs for OARs. The proposed strategy showed a statistically significant improvement (p<0.001) in coverage of the tumor and vagina, with absolute improvements of related DMs of (6.9 +/− 7.9)% and (28.2 +/− 12.0)%, respectively. This was achieved with a statistically significant (p<0.01) decrease of the high-dose-related DM for the tumor. The runtime of the optimization was (2.3 +/− 2.0) seconds. Conclusion: We demonstrated using clinical data that our novel approach allows rapid DM-based optimization with improved coverage of CTVs with fewer hot spots. Being up to three orders of magnitude faster than the current clinical practice, the method dramatically shortens planning time.« less

Current challenges and emerging drug delivery strategies for the treatment of psoriasis.

PubMed

Hoffman, Melissa B; Hill, Dane; Feldman, Steven R

2016-10-01

Psoriasis is a common skin disorder associated with physical, social, psychological and financial burden. Over the past two decades, advances in our understanding of pathogenesis and increased appreciation for the multifaceted burden of psoriasis has led to new treatment development and better patient outcomes. Yet, surveys demonstrate that many psoriasis patients are either undertreated or are dissatisfied with treatment. There are many barriers that need be overcome to optimize patient outcomes and satisfaction. This review covers the current challenges associated with each major psoriasis treatment strategy (topical, phototherapy, oral medications and biologics). It also reviews the challenges associated with the psychosocial aspects of the disease and how they affect treatment outcomes. Patient adherence, inconvenience, high costs, and drug toxicities are all discussed. Then, we review the emerging drug delivery strategies in topical, oral, and biologic therapy. By outlining current treatment challenges and emerging drug delivery strategies, we hope to highlight the deficits in psoriasis treatment and strategies for how to overcome them. Regardless of disease severity, clinicians should use a patient-centered approach. In all cases, we need to balance patients' psychosocial needs, treatment costs, convenience, and effectiveness with patients' preferences in order to optimize treatment outcomes.

Targeted Recovery as an Effective Strategy against Epidemic Spreading.

PubMed

Böttcher, L; Andrade, J S; Herrmann, H J

2017-10-30

We propose a targeted intervention protocol where recovery is restricted to individuals that have the least number of infected neighbours. Our recovery strategy is highly efficient on any kind of network, since epidemic outbreaks are minimal when compared to the baseline scenario of spontaneous recovery. In the case of spatially embedded networks, we find that an epidemic stays strongly spatially confined with a characteristic length scale undergoing a random walk. We demonstrate numerically and analytically that this dynamics leads to an epidemic spot with a flat surface structure and a radius that grows linearly with the spreading rate.

Spatial Distribution of Falciparum Malaria Infections in Zanzibar: Implications for Focal Drug Administration Strategies Targeting Asymptomatic Parasite Carriers

PubMed Central

Cook, Jackie; Sturrock, Hugh; Msellem, Mwinyi; Ali, Abdullah; Xu, Weiping; Molteni, Fabrizio; Gosling, Roly; Drakeley, Chris; Mårtensson, Andreas

2017-01-01

Abstract Background. Optimal use of mass/targeted screen-and-treat or mass or focal drug administration as malaria elimination strategies remains unclear. We therefore studied spatial distribution of Plasmodium falciparum infections to compare simulated effects of these strategies on reducing the parasite reservoir in a pre-elimination setting. Methods. P. falciparum rapid diagnostic tests (RDTs) and molecular (polymerase chain reaction [PCR]) and serological (enzyme-linked immunosorbent assay) analyses were performed on finger-prick blood samples from a population-based survey in 3 adjacent communities. Results. Among 5278 persons screened, 13 (0.2%) were positive by RDT and 123 (2.3%) by PCR. PCR-positive individuals were scattered over the study area, but logistic regression analysis suggested a propensity of these infections to cluster around RDT-positive individuals. The odds ratios for being PCR positive was 7.4 (95% confidence interval, 2.8–19.9) for those living in the household of an RDT-positive individual and 1.64 (1.0–2.8; P = .06) for those living within <300 m, compared with >1000 m. Treating everyone within households of RDT-positive individuals (1% population) would target 13% of those who are PCR positive. Treating all living within a radius of <300 or <1000 m (14% or 58% population) would target 30% or 66% of infections, respectively. Among 4431 serologically screened individuals, 26% were seropositive. Treating everyone within seropositive households (63% population) would target 77% of PCR-positive individuals. Conclusions. Presumptive malaria treatment seemed justified within RDT-positive households and potentially worth considering within, for example, a radius of <300 m. Serology was not discriminative enough in identifying ongoing infections for improving focal interventions in this setting but may rather be useful to detect larger transmission foci. PMID:28431115

Complex background suppression using global-local registration strategy for the detection of small-moving target on moving platform

NASA Astrophysics Data System (ADS)

Zou, Tianhao; Zuo, Zhengrong

2018-02-01

Target detection is a very important and basic problem of computer vision and image processing. The most often case we meet in real world is a detection task for a moving-small target on moving platform. The commonly used methods, such as Registration-based suppression, can hardly achieve a desired result. To crack this hard nut, we introduce a Global-local registration based suppression method. Differ from the traditional ones, the proposed Global-local Registration Strategy consider both the global consistency and the local diversity of the background, obtain a better performance than normal background suppression methods. In this paper, we first discussed the features about the small-moving target detection on unstable platform. Then we introduced a new strategy and conducted an experiment to confirm its noisy stability. In the end, we confirmed the background suppression method based on global-local registration strategy has a better perform in moving target detection on moving platform.

In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy.

PubMed

Sorensen, Annette; Mairs, Robert J; Braidwood, Lynne; Joyce, Craig; Conner, Joe; Pimlott, Sally; Brown, Moira; Boyd, Marie

2012-04-01

Oncolytic herpes viruses show promise for cancer treatment. However, it is unlikely that they will fulfill their therapeutic potential when used as monotherapies. An alternative strategy is to use these viruses not only as oncolytic agents but also as a delivery mechanism of therapeutic transgenes to enhance tumor cell killing. The herpes simplex virus 1 deletion mutant HSV1716 is a conditionally replicating oncolytic virus that selectively replicates in and lyses dividing tumor cells. It has a proven safety profile in clinical trials and has demonstrated efficacy as a gene-delivery vehicle. To enhance its therapeutic potential, we have engineered HSV1716 to convey the noradrenaline transporter (NAT) gene (HSV1716/NAT), whose expression endows infected cells with the capacity to accumulate the noradrenaline analog metaiodobenzylguanidine (MIBG). Thus, the NAT gene-infected cells are susceptible to targeted radiotherapy using radiolabeled (131)I-MIBG, a strategy that has already shown promise for combined targeted radiotherapy-gene therapy in cancer cells after plasmid-mediated transfection. We used HSV1716/NAT as a dual cell lysis-gene delivery vehicle for targeting the NAT transgene to human tumor xenografts in vivo. In tumor xenografts that did not express NAT, intratumoral or intravenous injection of HSV1716/NAT induced the capacity for active uptake of (131)I-MIBG. Administration of HSV1716/NAT and (131)I-MIBG resulted in decreased tumor growth and enhanced survival relative to injection of either agent alone. Efficacy was dependent on the scheduling of delivery of the 2 agents. These findings support a role for combination radiotherapy-gene therapy for cancer using HSV1716 expressing the NAT transgene and targeted radionuclide therapy.

Membrane-targeted strategies for modulating APP and Aβ-mediated toxicity

PubMed Central

Price, Katherine A; Crouch, Peter J; Donnelly, Paul S; Masters, Colin L; White, Anthony R; Curtain, Cyril C

2009-01-01

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by numerous pathological features including the accumulation of neurotoxic amyloid-β (Aβ) peptide. There is currently no effective therapy for AD, but the development of therapeutic strategies that target the cell membrane is gaining increased interest. The amyloid precursor protein (APP) from which Aβ is formed is a membrane-bound protein, and Aβ production and toxicity are both membrane mediated events. This review describes the critical role of cell membranes in AD with particular emphasis on how the composition and structure of the membrane and its specialized regions may influence toxic or benign Aβ/APP pathways in AD. The putative role of copper (Cu) in AD is also discussed, and we highlight how targeting the cell membrane with Cu complexes has therapeutic potential in AD. PMID:19278455

Structural and functional outcomes of a therapeutic strategy targeting low disease activity in patients with elderly-onset rheumatoid arthritis: a prospective cohort study (CRANE).

PubMed

Sugihara, Takahiko; Ishizaki, Tatsuro; Hosoya, Tadashi; Iga, Shoko; Yokoyama, Waka; Hirano, Fumio; Miyasaka, Nobuyuki; Harigai, Masayoshi

2015-05-01

The aim of this study was to evaluate structural damage and physical disability in patients with elderly-onset RA (EORA) who were treated in clinical practice with a therapeutic strategy targeting low disease activity (LDA). Data from 151 MTX-naive patients (mean age 74.9 years) with EORA from a prospective, monocentric registry were analysed. Treatment was adjusted every 3 months targeting LDA [28-joint DAS using ESR (DAS28-ESR) <3.2]. Treatment was initiated with non-biologic DMARDs (nbDMARDs), followed by TNF inhibitors (TNFis) or tocilizumab. The primary outcome was change from week 0 to week 52 in the modified total Sharp score (ΔmTSS). Secondary outcomes were derived from the HAQ Disability Index (HAQ-DI) and DAS28 at week 52. Predictors of clinically relevant radiographic progression [CRRP; ΔmTSS/year more than the smallest detectable change (2.1 points)] were examined using multivariate logistic regression models. Adherence to the treat-to-target strategy was observed in 83.4% of the 151 patients at week 24 and in 75.5% at week 52. At week 52, 67.6% of the patients were receiving a nbDMARD alone, 31.0% a TNFi with or without MTX and 1.4% tocilizumab. At week 52, structural remission (ΔmTSS/yr ≤0.5) was achieved in 49.7% of the patients, functional remission (HAQ-DI ≤0.5) in 63.4% and LDA in 51.0%. Clinical responses at weeks 12 and 24 were significant independent predictors of CRRP. Cumulative disease activity during the first 12 weeks predicted CRRP with a C-statistic of 0.888. Achieving structural remission, functional remission and LDA in clinical practice in EORA patients are realistic goals. Our results indicate significant benefits for a therapeutic strategy targeting LDA for EORA patients in clinical practice. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mesenchymal stem cell-mediated cancer therapy: A dual-targeted strategy of personalized medicine

PubMed Central

Sun, Xu-Yong; Nong, Jiang; Qin, Ke; Warnock, Garth L; Dai, Long-Jun

2011-01-01

Cancer remains one of the leading causes of mortality and morbidity throughout the world. To a significant extent, current conventional cancer therapies are symptomatic and passive in nature. The major obstacle to the development of effective cancer therapy is believed to be the absence of sufficient specificity. Since the discovery of the tumor-oriented homing capacity of mesenchymal stem cells (MSCs), the application of specific anticancer gene-engineered MSCs has held great potential for cancer therapies. The dual-targeted strategy is based on MSCs’ capacity of tumor-directed migration and incorporation and in situ expression of tumor-specific anticancer genes. With the aim of translating bench work into meaningful clinical applications, we describe the tumor tropism of MSCs and their use as therapeutic vehicles, the dual-targeted anticancer potential of engineered MSCs and a putative personalized strategy with anticancer gene-engineered MSCs. PMID:22180830

Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.

PubMed

Irving, Julie A E

2016-03-01

Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse. © 2015 John Wiley & Sons Ltd.

Strategy of Cancer Targeting Gene-Viro-Therapy (CTGVT) a trend in both cancer gene therapy and cancer virotherapy.

PubMed

Liu, Xin-Yuan; Li, Hua-Guang; Zhang, Kang-Jian; Gu, Jin-Fa

2012-07-01

Cancer Targeting Gene-Viro-Therapy (CTGVT) and Gene Armed Oncolytic Virus Therapy (GAOVT) both are identical by inserting an antitumor gene into an oncolytic virus. This approach has gradually become a hot topic in cancer therapy, because that CTGVT (GAOVT) has much higher antitumor than that of either gene therapy alone or oncolytic virotherapy alone. We proposed the CTGVT strategy in 1999-2001, insisted it as a long term systematic approach to be examined over 10 years and have published 68 SCI papers some in good Journals. The CD gene armed oncolytic adenovirus therapy (GAOVT) for cancer treatment with potent antitumor effect was also named in our laboratory in 2003. Several modifications to CTGVT will be carried out by our group and will be introduced briefly in this paper. Most importantly, the modifications of CTGVT usually resulted in complete eradication of xenograft tumors in nude mice. In future best antitumor drugs may emerge from the modified CTGVT strategy and not from either gene therapy or virotherapy alone.

