Rodent Models of Experimental Endometriosis: Identifying Mechanisms of Disease and Therapeutic Targets

PubMed Central

Bruner-Tran, Kaylon L.; Mokshagundam, Shilpa; Herington, Jennifer L.; Ding, Tianbing; Osteen, Kevin G.

2018-01-01

Background: Although it has been more than a century since endometriosis was initially described in the literature, understanding the etiology and natural history of the disease has been challenging. However, the broad utility of murine and rat models of experimental endometriosis has enabled the elucidation of a number of potentially targetable processes which may otherwise promote this disease. Objective: To review a variety of studies utilizing rodent models of endometriosis to illustrate their utility in examining mechanisms associated with development and progression of this disease. Results: Use of rodent models of endometriosis has provided a much broader understanding of the risk factors for the initial development of endometriosis, the cellular pathology of the disease and the identification of potential therapeutic targets. Conclusion: Although there are limitations with any animal model, the variety of experimental endometriosis models that have been developed has enabled investigation into numerous aspects of this disease. Thanks to these models, our under-standing of the early processes of disease development, the role of steroid responsiveness, inflammatory processes and the peritoneal environment has been advanced. More recent models have begun to shed light on how epigenetic alterations con-tribute to the molecular basis of this disease as well as the multiple comorbidities which plague many patients. Continued de-velopments of animal models which aid in unraveling the mechanisms of endometriosis development provide the best oppor-tunity to identify therapeutic strategies to prevent or regress this enigmatic disease.

Systematic screening identifies dual PI3K and mTOR inhibition as a conserved therapeutic vulnerability in osteosarcoma

PubMed Central

Gupte, Ankita; Baker, Emma K.; Wan, Soo-San; Stewart, Elizabeth; Loh, Amos; Shelat, Anang A.; Gould, Cathryn M.; Chalk, Alistair M.; Taylor, Scott; Lackovic, Kurt; Karlström, Åsa; Mutsaers, Anthony J.; Desai, Jayesh; Madhamshettiwar, Piyush B.; Zannettino, Andrew CW.; Burns, Chris; Huang, David CS.; Dyer, Michael A.; Simpson, Kaylene J.; Walkley, Carl R.

2015-01-01

Purpose Osteosarcoma (OS) is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of OS, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for OS patients. Experimental Design We have used genetically engineered murine models of human OS in a systematic, genome wide screen to identify new candidate therapeutic targets. We performed a genome wide siRNA screen, with or without doxorubicin. In parallel a screen of therapeutically relevant small molecules was conducted on primary murine and primary human OS derived cell cultures. All results were validated across independent cell cultures and across human and mouse OS. Results The results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary OS cell cultures in vitro in both human and mouse OS, while specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on OS cell cultures. Conclusions The approaches described here have identified dual inhibition of the PI3K/mTOR pathway as a sensitive, druggable target in OS and provide rationale for translational studies with these agents. PMID:25862761

The Therapeutic Alliance: Clients' Categorization of Client-Identified Factors

ERIC Educational Resources Information Center

Simpson, Arlene J.; Bedi, Robinder P.

2012-01-01

Clients' perspectives on the therapeutic alliance were examined using written descriptions of factors that clients believed to be helpful in developing a strong alliance. Fifty participants sorted previously collected statements into thematically similar piles and then gave each set of statements a title. Multivariate concept mapping statistical…

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer.

PubMed

Chang, Hae Ryung; Nam, Seungyoon; Lee, Jinhyuk; Kim, Jin-Hee; Jung, Hae Rim; Park, Hee Seo; Park, Sungjin; Ahn, Young Zoo; Huh, Iksoo; Balch, Curt; Ku, Ja-Lok; Powis, Garth; Park, Taesung; Jeong, Jin-Hyun; Kim, Yon Hui

2016-12-06

Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer "Big Data" has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of "hit" compounds.

The renaissance of complement therapeutics

PubMed Central

Ricklin, Daniel; Mastellos, Dimitrios C.; Reis, Edimara S.; Lambris, John D.

2018-01-01

The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond. PMID:29199277

Perceptions of Therapeutic Classrooms for Students Identified with Emotional Disturbances

ERIC Educational Resources Information Center

Everson, Shelly M.

2016-01-01

For various reasons, many students with emotional disturbances are unable to succeed in traditional classroom environments. The purpose of this qualitative case study was to explore the perceptions of administrators, teachers, paraprofessionals, parents, and related service providers towards therapeutic intervention classrooms for students…

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

PubMed Central

Jung, Hae Rim; Park, Hee Seo; Park, Sungjin; Ahn, Young Zoo; Huh, Iksoo; Balch, Curt; Ku, Ja-Lok; Powis, Garth; Park, Taesung; Jeong, Jin-Hyun; Kim, Yon Hui

2016-01-01

Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer “Big Data” has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of “hit” compounds. PMID:27806312

Therapeutic options to treat sulfur mustard poisoning--the road ahead.

PubMed

Smith, William J

2009-09-01

For the past 15 years the international research community has conducted a basic and applied research program aimed at identifying a medical countermeasure against chemical threat vesicant, or blistering, agents. The primary emphasis of this program has been the development of therapeutic protection against sulfur mustard and its cutaneous pathology-blister formation. In addition to the work on a medical countermeasures, significant research has been conducted on the development of topical skin protectants and medical strategies for wound healing. This review will focus on the pharmacological strategies investigated, novel therapeutic targets currently under investigation and therapeutic approaches being considered for transition to advanced development. Additionally, we will review the expansion of our understanding of the pathophysiological mechanisms of mustard injury that has come from this research. While great strides have been made through these investigations, the complexity of the mustard insult demands that further studies extend the inroads made and point the way toward better understanding of cellular and tissue disruptions caused by sulfur mustard.

Identifiability of Additive, Time-Varying Actuator and Sensor Faults by State Augmentation

NASA Technical Reports Server (NTRS)

Upchurch, Jason M.; Gonzalez, Oscar R.; Joshi, Suresh M.

2014-01-01

Recent work has provided a set of necessary and sucient conditions for identifiability of additive step faults (e.g., lock-in-place actuator faults, constant bias in the sensors) using state augmentation. This paper extends these results to an important class of faults which may affect linear, time-invariant systems. In particular, the faults under consideration are those which vary with time and affect the system dynamics additively. Such faults may manifest themselves in aircraft as, for example, control surface oscillations, control surface runaway, and sensor drift. The set of necessary and sucient conditions presented in this paper are general, and apply when a class of time-varying faults affects arbitrary combinations of actuators and sensors. The results in the main theorems are illustrated by two case studies, which provide some insight into how the conditions may be used to check the theoretical identifiability of fault configurations of interest for a given system. It is shown that while state augmentation can be used to identify certain fault configurations, other fault configurations are theoretically impossible to identify using state augmentation, giving practitioners valuable insight into such situations. That is, the limitations of state augmentation for a given system and configuration of faults are made explicit. Another limitation of model-based methods is that there can be large numbers of fault configurations, thus making identification of all possible configurations impractical. However, the theoretical identifiability of known, credible fault configurations can be tested using the theorems presented in this paper, which can then assist the efforts of fault identification practitioners.

Breast cancer stem cells, EMT and therapeutic targets

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

Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: s.bhattacharya@jiit.ac.in

Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they aremore » also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.« less

Inhalation delivery of protein therapeutics.

PubMed

Kane, Colleen; O'Neil, Karyn; Conk, Michelle; Picha, Kristen

2013-04-01

Inhaled therapeutics are used routinely to treat a variety of pulmonary diseases including asthma, COPD and cystic fibrosis. In addition, biological therapies represent the fastest growing segment of approved pharmaceuticals. However, despite the increased availability of biological therapies, nearly all inhaled therapeutics are small molecule drugs with only a single inhaled protein therapeutic approved. There remains a significant unmet need for therapeutics in pulmonary diseases, and biological therapies with potential to alter disease progression represent a significant opportunity to treat these challenging diseases. This review provides a background into efforts to develop inhaled biological therapies and highlights some of the associated challenges. In addition, we speculate on the ideal properties of a biologic therapy for inhaled delivery.

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

PubMed Central

Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

2012-01-01

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID:21814200

Comparison of GWAS models to identify non-additive genetic control of flowering time in sunflower hybrids.

PubMed

Bonnafous, Fanny; Fievet, Ghislain; Blanchet, Nicolas; Boniface, Marie-Claude; Carrère, Sébastien; Gouzy, Jérôme; Legrand, Ludovic; Marage, Gwenola; Bret-Mestries, Emmanuelle; Munos, Stéphane; Pouilly, Nicolas; Vincourt, Patrick; Langlade, Nicolas; Mangin, Brigitte

2018-02-01

This study compares five models of GWAS, to show the added value of non-additive modeling of allelic effects to identify genomic regions controlling flowering time of sunflower hybrids. Genome-wide association studies are a powerful and widely used tool to decipher the genetic control of complex traits. One of the main challenges for hybrid crops, such as maize or sunflower, is to model the hybrid vigor in the linear mixed models, considering the relatedness between individuals. Here, we compared two additive and three non-additive association models for their ability to identify genomic regions associated with flowering time in sunflower hybrids. A panel of 452 sunflower hybrids, corresponding to incomplete crossing between 36 male lines and 36 female lines, was phenotyped in five environments and genotyped for 2,204,423 SNPs. Intra-locus effects were estimated in multi-locus models to detect genomic regions associated with flowering time using the different models. Thirteen quantitative trait loci were identified in total, two with both model categories and one with only non-additive models. A quantitative trait loci on LG09, detected by both the additive and non-additive models, is located near a GAI homolog and is presented in detail. Overall, this study shows the added value of non-additive modeling of allelic effects for identifying genomic regions that control traits of interest and that could participate in the heterosis observed in hybrids.

Phosphotyrosine profiling identifies ephrin receptor A2 as a potential therapeutic target in esophageal squamous‐cell carcinoma

PubMed Central

Syed, Nazia; Barbhuiya, Mustafa A.; Pinto, Sneha M.; Nirujogi, Raja Sekhar; Renuse, Santosh; Datta, Keshava K.; Khan, Aafaque Ahmad; Srikumar, Kotteazeth; Prasad, T. S. Keshava; Kumar, M. Vijaya; Kumar, Rekha Vijay; Chatterjee, Aditi; Pandey, Akhilesh

2015-01-01

Esophageal squamous‐cell carcinoma (ESCC) is one of the most common malignancies in Asia. Currently, surgical resection of early‐stage tumor is the best available treatment. However, most patients present late when surgery is not an option. Data suggest that chemotherapy regimens are inadequate for clinical management of advanced cancer. Targeted therapy has emerged as one of the most promising approaches to treat several malignancies. A prerequisite for developing targeted therapy is prior knowledge of proteins and pathways that drive proliferation in malignancies. We carried out phosphotyrosine profiling across four different ESCC cell lines and compared it to non‐neoplastic Het‐1A cell line to identify activated tyrosine kinase signaling pathways in ESCC. A total of 278 unique phosphopeptides were identified across these cell lines. This included several tyrosine kinases and their substrates that were hyperphosphorylated in ESCC. Ephrin receptor A2 (EPHA2), a receptor tyrosine kinase, was hyperphosphorylated in all the ESCC cell lines used in the study. EPHA2 is reported to be oncogenic in several cancers and is also known to promote metastasis. Immunohistochemistry‐based studies have revealed EPHA2 is overexpressed in nearly 50% of ESCC. We demonstrated EPHA2 as a potential therapeutic target in ESCC by carrying out siRNA‐based knockdown studies. Knockdown of EPHA2 in ESCC cell line TE8 resulted in significant decrease in cell proliferation and invasion, suggesting it is a promising therapeutic target in ESCC that warrants further evaluation. PMID:25366905

Chemical screening platforms for autophagy drug discovery to identify therapeutic candidates for Huntington's disease and other neurodegenerative disorders.

PubMed

Sarkar, Sovan

2013-01-01

Autophagy is a cellular degradation process involved in the clearance of aggregate-prone proteins associated with neurodegenerative diseases. While the mTOR pathway has been known to be the major regulator of autophagy, recent advancements into the regulation of autophagy have identified mTOR-independent autophagy pathways that are amenable to chemical perturbations. Several chemical and genetic screens have been undertaken to identify small molecule and genetic regulators of autophagy, respectively. The small molecule autophagy enhancers offer great potential as therapeutic candidates not only for neurodegenerative diseases, but also for diverse human diseases where autophagy acts as a protective pathway. This review highlights the various chemical screening platforms for autophagy drug discovery pertinent for the treatment of neurodegenerative diseases.

Protein-Based Therapeutic Killing for Cancer Therapies.

PubMed

Serna, Naroa; Sánchez-García, Laura; Unzueta, Ugutz; Díaz, Raquel; Vázquez, Esther; Mangues, Ramón; Villaverde, Antonio

2018-03-01

The treatment of some high-incidence human diseases is based on therapeutic cell killing. In cancer this is mainly achieved by chemical drugs that are systemically administered to reach effective toxic doses. As an innovative alternative, cytotoxic proteins identified in nature can be adapted as precise therapeutic agents. For example, individual toxins and venom components, proapoptotic factors, and antimicrobial peptides from bacteria, animals, plants, and humans have been engineered as highly potent drugs. In addition to the intrinsic cytotoxic activities of these constructs, their biological fabrication by DNA recombination allows the recruitment, in single pharmacological entities, of diverse functions of clinical interest such as specific cell-surface receptor binding, self-activation, and self-assembling as nanoparticulate materials, with wide applicability in cell-targeted oncotherapy and theragnosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

A School-Based Therapeutic/Educational Program for Severely Disturbed Latency Aged Children.

ERIC Educational Resources Information Center

Shelby, Madge E.

Through joint efforts of mental health and education professionals, a school-based therapeutic/educational program for seriously emotionally disturbed children, some of whom had additional identified disabilities such as mental retardation, was initiated with 15 students (ages 8-13). The educational component of the program was based on an…

Ras-Driven Transcriptome Analysis Identifies Aurora Kinase A as a Potential Malignant Peripheral Nerve Sheath Tumor Therapeutic Target

PubMed Central

Patel, Ami V.; Eaves, David; Jessen, Walter J.; Rizvi, Tilat A.; Ecsedy, Jeffrey A.; Qian, Mark G.; Aronow, Bruce J.; Perentesis, John P.; Serra, Eduard; Cripe, Timothy P.; Miller, Shyra J.; Ratner, Nancy

2013-01-01

Purpose Patients with Neurofibromatosis Type 1 (NF1) develop malignant peripheral nerve sheath tumors (MPNST) which are often inoperable and do not respond well to current chemotherapies or radiation. The goal of this study was to utilize comprehensive gene expression analysis to identify novel therapeutic targets. Experimental Design Nerve Schwann cells and/or their precursors are the tumorigenic cell types in MPNST due to the loss of the NF1 gene, which encodes the RasGAP protein neurofibromin. Therefore, we created a transgenic mouse model, CNP-HRas12V, expressing constitutively-active HRas in Schwann cells and defined a Ras-induced gene expression signature to drive a Bayesian factor regression model analysis of differentially expressed genes in mouse and human neurofibromas and MPNSTs. We tested functional significance of Aurora kinase over-expression in MPNST in vitro and in vivo using Aurora kinase shRNAs and compounds that inhibit Aurora kinase. Results We identified 2000 genes with probability of linkage to nerve Ras signaling of which 339 were significantly differentially expressed in mouse and human NF1-related tumor samples relative to normal nerves, including Aurora kinase A (AURKA). AURKA was dramatically over-expressed and genomically amplified in MPNSTs but not neurofibromas. Aurora kinase shRNAs and Aurora kinase inhibitors blocked MPNST cell growth in vitro. Furthermore, an AURKA selective inhibitor, MLN8237, stabilized tumor volume and significantly increased survival of mice with MPNST xenografts. Conclusion Integrative cross-species transcriptome analyses combined with preclinical testing has provided an effective method for identifying candidates for molecular-targeted therapeutics. Blocking Aurora kinases may be a viable treatment platform for MPNST. PMID:22811580

Functional signaling pathway analysis of lung adenocarcinomas identifies novel therapeutic targets for KRAS mutant tumors

PubMed Central

Baldelli, Elisa; Bellezza, Guido; Haura, Eric B.; Crinó, Lucio; Cress, W. Douglas; Deng, Jianghong; Ludovini, Vienna; Sidoni, Angelo; Schabath, Matthew B.; Puma, Francesco; Vannucci, Jacopo; Siggillino, Annamaria; Liotta, Lance A.; Petricoin, Emanuel F.; Pierobon, Mariaelena

2015-01-01

Little is known about the complex signaling architecture of KRAS and the interconnected RAS-driven protein-protein interactions, especially as it occurs in human clinical specimens. This study explored the activated and interconnected signaling network of KRAS mutant lung adenocarcinomas (AD) to identify novel therapeutic targets. Thirty-four KRAS mutant (MT) and twenty-four KRAS wild-type (WT) frozen biospecimens were obtained from surgically treated lung ADs. Samples were subjected to laser capture microdissection and reverse phase protein microarray analysis to explore the expression/activation levels of 150 signaling proteins along with co-activation concordance mapping. An independent set of 90 non-small cell lung cancers (NSCLC) was used to validate selected findings by immunohistochemistry (IHC). Compared to KRAS WT tumors, the signaling architecture of KRAS MT ADs revealed significant interactions between KRAS downstream substrates, the AKT/mTOR pathway, and a number of Receptor Tyrosine Kinases (RTK). Approximately one-third of the KRAS MT tumors had ERK activation greater than the WT counterpart (p<0.01). Notably 18% of the KRAS MT tumors had elevated activation of the Estrogen Receptor alpha (ER-α) (p=0.02). This finding was verified in an independent population by IHC (p=0.03). KRAS MT lung ADs appear to have a more intricate RAS linked signaling network than WT tumors with linkage to many RTKs and to the AKT-mTOR pathway. Combination therapy targeting different nodes of this network may be necessary to treat this group of patients. In addition, for patients with KRAS MT tumors and activation of the ER-α, anti-estrogen therapy may have important clinical implications. PMID:26468985

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma.