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

A Cell-targeted Photodynamic Nanomedicine Strategy for Head & Neck Cancers

PubMed Central

Master, Alyssa; Malamas, Anthony; Solanki, Rachna; Clausen, Dana M.; Eiseman, Julie L.; Gupta, Anirban Sen

2013-01-01

Photodynamic Therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. To this end, we report on a cell-targeted nanomedicine approach for the photosensitizer silicon phthalocyanine-4 (Pc 4), by packaging it within polymeric micelles that are surface-decorated with GE11-peptides to promote enhanced cell-selective binding and receptor-mediated internalization in EGFR-overexpressing H&N cancer cells. Using fluorescence spectroscopy and confocal microscopy, we demonstrate in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N SCC-15 cells. We further demonstrate that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, we demonstrate that the EGFR-targeted Pc 4-nanoformulation results in significant intra-tumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise towards a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas. PMID:23531079

Assessing an ensemble docking-based virtual screening strategy for kinase targets by considering protein flexibility.

PubMed

Tian, Sheng; Sun, Huiyong; Pan, Peichen; Li, Dan; Zhen, Xuechu; Li, Youyong; Hou, Tingjun

2014-10-27

In this study, to accommodate receptor flexibility, based on multiple receptor conformations, a novel ensemble docking protocol was developed by using the naïve Bayesian classification technique, and it was evaluated in terms of the prediction accuracy of docking-based virtual screening (VS) of three important targets in the kinase family: ALK, CDK2, and VEGFR2. First, for each target, the representative crystal structures were selected by structural clustering, and the capability of molecular docking based on each representative structure to discriminate inhibitors from non-inhibitors was examined. Then, for each target, 50 ns molecular dynamics (MD) simulations were carried out to generate an ensemble of the conformations, and multiple representative structures/snapshots were extracted from each MD trajectory by structural clustering. On average, the representative crystal structures outperform the representative structures extracted from MD simulations in terms of the capabilities to separate inhibitors from non-inhibitors. Finally, by using the naïve Bayesian classification technique, an integrated VS strategy was developed to combine the prediction results of molecular docking based on different representative conformations chosen from crystal structures and MD trajectories. It was encouraging to observe that the integrated VS strategy yields better performance than the docking-based VS based on any single rigid conformation. This novel protocol may provide an improvement over existing strategies to search for more diverse and promising active compounds for a target of interest.

Targeted vs. systematic early antiviral treatment against A(H1N1)v influenza with neuraminidase inhibitors in patients with influenza-like symptoms: Clinical and economic impact

PubMed Central

Deuffic-Burban, Sylvie; Lenne, Xavier; Dervaux, Benoit; Julien Poissy; Lemaire, Xavier; Sloan, Caroline; Carrat, Fabrice; Desenclos, Jean-Claude; Delfraissy, Jean-Francois; Yazdanpanah, Yazdan

2009-01-01

Capitalizing on available data, we used a decision model to estimate the clinical and economic outcomes associated with early initiation of treatment with neuraminidase inhibitors in all patients with influenza-like illnesses ( ILI ) (systematic strategy) vs. only those at high risk of complications (targeted strategy). Systematic treatment of ILI during an A(H1N1)v influenza epidemic wave is both effective and cost-effective. Patients who present to care with ILI during an A(H1N1)v influenza epidemic wave should initiate treatment with neuraminidase inhibitors, regardless of risk status. Administering neuraminidase inhibitors between epidemic waves, when the probability of influenza is low, is less effective and cost-effective. PMID:20029659

Optical treatment strategies to slow myopia progression: Effects of the visual extent of the optical treatment zone

PubMed Central

Smith, Earl L.

2013-01-01

In order to develop effective optical treatment strategies for myopia, it is important to understand how visual experience influences refractive development. Beginning with the discovery of the phenomenon of form deprivation myopia, research involving many animal species has demonstrated that refractive development is regulated by visual feedback. In particular, animal studies have shown that optically imposed myopic defocus slows axial elongation, that the effects of vision are dominated by local retinal mechanisms, and that peripheral vision can dominate central refractive development. In this review, the results obtained from clinical trials of traditional optical treatment strategies employed in efforts to slow myopia progression in children are interpreted in light of the results from animal studies and are compared to the emerging results from preliminary clinical studies of optical treatment strategies that manipulate the effective focus of the peripheral retina. Overall, the results suggest that imposed myopic defocus can slow myopia progression in children and that the effectiveness of an optical treatment strategy in reducing myopia progression is influenced by the extent of the visual field that is manipulated. PMID:23290590

Targeting Tumor Microenvironment with Silibinin: Promise and Potential for a Translational Cancer Chemopreventive Strategy

PubMed Central

Deep, Gagan; Agarwal, Rajesh

2014-01-01

Tumor microenvironment (TME) refers to the dynamic cellular and extra-cellular components surrounding tumor cells at each stage of the carcinogenesis. TME has now emerged as an integral and inseparable part of the carcinogenesis that plays a critical role in tumor growth, angiogenesis, epithelial to mesenchymal transition (EMT), invasion, migration and metastasis. Besides its vital role in carcinogenesis, TME is also a better drug target because of its relative genetic stability with lesser probability for the development of drug-resistance. Several drugs targeting the TME (endothelial cells, macrophages, cancer-associated fibroblasts, or extra-cellular matrix) have either been approved or are in clinical trials. Recently, non-steroidal anti-inflammatory drugs targeting inflammation were reported to also prevent several cancers. These exciting developments suggest that cancer chemopreventive strategies targeting both tumor and TME would be better and effective towards preventing, retarding or reversing the process of carcinogenesis. Here, we have reviewed the effect of a well established hepatoprotective and chemopreventive agent silibinin on cellular (endothelial, fibroblast and immune cells) and non-cellular components (cytokines, growth factors, proteinases etc.) of the TME. Silibinin targets TME constituents as well as their interaction with cancer cells, thereby inhibiting tumor growth, angiogenesis, inflammation, EMT, and metastasis. Silibinin is already in clinical trials, and based upon completed studies we suggest that its chemopreventive effectiveness should be verified through its effect on biological end points in both tumor and TME. Overall, we believe that the chemopreventive strategies targeting both tumor and TME have practical and translational utility in lowering the cancer burden. PMID:23617249

Targeted Nanotechnology in Glioblastoma Multiforme

PubMed Central

Glaser, Talita; Han, Inbo; Wu, Liquan; Zeng, Xiang

2017-01-01

Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs. PMID:28408882

Novel targets for ATM-deficient malignancies

PubMed Central

Winkler, Johannes; Hofmann, Kay; Chen, Shuhua

2014-01-01

Conventional chemo- and radiotherapies for the treatment of cancer target rapidly dividing cells in both tumor and non-tumor tissues and can exhibit severe cytotoxicity in normal tissue and impair the patient's immune system. Novel targeted strategies aim for higher efficacy and tumor specificity. The role of ATM protein in the DNA damage response is well known and ATM deficiency frequently plays a role in tumorigenesis and development of malignancy. In addition to contributing to disease development, ATM deficiency also renders malignant cells heavily dependent on other pathways that cooperate with the ATM-mediated DNA damage response to ensure tumor cell survival. Disturbing those cooperative pathways by inhibiting critical protein components allows specific targeting of tumors while sparing healthy cells with normal ATM status. We review druggable candidate targets for the treatment of ATM-deficient malignancies and the mechanisms underlying such targeted therapies. PMID:27308314

Protein Drug Targets of Lavandula angustifolia on treatment of Rat Alzheimer's Disease

PubMed Central

Zali, Hakimeh; Zamanian-Azodi, Mona; Rezaei Tavirani, Mostafa; Akbar-zadeh Baghban, Alireza

2015-01-01

Different treatment strategies of Alzheimer's disease (AD) are being studied for treating or slowing the progression of AD. Many pharmaceutically important regulation systems operate through proteins as drug targets. Here, we investigate the drug target proteins in beta-amyloid (Aβ) injected rat hippocampus treated with Lavandula angustifolia (LA) by proteomics techniques. The reported study showed that lavender extract (LE) improves the spatial performance in AD animal model by diminishing Aβ production in histopathology of hippocampus, so in this study neuroprotective proteins expressed in Aβ injected rats treated with LE were scrutinized. Rats were divided into three groups including normal, Aβ injected, and Aβ injected that was treated with LE. Protein expression profiles of hippocampus tissue were determined by two-dimensional electrophoresis (2DE) method and dysregulated proteins such as Snca, NF-L, Hspa5, Prdx2, Apoa1, and Atp5a1were identified by MALDI-TOF/TOF. KEGG pathway and gene ontology (GO) categories were used by searching DAVID Bioinformatics Resources. All detected protein spots were used to determine predictedinteractions with other proteins in STRING online database. Different isoforms of important protein, Snca that exhibited neuroprotective effects by anti-apoptotic properties were expressed. NF-L involved in the maintenance of neuronal caliber. Hspa5 likewise Prdx2 displays as anti-apoptotic protein that Prdx2 also involved in the neurotrophic effects. Apoa1 has anti-inflammatory activity and Atp5a1, produces ATP from ADP. To sum up, these proteins as potential drug targets were expressed in hippocampus in response to effective components in LA may have therapeutic properties for the treatment of AD and other neurodegenerative diseases. PMID:25561935

Targeting of free fatty acid receptor 1 in EOC: A novel strategy to restrict the adipocyte-EOC dependence.

PubMed

Munkarah, Adnan; Mert, Ismail; Chhina, Jasdeep; Hamid, Suhail; Poisson, Laila; Hensley-Alford, Sharon; Giri, Shailendra; Rattan, Ramandeep

2016-04-01

Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets. The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas. The GPR 40 antagonist, GW1100, was used to inhibit FFAR1/GPR40 and cell survival was assayed by MTT in various cell lines. High Grade Serous carcinoma specimens expressed significantly increased GPR40 compared to normal ovaries (p=0.0020). Higher expression was noted in advanced stage disease. ID8 ovarian tumors from mice fed with high fat diet also showed higher GPR40 expression. Exposing EOC cells to FFAs, increased GPR40 expression. Treatment of EOC cell lines with GW100 resulted in growth inhibition and was associated with an alteration in their energy metabolism. FFA-induced cancer cell growth may be partly mediated through FFAR1/GPR40. Targeting of FFAR1/GPR40 may be an attractive treatment strategy in EOC, and possibly offers a targeted treatment for a subset of EOC patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Characterizing Types of Human Mobility to Inform Differential and Targeted Malaria Elimination Strategies in Northeast Cambodia

PubMed Central

Peeters Grietens, Koen; Gryseels, Charlotte; Dierickx, Susan; Bannister-Tyrrell, Melanie; Trienekens, Suzan; Uk, Sambunny; Phoeuk, Pisen; Suon, Sokha; Set, Srun; Gerrets, René; Hoibak, Sarah; Muela Ribera, Joan; Hausmann-Muela, Susanna; Tho, Sochantha; Durnez, Lies; Sluydts, Vincent; d’Alessandro, Umberto; Coosemans, Marc; Erhart, Annette

2015-01-01

Human population movements currently challenge malaria elimination in low transmission foci in the Greater Mekong Subregion. Using a mixed-methods design, combining ethnography (n = 410 interviews), malariometric data (n = 4996) and population surveys (n = 824 indigenous populations; n = 704 Khmer migrants) malaria vulnerability among different types of mobile populations was researched in the remote province of Ratanakiri, Cambodia. Different structural types of human mobility were identified, showing differential risk and vulnerability. Among local indigenous populations, access to malaria testing and treatment through the VMW-system and LLIN coverage was high but control strategies failed to account for forest farmers’ prolonged stays at forest farms/fields (61% during rainy season), increasing their exposure (p = 0.002). The Khmer migrants, with low acquired immunity, active on plantations and mines, represented a fundamentally different group not reached by LLIN-distribution campaigns since they were largely unregistered (79%) and unaware of the local VMW-system (95%) due to poor social integration. Khmer migrants therefore require control strategies including active detection, registration and immediate access to malaria prevention and control tools from which they are currently excluded. In conclusion, different types of mobility require different malaria elimination strategies. Targeting mobility without an in-depth understanding of malaria risk in each group challenges further progress towards elimination. PMID:26593245

Targeted mass treatment for syphilis with oral azithromycin.