PubMed

Arora, Shilpi; Gonzales, Irma M; Hagelstrom, R Tanner; Beaudry, Christian; Choudhary, Ashish; Sima, Chao; Tibes, Raoul; Mousses, Spyro; Azorsa, David O

2010-08-18

Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells. Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis. In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.

Cardiovascular pleiotropic actions of DPP-4 inhibitors: a step at the cutting edge in understanding their additional therapeutic potentials.

PubMed

Balakumar, Pitchai; Dhanaraj, Sokkalingam A

2013-09-01

Dipeptidyl peptidase 4 (DPP-4) is a serine protease enzyme expressed widely in many tissues, including the cardiovascular system. The incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the small intestine into the vasculature during a meal, and these incretins have a potential to release insulin from pancreatic beta cells of islets of Langerhans, affording a glucose-lowering action. However, both incretins are hurriedly degraded by the DPP-4. Inhibitors of DPP-4, therefore, enhance the bioavailability of GLP-1 and GIP, and thus have been approved for better glycemic management in patients afflicted with type 2 diabetes mellitus (T2DM). Five different DPP-4 inhibitors, often called as 'gliptins', namely sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin have been approved hitherto for clinical use. These drugs are used along with diet and exercise to lower blood sugar in diabetic subjects. T2DM is intricately related with an increased risk of cardiovascular disease. Growing body of evidence suggests that gliptins, in addition to their persuasive anti-diabetic action, have a beneficial pleiotropic action on the heart and vessels. In view of the fact of cardiovascular disease susceptibility of patients afflicted with T2DM, gliptins might offer additional therapeutic benefits in treating diabetic cardiovascular complications. Exploring further the cardiovascular pleiotropic potentials of gliptins might open a panorama in impeccably employing these agents for the dual management of T2DM and T2DM-associated perilous cardiovascular complications. This review will shed lights on the newly identified beneficial pleiotropic actions of gliptins on the cardiovascular system. Copyright © 2013 Elsevier Inc. All rights reserved.

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2011-08-17

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Designing highly active siRNAs for therapeutic applications.

PubMed

Walton, S Patrick; Wu, Ming; Gredell, Joseph A; Chan, Christina

2010-12-01

The discovery of RNA interference (RNAi) generated considerable interest in developing short interfering RNAs (siRNAs) for understanding basic biology and as the active agents in a new variety of therapeutics. Early studies showed that selecting an active siRNA was not as straightforward as simply picking a sequence on the target mRNA and synthesizing the siRNA complementary to that sequence. As interest in applying RNAi has increased, the methods for identifying active siRNA sequences have evolved from focusing on the simplicity of synthesis and purification, to identifying preferred target sequences and secondary structures, to predicting the thermodynamic stability of the siRNA. As more specific details of the RNAi mechanism have been defined, these have been incorporated into more complex siRNA selection algorithms, increasing the reliability of selecting active siRNAs against a single target. Ultimately, design of the best siRNA therapeutics will require design of the siRNA itself, in addition to design of the vehicle and other components necessary for it to function in vivo. In this minireview, we summarize the evolution of siRNA selection techniques with a particular focus on one issue of current importance to the field, how best to identify those siRNA sequences likely to have high activity. Approaches to designing active siRNAs through chemical and structural modifications will also be highlighted. As the understanding of how to control the activity and specificity of siRNAs improves, the potential utility of siRNAs as human therapeutics will concomitantly grow. © 2010 The Authors Journal compilation © 2010 FEBS.

Tissue phosphoproteomics with PolyMAC identifies potential therapeutic targets in a transgenic mouse model of HER2 positive breast cancer

PubMed Central

Searleman, Adam C.; Iliuk, Anton B.; Collier, Timothy S.; Chodosh, Lewis A.; Tao, W. Andy; Bose, Ron

2014-01-01

Altered protein phosphorylation is a feature of many human cancers that can be targeted therapeutically. Phosphopeptide enrichment is a critical step for maximizing the depth of phosphoproteome coverage by MS, but remains challenging for tissue specimens because of their high complexity. We describe the first analysis of a tissue phosphoproteome using polymer-based metal ion affinity capture (PolyMAC), a nanopolymer that has excellent yield and specificity for phosphopeptide enrichment, on a transgenic mouse model of HER2-driven breast cancer. By combining phosphotyrosine immunoprecipitation with PolyMAC, 411 unique peptides with 139 phosphotyrosine, 45 phosphoserine, and 29 phosphothreonine sites were identified from five LC-MS/MS runs. Combining reverse phase liquid chromatography fractionation at pH 8.0 with PolyMAC identified 1571 unique peptides with 1279 phosphoserine, 213 phosphothreonine, and 21 phosphotyrosine sites from eight LC-MS/MS runs. Linear motif analysis indicated that many of the phosphosites correspond to well-known phosphorylation motifs. Analysis of the tyrosine phosphoproteome with the Drug Gene Interaction database uncovered a network of potential therapeutic targets centered on Src family kinases with inhibitors that are either FDA-approved or in clinical development. These results demonstrate that PolyMAC is well suited for phosphoproteomic analysis of tissue specimens. PMID:24723360

Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia

PubMed Central

Geng, Huimin; Brennan, Sarah; Milne, Thomas A.; Chen, Wei-Yi; Li, Yushan; Hurtz, Christian; Kweon, Soo-Mi; Zickl, Lynette; Shojaee, Seyedmehdi; Neuberg, Donna; Huang, Chuanxin; Biswas, Debabrata; Xin, Yuan; Racevskis, Janis; Ketterling, Rhett P.; Luger, Selina M.; Lazarus, Hillard; Tallman, Martin S.; Rowe, Jacob M.; Litzow, Mark R.; Guzman, Monica L.; Allis, C. David; Roeder, Robert G.; Müschen, Markus; Paietta, Elisabeth; Elemento, Olivier; Melnick, Ari M.

2012-01-01

Genetic lesions such as BCR-ABL1, E2A-PBX1 and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point towards disease mechanisms and useful biomarkers and therapeutic targets. We therefore performed DNA methylation and gene expression profiling on a cohort of 215 adult B-ALL patients enrolled in a single phase III clinical trial (ECOG E2993) and normal control B-cells. In BCR-ABL1-positive B-ALL, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in ALL patients regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALL. In E2A-PBX1-positive B-ALL, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 ChIP sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6 targeted therapy as a new therapeutic strategy for MLLr B-ALL. PMID:23107779

Discovery and design of carbohydrate-based therapeutics.

PubMed

Cipolla, Laura; Araújo, Ana C; Bini, Davide; Gabrielli, Luca; Russo, Laura; Shaikh, Nasrin

2010-08-01

Till now, the importance of carbohydrates has been underscored, if compared with the two other major classes of biopolymers such as oligonucleotides and proteins. Recent advances in glycobiology and glycochemistry have imparted a strong interest in the study of this enormous family of biomolecules. Carbohydrates have been shown to be implicated in recognition processes, such as cell-cell adhesion, cell-extracellular matrix adhesion and cell-intruder recognition phenomena. In addition, carbohydrates are recognized as differentiation markers and as antigenic determinants. Due to their relevant biological role, carbohydrates are promising candidates for drug design and disease treatment. However, the growing number of human disorders known as congenital disorders of glycosylation that are being identified as resulting from abnormalities in glycan structures and protein glycosylation strongly indicates that a fast development of glycobiology, glycochemistry and glycomedicine is highly desirable. The topics give an overview of different approaches that have been used to date for the design of carbohydrate-based therapeutics; this includes the use of native synthetic carbohydrates, the use of carbohydrate mimics designed on the basis of their native counterpart, the use of carbohydrates as scaffolds and finally the design of glyco-fused therapeutics, one of the most recent approaches. The review covers mainly literature that has appeared since 2000, except for a few papers cited for historical reasons. The reader will gain an overview of the current strategies applied to the design of carbohydrate-based therapeutics; in particular, the advantages/disadvantages of different approaches are highlighted. The topic is presented in a general, basic manner and will hopefully be a useful resource for all readers who are not familiar with it. In addition, in order to stress the potentialities of carbohydrates, several examples of carbohydrate-based marketed therapeutics are given

Next Generation Sequencing Identifies Five Major Classes of Potentially Therapeutic Enzymes Secreted by Lucilia sericata Medical Maggots.

PubMed

Franta, Zdeněk; Vogel, Heiko; Lehmann, Rüdiger; Rupp, Oliver; Goesmann, Alexander; Vilcinskas, Andreas

2016-01-01

Lucilia sericata larvae are used as an alternative treatment for recalcitrant and chronic wounds. Their excretions/secretions contain molecules that facilitate tissue debridement, disinfect, or accelerate wound healing and have therefore been recognized as a potential source of novel therapeutic compounds. Among the substances present in excretions/secretions various peptidase activities promoting the wound healing processes have been detected but the peptidases responsible for these activities remain mostly unidentified. To explore these enzymes we applied next generation sequencing to analyze the transcriptomes of different maggot tissues (salivary glands, gut, and crop) associated with the production of excretions/secretions and/or with digestion as well as the rest of the larval body. As a result we obtained more than 123.8 million paired-end reads, which were assembled de novo using Trinity and Oases assemblers, yielding 41,421 contigs with an N50 contig length of 2.22 kb and a total length of 67.79 Mb. BLASTp analysis against the MEROPS database identified 1729 contigs in 577 clusters encoding five peptidase classes (serine, cysteine, aspartic, threonine, and metallopeptidases), which were assigned to 26 clans, 48 families, and 185 peptidase species. The individual enzymes were differentially expressed among maggot tissues and included peptidase activities related to the therapeutic effects of maggot excretions/secretions.

Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1

PubMed Central

Smith, Andrew H.; Jensen, Kevin P.; Li, Jin; Nunez, Yaira; Farrer, Lindsay A.; Hakonarson, Hakon; Cook-Sather, Scott D.; Kranzler, Henry R.; Gelernter, Joel

2017-01-01

Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the μ-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time-consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study (GWAS) of usual daily methadone dose. In African-American (AA) OD subjects (n = 383), we identified a genome-wide significant association between therapeutic methadone dose (mean = 68.0 mg, standard deviation (SD) = 30.1 mg) and rs73568641 (P = 2.8 × 10−8), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20 mg/day of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n = 1,027), no genome-wide significant associations with methadone dose (mean = 77.8 mg, SD = 33.9 mg) were observed. In an independent set of opioid-naïve AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n = 241, P = 3.9 × 10−2). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n = 1,410, genetic score P = 1.3 × 10−3). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction. PMID:28115739

Arrayed antibody library technology for therapeutic biologic discovery.

PubMed

Bentley, Cornelia A; Bazirgan, Omar A; Graziano, James J; Holmes, Evan M; Smider, Vaughn V

2013-03-15

Traditional immunization and display antibody discovery methods rely on competitive selection amongst a pool of antibodies to identify a lead. While this approach has led to many successful therapeutic antibodies, targets have been limited to proteins which are easily purified. In addition, selection driven discovery has produced a narrow range of antibody functionalities focused on high affinity antagonism. We review the current progress in developing arrayed protein libraries for screening-based, rather than selection-based, discovery. These single molecule per microtiter well libraries have been screened in multiplex formats against both purified antigens and directly against targets expressed on the cell surface. This facilitates the discovery of antibodies against therapeutically interesting targets (GPCRs, ion channels, and other multispanning membrane proteins) and epitopes that have been considered poorly accessible to conventional discovery methods. Copyright © 2013. Published by Elsevier Inc.

Language Patterns and Therapeutic Change.

ERIC Educational Resources Information Center

Phoenix, Valdemar G.; Lindeman, Mary L.

Noting that the mental health practitioner needs highly developed linguistic and communicative skills in order to precipitate therapeutic changes, this paper discusses the nature of the contexts of therapeutic interaction. It examines verb tense as a linguistic context marker and shows how various schools of therapy can use it. In addition, it…

Combination therapeutics in complex diseases.

PubMed

He, Bing; Lu, Cheng; Zheng, Guang; He, Xiaojuan; Wang, Maolin; Chen, Gao; Zhang, Ge; Lu, Aiping

2016-12-01

The biological redundancies in molecular networks of complex diseases limit the efficacy of many single drug therapies. Combination therapeutics, as a common therapeutic method, involve pharmacological intervention using several drugs that interact with multiple targets in the molecular networks of diseases and may achieve better efficacy and/or less toxicity than monotherapy in practice. The development of combination therapeutics is complicated by several critical issues, including identifying multiple targets, targeting strategies and the drug combination. This review summarizes the current achievements in combination therapeutics, with a particular emphasis on the efforts to develop combination therapeutics for complex diseases. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Functional Genomics to Identify Therapeutic Targets in Cancer Stem Cells Using a Novel Murine CRPC Model

DTIC Science & Technology

2015-11-01

REPORT 3 . DATES COVERED 6 Aug 2013 - 5 Aug 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Functional Genomics to Identify Therapeutic Targets in...4 3 . Accomplishments………..………………………………...…………...4 4. Impact…………………………...……………………….….…………21 5. Changes/Problems...Requirements……………………….…….………23 9. Appendices……………………………………………….…….………23 3 1. INTRODUCTION: Prostate cancer is the most common noncutaneous malignancy in men

Possibility of Exosome-Based Therapeutics and Challenges in Production of Exosomes Eligible for Therapeutic Application.

PubMed

Yamashita, Takuma; Takahashi, Yuki; Takakura, Yoshinobu

2018-01-01

Exosomes are cell-derived vesicles with a diameter 30-120 nm. Exosomes contain endogenous proteins and nucleic acids; delivery of these molecules to exosome-recipient cells causes biological effects. Exosomes derived from some types of cells such as mesenchymal stem cells and dendritic cells have therapeutic potential and may be biocompatible and efficient agents against various disorders such as organ injury. However, there are many challenges for the development of exosome-based therapeutics. In particular, producing exosomal formulations is the major barrier for therapeutic application because of their heterogeneity and low productivity. Development and optimization of producing methods, including methods for isolation and storage of exosome formulations, are required for realizing exosome-based therapeutics. In addition, improvement of therapeutic potential and delivery efficiency of exosomes are important for their therapeutic application. In this review, we summarize current knowledge about therapeutic application of exosomes and discuss some challenges in their successful use.

Biomimetic Particles as Therapeutics

PubMed Central

Green, Jordan J.

2015-01-01

In recent years, there have been major advances in the development of novel nanoparticle and microparticle-based therapeutics. An emerging paradigm is the incorporation of biomimetic features into these synthetic therapeutic constructs to enable them to better interface with biological systems. Through the control of size, shape, and material consistency, particle cores have been generated that better mimic natural cells and viruses. In addition, there have been significant advances in biomimetic surface functionalization of particles through the integration of bio-inspired artificial cell membranes and naturally derived cell membranes. Biomimetic technologies enable therapeutic particles to have increased potency to benefit human health. PMID:26277289

Sunitinib Possible Sex-Divergent Therapeutic Outcomes.

PubMed

Segarra, Ignacio; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L

2016-10-01

Sunitinib is a tyrosine kinase inhibitor used for the treatment of renal cell carcinoma and metastatic brain tumors. Preclinical pharmacokinetic studies have shown higher sunitinib hepatic and brain exposure in female mice and higher sunitinib kidney concentrations in male mice. We explored whether sex-divergent tissue pharmacokinetics may anticipate sex-divergent therapeutic and toxicology responses in male and female patients. The review of the available scientific literature identified case reports, case series reports, clinical trials, and other studies associating sex with sunitinib outcomes. The results suggest male patients may respond better to renal cell carcinoma treatment and female patients may have better brain tumor treatment outcomes but a higher incidence of adverse events. Although more high-quality evidence is needed, these results, as anticipated by the preclinical data, may indicate possible sunitinib sex-divergent therapeutic outcomes in patients. In addition, we propose the systematic analysis of sex-based outcomes in clinical trial reports and their inclusion and review in the ethics committees and review boards to prevent, amongst others, patient burden in upcoming clinical trials.

Next Generation Sequencing Identifies Five Major Classes of Potentially Therapeutic Enzymes Secreted by Lucilia sericata Medical Maggots

PubMed Central

Franta, Zdeněk; Vogel, Heiko; Lehmann, Rüdiger; Rupp, Oliver; Goesmann, Alexander; Vilcinskas, Andreas

2016-01-01

Lucilia sericata larvae are used as an alternative treatment for recalcitrant and chronic wounds. Their excretions/secretions contain molecules that facilitate tissue debridement, disinfect, or accelerate wound healing and have therefore been recognized as a potential source of novel therapeutic compounds. Among the substances present in excretions/secretions various peptidase activities promoting the wound healing processes have been detected but the peptidases responsible for these activities remain mostly unidentified. To explore these enzymes we applied next generation sequencing to analyze the transcriptomes of different maggot tissues (salivary glands, gut, and crop) associated with the production of excretions/secretions and/or with digestion as well as the rest of the larval body. As a result we obtained more than 123.8 million paired-end reads, which were assembled de novo using Trinity and Oases assemblers, yielding 41,421 contigs with an N50 contig length of 2.22 kb and a total length of 67.79 Mb. BLASTp analysis against the MEROPS database identified 1729 contigs in 577 clusters encoding five peptidase classes (serine, cysteine, aspartic, threonine, and metallopeptidases), which were assigned to 26 clans, 48 families, and 185 peptidase species. The individual enzymes were differentially expressed among maggot tissues and included peptidase activities related to the therapeutic effects of maggot excretions/secretions. PMID:27119084

Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target.

PubMed

Demeure, Michael J; Aziz, Meraj; Rosenberg, Richard; Gurley, Steven D; Bussey, Kimberly J; Carpten, John D

2014-06-01

Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In radioiodine resistant aggressive papillary thyroid cancers, there remain few effective therapeutic options. A 62-year-old man who underwent multiple operations for papillary thyroid cancer and whose metastases progressed despite standard treatments provided tumor tissue. We analyzed tumor and whole blood DNA by whole genome sequencing, achieving 80× or greater coverage over 94 % of the exome and 90 % of the genome. We determined somatic mutations and structural alterations. We found a total of 57 somatic mutations in 55 genes of the cancer genome. There was notably a lack of mutations in NRAS and BRAF, and no RET/PTC rearrangement. There was a mutation in the TRAPP oncogene and a loss of heterozygosity of the p16, p18, and RB1 tumor suppressor genes. The oncogenic driver for this tumor is a translocation involving the genes for anaplastic lymphoma receptor tyrosine kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4). The EML4-ALK translocation has been reported in approximately 5 % of lung cancers, as well as in pediatric neuroblastoma, and is a therapeutic target for crizotinib. This is the first report of the whole genomic sequencing of a papillary thyroid cancer in which we identified an EML4-ALK translocation of a TRAPP oncogene mutation. These findings suggest that this tumor has a more distinct oncogenesis than BRAF mutant papillary thyroid cancer. Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.

How collaboration in therapy becomes therapeutic: the therapeutic collaboration coding system.

PubMed

Ribeiro, Eugénia; Ribeiro, António P; Gonçalves, Miguel M; Horvath, Adam O; Stiles, William B

2013-09-01

The quality and strength of the therapeutic collaboration, the core of the alliance, is reliably associated with positive therapy outcomes. The urgent challenge for clinicians and researchers is constructing a conceptual framework to integrate the dialectical work that fosters collaboration, with a model of how clients make progress in therapy. We propose a conceptual account of how collaboration in therapy becomes therapeutic. In addition, we report on the construction of a coding system - the therapeutic collaboration coding system (TCCS) - designed to analyse and track on a moment-by-moment basis the interaction between therapist and client. Preliminary evidence is presented regarding the coding system's psychometric properties. The TCCS evaluates each speaking turn and assesses whether and how therapists are working within the client's therapeutic zone of proximal development, defined as the space between the client's actual therapeutic developmental level and their potential developmental level that can be reached in collaboration with the therapist. We applied the TCCS to five cases: a good and a poor outcome case of narrative therapy, a good and a poor outcome case of cognitive-behavioural therapy, and a dropout case of narrative therapy. The TCCS offers markers that may help researchers better understand the therapeutic collaboration on a moment-to-moment basis and may help therapists better regulate the relationship. © 2012 The British Psychological Society.

Identifying real and perceived barriers to therapeutic education programs for individuals with inflammatory arthritis.

PubMed

Bain, Lorna; Sangrar, Ruheena; Bornstein, Carolyn; Lukmanji, Sara; Hapuhennedige, Sandani; Thorne, Carter; Beattie, Karen A

2016-09-01

Therapeutic Education Programs (TEPs) grounded in self-management principles have been shown to improve quality of life of patients with chronic conditions and reduce patient-related healthcare costs. Though these programs are becoming more readily available, patients often experience barriers in participating. This study sought to identify barriers faced by inflammatory arthritis (IA) patients in attending a TEP and understand how patients overcame perceived barriers. A mixed-method study design was used. Questionnaires were distributed to individuals with IA who were invited to attend a TEP between 2010 and 2013. Respondents were those that chose not to attend (group A), individuals who attended ≤4 of 10 sessions (group B), individuals who attended ≥5 of 10 sessions prior to May 2013 (group C), and individuals who attended ≥5 of 10 sessions from June 2013 to November 2013 (group D). Individuals in group D were also invited to participate in focus groups to discuss how they had overcome perceived barriers. Real barriers identified by individuals in groups A and B included time, distance, and cost associated with attendance. Individuals who overcame perceived barriers (groups C and D) discussed strategies they used to do so. Aspects of the overall program experience and access to clinic and program also contributed to patients being able to overcome barriers. Time, distance, and cost are external barriers that prevented individuals from utilizing self-management education opportunities. These barriers were overcome if and when individuals had resources available to them. Readiness for behavior change also influenced commitment to participate in the program.

Theranostics Using Antibodies and Antibody-Related Therapeutics.

PubMed

Moek, Kirsten L; Giesen, Danique; Kok, Iris C; de Groot, Derk Jan A; Jalving, Mathilde; Fehrmann, Rudolf S N; Lub-de Hooge, Marjolijn N; Brouwers, Adrienne H; de Vries, Elisabeth G E

2017-09-01

In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibody-related therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as 89 Zr. In this review, we provide an overview of ongoing research on mAbs and antibody-related theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Integrative Therapeutic Approaches for the Management and Control of Nausea in Children Undergoing Cancer Treatment: A Systematic Review of Literature.

PubMed

Momani, Tha'er G; Berry, Donna L

Chemotherapy-induced nausea and vomiting (CINV) continues to be a common symptom experienced by children undergoing cancer treatment despite the use of contemporary antiemetics. Integrative therapeutic approaches in addition to standard pharmacologic antiemetic regimes offer potential to control CINV. The purpose of this review was to identify current evidence on integrative therapeutic approaches for the control of CINV in children with cancer. Online search engines (PubMed, CINAHL, PsychINFO) were queried using MESH terms. Titles, abstracts, and then full-text articles were reviewed for relevance to the review. The search resulted in 53 studies. Twenty-one studies met our review criteria. Integrative therapies identified included acupuncture/acupressure, aromatherapy, herbal supplements, hypnosis, and other cognitive behavioral interventions. Our review identified little information on the effectiveness and safety of most integrative therapeutic approaches for the control and management of CINV in children with cancer. However, evidence from adult cancer studies and some pediatric studies identify promising interventions for further testing.

Therapeutic cloning: from consequences to contradiction.

PubMed

Coors, Marilyn

2002-06-01

The British Parliament legalized therapeutic cloning in December 2000 despite opposition from the European Union. The watershed event in Parliament's move was the active and unprecedented government support for the generation and destruction of human embryonic life merely as a means of medical advancement. This article contends that the utilitarian analysis of this procedure is necessary to identify the real world risks of therapeutic cloning but insufficient to identify the breach of defensible ethical limits that this procedure represents. A value-oriented approach to Kantian ethics demonstrates that the utilitarian endorsement of therapeutic cloning entails a contradiction of the necessity of human vulnerability and a faulty valuation of the human embryo. The concern is that a narrow utilitarian focus ultimately commodifies human embryonic life and preferences outcomes as the sole determinant of moral value.

Transdermal delivery of therapeutic agent

NASA Technical Reports Server (NTRS)

Kwiatkowski, Krzysztof C. (Inventor); Hayes, Ryan T. (Inventor); Magnuson, James W. (Inventor); Giletto, Anthony (Inventor)

2008-01-01

A device for the transdermal delivery of a therapeutic agent to a biological subject that includes a first electrode comprising a first array of electrically conductive microprojections for providing electrical communication through a skin portion of the subject to a second electrode comprising a second array of electrically conductive microprojections. Additionally, a reservoir for holding the therapeutic agent surrounding the first electrode and a pulse generator for providing an exponential decay pulse between the first and second electrodes may be provided. A method includes the steps of piercing a stratum corneum layer of skin with two arrays of conductive microprojections, encapsulating the therapeutic agent into biocompatible charged carriers, surrounding the conductive microprojections with the therapeutic agent, generating an exponential decay pulse between the two arrays of conductive microprojections to create a non-uniform electrical field and electrokinetically driving the therapeutic agent through the stratum corneum layer of skin.

Why Additional Presentations Help Identify a Stimulus

ERIC Educational Resources Information Center

Guest, Duncan; Kent, Christopher; Adelman, James S.

2010-01-01

Nosofsky (1983) reported that additional stimulus presentations within a trial increase discriminability in absolute identification, suggesting that each presentation creates an independent stimulus representation, but it remains unclear whether exposure duration or the formation of independent representations improves discrimination in such…

Exploring the associations between drug side-effects and therapeutic indications.

PubMed

Wang, Fei; Zhang, Ping; Cao, Nan; Hu, Jianying; Sorrentino, Robert

2014-10-01

Drug therapeutic indications and side-effects are both measurable patient phenotype changes in response to the treatment. Inferring potential drug therapeutic indications and identifying clinically interesting drug side-effects are both important and challenging tasks. Previous studies have utilized either chemical structures or protein targets to predict indications and side-effects. In this study, we compared drug therapeutic indication prediction using various information including chemical structures, protein targets and side-effects. We also compared drug side-effect prediction with various information sources including chemical structures, protein targets and therapeutic indication. Prediction performance based on 10-fold cross-validation demonstrates that drug side-effects and therapeutic indications are the most predictive information source for each other. In addition, we extracted 6706 statistically significant indication-side-effect associations from all known drug-disease and drug-side-effect relationships. We further developed a novel user interface that allows the user to interactively explore these associations in the form of a dynamic bipartitie graph. Many relationship pairs provide explicit repositioning hypotheses (e.g., drugs causing postural hypotension are potential candidates for hypertension) and clear adverse-reaction watch lists (e.g., drugs for heart failure possibly cause impotence). All data sets and highly correlated disease-side-effect relationships are available at http://astro.temple.edu/∼tua87106/druganalysis.html. Copyright © 2014 Elsevier Inc. All rights reserved.

Therapeutics incorporating blood constituents.

PubMed

Charoenphol, Phapanin; Oswalt, Katie; Bishop, Corey J

2018-04-05

Blood deficiency and dysfunctionality can result in adverse events, which can primarily be treated by transfusion of blood or the re-introduction of properly functioning sub-components. Blood constituents can be engineered on the sub-cellular (i.e., DNA recombinant technology) and cellular level (i.e., cellular hitchhiking for drug delivery) for supplementing and enhancing therapeutic efficacy, in addition to rectifying dysfunctioning mechanisms (i.e., clotting). Herein, we report the progress of blood-based therapeutics, with an emphasis on recent applications of blood transfusion, blood cell-based therapies and biomimetic carriers. Clinically translated technologies and commercial products of blood-based therapeutics are subsequently highlighted and perspectives on challenges and future prospects are discussed. Blood-based therapeutics is a burgeoning field and has advanced considerably in recent years. Blood and its constituents, with and without modification (i.e., combinatorial), have been utilized in a broad spectrum of pre-clinical and clinically-translated treatments. This review article summarizes the most up-to-date progress of blood-based therapeutics in the following contexts: synthetic blood substitutes, acellular/non-recombinant therapies, cell-based therapies, and therapeutic sub-components. The article subsequently discusses clinically-translated technologies and future prospects thereof. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The central nervous system--an additional consideration in 'rotator cuff tendinopathy' and a potential basis for understanding response to loaded therapeutic exercise.

PubMed

Littlewood, Chris; Malliaras, Peter; Bateman, Marcus; Stace, Richmond; May, Stephen; Walters, Stephen

2013-12-01

Tendinopathy is a term used to describe a painful tendon disorder but despite being a well-recognised clinical presentation, a definitive understanding of the pathoaetiology of rotator cuff tendinopathy remains elusive. Current explanatory models, which relate to peripherally driven nocioceptive mechanisms secondary to structural abnormality, or failed healing, appear inadequate on their own in the context of current literature. In light of these limitations this paper presents an extension to current models that incorporates the integral role of the central nervous system in the pain experience. The role of the central nervous system (CNS) is described and justified along with a potential rationale to explain the favourable response to loaded therapeutic exercises demonstrated by previous studies. This additional consideration has the potential to offer a useful way to explain pain to patients, for clinicians to prescribe appropriate therapeutic management strategies and for researchers to advance knowledge in relation to this clinically challenging problem. Copyright © 2013 Elsevier Ltd. All rights reserved.

Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading.

PubMed

Sutaria, Dhruvitkumar S; Badawi, Mohamed; Phelps, Mitch A; Schmittgen, Thomas D

2017-05-01

Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics.

MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma.

PubMed

Gautam, Shailendra K; Kumar, Sushil; Cannon, Andrew; Hall, Bradley; Bhatia, Rakesh; Nasser, Mohd Wasim; Mahapatra, Sidharth; Batra, Surinder K; Jain, Maneesh

2017-07-01

Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance. Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC. Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.

Identifying Safer Anti-Wear Triaryl Phosphate Additives for Jet Engine Lubricants

PubMed Central

Baker, Paul E.; Cole, Toby B.; Cartwright, Megan; Suzuki, Stephanie M.; Thummel, Kenneth E.; Lin, Yvonne S.; Co, Aila L.; Rettie, Allan E.; Kim, Jerry H.; Furlong, Clement E.

2013-01-01

Individuals aboard jet aircraft may be exposed to potentially toxic triaryl organophosphate anti-wear lubricant additives (TAPs) that are converted by cytochromes P450 into toxic metabolites. Consequences of exposure could be reduced by using less toxic TAPs. Our goal was to determine whether an in vitro assay for inhibition of butyrylcholinesterase (BChE) by bioactivated TAPs would be predictive of inhibition of serine active-site enzymes in vivo. The in vitro assay involved TAP bioactivation with liver microsomes and NADPH, followed by incubation with human BChE and measurement of BChE activity. Of 19 TAPs tested, tert-butylated isomers produced the least BChE inhibition. To determine the relevance of these results in vivo, mice were exposed to Durad 125 (D125; a commercial mixture of TAP esters) or to TAPs demonstrating low or no BChE inhibition when assayed in vitro. Inhibition of BChE by bioactivated TAPs in vitro correlated well with inhibition of other serine active-site enzymes in vivo, with the exception of brain acetylcholinesterase and neuropathy target esterase (NTE), which were not inhibited by any TAP tested following single exposures. A recombinant catalytic domain of NTE (rNEST) exhibited classical kinetic properties of NTE. The metabolite of tri-(o-cresyl) phosphate (ToCP), 2-(o-cresyl)-4H-1,3,2-benzodioxaphosphoran-2-one (CBDP), inhibited rNEST in vitro, but with an IC50 value almost 6-times higher than for inhibition of BChE. Physiologically-relevant concentrations of the flavonoid, naringenin, dramatically reduced D125 bioconversion in vitro. The in vitro assay should provide a valuable tool for prescreening candidate TAP anti-wear additives, identifying safer additives and reducing the number of animals required for in vivo toxicity testing. PMID:23085349

Identifying safer anti-wear triaryl phosphate additives for jet engine lubricants.