PubMed

Rekart, Michael L; Patrick, David M; Chakraborty, Bubli; Maginley, Juanita J L; Jones, H D; Bajdik, Chris D; Pourbohloul, Babak; Brunham, Robert C

2003-01-25

From mid 1997 to end of 1999, there was a sexually-transmitted infectious syphilis outbreak mainly in heterosexual people in British Columbia, Canada, that was concentrated in Vancouver. The rate across the province increased from less than 0.5 to 3.4 per 100000, and the rate in Vancouver reached 12.9 per 100000. We aimed to eliminate the syphillis outbreak by treating people at risk of infection. In 2000, a targeted mass treatment programme provided azithromycin (1.8 g orally) to 4384 at-risk residents in this city. After the programme, syphilis frequency fell significantly for 6 months (p=0.016), but rose again in 2001. Results from curve fitting analyses showed that the number of cases in 2001 (177) was higher than expected (0.0001targeted mass treatment for syphilis, even though feasible, should not be done routinely.

Targeting Insulin Signaling for the Treatment of Alzheimer's Disease.

PubMed

Chen, Yanxing; Zhang, Jianfang; Zhang, Baorong; Gong, Cheng-Xin

2016-01-01

Sporadic Alzheimer's disease (AD) is caused by multiple etiological factors, among which impaired brain insulin signaling and decreased brain glucose metabolism are important metabolic factors. Contrary to previous belief that insulin would not act in the brain, studies in the last three decades have proven important roles of insulin and insulin signaling in various biological functions in the brain. Impaired brain insulin signaling or brain insulin resistance and its role in the molecular pathogenesis of sporadic AD have been demonstrated. Thus, targeting brain insulin signaling for the treatment of cognitive impairment and AD has now attracted much attention in the field of AD drug discovery. This article reviews recent studies that target brain insulin signaling, especially those investigations on intranasal insulin administration and drugs that improve insulin sensitivity, including incretins, dipeptidyl peptidase IV inhibitors, thiazolidinediones, and metformin. These drugs have been previously approved for the treatment of diabetes mellitus, which could expedite their development for the treatment of AD. Although larger clinical trials are needed for validating their efficacy for the treatment of cognitive impairment and AD, results of animal studies and clinical trials available to date are encouraging.

Advances in refractory ulcerative colitis treatment: A new therapeutic target, Annexin A2

PubMed Central

Tanida, Satoshi; Mizoshita, Tsutomu; Ozeki, Keiji; Katano, Takahito; Kataoka, Hiromi; Kamiya, Takeshi; Joh, Takashi

2015-01-01

Medical treatment has progressed significantly over the past decade towards achieving and maintaining clinical remission in patients with refractory ulcerative colitis (UC). Proposed mediators of inflammation in UC include pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-2, and the cell-surface adhesive molecule integrin α4β7. Conventional therapeutics for active UC include 5-aminosalicylic acid, corticosteroids and purine analogues (azathioprine and 6-mercaptopurine). Patients who fail to respond to conventional therapy are treated with agents such as the calicineurin inhibitors cyclosporine and tacrolimus, the TNF-α inhibitors infliximab or adalimumab, or a neutralizing antibody (vedolizumab) directed against integrin α4β7. These therapeutic agents are of benefit for patients with refractory UC, but are not universally effective. Our recent research on TNF-α shedding demonstrated that inhibition of annexin (ANX) A2 may be a new therapeutic strategy for the prevention of TNF-α shedding during inflammatory bowel disease (IBD) inflammation. In this review, we provide an overview of therapeutic treatments that are effective and currently available for UC patients, as well as some that are likely to be available in the near future. We also propose the potential of ANX A2 as a new molecular target for IBD treatment. PMID:26269667

Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness.

PubMed

Abdeen, Sanofar; Salim, Nilshad; Mammadova, Najiba; Summers, Corey M; Goldsmith-Pestana, Karen; McMahon-Pratt, Diane; Schultz, Peter G; Horwich, Arthur L; Chapman, Eli; Johnson, Steven M

2016-11-01

Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis-HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter-screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC 50 =7.9 and 3.1μM, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

An effective tumor-targeting strategy utilizing hypoxia-sensitive siRNA delivery system for improved anti-tumor outcome.

PubMed

Kang, Lin; Fan, Bo; Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Gao, Zhonggao

2016-10-15

Hypoxia is a feature of most solid tumors, targeting hypoxia is considered as the best validated yet not extensively exploited strategy in cancer therapy. Here, we reported a novel tumor-targeting strategy using a hypoxia-sensitive siRNA delivery system. In the study, 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazole (AI) through bioreduction under hypoxic conditions, was conjugated to the alkylated polyethyleneimine (bPEI1.8k-C6) to form amphiphilic bPEI1.8k-C6-NI polycations. bPEI1.8k-C6-NI could self-assemble into micelle-like aggregations in aqueous, which contributed to the improved stability of the bPEI1.8k-C6-NI/siRNA polyplexes, resulted in increased cellular uptake. After being transported into the hypoxic tumor cells, the selective nitro-to-amino reduction would cause structural change and elicit a relatively loose structure to facilitate the siRNA dissociation in the cytoplasm, for enhanced gene silencing efficiency ultimately. Therefore, the conflict between the extracellular stability and the intracellular siRNA release ability of the polyplexes was solved by introducing the hypoxia-responsive unit. Consequently, the survivin-targeted siRNA loaded polyplexes shown remarkable anti-tumor effect not only in hypoxic cells, but also in tumor spheroids and tumor-bearing mice, indicating that the hypoxia-sensitive siRNA delivery system had great potential for tumor-targeted therapy. Hypoxia is one of the most remarkable features of most solid tumors, and targeting hypoxia is considered as the best validated strategy in cancer therapy. However, in the past decades, there were few reports about using this strategy in the drug delivery system, especially in siRNA delivery system. Therefore, we constructed a hypoxia-sensitive siRNA delivery system utilizing a hypoxia-responsive unit, 2-nitroimidazole, by which the unavoidable conflict between improved extracellular stability and promoted intracellular si

Timing and Targeting of Treatment in Left Ventricular Hypertrophy.

PubMed

Nam, Deokhwa; Reineke, Erin L

2017-01-01

In most clinical cases, left ventricular hypertrophy (LVH) occurs over time from persistent cardiac stress. At the molecular level, this results in both transient and long-term changes to metabolic, sarcomeric, ion handling, and stress signaling pathways. Although this is initially an adaptive change, the mechanisms underlying LVH eventually lead to maladaptive changes including fibrosis, decreased cardiac function, and failure. Understanding the regulators of long-term changes, which are largely driven by transcriptional remodeling, is a crucial step in identifying novel therapeutic targets for preventing the downstream negative effects of LVH and treatments that could reverse or prevent it. The development of effective therapeutics, however, will require a critical understanding of what to target, how to modify important pathways, and how to identify the stage of pathology in which a specific treatment should be used.

Need for Optimisation of Immunisation Strategies Targeting Invasive Meningococcal Disease in the Netherlands.

PubMed

Bousema, Josefien Cornelie Minthe; Ruitenberg, Joost

2015-09-13

Invasive meningococcal disease (IMD) is a severe bacterial infectious disease with high mortality and morbidity rates worldwide. In recent years, industrialised countries have implemented vaccines targeting IMD in their National Immunisation Programmes (NIPs). In 2002, the Netherlands successfully implemented a single dose of meningococcal serogroup C conjugate vaccine at the age of 14 months and performed a single catch-up for children ≤18 years of age. Since then the disease disappeared in vaccinated individuals. Furthermore, herd protection was induced, leading to a significant IMD reduction in non-vaccinated individuals. However, previous studies revealed that the current programmatic immunisation strategy was insufficient to protect the population in the foreseeable future. In addition, vaccines that provide protection against additional serogroups are now available. This paper describes to what extent the current strategy to prevent IMD in the Netherlands is still sufficient, taking into account the burden of disease and the latest scientific knowledge related to IMD and its prevention. In particular, primary MenC immunisation seems not to provide long-term protection, indicating a risk for possible recurrence of the disease. This can be combatted by implementing a MenC or MenACWY adolescent booster vaccine. Additional health benefits can be achieved by replacing the primary MenC by a MenACWY vaccine. By implementation of a recently licensed MenB vaccine for infants in the NIP, the greatest burden of disease would be targeted. This paper shows that optimisation of the immunisation strategy targeting IMD in the Netherlands should be considered and contributes to create awareness concerning prevention optimisation in other countries. © 2015 by Kerman University of Medical Sciences.

Universal, colorimetric microRNA detection strategy based on target-catalyzed toehold-mediated strand displacement reaction

NASA Astrophysics Data System (ADS)

Park, Yeonkyung; Lee, Chang Yeol; Kang, Shinyoung; Kim, Hansol; Park, Ki Soo; Park, Hyun Gyu

2018-02-01

In this work, we developed a novel, label-free, and enzyme-free strategy for the colorimetric detection of microRNA (miRNA), which relies on a target-catalyzed toehold-mediated strand displacement (TMSD) reaction. The system employs a detection probe that specifically binds to the target miRNA and sequentially releases a catalyst strand (CS) intended to trigger the subsequent TMSD reaction. Thus, the presence of target miRNA releases the CS that mediates the formation of an active G-quadruplex DNAzyme which is initially caged and inactivated by a blocker strand. In addition, a fuel strand that is supplemented for the recycling of the CS promotes another TMSD reaction, consequently generating a large number of active G-quadruplex DNAzymes. As a result, a distinct colorimetric signal is produced by the ABTS oxidation promoted by the peroxidase mimicking activity of the released G-quadruplex DNAzymes. Based on this novel strategy, we successfully detected miR-141, a promising biomarker for human prostate cancer, with high selectivity. The diagnostic capability of this system was also demonstrated by reliably determining target miR-141 in human serum, showing its great potential towards real clinical applications. Importantly, the proposed approach is composed of separate target recognition and signal transduction modules. Thus, it could be extended to analyze different target miRNAs by simply redesigning the detection probe while keeping the same signal transduction module as a universal signal amplification unit, which was successfully demonstrated by analyzing another target miRNA, let-7d.

Universal, colorimetric microRNA detection strategy based on target-catalyzed toehold-mediated strand displacement reaction.

PubMed

Park, Yeonkyung; Lee, Chang Yeol; Kang, Shinyoung; Kim, Hansol; Park, Ki Soo; Park, Hyun Gyu

2018-02-23

In this work, we developed a novel, label-free, and enzyme-free strategy for the colorimetric detection of microRNA (miRNA), which relies on a target-catalyzed toehold-mediated strand displacement (TMSD) reaction. The system employs a detection probe that specifically binds to the target miRNA and sequentially releases a catalyst strand (CS) intended to trigger the subsequent TMSD reaction. Thus, the presence of target miRNA releases the CS that mediates the formation of an active G-quadruplex DNAzyme which is initially caged and inactivated by a blocker strand. In addition, a fuel strand that is supplemented for the recycling of the CS promotes another TMSD reaction, consequently generating a large number of active G-quadruplex DNAzymes. As a result, a distinct colorimetric signal is produced by the ABTS oxidation promoted by the peroxidase mimicking activity of the released G-quadruplex DNAzymes. Based on this novel strategy, we successfully detected miR-141, a promising biomarker for human prostate cancer, with high selectivity. The diagnostic capability of this system was also demonstrated by reliably determining target miR-141 in human serum, showing its great potential towards real clinical applications. Importantly, the proposed approach is composed of separate target recognition and signal transduction modules. Thus, it could be extended to analyze different target miRNAs by simply redesigning the detection probe while keeping the same signal transduction module as a universal signal amplification unit, which was successfully demonstrated by analyzing another target miRNA, let-7d.