PubMed

Baker, Paul E; Cole, Toby B; Cartwright, Megan; Suzuki, Stephanie M; Thummel, Kenneth E; Lin, Yvonne S; Co, Aila L; Rettie, Allan E; Kim, Jerry H; Furlong, Clement E

2013-03-25

Individuals aboard jet aircraft may be exposed to potentially toxic triaryl organophosphate anti-wear lubricant additives (TAPs) that are converted by cytochromes P450 into toxic metabolites. Consequences of exposure could be reduced by using less toxic TAPs. Our goal was to determine whether an in vitro assay for inhibition of butyrylcholinesterase (BChE) by bioactivated TAPs would be predictive of inhibition of serine active-site enzymes in vivo. The in vitro assay involved TAP bioactivation with liver microsomes and NADPH, followed by incubation with human BChE and measurement of BChE activity. Of 19 TAPs tested, tert-butylated isomers produced the least BChE inhibition. To determine the relevance of these results in vivo, mice were exposed to Durad 125 (D125; a commercial mixture of TAP esters) or to TAPs demonstrating low or no BChE inhibition when assayed in vitro. Inhibition of BChE by bioactivated TAPs in vitro correlated well with inhibition of other serine active-site enzymes in vivo, with the exception of brain acetylcholinesterase and neuropathy target esterase (NTE), which were not inhibited by any TAP tested following single exposures. A recombinant catalytic domain of NTE (rNEST) exhibited classical kinetic properties of NTE. The metabolite of tri-(o-cresyl) phosphate (ToCP), 2-(o-cresyl)-4H-1,3,2-benzodioxaphosphoran-2-one (CBDP), inhibited rNEST in vitro, but with an IC(50) value almost 6-times higher than for inhibition of BChE. Physiologically-relevant concentrations of the flavonoid naringenin dramatically reduced D125 bioconversion in vitro. The in vitro assay should provide a valuable tool for prescreening candidate TAP anti-wear additives, identifying safer additives and reducing the number of animals required for in vivo toxicity testing. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Cell-Based Small-Molecule Compound Screen Identifies Fenretinide as Potential Therapeutic for Translocation-Positive Rhabdomyosarcoma

PubMed Central

Herrero Martín, David; Boro, Aleksandar; Schäfer, Beat W.

2013-01-01

A subset of paediatric sarcomas are characterized by chromosomal translocations encoding specific oncogenic transcription factors. Such fusion proteins represent tumor specific therapeutic targets although so far it has not been possible to directly inhibit their activity by small-molecule compounds. In this study, we hypothesized that screening a small-molecule library might identify already existing drugs that are able to modulate the transcriptional activity of PAX3/FOXO1, the fusion protein specifically found in the pediatric tumor alveolar rhabdomyosarcoma (aRMS). Towards this end, we established a reporter cell line based on the well characterized PAX3/FOXO1 target gene AP2ß. A library enriched in mostly FDA approved drugs was screened using specific luciferase activity as read-out and normalized for cell viability. The most effective inhibitor identified from this screen was Fenretinide. Treatment with this compound resulted in down-regulation of PAX3/FOXO1 mRNA and protein levels as well as in reduced expression of several of its direct target genes, but not of wild-type FOXO1, in a dose- and time-dependent manner. Moreover, fenretinide induced reactive oxygen species and apoptosis as shown by caspase 9 and PARP cleavage and upregulated miR-9. Importantly, it demonstrated a significant anti-tumor effect in vivo. These results are similar to earlier reports for two other pediatric tumors, namely neuroblastoma and Ewing sarcoma, where fenretinide is under clinical development. Our results suggest that fenretinide might represent a novel treatment option also for translocation-positive rhabdomyosarcoma. PMID:23372815

Evaluation of scoring models for identifying the need for therapeutic intervention of upper gastrointestinal bleeding: A new prediction score model for Japanese patients.

PubMed

Iino, Chikara; Mikami, Tatsuya; Igarashi, Takasato; Aihara, Tomoyuki; Ishii, Kentaro; Sakamoto, Jyuichi; Tono, Hiroshi; Fukuda, Shinsaku

2016-11-01

Multiple scoring systems have been developed to predict outcomes in patients with upper gastrointestinal bleeding. We determined how well these and a newly established scoring model predict the need for therapeutic intervention, excluding transfusion, in Japanese patients with upper gastrointestinal bleeding. We reviewed data from 212 consecutive patients with upper gastrointestinal bleeding. Patients requiring endoscopic intervention, operation, or interventional radiology were allocated to the therapeutic intervention group. Firstly, we compared areas under the curve for the Glasgow-Blatchford, Clinical Rockall, and AIMS65 scores. Secondly, the scores and factors likely associated with upper gastrointestinal bleeding were analyzed with a logistic regression analysis to form a new scoring model. Thirdly, the new model and the existing model were investigated to evaluate their usefulness. Therapeutic intervention was required in 109 patients (51.4%). The Glasgow-Blatchford score was superior to both the Clinical Rockall and AIMS65 scores for predicting therapeutic intervention need (area under the curve, 0.75 [95% confidence interval, 0.69-0.81] vs 0.53 [0.46-0.61] and 0.52 [0.44-0.60], respectively). Multivariate logistic regression analysis retained seven significant predictors in the model: systolic blood pressure <100 mmHg, syncope, hematemesis, hemoglobin <10 g/dL, blood urea nitrogen ≥22.4 mg/dL, estimated glomerular filtration rate ≤ 60 mL/min per 1.73 m 2 , and antiplatelet medication. Based on these variables, we established a new scoring model with superior discrimination to those of existing scoring systems (area under the curve, 0.85 [0.80-0.90]). We developed a superior scoring model for identifying therapeutic intervention need in Japanese patients with upper gastrointestinal bleeding. © 2016 Japan Gastroenterological Endoscopy Society.

"Difficult" Colorectal Polyps - Therapeutic Approach.

PubMed

Alecu, M; Simion, L; Ionescu, S; Brătucu, E; Straja, N D

2015-01-01

Endoscopic polypectomy is the gold standard in the treatment of colorectal polyps. The importance of polypectomy rests primarily on the fact that polyp-type lesions present a high risk of malignant degeneration, colorectal polyps being able, if left unattended therapeutically, to generate a colorectal cancer (CRC) - a lesion with a far more negative prognosis. Although preferable, endoscopic polypectomy of colorectal polyps is not always possible, multiple factors generating difficulties in performing this therapeutic measure. We performed a retrospective study in the First Surgical Clinic of the "Prof. Dr. Alexandu Trestioreanu" Bucharest Oncology Institute, spanning a period of 3 years (2008-2011), in which time 224 patients were diagnosed by colonoscopy with colorectal polyps, of whom 222 patients benefited from endoscopic polypectomy. The aim of the study was to identify "difficult" polyps and to identify the criteria for endoscopic surgery versus classic surgery as a therapeutic indication. Presence of "difficult" polyps was observed in 37.56% of the patients diagnosed with colorectal polyps. In over 88% of cases endoscopic polypectomy was possible, and for the remaining patients classic surgery was the therapeutic solution opted for. Presence of "difficult" polyps generates inconveniences in performing endoscopic polypectomy, increasing the risk of postoperative complication occurrence, as well as the duration of the operation. If the criteria for characterizing polyps as "difficult" are relatively well-established, the choice between endoscopic and classic surgery as a therapeutic measure is left at the free will of the operating surgeon, with the exception of situations in which classic surgery is resorted to for oncological reasons. Celsius.

Additional lesions detected in therapeutic scans with 177Lu-DOTATATE reflect higher affinity of 177Lu-DOTATATE for somatostatin receptors.

PubMed

Mirzaei, Siroos; Bastati, Brigitte; Lipp, Rainer W; Knoll, Peter; Zojer, Niklas; Ludwig, Heinz

2011-01-01

Peptide receptor-targeted radionuclide therapy (PRRT) of somatostatin receptor (SR)-expressing neuroendocrine tumors (NETs) has become an established therapeutic option in patients with advanced NETs. The aim of this study was to compare the lesion detection rate of (99m)Tc-EDDA/HYNIC-TOC, a newly developed tracer for NET imaging, with (177)Lu-DOTATATE used for PRRT. 8 patients (4 women, 4 men, age range 46-76 years) with histologically proven NETs, who showed high SR loads by (99m)Tc-EDDA/HYNIC-TOC scintigraphy, were treated with (177)Lu-DOTATATE. After treatment, all patients were subjected to whole-body scintigraphy with additional low-dose single-photon emission computed tomography (SPECT-CT) of the chest and abdomen. All patients demonstrated (177)Lu-DOTATATE accumulation in all lesions previously detected by (99m)Tc- EDDA/HYNIC-TOC scintigraphy. Three patients showed additional lesions in the liver and lungs. SPECT-CT after (177)Lu-DOTATATE therapy may be helpful in detecting additional lesions not seen using (99m)Tc-EDDA/HYNIC-TOC. This could reflect the broader affinity of (177)Lu-DOTATATE for SRs compared with (99m)Tc-EDDA/HYNIC-TOC. Copyright © 2011 S. Karger AG, Basel.

Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.

PubMed

Dey-Rao, Rama; Sinha, Animesh A

2017-01-28

Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address

The Diagnostic/Therapeutic Preabortion Interview.

ERIC Educational Resources Information Center

Boekelheide, Priscilla Day

1978-01-01

The therapeutic and diagnostic aspect of the preabortion interview are discussed with attention to specifics that will identify students with the greatest likelihood for psychological problems and/or repeat abortions. (JD)

Podocytes from the diagnostic and therapeutic point of view.

PubMed

Müller-Deile, Janina; Schiffer, Mario

2017-08-01

The central role of podocytes in glomerular diseases makes this cell type an interesting diagnostic tool as well as a therapeutic target. In this review, we discuss the current literature on the use of podocytes and podocyte-specific markers as non-invasive diagnostic tools in different glomerulopathies. Furthermore, we highlight the direct effects of drugs currently used to treat primary glomerular diseases and describe their direct cellular effects on podocytes. A new therapeutic potential is seen in drugs targeting the podocytic actin cytoskeleton which is essential for podocyte foot process structure and function. Incubation of cultured human podocyte cell lines with sera from patients with active glomerular diseases is currently also used to identify novel circulating factors with pathophysiological relevance for the glomerular filtration barrier. In addition, treatment of detached urinary podocytes from patients with substances that restore their cytoskeleton might serve as a novel personalized tool to estimate their potential for podocyte recovery ex vivo.

Modifications of Glycans: Biological Significance and Therapeutic Opportunities

PubMed Central

Muthana, Saddam M.; Campbell, Christopher; Gildersleeve, Jeffrey C.

2012-01-01

Carbohydrates play a central role in a wide range of biological processes. As with nucleic acids and proteins, modifications of specific sites within the glycan chain can modulate a carbohydrate’s overall biological function. For example, acylation, methylation, sulfation, epimerization, and phosphorylation can occur at various positions within a carbohydrate to modulate bioactivity. Therefore, there is significant interest in identifying discrete carbohydrate modifications and understanding their biological effects. Additionally, enzymes that catalyze those modifications and proteins that bind modified glycans provide numerous targets for therapeutic intervention. This review will focus on modifications of glycans that occur after the oligomer/polymer has been assembled, generally referred to as postglycosylational modifications. PMID:22195988

Combating Multidrug-Resistant Pathogens with Host-Directed Nonantibiotic Therapeutics.

PubMed

Andersson, Jourdan A; Sha, Jian; Kirtley, Michelle L; Reyes, Emily; Fitts, Eric C; Dann, Sara M; Chopra, Ashok K

2018-01-01

Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral Clostridium difficile infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with Klebsiella pneumoniae when it was administered at the time of infection or at 24 h postinfection. Using the same in vitro cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against K. pneumoniae For Acinetobacter baumannii , 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new

ACHIEVING THE PROMISE OF THERAPEUTIC EXTRACELLULAR VESICLES: THE DEVIL IS IN DETAILS OF THERAPEUTIC LOADING

PubMed Central

Sutaria, Dhruvitkumar S.; Badawi, Mohamed; Phelps, Mitch A.; Schmittgen, Thomas D.

2017-01-01

Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics. PMID:28315083

Therapeutic touch and post-Hurricane Hugo stress.

PubMed

Olson, M; Sneed, N; Bonadonna, R; Ratliff, J; Dias, J

1992-06-01

This repeated-session design sought to answer questions about the effectiveness of therapeutic touch in reduction of stress for 23 individuals following a natural disaster. In addition, methodological issues related to the average length of time for a therapeutic-touch treatment and a method of documenting the nonverbal interaction between subject and toucher were investigated. Findings indicate that stressed people report themselves to be less stressed following therapeutic touch (p = .05). Time of therapeutic-touch intervention varied significantly between the touchers, with a range of 6.8 to 20 minutes. Qualitative data examining the interaction of toucher and subject raised a number of questions that require further study.

[Therapeutic touch and anorexia nervosa].

PubMed

Satori, Nadine

2016-01-01

An innovative practice, therapeutic touch has been used for around ten years in the treatment of eating disorders. Delivered by nurse clinicians having received specific training, this approach is based on nursing diagnoses which identify the major symptoms of this pathology. The support is built around the body and its perceptions. Through the helping relationship, it mobilises the patient's resources to favour a relationship of trust, a letting-go, physical, psychological and emotional relaxation, and improves the therapeutic alliance. Copyright © 2016. Published by Elsevier Masson SAS.

In vivo therapeutic potential of Dicer-hunting siRNAs targeting infectious hepatitis C virus.

PubMed

Watanabe, Tsunamasa; Hatakeyama, Hiroto; Matsuda-Yasui, Chiho; Sato, Yusuke; Sudoh, Masayuki; Takagi, Asako; Hirata, Yuichi; Ohtsuki, Takahiro; Arai, Masaaki; Inoue, Kazuaki; Harashima, Hideyoshi; Kohara, Michinori

2014-04-23

The development of RNA interference (RNAi)-based therapy faces two major obstacles: selecting small interfering RNA (siRNA) sequences with strong activity, and identifying a carrier that allows efficient delivery to target organs. Additionally, conservative region at nucleotide level must be targeted for RNAi in applying to virus because hepatitis C virus (HCV) could escape from therapeutic pressure with genome mutations. In vitro preparation of Dicer-generated siRNAs targeting a conserved, highly ordered HCV 5' untranslated region are capable of inducing strong RNAi activity. By dissecting the 5'-end of an RNAi-mediated cleavage site in the HCV genome, we identified potent siRNA sequences, which we designate as Dicer-hunting siRNAs (dh-siRNAs). Furthermore, formulation of the dh-siRNAs in an optimized multifunctional envelope-type nano device inhibited ongoing infectious HCV replication in human hepatocytes in vivo. Our efforts using both identification of optimal siRNA sequences and delivery to human hepatocytes suggest therapeutic potential of siRNA for a virus.

Recent developments in emerging therapeutic targets of osteoarthritis.

PubMed

Sun, Margaret Man-Ger; Beier, Frank; Pest, Michael A

2017-01-01

Despite the tremendous individual suffering and socioeconomic burden caused by osteoarthritis, there are currently no effective disease-modifying treatment options. This is in part because of our incomplete understanding of osteoarthritis disease mechanism. This review summarizes recent developments in therapeutic targets identified from surgical animal models of osteoarthritis that provide novel insight into osteoarthritis pathology and possess potential for progression into preclinical studies. Several candidate pathways and processes that have been identified include chondrocyte autophagy, growth factor signaling, inflammation, and nociceptive signaling. Major strategies that possess therapeutic potential at the cellular level include inhibiting autophagy suppression and decreasing reactive oxygen species (ROS) production. Cartilage anabolism and prevention of cartilage degradation has been shown to result from growth factor signaling modulation, such as TGF-β, TGF-α, and FGF; however, the results are context-dependent and require further investigation. Pain assessment studies in rodent surgical models have demonstrated potential in employing anti-NGF strategies for minimizing osteoarthritis-associated pain. Studies of potential therapeutic targets in osteoarthritis using animal surgical models are helping to elucidate osteoarthritis pathology and propel therapeutics development. Further studies should continue to elucidate pathological mechanisms and therapeutic targets in various joint tissues to improve overall joint health.

Reflection of a therapeutic touch experience: case study 2.

PubMed

Green, C A

1998-02-01

The purpose of this case study was to explore the experience of both giving and receiving Therapeutic Touch. A subjective account of the Therapeutic Touch experience is given in an attempt to throw light on its unique creative and therapeutic qualities. In most instances it was shown that the experience of both giving and receiving Therapeutic Touch was a parallel experience. This case study explores the effects of Therapeutic Touch on a client experiencing pain and associated anxiety. Whilst a response to treatment was observed, the need for further case studies and research studies in this area was identified.

Therapeutic enhancement: nursing intervention category for patients diagnosed with Readiness for Therapeutic Regimen Management.

PubMed

Kelly, Cynthia W

2008-04-01

To present a new nursing intervention category called therapeutic enhancement. Fewer than half of North Americans follow their physician's recommendations for diet and exercise, even when such are crucial to their health or recovery. It is imperative that nurses consider new ways to promote healthy behaviours. Therapeutic enhancement is intended to provide such a fresh approach. Traditional intervention techniques focusing on education, contracts, social support and more frequent interaction with physicians appear not to be effective when used alone. Successful strategies have been multidisciplinary; and have included interventions by professional nurses who assist patients to understand their disease and the disease process and that helps them to develop disease-management and self-management skills. Therapeutic enhancement incorporates The Stages of Change Theory, Commitment to Health Theory, Motivational Interviewing techniques and instrumentation specifically designed for process evaluation of health-promoting interventions. This is a critical review of approaches that, heretofore, have not been synthesised in a single published article. Based on the commonly used Stages of Change model, therapeutic enhancement is useful for patients who are at the action stage of change. Using therapeutic enhancement as well as therapeutic strategies identified in Stages of Change Theory, such as contingency management, helping relationships, counterconditioning, stimulus control and Motivational Interviewing techniques, nursing professionals can significantly increase the chances of patients moving from action to the maintenance stage of change for a specific health behaviour. Using the nursing intervention category, therapeutic enhancement can increase caregivers' success in helping patients maintain healthy behaviours.

Colon Cancer Biomarkers To Identify Patients Suitable For Therapeutic Intervention | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute's Laboratory of Human Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cancer biomarkers and therapeutic targets.

Gene expression-based chemical genomics identifies potential therapeutic drugs in hepatocellular carcinoma.

PubMed

Chen, Ming-Huang; Yang, Wu-Lung R; Lin, Kuan-Ting; Liu, Chia-Hung; Liu, Yu-Wen; Huang, Kai-Wen; Chang, Peter Mu-Hsin; Lai, Jin-Mei; Hsu, Chun-Nan; Chao, Kun-Mao; Kao, Cheng-Yan; Huang, Chi-Ying F

2011-01-01

Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Currently, only sorafenib is approved by the FDA for advanced HCC treatment; therefore, there is an urgent need to discover candidate therapeutic drugs for HCC. We hypothesized that if a drug signature could reverse, at least in part, the gene expression signature of HCC, it might have the potential to inhibit HCC-related pathways and thereby treat HCC. To test this hypothesis, we first built an integrative platform, the "Encyclopedia of Hepatocellular Carcinoma genes Online 2", dubbed EHCO2, to systematically collect, organize and compare the publicly available data from HCC studies. The resulting collection includes a total of 4,020 genes. To systematically query the Connectivity Map (CMap), which includes 6,100 drug-mediated expression profiles, we further designed various gene signature selection and enrichment methods, including a randomization technique, majority vote, and clique analysis. Subsequently, 28 out of 50 prioritized drugs, including tanespimycin, trichostatin A, thioguanosine, and several anti-psychotic drugs with anti-tumor activities, were validated via MTT cell viability assays and clonogenic assays in HCC cell lines. To accelerate their future clinical use, possibly through drug-repurposing, we selected two well-established drugs to test in mice, chlorpromazine and trifluoperazine. Both drugs inhibited orthotopic liver tumor growth. In conclusion, we successfully discovered and validated existing drugs for potential HCC therapeutic use with the pipeline of Connectivity Map analysis and lab verification, thereby suggesting the usefulness of this procedure to accelerate drug repurposing for HCC treatment.

Conformational stability and aggregation of therapeutic monoclonal antibodies studied with ANS and Thioflavin T binding.

PubMed

Kayser, Veysel; Chennamsetty, Naresh; Voynov, Vladimir; Helk, Bernhard; Trout, Bernhardt L

2011-01-01

Characterization of aggregation profiles of monoclonal antibodies (mAb) is gaining importance because an increasing number of mAb-based therapeutics are entering clinical studies and gaining marketing approval. To develop a successful formulation, it is imperative to identify the critical biochemical properties of each potential mAb drug candidate. We investigated the conformational change and aggregation of a human IgG1 using external dye-binding experiments with fluorescence spectroscopy and compared the aggregation profiles obtained to the results of size-exclusion chromatography. We show that using an appropriate dye at selected mAb concentration, unfolding or aggregation can be studied. In addition, dye-binding experiments may be used as conventional assays to study therapeutic mAb stability.

Curcumin Nanomedicine: A Road to Cancer Therapeutics

PubMed Central

Yallapu, Murali M.; Jaggi, Meena; Chauhan, Subhash C.

2013-01-01

Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemo-preventive, chemo- and radio-sensitization properties. Curcumin’s widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin’s limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics. PMID:23116309

Therapeutic approaches for celiac disease

PubMed Central

Plugis, Nicholas M.; Khosla, Chaitan

2015-01-01

Celiac disease is a common, lifelong autoimmune disorder for which dietary control is the only accepted form of therapy. A strict gluten-free diet is burdensome to patients and can be limited in efficacy, indicating there is an unmet need for novel therapeutic approaches to supplement or supplant dietary therapy. Many molecular events required for disease pathogenesis have been recently characterized and inspire most current and emerging drug-discovery efforts. Genome-wide association studies (GWAS) confirm the importance of human leukocyte antigen genes in our pathogenic model and identify a number of new risk loci in this complex disease. Here, we review the status of both emerging and potential therapeutic strategies in the context of disease pathophysiology. We conclude with a discussion of how genes identified during GWAS and follow-up studies that enhance susceptibility may offer insight into developing novel therapies. PMID:26060114

Anti-infective therapeutics from the Lepidopteran model host Galleria mellonella.

PubMed

Vilcinskas, Andreas

2011-01-01

The larvae of the greater wax moth Galleria mellonella prosper in use both as surrogate alternative model hosts for human pathogens and as a whole-animal-high-throughput-system for in vivo testing of antibiotics or mutant-libraries of pathogens. In addition, a broad spectrum of antimicrobial peptides and proteins has been identified in this insect during past decade among which some appear to be specific for Lepidoptera. Its arsenal of immunity-related effector molecules encompasses peptides and proteins exhibiting potent activity against bacteria, fungi or both, whose potential as new anti-infective therapeutics are presently being explored. Of particular interest is the insect metalloproteinase inhibitor (IMPI) which has been discovered in G. mellonella. The IMPI exhibits a specific and potent activity against thermolysin-like microbial metalloproteinases including a number of prominent virulence and/or pathogenic factors of human pathogens which are responsible for severe symptoms such as septicemia, hemorrhagic tissue bleeding, necrosis and enhancement of vascular permeability. The IMPI and antimicrobial peptides from G. mellonella may provide promising templates for the rational design of new drugs since evidence is available that the combination of antibiotics with inhibitors of pathogen-associated proteolytic enzymes yields synergistic therapeutic effects. The potential and limitations of insect-derived gene-encoded antimicrobial compounds as anti-infective therapeutics are discussed.

Are Mammographically Occult Additional Tumors Identified More Than 2 Cm Away From the Primary Breast Cancer on MRI Clinically Significant?

PubMed

Goodman, Sarah; Mango, Victoria; Friedlander, Lauren; Desperito, Elise; Wynn, Ralph; Ha, Richard

2018-06-08

To evaluate the clinical significance of mammographically occult additional tumors identified more than 2cm away from the primary breast cancer on preoperative magnetic resonance imaging (MRI). An Institutional Review Board approved review of consecutive preoperative breast MRIs performed from 1/1/08 to 12/31/14, yielded 667 patients with breast cancer. These patients underwent further assessment to identify biopsy proven mammographically occult breast tumors located more than 2cm away from the edge of the primary tumor. Additional MRI characteristics of the primary and secondary tumors and pathology were reviewed. Statistical analysis was performed using SPSS (v. 24). Of 667 patients with breast cancer, 129 patients had 150 additional ipsilateral mammographically occult tumors that were more than 2cm away from the edge of the primary tumor. One hundred twelve of 129 (86.8%) patients had one additional tumor and 17/129 (13.2%) had two or more additional tumors. In 71/129 (55.0%), additional tumors were located in a different quadrant and in 58/129 (45.0%) additional tumors were in the same quadrant but ≥2cm away. Overall, primary tumor size was significantly larger (mean 1.87± 1.25 cm) than the additional tumors (mean 0.79 ± 0.61cm, p < 0.001). However, in 20/129 (15.5%) the additional tumor was larger and in 26/129 (20.2%) the additional tumor was ≥1cm. The primary tumor was significantly more likely to be invasive (81.4%, 105/129) compared to additional tumors (70%, 105/150, p = 0.03). In 9/129 (7.0%) patients, additional tumors yielded unsuspected invasive cancer orhigher tumor grade. The additional tumor was more likely to be nonmass lesion type (37.3% vs 24% p = 0.02) and focus lesion type (10% vs 0.08%, p < 0.001) compared to primary tumor. Mammographically occult additional tumors identified more than 2cm away from the primary breast tumor on MRI are unlikely to be surgically treated if undiagnosed and may be clinically significant. Copyright �

Evaluation of genotoxicity testing of FDA approved large molecule therapeutics.

PubMed

Sawant, Satin G; Fielden, Mark R; Black, Kurt A

2014-10-01

Large molecule therapeutics (MW>1000daltons) are not expected to enter the cell and thus have reduced potential to interact directly with DNA or related physiological processes. Genotoxicity studies are therefore not relevant and typically not required for large molecule therapeutic candidates. Regulatory guidance supports this approach; however there are examples of marketed large molecule therapeutics where sponsors have conducted genotoxicity studies. A retrospective analysis was performed on genotoxicity studies of United States FDA approved large molecule therapeutics since 1998 identified through the Drugs@FDA website. This information was used to provide a data-driven rationale for genotoxicity evaluations of large molecule therapeutics. Fifty-three of the 99 therapeutics identified were tested for genotoxic potential. None of the therapeutics tested showed a positive outcome in any study except the peptide glucagon (GlucaGen®) showing equivocal in vitro results, as stated in the product labeling. Scientific rationale and data from this review indicate that testing of a majority of large molecule modalities do not add value to risk assessment and support current regulatory guidance. Similarly, the data do not support testing of peptides containing only natural amino acids. Peptides containing non-natural amino acids and small molecules in conjugated products may need to be tested. Copyright © 2014 Elsevier Inc. All rights reserved.

Therapeutic touch for anxiety disorders.

PubMed

Robinson, J; Biley, F C; Dolk, H

2007-07-18

Anxiety disorders are a common occurrence in today's society. There is interest from the community in the use of complementary therapies for anxiety disorders. This review examined the currently available evidence supporting the use of therapeutic touch in treating anxiety disorders. To examine the efficacy and adverse effects of therapeutic touch for anxiety disorders. We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References) (search date 13/01/06), the Controlled Trials website and Dissertation Abstracts International. Searches of reference lists of retrieved papers were also carried out and experts in the field were contacted. Inclusion criteria included all published and unpublished randomised and quasi-randomised controlled trials comparing therapeutic touch with sham (mimic) TT, pharmacological therapy, psychological treatment, other treatment or no treatment /waiting list. The participants included adults with an anxiety disorder defined by the Diagnostic and Statistical Manual (DSM-IV),the International Classification of Diseases (ICD-10), validated diagnostic instruments, or other validated clinician or self-report instruments. Two review authors independently applied inclusion criteria. Further information was sought from trialists where papers contained insufficient information to make a decision about eligibility. No randomised or quasi-randomised controlled trials of therapeutic touch for anxiety disorders were identified. Given the high prevalence of anxiety disorders and the current paucity of evidence on therapeutic touch in this population, there is a need for well conducted randomised controlled trials to examine the effectiveness of therapeutic touch for anxiety disorders.

An integrated molecular analysis of lung adenocarcinomas identifies potential therapeutic targets among TTF1-negative tumors including DNA repair proteins and Nrf2

PubMed Central

Cardnell, Robert J.G.; Behrens, Carmen; Diao, Lixia; Fan, YouHong; Tang, Ximing; Tong, Pan; John D., Minna; Mills, Gordon B.; Heymach, John V.; Wistuba, Ignacio I.; Wang, Jing; Byers., Lauren A.

2015-01-01

Purpose Thyroid transcription factor-1 (TTF1) immunohistochemistry (IHC) is used clinically to differentiate primary lung adenocarcinomas (LUAD) from squamous lung cancers and metastatic adenocarcinomas from other primary sites. However, a subset of LUAD (15-20%) does not express TTF1 and TTF1-negative patients have worse clinical outcomes. As there are no established targeted agents with activity in TTF1-negative LUAD, we performed an integrated molecular analysis to identify potential therapeutic targets. Experimental Design Using two clinical LUAD cohorts (274 tumors), one from our institution (PROSPECT) and the TCGA, we interrogated proteomic profiles (by reverse-phase protein array (RPPA)), gene expression, and mutational data. Drug response data from 74 cell lines were used to validate potential therapeutic agents. Results Strong correlations were observed between TTF1 IHC and TTF1 measurements by RPPA (Rho=0.57, p<0.001) and gene expression (NKX2-1, Rho=0.61, p<0.001). Established driver mutations (e.g. BRAF and EGFR) were associated with high TTF1 expression. In contrast, TTF1-negative LUAD had a higher frequency of inactivating KEAP1 mutations (p=0.001). Proteomic profiling identified increased expression of DNA repair proteins (e.g., Chk1 and the DNA repair score) and suppressed PI3K/MAPK signaling among TTF1-negative tumors, with differences in total proteins confirmed at the mRNA level. Cell line analysis showed drugs targeting DNA repair to be more active in TTF1-low cell lines. Conclusions Combined genomic and proteomic analyses demonstrated infrequent alteration of validated lung cancer targets (including the absence of BRAF mutations in TTF1-negative LUAD), but identified novel potential targets for TTF1-negative LUAD includingKEAP1/Nrf2 and DNA repair pathways. PMID:25878335

Marketing therapeutic recreation services.

PubMed

Thorn, B E

1984-01-01

The use of marketing strategies can enhance the delivery of therapeutic recreation services. This article discusses how agencies can adapt marketing techniques and use them to identify potential markets, improve image, evaluate external pressures, and maximize internal strengths. Four variables that can be controlled and manipulated in a proposed marketing plan are product, price, place and promotion.

The effects of therapeutic touch on pain.

PubMed

Monroe, Carolyn Magdalen

2009-06-01

To better understand how Therapeutic Touch can be used in today's health care arena, this integrative literature review will examine current research that will help answer the question, Does Therapeutic Touch reduce pain? An extensive search was conducted of the online databases MEDLINE, CINAHL, Cochrane Library, EMBASE, PsychLIT, and PubMed to retrieve research articles published from 1997 to 2007. Seven studies that were conducted between 1997 and 2004 were found and only five of the seven were included as pertinent evidence to answer the question. All of the research that was reviewed to answer whether Therapeutic Touch could significantly reduce pain revealed a majority of statistically significant positive results for implementing this intervention. Because there are no identified risks to Therapeutic Touch as a pain relief measure, it is safe to recommend despite the limitations of current research. Therapeutic Touch should be considered among the many possible nursing interventions for the treatment of pain.

Identifiability of Additive Actuator and Sensor Faults by State Augmentation

NASA Technical Reports Server (NTRS)

Joshi, Suresh; Gonzalez, Oscar R.; Upchurch, Jason M.

2014-01-01

A class of fault detection and identification (FDI) methods for bias-type actuator and sensor faults is explored in detail from the point of view of fault identifiability. The methods use state augmentation along with banks of Kalman-Bucy filters for fault detection, fault pattern determination, and fault value estimation. A complete characterization of conditions for identifiability of bias-type actuator faults, sensor faults, and simultaneous actuator and sensor faults is presented. It is shown that FDI of simultaneous actuator and sensor faults is not possible using these methods when all sensors have unknown biases. The fault identifiability conditions are demonstrated via numerical examples. The analytical and numerical results indicate that caution must be exercised to ensure fault identifiability for different fault patterns when using such methods.