Molecular Imaging: Current Status and Emerging Strategies

PubMed Central

Pysz, Marybeth A.; Gambhir, Sanjiv S.; Willmann, Jürgen K.

2011-01-01

In vivo molecular imaging has a great potential to impact medicine by detecting diseases in early stages (screening), identifying extent of disease, selecting disease- and patient-specific therapeutic treatment (personalized medicine), applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current clinical molecular imaging approaches primarily use PET- or SPECT-based techniques. In ongoing preclinical research novel molecular targets of different diseases are identified and, sophisticated and multifunctional contrast agents for imaging these molecular targets are developed along with new technologies and instrumentation for multimodality molecular imaging. Contrast-enhanced molecular ultrasound with molecularly-targeted contrast microbubbles is explored as a clinically translatable molecular imaging strategy for screening, diagnosing, and monitoring diseases at the molecular level. Optical imaging with fluorescent molecular probes and ultrasound imaging with molecularly-targeted microbubbles are attractive strategies since they provide real-time imaging, are relatively inexpensive, produce images with high spatial resolution, and do not involve exposure to ionizing irradiation. Raman spectroscopy/microscopy has emerged as a molecular optical imaging strategy for ultrasensitive detection of multiple biomolecules/biochemicals with both in vivo and ex vivo versatility. Photoacoustic imaging is a hybrid of optical and ultrasound modalities involving optically-excitable molecularly-targeted contrast agents and quantitative detection of resulting oscillatory contrast agent movement with ultrasound. Current preclinical findings and advances in instrumentation such as endoscopes and microcatheters suggest that these molecular imaging modalities have numerous clinical applications and will be translated into clinical use in the near future. PMID:20541650

Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy.

PubMed

Pergola, Carlo; Schubert, Katrin; Pace, Simona; Ziereisen, Jana; Nikels, Felix; Scherer, Olga; Hüttel, Stephan; Zahler, Stefan; Vollmar, Angelika M; Weinigel, Christina; Rummler, Silke; Müller, Rolf; Raasch, Martin; Mosig, Alexander; Koeberle, Andreas; Werz, Oliver

2017-01-30

Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells.

Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy

PubMed Central

Pergola, Carlo; Schubert, Katrin; Pace, Simona; Ziereisen, Jana; Nikels, Felix; Scherer, Olga; Hüttel, Stephan; Zahler, Stefan; Vollmar, Angelika M.; Weinigel, Christina; Rummler, Silke; Müller, Rolf; Raasch, Martin; Mosig, Alexander; Koeberle, Andreas; Werz, Oliver

2017-01-01

Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells. PMID:28134280

Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment.

PubMed

Pan, Changqie; Liu, Yuqing; Zhou, Minyu; Wang, Wensheng; Shi, Min; Xing, Malcolm; Liao, Wangjun

2018-01-01

A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical ( 1 H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer.

Cost-effectiveness of sequenced treatment of rheumatoid arthritis with targeted immune modulators.

PubMed

Jansen, Jeroen P; Incerti, Devin; Mutebi, Alex; Peneva, Desi; MacEwan, Joanna P; Stolshek, Bradley; Kaur, Primal; Gharaibeh, Mahdi; Strand, Vibeke

2017-07-01

To determine the cost-effectiveness of treatment sequences of biologic disease-modifying anti-rheumatic drugs or Janus kinase/STAT pathway inhibitors (collectively referred to as bDMARDs) vs conventional DMARDs (cDMARDs) from the US societal perspective for treatment of patients with moderately to severely active rheumatoid arthritis (RA) with inadequate responses to cDMARDs. An individual patient simulation model was developed that assesses the impact of treatments on disease based on clinical trial data and real-world evidence. Treatment strategies included sequences starting with etanercept, adalimumab, certolizumab, or abatacept. Each of these treatment strategies was compared with cDMARDs. Incremental cost, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each treatment sequence relative to cDMARDs. The cost-effectiveness of each strategy was determined using a US willingness-to-pay (WTP) threshold of $150,000/QALY. For the base-case scenario, bDMARD treatment sequences were associated with greater treatment benefit (i.e. more QALYs), lower lost productivity costs, and greater treatment-related costs than cDMARDs. The expected ICERs for bDMARD sequences ranged from ∼$126,000 to $140,000 per QALY gained, which is below the US-specific WTP. Alternative scenarios examining the effects of homogeneous patients, dose increases, increased costs of hospitalization for severely physically impaired patients, and a lower baseline Health Assessment Questionnaire (HAQ) Disability Index score resulted in similar ICERs. bDMARD treatment sequences are cost-effective from a US societal perspective.

Targeted Treatments in Autism and Fragile X Syndrome

ERIC Educational Resources Information Center

Gurkan, C. Kagan; Hagerman, Randi J.

2012-01-01

Autism is a neurodevelopmental disorder consisting of a constellation of symptoms that sometimes occur as part of a complex disorder characterized by impairments in social interaction, communication and behavioral domains. It is a highly disabling disorder and there is a need for treatment targeting the core symptoms. Although autism is accepted…

Novel treatment strategies for smooth muscle disorders: Targeting Kv7 potassium channels.

PubMed

Haick, Jennifer M; Byron, Kenneth L

2016-09-01

Smooth muscle cells provide crucial contractile functions in visceral, vascular, and lung tissues. The contractile state of smooth muscle is largely determined by their electrical excitability, which is in turn influenced by the activity of potassium channels. The activity of potassium channels sustains smooth muscle cell membrane hyperpolarization, reducing cellular excitability and thereby promoting smooth muscle relaxation. Research over the past decade has indicated an important role for Kv7 (KCNQ) voltage-gated potassium channels in the regulation of the excitability of smooth muscle cells. Expression of multiple Kv7 channel subtypes has been demonstrated in smooth muscle cells from viscera (gastrointestinal, bladder, myometrial), from the systemic and pulmonary vasculature, and from the airways of the lung, from multiple species, including humans. A number of clinically used drugs, some of which were developed to target Kv7 channels in other tissues, have been found to exert robust effects on smooth muscle Kv7 channels. Functional studies have indicated that Kv7 channel activators and inhibitors have the ability to relax and contact smooth muscle preparations, respectively, suggesting a wide range of novel applications for the pharmacological tool set. This review summarizes recent findings regarding the physiological functions of Kv7 channels in smooth muscle, and highlights potential therapeutic applications based on pharmacological targeting of smooth muscle Kv7 channels throughout the body. Published by Elsevier Inc.

Mitochondria-targeting nanomedicine: An effective and potent strategy against aminoglycosides-induced ototoxicity.

PubMed

Zhou, Shuang; Sun, Yanhui; Kuang, Xiao; Hou, Shanshan; Yang, YinXian; Wang, Zhenjie; Liu, Hongzhuo

2018-04-21

We report a proof-of-concept for the development of mitochondria-targeting nanoparticles (NPs) loaded with geranylgeranylacetone (GGA) to protect against a wide range of gentamicin-induced ototoxicity symptoms in a zebrafish model. The polymeric NPs were functionalized with a mitochondrial-homing peptide (d‑Arg‑Dmt‑Orn‑Phe‑NH 2 ) and exhibited greater mitochondrial uptake and lower gentamicin uptake in hair cells via mechanotransduction (MET) channels and tuned machinery in the hair bundle than the ordinary NPs did. Blockade of MET channels rapidly reversed this effect, indicating the reversible responses of hair cells to the targeting NPs were mediated by MET channels. Pretreatment of hair cells with mitochondria-targeting GGA-loaded NPs exhibited a superior acute or chronic protective efficacy against subsequent exposure to gentamicin compared with unmodified formulations. Mitochondrial delivery regulating the death pathway of hair cells appeared to cause the therapeutic failure of untargeted NPs. Thus, peptide-directed mitochondria-targeting NPs may represent a novel therapeutic strategy for mitochondrial dysfunction-linked diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies

PubMed Central

Solé, Brisa; Jiménez, Esther; Torrent, Carla; Reinares, Maria; Bonnin, Caterina del Mar; Torres, Imma; Varo, Cristina; Grande, Iria; Valls, Elia; Salagre, Estela; Sanchez-Moreno, Jose; Martinez-Aran, Anabel; Carvalho, André F

2017-01-01

Abstract Over the last decade, there has been a growing appreciation of the importance of identifying and treating cognitive impairment associated with bipolar disorder, since it persists in remission periods. Evidence indicates that neurocognitive dysfunction may significantly influence patients’ psychosocial outcomes. An ever-increasing body of research seeks to achieve a better understanding of potential moderators contributing to cognitive impairment in bipolar disorder in order to develop prevention strategies and effective treatments. This review provides an overview of the available data from studies examining treatments for cognitive dysfunction in bipolar disorder as well as potential novel treatments, from both pharmacological and psychological perspectives. All these data encourage the development of further studies to find effective strategies to prevent and treat cognitive impairment associated with bipolar disorder. These efforts may ultimately lead to an improvement of psychosocial functioning in these patients. PMID:28498954

MicroRNA as therapeutic targets for treatment of depression

PubMed Central

Hansen, Katelin F; Obrietan, Karl

2013-01-01

Depression is a potentially life-threatening mental disorder affecting approximately 300 million people worldwide. Despite much effort, the molecular underpinnings of clinical depression remain poorly defined, and current treatments carry limited therapeutic efficacy and potentially burdensome side effects. Recently, small noncoding RNA molecules known as microRNA (miRNA) have gained prominence as a target for therapeutic intervention, given their capacity to regulate neuronal physiology. Further, mounting evidence suggests a prominent role for miRNA in depressive molecular signaling. Recent studies have demonstrated that dysregulation of miRNA expression occurs in animal models of depression, and in the post-mortem tissue of clinically depressed patients. Investigations into depression-associated miRNA disruption reveals dramatic effects on downstream targets, many of which are thought to contribute to depressive symptoms. Furthermore, selective serotonin reuptake inhibitors, as well as other antidepressant drugs, have the capacity to reverse aberrant depressive miRNA expression and their downstream targets. Given the powerful effects that miRNA have on the central nervous system transcriptome, and the aforementioned studies, there is a compelling rationale to begin to assess the potential contribution of miRNA to depressive etiology. Here, we review the molecular biology of miRNA, our current understanding of miRNA in relation to clinical depression, and the utility of targeting miRNA for antidepressant treatment. PMID:23935365

Treatment strategy for a multidrug-resistant Klebsiella UTI.

PubMed

Fleming, Erin; Heil, Emily L; Hynicka, Lauren M

2014-01-01

To describe the management strategy for a multidrug-resistant (MDR) Klebsiella urinary tract infection (UTI). A 69-year-old Caucasian woman with a past medical history of recurrent UTIs and a right-lung transplant presented with fever to 101.4°F, chills, malaise, and cloudy, foul-smelling urine for approximately 1 week. She was found to have a MDR Klebsiella UTI that was sensitive to tigecycline and cefepime. To further evaluate the degree of resistance Etest minimum inhibitory concentrations were requested for cefepime, amikacin, meropenem, and ertapenem. The patient received a 14-day course of amikacin, which resulted in resolution of her symptoms. One month later, the patient's UTI symptoms returned. The urine culture again grew MDR Klebsiella, sensitive only to tigecycline. Fosfomycin was initiated and resulted in limited resolution of her symptoms. Colistin was started, however, therapy was discontinued on day 5 secondary to the development of acute kidney injury. Despite the short course of therapy, the patient's symptoms resolved. The case presented lends itself well to numerous discussion items that are important to consider when determining optimal treatment for MDR Gram-negative bacilli (GNBs). Susceptibility testing is an important tool for optimizing antibiotic therapy, however, automated systems may overestimate the susceptibility profile for a MDR GNB. Treatment strategies evaluated to treat MDR GNB, include combination therapy with a carbepenem and synergy using polymyxin. We have described the management strategy for a MDR Klebsiella UTI, the consequences of the initial management strategy, and potential strategies to manage these types of infections in future patients.

Targeting the dopamine D3 receptor: an overview of drug design strategies.