The IGF-1 Receptor Identifies a Pool of Human Cardiac Stem Cells with Superior Therapeutic Potential for Myocardial Regeneration

PubMed Central

D’Amario, Domenico; Cabral-Da-Silva, Mauricio; Zheng, Hanqiao; Fiorini, Claudia; Goichberg, Polina; Steadman, Elisabeth; Ferreira-Martins, João; Sanada, Fumihiro; Piccoli, Marco; Cappetta, Donato; D’Alessandro, David A.; Michler, Robert E.; Hosoda, Toru; Anastasia, Luigi; Rota, Marcello; Leri, Annarosa; Anversa, Piero; Kajstura, Jan

2012-01-01

Rationale Age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart. Objective Insulin-like growth factor 1 (IGF-1) and 2 (IGF-2), and angiotensin II (Ang II) and their receptors, IGF-1R, IGF-2R and AT1R, were characterized in c-kit-positive-hCSCs to establish whether these systems would allow us to separate hCSC classes with different growth reserve in the aging and diseased myocardium. Methods and Results C-kit-positive-hCSCs were collected from myocardial samples obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac surgery for coronary artery disease. The expression of IGF-1R in hCSCs recognized a young cell phenotype defined by long telomeres, high telomerase activity, enhanced cell proliferation and attenuated apoptosis. In addition to IGF-1, IGF-1R-positive-hCSCs secreted IGF-2 that promoted myocyte differentiation. Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, identified senescent hCSCs with impaired growth reserve and increased susceptibility to apoptosis. The ability of IGF-1R-positive-hCSCs to regenerate infarcted myocardium was then compared with that of unselected c-kit-positive-hCSCs. IGF-1R-positive-hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of IGF-1R-positive-hCSCs with IGF-2 resulted in the formation of more mature myocytes and superior recovery of ventricular structure. Conclusions hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which are potent modulators of stem cell replication, commitment to the myocyte lineage and myocyte differentiation, pointing to this hCSC subset as the ideal candidate cell for the management of human heart failure. PMID:21546606

A web-based resource for designing therapeutics against Ebola Virus.

PubMed

Dhanda, Sandeep Kumar; Chaudhary, Kumardeep; Gupta, Sudheer; Brahmachari, Samir Kumar; Raghava, Gajendra P S

2016-04-26

In this study, we describe a web-based resource, developed for assisting the scientific community in designing an effective therapeutics against the Ebola virus. Firstly, we predicted and identified experimentally validated epitopes in each of the antigens/proteins of the five known ebolaviruses. Secondly, we generated all the possible overlapping 9mer peptides from the proteins of ebolaviruses. Thirdly, conserved peptides across all the five ebolaviruses (four human pathogenic species) with no identical sequence in the human proteome, based on 1000 Genomes project, were identified. Finally, we identified peptide or epitope-based vaccine candidates that could activate both the B- and T-cell arms of the immune system. In addition, we also identified efficacious siRNAs against the mRNA transcriptome (absent in human transcriptome) of all the five ebolaviruses. It was observed that three species can potentially be targeted by a single siRNA (19mer) and 75 siRNAs can potentially target at least two species. A web server, EbolaVCR, has been developed that incorporates all the above information and useful computational tools (http://crdd.osdd.net/oscadd/ebola/).

A web-based resource for designing therapeutics against Ebola Virus

NASA Astrophysics Data System (ADS)

Dhanda, Sandeep Kumar; Chaudhary, Kumardeep; Gupta, Sudheer; Brahmachari, Samir Kumar; Raghava, Gajendra P. S.

2016-04-01

In this study, we describe a web-based resource, developed for assisting the scientific community in designing an effective therapeutics against the Ebola virus. Firstly, we predicted and identified experimentally validated epitopes in each of the antigens/proteins of the five known ebolaviruses. Secondly, we generated all the possible overlapping 9mer peptides from the proteins of ebolaviruses. Thirdly, conserved peptides across all the five ebolaviruses (four human pathogenic species) with no identical sequence in the human proteome, based on 1000 Genomes project, were identified. Finally, we identified peptide or epitope-based vaccine candidates that could activate both the B- and T-cell arms of the immune system. In addition, we also identified efficacious siRNAs against the mRNA transcriptome (absent in human transcriptome) of all the five ebolaviruses. It was observed that three species can potentially be targeted by a single siRNA (19mer) and 75 siRNAs can potentially target at least two species. A web server, EbolaVCR, has been developed that incorporates all the above information and useful computational tools (http://crdd.osdd.net/oscadd/ebola/).

BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations.

PubMed

Markowski, Mark C; De Marzo, Angelo M; Antonarakis, Emmanuel S

2017-12-01

The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review. Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.

A concise review on advances in development of small molecule anti-inflammatory therapeutics emphasising AMPK: An emerging target.

PubMed

Gejjalagere Honnappa, Chethan; Mazhuvancherry Kesavan, Unnikrishnan

2016-12-01

Inflammatory diseases are complex, multi-factorial outcomes of evolutionarily conserved tissue repair processes. For decades, non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors, the primary drugs of choice for the management of inflammatory diseases, addressed individual targets in the arachidonic acid pathway. Unsatisfactory safety and efficacy profiles of the above have necessitated the development of multi-target agents to treat complex inflammatory diseases. Current anti-inflammatory therapies still fall short of clinical needs and the clinical trial results of multi-target therapeutics are anticipated. Additionally, new drug targets are emerging with improved understanding of molecular mechanisms controlling the pathophysiology of inflammation. This review presents an outline of small molecules and drug targets in anti-inflammatory therapeutics with a summary of a newly identified target AMP-activated protein kinase, which constitutes a novel therapeutic pathway in inflammatory pathology. © The Author(s) 2016.

Therapeutic Plasma Transfusion in Bleeding Patients: A Systematic Review.

PubMed

Levy, Jerrold H; Grottke, Oliver; Fries, Dietmar; Kozek-Langenecker, Sibylle

2017-04-01

Plasma products, including fresh frozen plasma, are administered extensively in a variety of settings from massive transfusion to vitamin K antagonist reversal. Despite the widespread use of plasma as a hemostatic agent in bleeding patients, its effect in comparison with other available choices of hemostatic therapies is unclear. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed Central, and databases of ongoing trials for randomized controlled trials that assessed the efficacy and/or safety of therapeutic plasma as an intervention to treat bleeding patients compared with other interventions or placebo. Of 1243 unique publications retrieved in our initial search, no randomized controlled trials were identified. Four nonrandomized studies described the effect of therapeutic plasma in bleeding patients; however, data gathered from these studies did not allow for comparison with other therapeutic interventions primarily as a result of the low number of patients and the use of different (or lack of) comparators. We identified two ongoing trials investigating the efficacy and safety of therapeutic plasma, respectively; however, no data have been released as yet. Although plasma is used extensively in the treatment of bleeding patients, evidence from randomized controlled trials comparing its effect with those of other therapeutic interventions is currently lacking.

Clinically advancing and promising polymer-based therapeutics.

PubMed

Souery, Whitney N; Bishop, Corey J

2018-02-01

In this review article, we will examine the history of polymers and their evolution from provisional World War II materials to medical therapeutics. To provide a comprehensive look at the current state of polymer-based therapeutics, we will classify technologies according to targeted areas of interest, including central nervous system-based and intraocular-, gastrointestinal-, cardiovascular-, dermal-, reproductive-, skeletal-, and neoplastic-based systems. Within each of these areas, we will consider several examples of novel, clinically available polymer-based therapeutics; in addition, this review will also include a discussion of developing therapies, ranging from the in vivo to clinical trial stage, for each targeted area of treatment. Finally, we will emphasize areas of patient care in need of more effective, accessible, and targeted treatment approaches where polymer-based therapeutics may offer potential solutions. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Genotypic variability-based genome-wide association study identifies non-additive loci HLA-C and IL12B for psoriasis.

PubMed

Wei, Wen-Hua; Massey, Jonathan; Worthington, Jane; Barton, Anne; Warren, Richard B

2018-03-01

Genome-wide association studies (GWASs) have identified a number of loci for psoriasis but largely ignored non-additive effects. We report a genotypic variability-based GWAS (vGWAS) that can prioritize non-additive loci without requiring prior knowledge of interaction types or interacting factors in two steps, using a mixed model to partition dichotomous phenotypes into an additive component and non-additive environmental residuals on the liability scale and then the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups genome widely. The vGWAS identified two genome-wide significant (P < 5.0e-08) non-additive loci HLA-C and IL12B that were also genome-wide significant in an accompanying GWAS in the discovery cohort. Both loci were statistically replicated in vGWAS of an independent cohort with a small sample size. HLA-C and IL12B were reported in moderate gene-gene and/or gene-environment interactions in several occasions. We found a moderate interaction with age-of-onset of psoriasis, which was replicated indirectly. The vGWAS also revealed five suggestive loci (P < 6.76e-05) including FUT2 that was associated with psoriasis with environmental aspects triggered by virus infection and/or metabolic factors. Replication and functional investigation are needed to validate the suggestive vGWAS loci.

Therapeutic Plasma Exchange in Critically Ill Children Requiring Intensive Care.

PubMed

Cortina, Gerard; McRae, Rosemary; Chiletti, Roberto; Butt, Warwick

2018-02-01

To characterize the clinical indications, procedural safety, and outcome of critically ill children requiring therapeutic plasma exchange. Retrospective observational study based on a prospective registry. Tertiary and quaternary referral 30-bed PICU. Forty-eight critically ill children who received therapeutic plasma exchange during an 8-year period (2007-2014) were included in the study. Therapeutic plasma exchange. A total of 48 patients underwent 244 therapeutic plasma exchange sessions. Of those, therapeutic plasma exchange was performed as sole procedure in 193 (79%), in combination with continuous renal replacement therapy in 40 (16.4%) and additional extracorporeal membrane oxygenation in 11 (4.6%) sessions. The most common admission diagnoses were hematologic disorders (30%), solid organ transplantation (20%), neurologic disorders (20%), and rheumatologic disorders (15%). Complications associated with the procedure occurred in 50 (21.2%) therapeutic plasma exchange sessions. Overall, patient survival from ICU was 82%. Although patients requiring therapeutic plasma exchange alone (n = 31; 64%) had a survival rate of 97%, those with additional continuous renal replacement therapy (n = 13; 27%) and extracorporeal membrane oxygenation (n = 4; 8%) had survival rates of 69% and 50%, respectively. Factors associated with increased mortality were lower Pediatric Index of Mortality 2 score, need for mechanical ventilation, higher number of failed organs, and longer ICU stay. Our results indicate that, in specialized centers, therapeutic plasma exchange can be performed relatively safely in critically ill children, alone or in combination with continuous renal replacement therapy and extracorporeal membrane oxygenation. Outcome in children requiring therapeutic plasma exchange alone is excellent. However, survival decreases with the number of failed organs and the need for continuous renal replacement therapy and extracorporeal membrane oxygenation.

SATPdb: a database of structurally annotated therapeutic peptides

PubMed Central

Singh, Sandeep; Chaudhary, Kumardeep; Dhanda, Sandeep Kumar; Bhalla, Sherry; Usmani, Salman Sadullah; Gautam, Ankur; Tuknait, Abhishek; Agrawal, Piyush; Mathur, Deepika; Raghava, Gajendra P.S.

2016-01-01

SATPdb (http://crdd.osdd.net/raghava/satpdb/) is a database of structurally annotated therapeutic peptides, curated from 22 public domain peptide databases/datasets including 9 of our own. The current version holds 19192 unique experimentally validated therapeutic peptide sequences having length between 2 and 50 amino acids. It covers peptides having natural, non-natural and modified residues. These peptides were systematically grouped into 10 categories based on their major function or therapeutic property like 1099 anticancer, 10585 antimicrobial, 1642 drug delivery and 1698 antihypertensive peptides. We assigned or annotated structure of these therapeutic peptides using structural databases (Protein Data Bank) and state-of-the-art structure prediction methods like I-TASSER, HHsearch and PEPstrMOD. In addition, SATPdb facilitates users in performing various tasks that include: (i) structure and sequence similarity search, (ii) peptide browsing based on their function and properties, (iii) identification of moonlighting peptides and (iv) searching of peptides having desired structure and therapeutic activities. We hope this database will be useful for researchers working in the field of peptide-based therapeutics. PMID:26527728

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

PubMed Central

Klarenbeek, Alex; Mazouari, Khalil El; Desmyter, Aline; Blanchetot, Christophe; Hultberg, Anna; de Jonge, Natalie; Roovers, Rob C; Cambillau, Christian; Spinelli, Sylvia; Del-Favero, Jurgen; Verrips, Theo; de Haard, Hans J; Achour, Ikbel

2015-01-01

Camelid immunoglobulin variable (IGV) regions were found homologous to their human counterparts; however, the germline V repertoires of camelid heavy and light chains are still incomplete and their therapeutic potential is only beginning to be appreciated. We therefore leveraged the publicly available HTG and WGS databases of Lama pacos and Camelus ferus to retrieve the germline repertoire of V genes using human IGV genes as reference. In addition, we amplified IGKV and IGLV genes to uncover the V germline repertoire of Lama glama and sequenced BAC clones covering part of the Lama pacos IGK and IGL loci. Our in silico analysis showed that camelid counterparts of all human IGKV and IGLV families and most IGHV families could be identified, based on canonical structure and sequence homology. Interestingly, this sequence homology seemed largely restricted to the Ig V genes and was far less apparent in other genes: 6 therapeutically relevant target genes differed significantly from their human orthologs. This contributed to efficient immunization of llamas with the human proteins CD70, MET, interleukin (IL)-1β and IL-6, resulting in large panels of functional antibodies. The in silico predicted human-homologous canonical folds of camelid-derived antibodies were confirmed by X-ray crystallography solving the structure of 2 selected camelid anti-CD70 and anti-MET antibodies. These antibodies showed identical fold combinations as found in the corresponding human germline V families, yielding binding site structures closely similar to those occurring in human antibodies. In conclusion, our results indicate that active immunization of camelids can be a powerful therapeutic antibody platform. PMID:26018625

Clinicopathological characteristics and therapeutic outcomes of synchronous gastric adenocarcinoma and gastric lymphoma.

PubMed

Namikawa, Tsutomu; Munekage, Eri; Fukudome, Ian; Maeda, Hiromichi; Kitagawa, Hiroyuki; Togitani, Kazuto; Takasaki, Motohiro; Yokoyama, Akihito; Kobayashi, Michiya; Hanazaki, Kazuhiro

2014-09-01

Synchronous primary gastric adenocarcinoma and lymphoma is a rare occurrence. The aim of the present retrospective study was to analyze the clinicopathological characteristics and therapeutic outcomes of patients with this rare condition to identify post-therapeutic prognostic factors. A PubMed and MEDLINE search was performed to identify relevant articles, using the keywords 'gastric cancer' and 'gastric malignant lymphoma', while additional articles were obtained from references within these papers. A total of 57 patients who were treated for synchronous primary gastric adenocarcinoma and lymphoma were included in the study. A retrospective review was performed on the clinical characteristics of this disease. The median survival time for patients in this study was 81 months and the overall 1- and 5-year survival rates after therapy were 77.6% and 69.0%, respectively. The median survival period of patients with an advanced gastric cancer was significantly shorter than for early gastric cancer (p<0.001), while the depth of gastric lymphoma invasion did not significantly affect survival time. The median survival period of patients who underwent total gastrectomy was significantly shorter than that of those who underwent distal gastrectomy (p=0.035). Gastric lymphomas were significantly larger than the gastric adenocarcinomas (6.0 vs. 2.7 cm, respectively; p=0.012). The prognosis for synchronous gastric adenocarcinoma and lymphoma might depend more on the behavior of the adenocarcinoma than on the lymphoma, in which case the treatment and therapeutic outcomes could depend on the adenocarcinoma status. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Effective Delivery of Therapeutic Interventions: Findings from Four Site Visits

ERIC Educational Resources Information Center

Atkinson, Cathy; Squires, Garry; Bragg, Joanna; Wasilewski, David; Muscutt, Janet

2013-01-01

This project follows a survey into the role of UK educational psychologists (EPs) in delivering therapeutic interventions to children and young people. Four educational psychology services (EPSs) that identified themselves as providing effective therapeutic practice were selected on the basis of their qualitative responses to the survey. Site…

Recent Progress in Nanomedicine: Therapeutic, Diagnostic and Theranostic Applications

PubMed Central

Rizzo, Larissa Y.; Theek, Benjamin; Storm, Gert; Kiessling, Fabian; Lammers, Twan

2013-01-01

In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-) physiological processes. In addition, ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions. PMID:23578464

Proteases as therapeutics

PubMed Central

Craik, Charles S.; Page, Michael J.; Madison, Edwin L.

2015-01-01

Proteases are an expanding class of drugs that hold great promise. The U.S. FDA (Food and Drug Administration) has approved 12 protease therapies, and a number of next generation or completely new proteases are in clinical development. Although they are a well-recognized class of targets for inhibitors, proteases themselves have not typically been considered as a drug class despite their application in the clinic over the last several decades; initially as plasma fractions and later as purified products. Although the predominant use of proteases has been in treating cardiovascular disease, they are also emerging as useful agents in the treatment of sepsis, digestive disorders, inflammation, cystic fibrosis, retinal disorders, psoriasis and other diseases. In the present review, we outline the history of proteases as therapeutics, provide an overview of their current clinical application, and describe several approaches to improve and expand their clinical application. Undoubtedly, our ability to harness proteolysis for disease treatment will increase with our understanding of protease biology and the molecular mechanisms responsible. New technologies for rationally engineering proteases, as well as improved delivery options, will expand greatly the potential applications of these enzymes. The recognition that proteases are, in fact, an established class of safe and efficacious drugs will stimulate investigation of additional therapeutic applications for these enzymes. Proteases therefore have a bright future as a distinct therapeutic class with diverse clinical applications. PMID:21406063

PIM kinases as therapeutic targets against advanced melanoma

PubMed Central

Shannan, Batool; Watters, Andrea; Chen, Quan; Mollin, Stefan; Dörr, Markus; Meggers, Eric; Xu, Xiaowei; Gimotty, Phyllis A.; Perego, Michela; Li, Ling; Benci, Joseph; Krepler, Clemens; Brafford, Patricia; Zhang, Jie; Wei, Zhi; Zhang, Gao; Liu, Qin; Yin, Xiangfan; Nathanson, Katherine L.; Herlyn, Meenhard; Vultur, Adina

2016-01-01

Therapeutic strategies for the treatment of metastatic melanoma show encouraging results in the clinic; however, not all patients respond equally and tumor resistance still poses a challenge. To identify novel therapeutic targets for melanoma, we screened a panel of structurally diverse organometallic inhibitors against human-derived normal and melanoma cells. We observed that a compound that targets PIM kinases (a family of Ser/Thr kinases) preferentially inhibited melanoma cell proliferation, invasion, and viability in adherent and three-dimensional (3D) melanoma models. Assessment of tumor tissue from melanoma patients showed that PIM kinases are expressed in pre- and post-treatment tumors, suggesting PIM kinases as promising targets in the clinic. Using knockdown studies, we showed that PIM1 contributes to melanoma cell proliferation and tumor growth in vivo; however, the presence of PIM2 and PIM3 could also influence the outcome. The inhibition of all PIM isoforms using SGI-1776 (a clinically-available PIM inhibitor) reduced melanoma proliferation and survival in preclinical models of melanoma. This was potentiated in the presence of the BRAF inhibitor PLX4720 and in the presence of PI3K inhibitors. Our findings suggest that PIM inhibitors provide promising additions to the targeted therapies available to melanoma patients. PMID:27448973

Developing anti-inflammatory therapeutics for patients with osteoarthritis.

PubMed

Philp, Ashleigh M; Davis, Edward T; Jones, Simon W

2017-06-01

OA is the most common joint disorder in the world, but there are no approved therapeutics to prevent disease progression. Historically, OA has been considered a wear-and-tear joint disease, and efforts to identify and develop disease-modifying therapeutics have predominantly focused on direct inhibition of cartilage degeneration. However, there is now increasing evidence that inflammation is a key mediator of OA joint pathology, and also that the link between obesity and OA is not solely due to excessive load-bearing, suggesting therefore that targeting inflammation in OA could be a rewarding therapeutic strategy. In this review we therefore re-evaluate historical clinical trial data on anti-inflammatory therapeutics in OA patients, highlight some of the more promising emerging therapeutic targets and discuss the implications for future clinical trial design. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials

PubMed Central

MacKay, Helen J.; Levine, Douglas A.; Bae-Jump, Victoria L.; Bell, Daphne W.; McAlpine, Jessica N.; Santin, Alessandro; Fleming, Gini F.; Mutch, David G.; Nephew, Kenneth P.; Wentzensen, Nicolas; Goodfellow, Paul J.; Dorigo, Oliver; Nijman, Hans W.; Broaddus, Russell; Kohn, Elise C.

2017-01-01

The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials. PMID:29137450

Challenges of therapeutic substitution of drugs for economic reasons: focus on CVD prevention.

PubMed

Johnston, Atholl

2010-04-01

Healthcare systems throughout the world are under increasing pressure to control and minimise costs. The substitution of initially-prescribed drugs with cheaper equivalents is an obvious option which presents a rapid and visible means to reduce these costs. Whether the substitution improves patient and/or population outcomes must be appraised and this paper highlights the conditions under which therapeutic substitution may require additional thought and consideration. In this paper, some of the medical evidence and the regulatory environment for and against the three types of therapeutic substitution - generic, within-class and between-class - are discussed. This article is not an exhaustive review of the literature, but captures some of the key clinical, pharmacological, economic, policy and ethical issues regarding generic and therapeutic substitution. Search criteria of the most commonly used terms, i.e. therapeutic substitution, switching, interchange, and bioequivalence, were applied to Embase, PubMed and Google Scholar to identify relevant publications. Although population studies support therapeutic substitution in principle, there is evidence that substitution may not always result in therapeutic equivalence in individual patients, with the consequent potential for greater risks of decreased efficacy and/or increased safety concerns. Factors such as patient choice and therapeutic equivalence also play an important role in the effectiveness of the treatment and overall management of the patient. The pan-European regulatory environment provides another contradiction, encouraging widespread cost containment through reduction in drug acquisition costs, while simultaneously promoting an increased role for patients in defining and managing their own treatment. There is a strong rationale for careful management in some patients with cardiovascular disease. Treatment decisions should be transparent and based on strong clinical evidence. If not, drug substitution on

Potential role of bromelain in clinical and therapeutic applications

PubMed Central

Rathnavelu, Vidhya; Alitheen, Noorjahan Banu; Sohila, Subramaniam; Kanagesan, Samikannu; Ramesh, Rajendran

2016-01-01

Pineapple has been used as part of traditional folk medicine since ancient times and it continues to be present in various herbal preparations. Bromelain is a complex mixture of protease extracted from the fruit or stem of the pineapple plant. Although the complete molecular mechanism of action of bromelain has not been completely identified, bromelain gained universal acceptability as a phytotherapeutic agent due to its history of safe use and lack of side effects. Bromelain is widely administered for its well-recognized properties, such as its anti-inflammatory, antithrombotic and fibrinolytic affects, anticancer activity and immunomodulatory effects, in addition to being a wound healing and circulatory improvement agent. The current review describes the promising clinical applications and therapeutic properties of bromelain. PMID:27602208

Developing patient rapport, trust and therapeutic relationships.

PubMed

Price, Bob

2017-08-09

Rapport is established at the first meeting between the patient and nurse, and is developed throughout the therapeutic relationship. However, challenges can arise during this process. Initially, nurses can establish trust with the patient through the questions they ask, however, as care progresses, the nurse will be required to demonstrate a commitment to maintaining the patient's psychological well-being. When the therapeutic relationship ends, the nurse should assist the patient to assess progress and plan the next stage of recovery. This article provides three reflective exercises using case study examples to demonstrate how rapport is developed and sustained. Evidence is provided to identify why challenges arise in the therapeutic relationship and how the nurse can ensure they provide care that the patient regards as genuine.

Challenges and opportunities in absorption, distribution, metabolism, and excretion studies of therapeutic biologics.

PubMed

Xu, Xin; Vugmeyster, Yulia

2012-12-01

With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for delivering therapeutic biologics (e.g., needle-free devices, nanoparticle complexes), as well as novel approaches for disease treatments (e.g., stem cell therapy, individualized medicine), continue to be developed. While pharmacokinetic studies are routinely carried out for therapeutic biologics, experiments that elucidate underlying mechanisms for clearance and biodistribution or identify key factors that govern absorption, distribution, metabolism, and excretion (ADME) of biologics often are not thoroughly conducted. Realizing the importance of biologics as therapeutic agents, pharmaceutical industry has recently begun to move the research focus from small molecules only to a blended portfolio consisting of both small molecules and biologics. This trend brings many opportunities for scientists working in the drug disposition research field. In anticipation of these opportunities and associated challenges, this review highlights impact of ADME studies on clinical and commercial success of biologics, with a particular focus on emerging applications and technologies and linkage with mechanistic pharmacokinetic/pharmacodynamic modeling and biomarker research.

Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology.

PubMed

Chiba, Tetsuhiro; Iwama, Atsushi; Yokosuka, Osamu

2016-01-01

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide. Despite advances in its diagnosis and treatment, the prognosis of patients with advanced HCC remains unfavorable. Recent advances in stem cell biology and associated technologies have enabled the identification of minor components of tumorigenic cells, termed cancer stem cells (CSC) or tumor-initiating cells, in cancers such as HCC. Furthermore, because CSC play a central role in tumor development, metastasis and recurrence, they are considered to be a therapeutic target in cancer treatment. Hepatic CSC have been successfully identified using functional and cell surface markers. The analysis of purified hepatic CSC has revealed the molecular machinery and signaling pathways involved in their maintenance. In addition, epigenetic transcriptional regulation has been shown to be important in the development and maintenance of CSC. Although inhibitors of CSC show promise as CSC-targeting drugs, novel therapeutic approaches for the eradication of CSC are yet to be established. In this review, we describe recent progress in hepatic CSC research and provide a perspective on the available therapeutic approaches based on stem cell biology. © 2015 The Japan Society of Hepatology.

Design of siRNA Therapeutics from the Molecular Scale

PubMed Central

Angart, Phillip; Vocelle, Daniel; Chan, Christina; Walton, S. Patrick

2013-01-01

While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics. PMID:23976875

Xenograft model for therapeutic drug testing in recurrent respiratory papillomatosis.

PubMed

Ahn, Julie; Bishop, Justin A; Akpeng, Belinda; Pai, Sara I; Best, Simon R A

2015-02-01

Identifying effective treatment for papillomatosis is limited by a lack of animal models, and there is currently no preclinical model for testing potential therapeutic agents. We hypothesized that xenografting of papilloma may facilitate in vivo drug testing to identify novel treatment options. A biopsy of fresh tracheal papilloma was xenografted into a NOD-scid-IL2Rgamma(null) (NSG) mouse. The xenograft began growing after 5 weeks and was serially passaged over multiple generations. Each generation showed a consistent log-growth pattern, and in all xenografts, the presence of the human papillomavirus (HPV) genome was confirmed by polymerase chain reaction (PCR). Histopathologic analysis demonstrated that the squamous architecture of the original papilloma was maintained in each generation. In vivo drug testing with bevacizumab (5 mg/kg i.p. twice weekly for 3 weeks) showed a dramatic therapeutic response compared to saline control. We report here the first successful case of serial xenografting of a tracheal papilloma in vivo with a therapeutic response observed with drug testing. In severely immunocompromised mice, the HPV genome and squamous differentiation of the papilloma can be maintained for multiple generations. This is a feasible approach to identify therapeutic agents in the treatment of recurrent respiratory papillomatosis. © The Author(s) 2014.

An antidote approach to reduce risk and broaden utility of antibody-based therapeutics.

PubMed

Portnoff, Alyse D; Gao, Cuihua; Borrok, M Jack; Gao, Xizhe; Gao, Changshou; Rainey, G Jonah

2017-05-19

Antibody therapeutics offer effective treatment options for a broad range of diseases. One of the greatest benefits of antibody therapeutics is their extraordinarily long serum half-life, allowing infrequent dosing with long-lasting effects. A characteristic of antibodies that drives long half-life is the ability to interact with the recycling receptor, FcRn, in a pH-dependent manner. The benefit of long half-life, however, carries with it liabilities. Although the positive effects of antibody therapeutics are long-lasting, any acute adverse events or chronic negative impacts, such as immunosuppression in the face of an infection, are also long-lasting. Therefore, we sought to develop antibodies with a chemical handle that alone would enjoy the long half-life of normal antibodies but, upon addition of a small-molecule antidote, would interact with the chemical handle and inhibit the antibody recycling mechanism, thus leading to rapid degradation and shortened half-life in vivo Here we present a proof of concept study where we identify sites to incorporate a non-natural amino acid that can be chemically modified to modulate FcRn interaction in vitro and antibody half-life in vivo This is an important first step in developing safer therapeutics, and the next step will be development of technology that can perform the modifying chemistry in vivo . © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Meta-Analysis Identifies NF-κB as a Therapeutic Target in Renal Cancer

PubMed Central

Peri, Suraj; Devarajan, Karthik; Yang, Dong-Hua; Knudson, Alfred G.; Balachandran, Siddharth

2013-01-01

Objective To determine the expression patterns of NF-κB regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes. Methods Meta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-κB regulators and targets to determine the nature and extent of NF-κB deregulation in ccRCC. Results A highly-disproportionate fraction (~40%; p < 0.001) of NF-κB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-κB activity in this cancer. A subset of these genes, comprising a key NF-κB regulator (IKBKB) and established mediators of the NF-κB cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an ‘interferon signature’ may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-κB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-κB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-κB activity, and the appearance of an interferon signature during ccRCC tumorigenesis. Conclusions These findings identify NF-κB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-κB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-κB targets for potential therapeutic intervention in this currently

Level 2 Therapeutic Model Site

ERIC Educational Resources Information Center

Spears, Brad; Sanchez, David; Bishop, Jane; Rogers, Sharon; DeJong, Judith A.

2006-01-01

L2, one of the original sites first funded under the Therapeutic Residential Model Initiative in 2001-2002, is operated as a peripheral dormitory This dormitory cares for 185 boys and girls in grades 1-12 who attend local public schools. L2 presented an outstanding proposal which identified gaps in services and presented a reasonable budget to…

RNA therapeutics targeting osteoclast-mediated excessive bone resorption

PubMed Central

Wang, Yuwei; Grainger, David W

2011-01-01

RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing technique developed with dramatically increasing utility for both scientific and therapeutic purposes. Short interfering RNA (siRNA) is currently exploited to regulate protein expression relevant to many therapeutic applications, and commonly used as a tool for elucidating disease-associated genes. Osteoporosis and their associated osteoporotic fragility fractures in both men and women are rapidly becoming a global healthcare crisis as average life expectancy increases worldwide. New therapeutics are needed for this increasing patient population. This review describes the diversity of molecular targets suitable for RNAi-based gene knock-down in osteoclasts to control osteoclast-mediated excessive bone resorption. We identify strategies for developing targeted siRNA delivery and efficient gene silencing, and describe opportunities and challenges of introducing siRNA as a therapeutic approach to hard and connective tissue disorders. PMID:21945356

Microbiome therapeutics - Advances and challenges.

PubMed

Mimee, Mark; Citorik, Robert J; Lu, Timothy K

2016-10-01

The microbial community that lives on and in the human body exerts a major impact on human health, from metabolism to immunity. In order to leverage the close associations between microbes and their host, development of therapeutics targeting the microbiota has surged in recent years. Here, we discuss current additive and subtractive strategies to manipulate the microbiota, focusing on bacteria engineered to produce therapeutic payloads, consortia of natural organisms and selective antimicrobials. Further, we present challenges faced by the community in the development of microbiome therapeutics, including designing microbial therapies that are adapted for specific geographies in the body, stable colonization with microbial therapies, discovery of clinically relevant biosensors, robustness of engineered synthetic gene circuits and addressing safety and biocontainment concerns. Moving forward, collaboration between basic and applied researchers and clinicians to address these challenges will poise the field to herald an age of next-generation, cellular therapies that draw on novel findings in basic research to inform directed augmentation of the human microbiota. Copyright © 2016. Published by Elsevier B.V.

Therapeutic clinical applications of reactor-produced radioisotopes

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

Knapp, F.F. Jr.