PubMed

Cortés, Antoni; Moreno, Estefanía; Rodríguez-Ruiz, Mar; Canela, Enric I; Casadó, Vicent

2016-07-01

Dopamine is a neurotransmitter widely distributed in both the periphery and the central nervous system (CNS). Its physiological effects are mediated by five closely related G protein-coupled receptors (GPCRs) that are divided into two major subclasses: the D1-like (D1, D5) and the D2-like (D2, D3, D4) receptors. D3 receptors (D3Rs) have the highest density in the limbic areas of the brain, which are associated with cognitive and emotional functions. These receptors are therefore attractive targets for therapeutic management. This review summarizes the functional and pharmacological characteristics of D3Rs, including the design and clinical relevance of full agonists, partial agonists and antagonists, as well as the capacity of these receptors to form active homodimers, heterodimers or higher order receptor complexes as pharmacological targets in several neurological and neurodegenerative disorders. The high sequence homology between D3R and the D2-type challenges the development of D3R-selective compounds. The design of new D3R-preferential ligands with improved physicochemical properties should provide a better pharmacokinetic/bioavailability profile and lesser toxicity than is found with existing D3R ligands. It is also essential to optimize D3R affinity and, especially, D3R vs. D2-type binding and functional selectivity ratios. Developing allosteric and bitopic ligands should help to improve the D3R selectivity of these drugs. As most evidence points to the ability of GPCRs to form homomers and heteromers, the most promising therapeutic strategy in the future is likely to involve the application of heteromer-selective drugs. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer. Therefore, designing novel compounds that specifically target and modulate D1R-D3R heteromers would be an interesting approach for the treatment of levodopa (L-DOPA)-induced dyskinesias.

Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management.

PubMed

Goldman, Jonathan W; Mendenhall, Melody A; Rettinger, Sarah R

2016-07-29

: Molecularly targeted cancer therapy has rapidly changed the landscape of oncologic care, often improving patients' prognosis without causing as substantial a quality-of-life decrement as cytotoxic chemotherapy does. Nevertheless, targeted agents can cause side effects that may be less familiar to medical oncologists and that require the attention and expertise of subspecialists. In this review, we focus on hyperglycemia, which can occur with use of new anticancer agents that interact with cell proliferation pathways. Key mediators of these pathways include the tyrosine kinase receptors insulin growth factor receptor 1 (IGF-1R) and epidermal growth factor receptor (EGFR), as well as intracellular signaling molecules phosphatidylinositol 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). We summarize available information on hyperglycemia associated with agents that inhibit these molecules within the larger context of adverse event profiles. The highest incidence of hyperglycemia is observed with inhibition of IGF-1R or mTOR, and although the incidence is lower with PI3K, AKT, and EGFR inhibitors, hyperglycemia is still a common adverse event. Given the interrelationships between the IGF-1R and cell proliferation pathways, it is important for oncologists to understand the etiology of hyperglycemia caused by anticancer agents that target those pathways. We also discuss monitoring and management approaches for treatment-related hyperglycemia for some of these agents, with a focus on our experience during the clinical development of the EGFR inhibitor rociletinib. Treatment-related hyperglycemia is associated with several anticancer agents. Many cancer patients may also have preexisting or undiagnosed diabetes or glucose intolerance. Screening can identify patients at risk for hyperglycemia before treatment with these agents. Proper monitoring and management of symptoms, including lifestyle changes and pharmacologic intervention, may allow patients to

Therapies based on targeting EBV lytic replication for EBV-associated malignancies.

PubMed

Li, Hongde; Hu, Jianmin; Luo, Xiangjian; Bode, Ann M; Dong, Zigang; Cao, Ya

2018-05-11

In recent years, EBV lytic infection has been shown to significantly contribute to carcinogenesis. Thus, therapies aimed at targeting the EBV lytic cycle have been developed as novel strategies for treatment of EBV-associated diseases malignancies. In this review, focusing on the viral lytic proteins, we describe recent advances regarding the involvement of the EBV lytic cycle in carcinogenesis. Moreover, we further discuss two distinct EBV lytic cycle-targeted therapeutic strategies against EBV-induced malignancies: One of the strategies involves inhibition of the EBV lytic cycle by natural compounds known to have anti-EBV properties; another one is to intentionally induce EBV lytic replication in combination with nucleotide analogues. Recent advances in EBV lytic-based strategies are beginning to show promise in the treatment and/or prevention of EBV-related tumors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Therapeutic Targeting of Siglecs using Antibody- and Glycan-based Approaches

PubMed Central

Angata, Takashi; Nycholat, Corwin M.; Macauley, Matthew S.

2015-01-01

The sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of immunomodulatory receptors whose functions are regulated by their glycan ligands. Siglecs are attractive therapeutic targets because of their cell-type specific expression pattern, endocytic properties, high expression on certain lymphomas/leukemias, and ability to modulate receptor signaling. Siglec-targeting approaches with therapeutic potential encompass antibody- and glycan-based strategies. Several antibody-based therapies are in clinical trials and continue to be developed for the treatment of lymphoma/leukemia and autoimmune disease, while the therapeutic potential of glycan-based strategies for cargo-delivery and immunomodulation is a promising new approach. Here, we review these strategies with special emphasis on emerging approaches and disease areas that may benefit from targeting the Siglec family. PMID:26435210

Application of Nanotechnology in the Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment

DTIC Science & Technology

2007-12-01

used in detection, diagnosis, and treatment of cancer . When loaded with chemotherapeutic agents, nanoparticle delivery to cancerous tissues...Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment PRINCIPAL INVESTIGATOR: Colleen Feltmate, M.D. CONTRACTING ORGANIZATION...5a. CONTRACT NUMBER Application of Nanotechnology in the Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment 5b. GRANT NUMBER

In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

PubMed

Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

2012-01-01

Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.

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.

Asthma in pregnancy: management strategies.

PubMed

McCallister, Jennifer W

2013-01-01

Asthma is one of the most prevalent chronic medical conditions to complicate pregnancy. With approximately one-third of women experiencing a worsening of control during the course of their pregnancy, identifying those at greatest risk has the potential to improve maternal and fetal outcomes for a large number of pregnancies. Similarly, active management strategies that prioritize asthma control in this vulnerable population can have a far-reaching impact. Demographic characteristics and patient noncompliance place certain populations of pregnant women at increased risk of poor asthma control during pregnancy. In addition, undertreatment and disparities in care of acute exacerbations during pregnancy likely contribute. Targeted educational interventions and treatment algorithms using objective markers of disease activity have shown improved outcomes in asthma control. Active management strategies which focus on identifying patient-specific risk factors, patient and provider education, and targeted treatment interventions can improve asthma care for women during pregnancy.

Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.

PubMed

Yoshida, Go J

2017-03-09

attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.

New Strategies in Engineering T-cell Receptor Gene-Modified T cells to More Effectively Target Malignancies.

PubMed

Schmitt, Thomas M; Stromnes, Ingunn M; Chapuis, Aude G; Greenberg, Philip D

2015-12-01

The immune system, T cells in particular, have the ability to target and destroy malignant cells. However, antitumor immune responses induced from the endogenous T-cell repertoire are often insufficient for the eradication of established tumors, as illustrated by the failure of cancer vaccination strategies or checkpoint blockade for most tumors. Genetic modification of T cells to express a defined T-cell receptor (TCR) can provide the means to rapidly generate large numbers of tumor-reactive T cells capable of targeting tumor cells in vivo. However, cell-intrinsic factors as well as immunosuppressive factors in the tumor microenvironment can limit the function of such gene-modified T cells. New strategies currently being developed are refining and enhancing this approach, resulting in cellular therapies that more effectively target tumors and that are less susceptible to tumor immune evasion. ©2015 American Association for Cancer Research.

Magnetic targeting as a strategy to enhance therapeutic effects of mesenchymal stromal cells.

PubMed

Silva, Luisa H A; Cruz, Fernanda F; Morales, Marcelo M; Weiss, Daniel J; Rocco, Patricia R M

2017-03-09

Mesenchymal stromal cells (MSCs) have been extensively investigated in the field of regenerative medicine. It is known that the success of MSC-based therapies depends primarily on effective cell delivery to the target site where they will secrete vesicles and soluble factors with immunomodulatory and potentially reparative properties. However, some lesions are located in sites that are difficult to access, such as the heart, spinal cord, and joints. Additionally, low MSC retention at target sites makes cell therapy short-lasting and, therefore, less effective. In this context, the magnetic targeting technique has emerged as a new strategy to aid delivery, increase retention, and enhance the effects of MSCs. This approach uses magnetic nanoparticles to magnetize MSCs and static magnetic fields to guide them in vivo, thus promoting more focused, effective, and lasting retention of MSCs at the target site. In the present review, we discuss the magnetic targeting technique, its principles, and the materials most commonly used; we also discuss its potential for MSC enhancement, and safety concerns that should be addressed before it can be applied in clinical practice.

Immunotherapy targeting α-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders.

PubMed

Lindström, Veronica; Ihse, Elisabet; Fagerqvist, Therese; Bergström, Joakim; Nordström, Eva; Möller, Christer; Lannfelt, Lars; Ingelsson, Martin

2014-01-01

Immunotherapy targeting α-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. α-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of α-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against α-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting α-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other α-synucleinopathies.

Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

PubMed Central

Audsley, Michelle D; Moseley, Gregory W

2013-01-01

The paramyxoviruses are a family of > 30 viruses that variously infect humans, other mammals and fish to cause diverse outcomes, ranging from asymptomatic to lethal disease, with the zoonotic paramyxoviruses Nipah and Hendra showing up to 70% case-fatality rate in humans. The capacity to evade host immunity is central to viral infection, and paramyxoviruses have evolved multiple strategies to overcome the host interferon (IFN)-mediated innate immune response through the activity of their IFN-antagonist proteins. Although paramyxovirus IFN antagonists generally target common factors of the IFN system, including melanoma differentiation associated factor 5, retinoic acid-inducible gene-I, signal transducers and activators of transcription (STAT)1 and STAT2, and IFN regulatory factor 3, the mechanisms of antagonism show remarkable diversity between different genera and even individual members of the same genus; the reasons for this diversity, however, are not currently understood. Here, we review the IFN antagonism strategies of paramyxoviruses, highlighting mechanistic differences observed between individual species and genera. We also discuss potential sources of this diversity, including biological differences in the host and/or tissue specificity of different paramyxoviruses, and potential effects of experimental approaches that have largely relied on in vitro systems. Importantly, recent studies using recombinant virus systems and animal infection models are beginning to clarify the importance of certain mechanisms of IFN antagonism to in vivo infections, providing important indications not only of their critical importance to virulence, but also of their potential targeting for new therapeutic/vaccine approaches. PMID:24175230

Selective Targeting of Antiviral and Immunomodulating Agents in the Treatment of Arenavirus Infections

DTIC Science & Technology

1987-10-01

observed with free MTP-PE. In addition to our observations on peritoneal and alveolar macrophages, we also examined the effect of MTP-PE treatment on liver...Ir OIC FILE COPY C2 ILn 00 NM AD _____ N SELECTIVE TARGETING OF ANTIVIRAL AND IMMUNOMODULATING AGENTS IN THE TREATMENT OF ARENAVIRUS INFECTIONS "Kc...Selective Targeting of Antiviral and Immunomodulating Agents in the Treatment of Arenavirus Injections 12. PERSONAL AUTHOR(S) J. David Gangemi 13a. TYPE OF

Small Intracranial Aneurysm Treatment Using Target (®) Ultrasoft (™) Coils.

PubMed

Jindal, Gaurav; Miller, Timothy; Iyohe, Moronke; Shivashankar, Ravi; Prasad, Vikram; Gandhi, Dheeraj

2016-06-01

The introduction of small, soft, complex-shaped microcoils has helped facilitate the endovascular treatment of small intracranial aneurysms (IAs) over the last several years. Here, we evaluate the initial safety and efficacy of treating small IAs using only Target(®) Ultrasoft(™) coils. A retrospective review of a prospectively maintained clinical database at a single, high volume, teaching hospital was performed from September 2011 to May 2015. IAs smaller than or equal to 5.0 mm in maximal dimension treated with only Target(®) Ultrasoft(™) coils were included. A total of 50 patients with 50 intracranial aneurysms were included. Subarachnoid hemorrhage from index aneurysm rupture was the indication for treatment in 23 of 50 (46%) cases, and prior subarachnoid hemorrhage (SAH) from another aneurysm was the indication for treatment in eight of 50 (16%) cases. The complete aneurysm occlusion rate was 70% (35/50), the minimal residual aneurysm rate was 14% (7/50), and residual aneurysm rate was 16% (8/50). One intraoperative aneurysm rupture occurred. Three patients died during hospitalization from clinical sequelae of subarachnoid hemorrhage. Follow-up at a mean of 13.6 months demonstrated complete aneurysm occlusion in 75% (30/40) of cases, near complete occlusion in 15% (6/40) of cases, and residual aneurysm in 10% (4/40) of cases, all four of which were retreated. Our initial results using only Target(®) Ultrasoft(™) coils for the endovascular treatment of small intracranial aneurysms demonstrate initial excellent safety and efficacy profiles.

Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma

PubMed Central

Tsoli, Maria; Liu, Jie; Franshaw, Laura; Shen, Han; Cheng, Cecilia; Jung, MoonSun; Joshi, Swapna; Ehteda, Anahid; Khan, Aaminah; Montero-Carcabosso, Angel; Dilda, Pierre J.; Hogg, Philip; Ziegler, David S.

2018-01-01

Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK. In vivo experiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor penetration of the inhibitors into the brain. Further testing of this anti-DIPG strategy with compounds that penetrate the BBB is warranted. PMID:29484131

Development of Bone Targeting Drugs.

PubMed

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J; Mackenzie, William G; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

2017-06-23

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca 2+ . The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments.

Development of Bone Targeting Drugs

PubMed Central

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J.; Mackenzie, William G.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2017-01-01

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID:28644392

Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.

PubMed

Suebsuwong, Chalada; Pinkas, Daniel M; Ray, Soumya S; Bufton, Joshua C; Dai, Bing; Bullock, Alex N; Degterev, Alexei; Cuny, Gregory D

2018-02-15

Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Rehabilitating antisocial personalities: treatment through self-governance strategies

PubMed Central

McRae, Leon

2012-01-01

Offenders with antisocial personality disorder (ASPD) are widely assumed to reject psychotherapeutic intervention. Some commentators, therefore, argue that those with the disorder are better managed in the criminal justice system, where, following the introduction of indeterminate sentences, engagement with psychological treatment is coercively linked to the achievement of parole. By comparison, National Institute of Clinical Excellence guidelines on the management and treatment of ASPD recommend that those who are treatment seeking should be considered for admission to specialist psychiatric hospitals. The rationale is that prison-based interventions are underresourced, and the treatment of ASPD is underprioritised. The justification is that offenders with ASPD can be rehabilitated, if they are motivated. One problem, however, is that little is known about why offenders with ASPD seek treatment or what effect subsequent treatment has on their self-understanding. The aim of this paper is to address these unresolved issues. It draws on the findings of Economic and Social Research Council (ESRC) funded qualitative study examining the experiences of sentenced male offenders admitted to a specialist personality disorder ward within the medium secure estate and the medical practitioners who treat them. The data are analysed with reference to Michel Foucault's work on governmentality and strategy in power relations. Two arguments are advanced: first, offenders with ASPD are motivated by legal coercive pressures to implement a variety of Foucauldian-type strategies to give the false impression of treatment progress. Second, and related, treatment does not result in changes in self-understanding in the resistive client with ASPD. This presupposes that, in respect of this group at least, Foucault was mistaken in his claim that resistive behaviours merely mask the effectiveness of treatment norms over time. Nevertheless, the paper concludes that specialist treatment in the

Clinical correlates of augmentation/combination treatment strategies in major depressive disorder.

PubMed

Dold, M; Bartova, L; Mendlewicz, J; Souery, D; Serretti, A; Porcelli, S; Zohar, J; Montgomery, S; Kasper, S

2018-05-01

This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 ± 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Åsberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. Our findings suggest a clear association between augmentation/combination strategies and treatment-resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities. © 2018 The Authors Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.

A global logrank test for adaptive treatment strategies based on observational studies.

PubMed

Li, Zhiguo; Valenstein, Marcia; Pfeiffer, Paul; Ganoczy, Dara

2014-02-28

In studying adaptive treatment strategies, a natural question that is of paramount interest is whether there is any significant difference among all possible treatment strategies. When the outcome variable of interest is time-to-event, we propose an inverse probability weighted logrank test for testing the equivalence of a fixed set of pre-specified adaptive treatment strategies based on data from an observational study. The weights take into account both the possible selection bias in an observational study and the fact that the same subject may be consistent with more than one treatment strategy. The asymptotic distribution of the weighted logrank statistic under the null hypothesis is obtained. We show that, in an observational study where the treatment selection probabilities need to be estimated, the estimation of these probabilities does not have an effect on the asymptotic distribution of the weighted logrank statistic, as long as the estimation of the parameters in the models for these probabilities is n-consistent. Finite sample performance of the test is assessed via a simulation study. We also show in the simulation that the test can be pretty robust to misspecification of the models for the probabilities of treatment selection. The method is applied to analyze data on antidepressant adherence time from an observational database maintained at the Department of Veterans Affairs' Serious Mental Illness Treatment Research and Evaluation Center. Copyright © 2013 John Wiley & Sons, Ltd.

Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis

DOE PAGES

Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; ...

2016-06-23

Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited withmore » enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE 2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE 2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic

Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis

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

Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.

Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited withmore » enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE 2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE 2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic

Current and emerging treatment strategies for Duchenne muscular dystrophy

PubMed Central

Mah, Jean K

2016-01-01

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying

Factor Analysis of Therapist-Identified Treatment Targets in Community-Based Children's Mental Health.

PubMed

Love, Allison R; Okado, Izumi; Orimoto, Trina E; Mueller, Charles W

2018-01-01

The present study used exploratory and confirmatory factor analyses to identify underlying latent factors affecting variation in community therapists' endorsement of treatment targets. As part of a statewide practice management program, therapist completed monthly reports of treatment targets (up to 10 per month) for a sample of youth (n = 790) receiving intensive in-home therapy. Nearly 75 % of youth were diagnosed with multiple co-occurring disorders. Five factors emerged: Disinhibition, Societal Rules Evasion, Social Engagement Deficits, Emotional Distress, and Management of Biodevelopmental Outcomes. Using logistic regression, primary diagnosis predicted therapist selection of Disinhibition and Emotional Distress targets. Client age predicted endorsement of Societal Rules Evasion targets. Practice-to-research implications are discussed.

Strategies to Combat Antibiotic Resistance in the Wastewater Treatment Plants

PubMed Central

Barancheshme, Fateme; Munir, Mariya

2018-01-01

The main goal of this manuscript is to review different treatment strategies and mechanisms for combating the antibiotic resistant bacteria (ARB) and antibiotic resistant genes (ARGs) in the wastewater environment. The high amount of antibiotics is released into the wastewater that may promote selection of ARB and ARGs which find their way into natural environments. Emerging microbial pathogens and increasing antibiotic resistance among them is a global public health issue. The propagation and spread of ARB and ARGs in the environment may result in an increase of antibiotic resistant microbial pathogens which is a worldwide environmental and public health concern. A proper treatment of wastewater is essential before its discharge into rivers, lake, or sewage system to prevent the spread of ARB and ARGs into the environment. This review discusses various treatment options applied for combating the spread of ARB and ARGs in wastewater treatment plants (WWTPs). It was reported that low-energy anaerobic–aerobic treatment reactors, constructed wetlands, and disinfection processes have shown good removal efficiencies. Nanomaterials and biochar combined with other treatment methods and coagulation process are very recent strategies regarding ARB and ARGs removal and need more investigation and research. Based on current studies a wide-ranging removal efficiency of ARGs can be achieved depending on the type of genes present and treatment processes used, still, there are gaps that need to be further investigated. In order to find solutions to control dissemination of antibiotic resistance in the environment, it is important to (1) study innovative strategies in large scale and over a long time to reach an actual evaluation, (2) develop risk assessment studies to precisely understand occurrence and abundance of ARB/ARGs so that their potential risks to human health can be determined, and (3) consider operating and environmental factors that affect the efficiency of each

Amblyopia treatment strategies and new drug therapies.

PubMed

Pescosolido, Nicola; Stefanucci, Alessio; Buomprisco, Giuseppe; Fazio, Stefano

2014-01-01

Amblyopia is a unilateral or bilateral reduction of visual acuity secondary to abnormal visual experience during early childhood. It is one of the most common causes of vision loss and monocular blindness and is commonly associated with strabismus, anisometropia, and visual deprivation (in particular congenital cataract and ptosis). It is clinically defined as a two-line difference of best-corrected visual acuity between the eyes. The purpose of this study was to understand the neural mechanisms of amblyopia and summarize the current therapeutic strategies. In particular, the authors focused on the concept of brain plasticity and its implication for new treatment strategies for children and adults with amblyopia. Copyright 2014, SLACK Incorporated.

Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies.

PubMed

Solé, Brisa; Jiménez, Esther; Torrent, Carla; Reinares, Maria; Bonnin, Caterina Del Mar; Torres, Imma; Varo, Cristina; Grande, Iria; Valls, Elia; Salagre, Estela; Sanchez-Moreno, Jose; Martinez-Aran, Anabel; Carvalho, André F; Vieta, Eduard

2017-08-01

Over the last decade, there has been a growing appreciation of the importance of identifying and treating cognitive impairment associated with bipolar disorder, since it persists in remission periods. Evidence indicates that neurocognitive dysfunction may significantly influence patients' psychosocial outcomes. An ever-increasing body of research seeks to achieve a better understanding of potential moderators contributing to cognitive impairment in bipolar disorder in order to develop prevention strategies and effective treatments. This review provides an overview of the available data from studies examining treatments for cognitive dysfunction in bipolar disorder as well as potential novel treatments, from both pharmacological and psychological perspectives. All these data encourage the development of further studies to find effective strategies to prevent and treat cognitive impairment associated with bipolar disorder. These efforts may ultimately lead to an improvement of psychosocial functioning in these patients. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Strategies for Prevention and Treatment of Trichomonas vaginalis Infections.

PubMed

Bouchemal, Kawthar; Bories, Christian; Loiseau, Philippe M

2017-07-01

The last estimated annual incidence of Trichomonas vaginalis worldwide exceeds that of chlamydia and gonorrhea combined. This critical review updates the state of the art on advances in T. vaginalis diagnostics and strategies for treatment and prevention of trichomoniasis. In particular, new data on treatment outcomes for topical administration of formulations are reviewed and discussed. Copyright © 2017 American Society for Microbiology.

Big brown bats (Eptesicus fuscus) reveal diverse strategies for sonar target tracking in clutter.

PubMed

Mao, Beatrice; Aytekin, Murat; Wilkinson, Gerald S; Moss, Cynthia F

2016-09-01

Bats actively adjust the acoustic features of their sonar calls to control echo information specific to a given task and environment. A previous study investigated how bats adapted their echolocation behavior when tracking a moving target in the presence of a stationary distracter at different distances and angular offsets. The use of only one distracter, however, left open the possibility that a bat could reduce the interference of the distracter by turning its head. Here, bats tracked a moving target in the presence of one or two symmetrically placed distracters to investigate adaptive echolocation behavior in a situation where vocalizing off-axis would result in increased interference from distracter echoes. Both bats reduced bandwidth and duration but increased sweep rate in more challenging distracter conditions, and surprisingly, made more head turns in the two-distracter condition compared to one, but only when distracters were placed at large angular offsets. However, for most variables examined, subjects showed distinct strategies to reduce clutter interference, either by (1) changing spectral or temporal features of their calls, or (2) producing large numbers of sonar sound groups and consistent head-turning behavior. The results suggest that individual bats can use different strategies for target tracking in cluttered environments.

Cancer gene therapy with targeted adenoviruses.

PubMed

Bachtarzi, Houria; Stevenson, Mark; Fisher, Kerry

2008-11-01

Clinical experience with adenovirus vectors has highlighted the need for improved delivery and targeting. This manuscript aims to provide an overview of the techniques currently under development for improving adenovirus delivery to malignant cells in vivo. Primary research articles reporting improvements in adenoviral gene delivery are described. Strategies include genetic modification of viral coat proteins, non-genetic modifications including polymer encapsulation approaches and pharmacological interventions. Reprogramming adenovirus tropism in vitro has been convincingly demonstrated using a range of genetic and physical strategies. These studies have provided new insights into our understanding of virology and the field is progressing. However, there are still some limitations that need special consideration before adenovirus-targeted cancer gene therapy emerges as a routine treatment in the clinical setting.

Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies.

PubMed

Dodson, Shontelle; Baracos, Vickie E; Jatoi, Aminah; Evans, William J; Cella, David; Dalton, James T; Steiner, Mitchell S

2011-01-01

Cancer cachexia is a complex metabolic condition characterized by loss of skeletal muscle. Common clinical manifestations include muscle wasting, anemia, reduced caloric intake, and altered immune function, which contribute to increased disability, fatigue, diminished quality of life, and reduced survival. The prevalence of cachexia and the impact of this disorder on the patient and family underscore the need for effective management strategies. Dietary supplementation and appetite stimulation alone are inadequate to reverse the underlying metabolic abnormalities of cancer cachexia and have limited long-term impact on patient quality of life and survival. Therapies that can increase muscle mass and physical performance may be a promising option; however, there are currently no drugs approved for the prevention or treatment of cancer cachexia. Several agents are in clinical development, including anabolic agents, such as selective androgen receptor modulators and drugs targeting inflammatory cytokines that promote skeletal muscle catabolism.

Basic immunology of antibody targeted radiotherapy

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

Wong, Jeffrey Y.C.

2006-10-01

Antibody targeted radiotherapy brings an important new treatment modality to Radiation oncology clinic. Radiation dose to tumor and normal tissues are determined by a complex interplay of antibody, antigen, tumor, radionuclide, and host-related factors. A basic understanding of these immunologic and physiologic factors is important to optimally utilize this therapy in the clinic. Preclinical and clinical studies need to be continued to broaden our understanding and to develop new strategies to further improve the efficacy of this promising form of targeted therapy.

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

PubMed

Prabhu, Venugopal Vinod; Devaraj, Niranjali

2017-01-01

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

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

DTIC Science & Technology

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

A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin.

PubMed

Saw, Phei Er; Park, Jinho; Jon, Sangyong; Farokhzad, Omid C

2017-02-01

A major problem with cancer chemotherapy begins when cells acquire resistance. Drug-resistant cancer cells typically upregulate multi-drug resistance proteins such as P-glycoprotein (P-gp). However, the lack of overexpressed surface biomarkers has limited the targeted therapy of drug-resistant cancers. Here we report a drug-delivery carrier decorated with a targeting ligand for a surface marker protein extra-domain B(EDB) specific to drug-resistant breast cancer cells as a new therapeutic option for the aggressive cancers. We constructed EDB-specific aptide (APT EDB )-conjugated liposome to simultaneously deliver siRNA(siMDR1) and Dox to drug-resistant breast cancer cells. APT EDB -LS(Dox,siMDR1) led to enhanced delivery of payloads into MCF7/ADR cells and showed significantly higher accumulation and retention in the tumors. While either APT EDB -LS(Dox) or APT EDB -LS(siMDR1) did not lead to appreciable tumor retardation in MCF7/ADR orthotropic model, APT EDB -LS(Dox,siMDR1) treatment resulted in significant reduction of the drug-resistant breast tumor. Taken together, this study provides a new strategy of drug delivery for drug-resistant cancer therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2012-11-01

DATES COVERED 4 October 2011- 3 October 2012 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a...interventions aimed at modulation of the endocannabinoid (EC) system targeting degradation of 20arachidonoyl glycerlol (2- AG) and N-arachidonoyl...percussion, traumatic brain injury, blood brain barrier, neuroinflammination, neurological dysfunction, endocannabinoids . 16. SECURITY CLASSIFICATION

Targeting HER2 in the treatment of non-small cell lung cancer.

PubMed

Mar, Nataliya; Vredenburgh, James J; Wasser, Jeffrey S

2015-03-01

Oncogenic driver mutations have emerged as major treatment targets for molecular therapies in a variety of cancers. HER2 positivity has been well-studied in breast cancer, but its importance is still being explored in non-small cell lung cancer (NSCLC). Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for gene mutations. The prognostic and predictive significance of these tests remain to be validated, with an emerging association between HER2 gene mutations and response to HER2 targeted therapies. Despite the assay used to determine the HER2 status of lung tumors, all patients with advanced HER2 positive lung adenocarcinoma should be evaluated for treatment with targeted agents. Several clinical approaches for inclusion of these drugs into patient treatment plans exist, but there is no defined algorithm specific to NSCLC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nanocarriers for cancer-targeted drug delivery.

PubMed

Kumari, Preeti; Ghosh, Balaram; Biswas, Swati

2016-01-01

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed.

Consensus guidelines for the use of empiric and diagnostic-driven antifungal treatment strategies in haematological malignancy, 2014.

PubMed

Morrissey, C O; Gilroy, N M; Macesic, N; Walker, P; Ananda-Rajah, M; May, M; Heath, C H; Grigg, A; Bardy, P G; Kwan, J; Kirsa, S W; Slavin, M; Gottlieb, T; Chen, S

2014-12-01

Invasive fungal disease (IFD) causes significant morbidity and mortality in patients undergoing allogeneic haemopoietic stem cell transplantation or chemotherapy for haematological malignancy. Much of these adverse outcomes are due to the limited ability of traditional diagnostic tests (i.e. culture and histology) to make an early and accurate diagnosis. As persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients despite broad-spectrum antibiotics have been associated with the development of IFD, most centres have traditionally administered empiric antifungal therapy (EAFT) to patients with PFUO. However, use of an EAFT strategy has not been shown to have an overall survival benefit and is associated with excessive antifungal therapy use. As a result, the focus has shifted to developing more sensitive and specific diagnostic tests for early and more targeted antifungal treatment. These tests, including the galactomannan enzyme-linked immunosorbent assay and Aspergillus polymerase chain reaction (PCR), have enabled the development of diagnostic-driven antifungal treatment (DDAT) strategies, which have been shown to be safe and feasible, reducing antifungal usage. In addition, the development of effective antifungal prophylactic strategies has changed the landscape in terms of the incidence and types of IFD that clinicians have encountered. In this review, we examine the current role of EAFT and provide up-to-date data on the newer diagnostic tests and algorithms available for use in EAFT and DDAT strategies, within the context of patient risk and type of antifungal prophylaxis used. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Short-Term Group Psychotherapy: A Clinical Trial of a New Combination of Pretreatment and Treatment Strategies.

ERIC Educational Resources Information Center

Merkel, William T.; Willis, Stephen L.

1985-01-01

The paper discusses a clinical trial of pretreatment and treatment strategies to enhance the effectiveness of short-term groups. Pretreatment strategies included preparing patients and increasing the perceived authority of the therapists. Treatment strategies include delineation of a specific treatment focus and a directive approach by the…

Dual Drug Targeting of Mutant Bcr-Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance.

PubMed

El Rashedy, Ahmed A; Olotu, Fisayo A; Soliman, Mahmoud E S

2018-03-01

Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and ABL-001 induced a 'bent' conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr-Abl by dual targeting. Our findings revealed that unlike in the Bcr-Abl-Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C-terminal helix that varied with time. This was coupled with significant alteration in Bcr-Abl stability, flexibility, and compactness and an overall structural re-orientation inwards towards the hydrophobic core, which reduced the solvent-exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

Application of a multivariate analysis method for non-target screening detection of persistent transformation products during the cork boiling wastewater treatment.

PubMed

Ponce-Robles, L; Oller, I; Agüera, A; Trinidad-Lozano, M J; Yuste, F J; Malato, S; Perez-Estrada, L A

2018-08-15

Cork boiling wastewater is a very complex mixture of naturally occurring compounds leached and partially oxidized during the boiling cycles. The effluent generated is recalcitrant and could cause a significant environmental impact. Moreover, if this untreated industrial wastewater enters a municipal wastewater treatment plant it could hamper or reduce the efficiency of most activated sludge degradation processes. Despite the efforts to treat the cork boiling wastewater for reusing purposes, is still not well-known how safe these compounds (original compounds and oxidation by-products) will be. The purpose of this work was to apply an HPLC-high resolution mass spectrometry method and subsequent non-target screening using a multivariate analysis method (PCA), to explore relationships between samples (treatments) and spectral features (masses or compounds) that could indicate changes in formation, degradation or polarity, during coagulation/flocculation (C/F) and photo-Fenton (PhF). Although, most of the signal intensities were reduced after the treatment line, 16 and 4 new peaks were detected to be formed after C/F and PhF processes respectively. The use of this non-target approach showed to be an effective strategy to explore, classify and detect transformation products during the treatment of an unknown complex mixture. Copyright © 2018 Elsevier B.V. All rights reserved.

Targeting Beta-Amyloid at the CSF: A New Therapeutic Strategy in Alzheimer's Disease.

PubMed

Menendez-Gonzalez, Manuel; Padilla-Zambrano, Huber S; Alvarez, Gabriel; Capetillo-Zarate, Estibaliz; Tomas-Zapico, Cristina; Costa, Agustin

2018-01-01

Although immunotherapies against the amyloid-β (Aβ) peptide tried so date failed to prove sufficient clinical benefit, Aβ still remains the main target in Alzheimer's disease (AD). This article aims to show the rationale of a new therapeutic strategy: clearing Aβ from the CSF continuously (the "CSF-sink" therapeutic strategy). First, we describe the physiologic mechanisms of Aβ clearance and the resulting AD pathology when these mechanisms are altered. Then, we review the experiences with peripheral Aβ-immunotherapy and discuss the related hypothesis of the mechanism of action of "peripheral sink." We also present Aβ-immunotherapies acting on the CNS directly. Finally, we introduce alternative methods of removing Aβ including the "CSF-sink" therapeutic strategy. As soluble peptides are in constant equilibrium between the ISF and the CSF, altering the levels of Aβ oligomers in the CSF would also alter the levels of such proteins in the brain parenchyma. We conclude that interventions based in a "CSF-sink" of Aβ will probably produce a steady clearance of Aβ in the ISF and therefore it may represent a new therapeutic strategy in AD.

The prelude on novel receptor and ligand targets involved in the treatment of diabetes mellitus.

PubMed

Jonnalagadda, Venu Gopal; Ram Raju, Allam Venkata Sita; Pittala, Srinivas; Shaik, Afsar; Selkar, Nilakash Annaji

2014-01-01

Metabolic disorders are a group of disorders, due to the disruption of the normal metabolic process at a cellular level. Diabetes Mellitus and Tyrosinaemia are the majorly reported metabolic disorders. Among them, Diabetes Mellitus is a one of the leading metabolic syndrome, affecting 5 to 7 % of the population worldwide and mainly characterised by elevated levels of glucose and is associated with two types of physiological event disturbances such as impaired insulin secretion and insulin resistance. Up to now, various treatment strategies are like insulin, alphaglucosidase inhibitors, biguanides, incretins were being followed. Concurrently, various novel therapeutic strategies are required to advance the therapy of Diabetes mellitus. For the last few decades, there has been an extensive research in understanding the metabolic pathways involved in Diabetes Mellitus at the cellular level and having the profound knowledge on cell-growth, cell-cycle, and apoptosis at a molecular level provides new targets for the treatment of Diabetes Mellitus. Receptor signalling has been involved in these mechanisms, to translate the information coming from outside. To understand the various receptors involved in these pathways, we must have a sound knowledge on receptors and ligands involved in it. This review mainly summarises the receptors and ligands which are involved the Diabetes Mellitus. Finally, researchers have to develop the alternative chemical moieties that retain their affinity to receptors and efficacy. Diabetes Mellitus being a metabolic disorder due to the glucose surfeit, demands the need for regular exercise along with dietary changes.

Optically Based Rapid Screening Method for Proven Optimal Treatment Strategies Before Treatment Begins

DTIC Science & Technology

to rapidly test /screen breast cancer therapeutics as a strategy to streamline drug development and provide individualized treatment. The results...system can therefore be used to streamline pre-clinical drug development, by reducing the number of animals , cost, and time required to screen new drugs

Decisional strategy determines whether frame influences treatment preferences for medical decisions.

PubMed

Woodhead, Erin L; Lynch, Elizabeth B; Edelstein, Barry A

2011-06-01

Decision makers are influenced by the frame of information such that preferences vary depending on whether survival or mortality data are presented. Research is inconsistent as to whether and how age impacts framing effects. This paper presents two studies that used qualitative analyses of think-aloud protocols to understand how the type of information used in the decision making process varies by frame and age. In Study 1, 40 older adults, age 65 to 89, and 40 younger adults, age 18 to 24, responded to a hypothetical lung cancer scenario in a within-subject design. Participants received both a survival and mortality frame. Qualitative analyses revealed that two main decisional strategies were used by all participants: one strategy reflected a data-driven decisional process, whereas the other reflected an experience-driven process. Age predicted decisional strategy, with older adults less likely to use a data-driven strategy. Frame interacted with strategy to predict treatment choice; only those using a data-driven strategy demonstrated framing effects. In Study 2, 61 older adults, age 65 to 98, and 63 younger adults, age 18 to 30, responded to the same scenarios as in Study 1 in a between-subject design. The results of Study 1 were replicated, with age significantly predicting decisional strategy and frame interacting with strategy to predict treatment choice. Findings suggest that framing effects may be more related to decisional strategy than to age. (c) 2011 APA, all rights reserved.

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

PubMed Central

Elvington, Michelle; Huang, Yuxiang; Morgan, B. Paul; Qiao, Fei; van Rooijen, Nico; Atkinson, Carl

2012-01-01

Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer. PMID:22442351

Strategies to improve energy efficiency in sewage treatment plants

NASA Astrophysics Data System (ADS)

Au, Mau Teng; Pasupuleti, Jagadeesh; Chua, Kok Hua

2013-06-01

This paper discusses on strategies to improve energy efficiency in Sewage Treatment Plant (STP). Four types of STP; conventional activated sludge, extended aeration, oxidation ditch, and sequence batch reactor are presented and strategized to reduce energy consumption based on their influent flow. Strategies to reduce energy consumption include the use of energy saving devices, energy efficient motors, automation/control and modification of processes. It is envisaged that 20-30% of energy could be saved from these initiatives.

Molecular mechanisms of depression: perspectives on new treatment strategies.

PubMed

Lang, Undine E; Borgwardt, Stefan

2013-01-01

observed by ketamine, which acts via the glutamatergic system. Hence, GABA, AMPA, EAAT, NMDA- and metabotropic glutamate receptors (mGluR1 to mGluR8) have gained interest in depression recently. Alternative, causative or also easy available treatment strategies beyond serotonin and noradrenaline reuptake inhibition might be a major topic of future psychiatric care. In this review, an attempt is made to overview concepts of the disease and search for perspectives on antidepressant treatment strategies beyond approved medications. Copyright © 2013 S. Karger AG, Basel.

Heart failure—potential new targets for therapy

PubMed Central

Nabeebaccus, Adam; Zheng, Sean; Shah, Ajay M.

2016-01-01

Abstract Introduction/background Heart failure is a major cause of cardiovascular morbidity and mortality. This review covers current heart failure treatment guidelines, emerging therapies that are undergoing clinical trial, and potential new therapeutic targets arising from basic science advances. Sources of data A non-systematic search of MEDLINE was carried out. International guidelines and relevant reviews were searched for additional articles. Areas of agreement Angiotensin-converting enzyme inhibitors and beta-blockers are first line treatments for chronic heart failure with reduced left ventricular function. Areas of controversy Treatment strategies to improve mortality in heart failure with preserved left ventricular function are unclear. Growing points Many novel therapies are being tested for clinical efficacy in heart failure, including those that target natriuretic peptides and myosin activators. A large number of completely novel targets are also emerging from laboratory-based research. Better understanding of pathophysiological mechanisms driving heart failure in different settings (e.g. hypertension, post-myocardial infarction, metabolic dysfunction) may allow for targeted therapies. Areas timely for developing research Therapeutic targets directed towards modifying the extracellular environment, angiogenesis, cell viability, contractile function and microRNA-based therapies. PMID:27365454

Cancer active targeting by nanoparticles: a comprehensive review of literature

PubMed Central

Bazak, Remon; Houri, Mohamad; Achy, Samar El; Kamel, Serag

2016-01-01

Purpose Cancer is one of the leading causes of death, and thus, the scientific community has but great efforts to improve cancer management. Among the major challenges in cancer management is development of agents that can be used for early diagnosis and effective therapy. Conventional cancer management frequently lacks accurate tools for detection of early tumors and has an associated risk of serious side effects of chemotherapeutics. The need to optimize therapeutic ratio as the difference with which a treatment affects cancer cells versus healthy tissues lead to idea that it is needful to have a treatment that could act a the “magic bullet”—recognize cancer cells only. Nanoparticle platforms offer a variety of potentially efficient solutions for development of targeted agents that can be exploited for cancer diagnosis and treatment. There are two ways by which targeting of nanoparticles can be achieved, namely passive and active targeting. Passive targeting allows for the efficient localization of nanoparticles within the tumor microenvironment. Active targeting facilitates the active uptake of nanoparticles by the tumor cells themselves. Methods Relevant English electronic databases and scientifically published original articles and reviews were systematically searched for the purpose of this review. Results In this report, we present a comprehensive review of literatures focusing on the active targeting of nanoparticles to cancer cells, including antibody and antibody fragment-based targeting, antigen-based targeting, aptamer-based targeting, as well as ligand-based targeting. Conclusion To date, the optimum targeting strategy has not yet been announced, each has its own advantages and disadvantages even though a number of them have found their way for clinical application. Perhaps, a combination of strategies can be employed to improve the precision of drug delivery, paving the way for a more effective personalized therapy. PMID:25005786

Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases

PubMed Central

Geldenhuys, Werner J.; Lin, Li; Darvesh, Altaf S.; Sadana, Prabodh

2017-01-01

Although statins and other pharmacological approaches have improved the management of lipid abnormalities, there exists a need for newer treatment modalities especially for the management of hypertriglyceridemia. Lipoprotein lipase (LPL), by promoting hydrolytic cleavage of the triglyceride core of lipoproteins, is a crucial node in the management of plasma lipid levels. Although LPL expression and activity modulation is observed as a pleiotropic action of some the commonly used lipid lowering drugs, the deliberate development of drugs targeting LPL has not occurred yet. In this review, we present the biology of LPL, highlight the LPL modulation property of currently used drugs and review the novel emerging approaches to target LPL. PMID:27771332

Molecular Targeted Intervention for Pancreatic Cancer

PubMed Central

Mohammed, Altaf; Janakiram, Naveena B.; Pant, Shubham; Rao, Chinthalapally V.

2015-01-01

Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. PMID:26266422

Targeting the Thioredoxin System for Cancer Therapy.

PubMed

Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

2017-09-01

Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Copyright © 2017 Elsevier Ltd. All rights reserved.

Renal Hemodynamics in AKI: In Search of New Treatment Targets.

PubMed

Matejovic, Martin; Ince, Can; Chawla, Lakhmir S; Blantz, Roland; Molitoris, Bruce A; Rosner, Mitchell H; Okusa, Mark D; Kellum, John A; Ronco, Claudio

2016-01-01

Novel therapeutic interventions are required to prevent or treat AKI. To expedite progress in this regard, a consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 to develop recommendations for research priorities and future directions. Here, we highlight the concepts related to renal hemodynamics in AKI that are likely to reveal new treatment targets on investigation. Overall, we must better understand the interactions between systemic, total renal, and glomerular hemodynamics, including the role of tubuloglomerular feedback. Furthermore, the net consequences of therapeutic maneuvers aimed at restoring glomerular filtration need to be examined in relation to the nature, magnitude, and duration of the insult. Additionally, microvascular blood flow heterogeneity in AKI is now recognized as a common occurrence; timely interventions to preserve the renal microcirculatory flow may interrupt the downward spiral of injury toward progressive kidney failure and should, therefore, be investigated. Finally, development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies. Copyright © 2016 by the American Society of Nephrology.

Renal Hemodynamics in AKI: In Search of New Treatment Targets

PubMed Central

Matejovic, Martin; Ince, Can; Chawla, Lakhmir S.; Blantz, Roland; Molitoris, Bruce A.; Okusa, Mark D.; Kellum, John A.; Ronco, Claudio

2016-01-01

Novel therapeutic interventions are required to prevent or treat AKI. To expedite progress in this regard, a consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 to develop recommendations for research priorities and future directions. Here, we highlight the concepts related to renal hemodynamics in AKI that are likely to reveal new treatment targets on investigation. Overall, we must better understand the interactions between systemic, total renal, and glomerular hemodynamics, including the role of tubuloglomerular feedback. Furthermore, the net consequences of therapeutic maneuvers aimed at restoring glomerular filtration need to be examined in relation to the nature, magnitude, and duration of the insult. Additionally, microvascular blood flow heterogeneity in AKI is now recognized as a common occurrence; timely interventions to preserve the renal microcirculatory flow may interrupt the downward spiral of injury toward progressive kidney failure and should, therefore, be investigated. Finally, development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies. PMID:26510884

Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections.

PubMed

Wares, Joanna R; Crivelli, Joseph J; Yun, Chae-Ok; Choi, Il-Kyu; Gevertz, Jana L; Kim, Peter S

2015-12-01

Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.

The application of the fibroblast activation protein α-targeted immunotherapy strategy

PubMed Central

Du, Jun; Zhang, Kun-Shui; Zhang, Qiu-Gui; Wang, Xiao-Wei; Liu, Zhi-Gang; Liu, Shuang-Quan; Xie, Wan-Ying; Liu, Hui-Fang; Liu, Jing-Shi; Wu, Bai-Ping

2016-01-01

Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein α (FAP α) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP α has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP α-expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP α antibody, FAP α vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP α is an adaptive tumor-associated antigen. This review highlights the role of FAP α in tumor development, explores the relationship between FAP α and immune suppression in the TME, and discusses FAP α as a potential immunotherapeutic target. PMID:26985769

Overview on the target fabrication facilities at ELI-NP and ongoing strategies

NASA Astrophysics Data System (ADS)

Gheorghiu, C. C.; Leca, V.; Popa, D.; Cernaianu, M. O.; Stutman, D.

2016-10-01

Along with the development of petawatt class laser systems, the interaction between high power lasers and matter flourished an extensive research, with high-interest applications like: laser nuclear physics, proton radiography or cancer therapy. The new ELI-NP (Extreme Light Infrastructure - Nuclear Physics) petawatt laser facility, with 10PW and ~ 1023W/cm2 beam intensity, is one of the innovative projects that will provide novel research of fundamental processes during light-matter interaction. As part of the ELI-NP facility, Targets Laboratory will provide the means for in-house manufacturing and characterization of the required targets (mainly solid ones) for the experiments, in addition to the research activity carried out in order to develop novel target designs with improved performances. A description of the Targets Laboratory with the main pieces of equipment and their specifications are presented. Moreover, in view of the latest progress in the target design, one of the proposed strategies for the forthcoming experiments at ELI-NP is also described, namely: ultra-thin patterned foil of diamond-like carbon (DLC) coated with a carbon-based ultra-low density layer. The carbon foam which behaves as a near-critical density plasma, will allow the controlled-shaping of the laser pulse before the main interaction with the solid foil. Particular emphasis will be directed towards the target's design optimization, by simulation tests and tuning the key-properties (thickness/length, spacing, density foam, depth, periodicity etc.) which are expected to have a crucial effect on the laser-matter interaction process.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

PubMed

Saiz, Luis Carlos; Gorricho, Javier; Garjón, Javier; Celaya, Mª Concepción; Muruzábal, Lourdes; Malón, Mª Del Mar; Montoya, Rodolfo; López, Antonio

2017-10-11

Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. To determine if 'lower' blood pressure targets (≤ 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with 'standard' blood pressure targets (≤ 140 to 160/ 90 to 100 mmHg) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the Latin American and Caribbean Health Science Literature Database (from 1982) and contacted authors of relevant papers regarding further published and unpublished work. There were no language restrictions. We included randomized controlled trials (RCTs) with more than 50 participants per group and at least six months follow-up. Trial reports needed to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions were lower target for systolic/diastolic blood pressure (≤ 135/85 mmHg) compared with standard target for blood pressure (≤ 140 to 160/90 to 100 mmHg).Participants were adults with documented hypertension or who were