1997-12-01

One of the most rapidly growing areas of clinical nuclear medicine is the therapeutic use of radioisotopes for applications in oncology, rheumatology and, more recently, interventional cardiology. With the rapidly increasing development and evaluation of new agents, their introduction into clinical use, and commercialization, the availability of high levels of therapeutic reactor-produced neutron-rich radioisotopes is of increasing importance. The goals of this paper are to discuss the issues associated with optimization of the production and processing of reactor-produced radioisotopes for therapy, with special emphasis on {sup 188}W, and the optimization of the use of the {sup 188}W/{sup 188}Re generator. Inmore » addition, other key examples of therapeutic radioisotopes of current interest and their specific clinical applications are discussed.« less

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

PubMed

Anderson, Carl A; Boucher, Gabrielle; Lees, Charlie W; Franke, Andre; D'Amato, Mauro; Taylor, Kent D; Lee, James C; Goyette, Philippe; Imielinski, Marcin; Latiano, Anna; Lagacé, Caroline; Scott, Regan; Amininejad, Leila; Bumpstead, Suzannah; Baidoo, Leonard; Baldassano, Robert N; Barclay, Murray; Bayless, Theodore M; Brand, Stephan; Büning, Carsten; Colombel, Jean-Frédéric; Denson, Lee A; De Vos, Martine; Dubinsky, Marla; Edwards, Cathryn; Ellinghaus, David; Fehrmann, Rudolf S N; Floyd, James A B; Florin, Timothy; Franchimont, Denis; Franke, Lude; Georges, Michel; Glas, Jürgen; Glazer, Nicole L; Guthery, Stephen L; Haritunians, Talin; Hayward, Nicholas K; Hugot, Jean-Pierre; Jobin, Gilles; Laukens, Debby; Lawrance, Ian; Lémann, Marc; Levine, Arie; Libioulle, Cecile; Louis, Edouard; McGovern, Dermot P; Milla, Monica; Montgomery, Grant W; Morley, Katherine I; Mowat, Craig; Ng, Aylwin; Newman, William; Ophoff, Roel A; Papi, Laura; Palmieri, Orazio; Peyrin-Biroulet, Laurent; Panés, Julián; Phillips, Anne; Prescott, Natalie J; Proctor, Deborah D; Roberts, Rebecca; Russell, Richard; Rutgeerts, Paul; Sanderson, Jeremy; Sans, Miquel; Schumm, Philip; Seibold, Frank; Sharma, Yashoda; Simms, Lisa A; Seielstad, Mark; Steinhart, A Hillary; Targan, Stephan R; van den Berg, Leonard H; Vatn, Morten; Verspaget, Hein; Walters, Thomas; Wijmenga, Cisca; Wilson, David C; Westra, Harm-Jan; Xavier, Ramnik J; Zhao, Zhen Z; Ponsioen, Cyriel Y; Andersen, Vibeke; Torkvist, Leif; Gazouli, Maria; Anagnou, Nicholas P; Karlsen, Tom H; Kupcinskas, Limas; Sventoraityte, Jurgita; Mansfield, John C; Kugathasan, Subra; Silverberg, Mark S; Halfvarson, Jonas; Rotter, Jerome I; Mathew, Christopher G; Griffiths, Anne M; Gearry, Richard; Ahmad, Tariq; Brant, Steven R; Chamaillard, Mathias; Satsangi, Jack; Cho, Judy H; Schreiber, Stefan; Daly, Mark J; Barrett, Jeffrey C; Parkes, Miles; Annese, Vito; Hakonarson, Hakon; Radford-Smith, Graham; Duerr, Richard H; Vermeire, Séverine; Weersma, Rinse K; Rioux, John D

2011-03-01

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Bridging the gap to therapeutic strategies based on connexin/pannexin biology.

PubMed

Naus, Christian C; Giaume, Christian

2016-11-29

A unique workshop was recently held focusing on enhancing collaborations leading to identify and update the development of therapeutic strategies targeting connexin/pannexin large pore channels. Basic scientists exploring the functions of these channels in various pathologies gathered together with leading pharma companies which are targeting gap junction proteins for specific therapeutic applications. This highlights how paths of discovery research can converge with therapeutic strategies in innovative ways to enhance target identification and validation.

Effectiveness of the addition of therapeutic alliance with minimal intervention in the treatment of patients with chronic, nonspecific low back pain and low risk of involvement of psychosocial factors: a study protocol for a randomized controlled trial (TalkBack trial).

PubMed

Fagundes, Felipe Ribeiro Cabral; de Melo do Espírito Santo, Caique; de Luna Teixeira, Francine Mendonça; Tonini, Thaís Vanelli; Cabral, Cristina Maria Nunes

2017-01-31

The stratified model of care has been an effective approach for the treatment of low back pain. However, the treatment of patients with low risk of psychosocial-factor involvement is unclear. The addition of the therapeutic alliance to a minimal intervention may be an option for the treatment of low back pain. This paper reports on the rationale, design and protocol for a randomized controlled trial with blind assessor to assess the effectiveness of the addition of therapeutic alliance with minimal intervention on pain and disability in patients with chronic, nonspecific low back pain. Two hundred and twenty-two patients with chronic, nonspecific low back pain and low risk of involvement of psychosocial factors will be assessed and randomly allocated into three groups (n = 74 patients per group). The Positive Therapeutic Alliance group will receive counseling and guidance with an emphasis on therapeutic alliance and empathy. The Usual Treatment group will receive the same information and counseling with limited interaction with the therapist. The Control group will not receive any intervention. The treatment will be composed by two intervention sessions with a 1-week interval. A blinded assessor will collect the following outcomes at baseline, 1 month, 6 months and 12 months after randomization: pain intensity (Pain Numerical Rating Scale), specific disability (Patient-specific Functional Scale), general disability (Oswestry Disability Index), global perceived effect (Global Perceived Effect Scale), empathy (Consultation and Relational Empathy Measure), credibility and expectations related to treatment. The analysis will be performed using linear mixed models. This will be the first study to understand the effect of combining enhanced therapeutic alliance to a treatment based on counseling, information and advice (minimal intervention). The addition of the therapeutic alliance to minimal intervention may improve the treatment of chronic, nonspecific low back

Generation of Well-Defined Micro/Nanoparticles via Advanced Manufacturing Techniques for Therapeutic Delivery

PubMed Central

Zhang, Peipei; Xia, Junfei; Luo, Sida

2018-01-01

Micro/nanoparticles have great potentials in biomedical applications, especially for drug delivery. Existing studies identified that major micro/nanoparticle features including size, shape, surface property and component materials play vital roles in their in vitro and in vivo applications. However, a demanding challenge is that most conventional particle synthesis techniques such as emulsion can only generate micro/nanoparticles with a very limited number of shapes (i.e., spherical or rod shapes) and have very loose control in terms of particle sizes. We reviewed the advanced manufacturing techniques for producing micro/nanoparticles with precisely defined characteristics, emphasizing the use of these well-controlled micro/nanoparticles for drug delivery applications. Additionally, to illustrate the vital roles of particle features in therapeutic delivery, we also discussed how the above-mentioned micro/nanoparticle features impact in vitro and in vivo applications. Through this review, we highlighted the unique opportunities in generating controllable particles via advanced manufacturing techniques and the great potential of using these micro/nanoparticles for therapeutic delivery. PMID:29670013

Therapeutic Hypothermia for Neuroprotection

PubMed Central

Karnatovskaia, Lioudmila V.; Wartenberg, Katja E.

2014-01-01

The earliest recorded application of therapeutic hypothermia in medicine spans about 5000 years; however, its use has become widespread since 2002, following the demonstration of both safety and efficacy of regimens requiring only a mild (32°C-35°C) degree of cooling after cardiac arrest. We review the mechanisms by which hypothermia confers neuroprotection as well as its physiological effects by body system and its associated risks. With regard to clinical applications, we present evidence on the role of hypothermia in traumatic brain injury, intracranial pressure elevation, stroke, subarachnoid hemorrhage, spinal cord injury, hepatic encephalopathy, and neonatal peripartum encephalopathy. Based on the current knowledge and areas undergoing or in need of further exploration, we feel that therapeutic hypothermia holds promise in the treatment of patients with various forms of neurologic injury; however, additional quality studies are needed before its true role is fully known. PMID:24982721

The Therapeutic School.

ERIC Educational Resources Information Center

Rice, John Steadman

2002-01-01

Contributes to the recent research on specific institutional carriers of the therapeutic culture, such as the state, the corporation, and the self- help movement, defining therapeutic discourse and discussing the therapeutic ethic, the therapeutic school, schools of education and their critics, and disappointing results of therapeutic schooling.…

Biochemistry and neurobiology of prosaposin: a potential therapeutic neuro-effector.

PubMed

Misasi, Roberta; Hozumi, Isao; Inuzuka, Takashi; Capozzi, Antonella; Mattei, Vincenzo; Kuramoto, Yukako; Shimeno, Hiroshi; Soeda, Shinji; Azuma, Norihiro; Yamauchi, Toyoaki; Hiraiwa, Masao

2009-06-01

Prosaposin, a 66 kDa glycoprotein, was identified initially as the precursor of the sphingolipid activator proteins, saposins A-D, which are required for the enzymatic hydrolysis of certain sphingolipids by lysosomal hydrolases. While mature saposins are distributed to lysosomes, prosaposin exists in secretory body fluids and plasma membranes. In addition to its role as the precursor, prosaposin shows a variety of neurotrophic and myelinotrophic activities through a receptor-mediated mechanism. In studies in vivo, prosaposin was demonstrated to exert a variety of neuro-efficacies capable of preventing neuro-degeneration following neuro-injury and promoting the amelioration of allodynia and hyperalgesia in pain models. Collective findings indicate that prosaposin is not a simple house-keeping precursor protein; instead, it is a protein essentially required for the development and maintenance of the central and peripheral nervous systems. Accumulating evidence over the last decade has attracted interests in exploring and developing new therapeutic approaches using prosaposin for human disorders associated with neuro-degeneration. In this review we detail the structure characteristics, cell biological feature, in vivo efficacy, and neuro-therapeutic potential of prosaposin, thereby providing future prospective in clinical application of this multifunctional protein.

Microbiome Therapeutics – Advances and Challenges

PubMed Central

Mimee, Mark; Citorik, Robert J.; Lu, Timothy K.

2016-01-01

The microbial community that lives on and in the human body exerts a major impact on human health, from metabolism to immunity. In order to leverage the close associations between microbes and their host, development of therapeutics targeting the microbiota has surged in recent years. Here, we discuss current additive and subtractive strategies to manipulate the microbiota, focusing on bacteria engineered to produce therapeutic payloads, consortia of natural organisms and selective antimicrobials. Further, we present challenges faced by the community in the development of microbiome therapeutics, including designing microbial therapies that are adapted for specific geographies in the body, stable colonization with microbial therapies, discovery of clinically relevant biosensors, robustness of engineered synthetic gene circuits and addressing safety and biocontainment concerns. Moving forward, collaboration between basic and applied researchers and clinicians to address these challenges will poise the field to herald an age of next-generation, cellular therapies that draw on novel findings in basic research to inform directed augmentation of the human microbiota. PMID:27158095

Therapeutic physical exercise in neural injury: friend or foe?

PubMed

Park, Kanghui; Lee, Seunghoon; Hong, Yunkyung; Park, Sookyoung; Choi, Jeonghyun; Chang, Kyu-Tae; Kim, Joo-Heon; Hong, Yonggeun

2015-12-01

[Purpose] The intensity of therapeutic physical exercise is complex and sometimes controversial in patients with neural injuries. This review assessed whether therapeutic physical exercise is beneficial according to the intensity of the physical exercise. [Methods] The authors identified clinically or scientifically relevant articles from PubMed that met the inclusion criteria. [Results] Exercise training can improve body strength and lead to the physiological adaptation of skeletal muscles and the nervous system after neural injuries. Furthermore, neurophysiological and neuropathological studies show differences in the beneficial effects of forced therapeutic exercise in patients with severe or mild neural injuries. Forced exercise alters the distribution of muscle fiber types in patients with neural injuries. Based on several animal studies, forced exercise may promote functional recovery following cerebral ischemia via signaling molecules in ischemic brain regions. [Conclusions] This review describes several types of therapeutic forced exercise and the controversy regarding the therapeutic effects in experimental animals versus humans with neural injuries. This review also provides a therapeutic strategy for physical therapists that grades the intensity of forced exercise according to the level of neural injury.

Targeting histone deacetylases in endometrial cancer: a paradigm-shifting therapeutic strategy?

PubMed

Garmpis, N; Damaskos, C; Garmpi, A; Spartalis, E; Kalampokas, E; Kalampokas, T; Margonis, G-A; Schizas, D; Andreatos, N; Angelou, A; Lavaris, A; Athanasiou, A; Apostolou, K G; Spartalis, M; Damaskou, Z; Daskalopoulou, A; Diamantis, E; Tsivelekas, K; Alavanos, A; Valsami, S; Moschos, M M; Sampani, A; Nonni, A; Antoniou, E A; Mantas, D; Tsourouflis, G; Markatos, K; Kontzoglou, K; Perrea, D; Nikiteas, N; Kostakis, A; Dimitroulis, D

2018-02-01

Endometrial cancer is increasingly prevalent in western societies and affects mainly postmenopausal women; notably incidence rates have been rising by 1.9% per year on average since 2005. Although the early-stage endometrial cancer can be effectively managed with surgery, more advanced stages of the disease require multimodality treatment with varying results. In recent years, endometrial cancer has been extensively studied at the molecular level in an attempt to develop effective therapies. Recently, a family of compounds that alter epigenetic expression, namely histone deacetylase inhibitors, have shown promise as possible therapeutic agents in endometrial cancer. The present review aims to discuss the therapeutic potential of these agents. This literature review was performed using the MEDLINE database; the search terms histone, deacetylase, inhibitors, endometrial, targeted therapies for endometrial cancer were employed to identify relevant studies. We only reviewed English language publications and also considered studies that were not entirely focused on endometrial cancer. Ultimately, sixty-four articles published until January 2018 were incorporated into our review. Studies in cell cultures have demonstrated that histone deacetylase inhibitors exert their antineoplastic activity by promoting expression of p21WAF1 and p27KIP1, cyclin-dependent kinase inhibitors, that have important roles in cell cycle regulation; importantly, the transcription of specific genes (e.g., E-cadherin, PTEN) that are commonly silenced in endometrial cancer is also enhanced. In addition to these abstracts effects, novel compounds with histone deacetylase inhibitor activity (e.g., scriptaid, trichostatin, entinostat) have also demonstrated significant antineoplastic activity both in vitro and in vivo, by liming tumor growth, inducing apoptosis, inhibiting angiogenesis and potentiating the effects of chemotherapy. The applications of histone deacetylase inhibitors in endometrial

Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors

PubMed Central

Bii, Victor M.; Trobridge, Grant D.

2016-01-01

Identifying novel genes that drive tumor metastasis and drug resistance has significant potential to improve patient outcomes. High-throughput sequencing approaches have identified cancer genes, but distinguishing driver genes from passengers remains challenging. Insertional mutagenesis screens using replication-incompetent retroviral vectors have emerged as a powerful tool to identify cancer genes. Unlike replicating retroviruses and transposons, replication-incompetent retroviral vectors lack additional mutagenesis events that can complicate the identification of driver mutations from passenger mutations. They can also be used for almost any human cancer due to the broad tropism of the vectors. Replication-incompetent retroviral vectors have the ability to dysregulate nearby cancer genes via several mechanisms including enhancer-mediated activation of gene promoters. The integrated provirus acts as a unique molecular tag for nearby candidate driver genes which can be rapidly identified using well established methods that utilize next generation sequencing and bioinformatics programs. Recently, retroviral vector screens have been used to efficiently identify candidate driver genes in prostate, breast, liver and pancreatic cancers. Validated driver genes can be potential therapeutic targets and biomarkers. In this review, we describe the emergence of retroviral insertional mutagenesis screens using replication-incompetent retroviral vectors as a novel tool to identify cancer driver genes in different cancer types. PMID:27792127

A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets.

PubMed

Adamia, Sophia; Haibe-Kains, Benjamin; Pilarski, Patrick M; Bar-Natan, Michal; Pevzner, Samuel; Avet-Loiseau, Herve; Lode, Laurence; Verselis, Sigitas; Fox, Edward A; Burke, John; Galinsky, Ilene; Dagogo-Jack, Ibiayi; Wadleigh, Martha; Steensma, David P; Motyckova, Gabriela; Deangelo, Daniel J; Quackenbush, John; Stone, Richard; Griffin, James D

2014-03-01

Despite new treatments, acute myeloid leukemia (AML) remains an incurable disease. More effective drug design requires an expanded view of the molecular complexity that underlies AML. Alternative splicing of RNA is used by normal cells to generate protein diversity. Growing evidence indicates that aberrant splicing of genes plays a key role in cancer. We investigated genome-wide splicing abnormalities in AML and based on these abnormalities, we aimed to identify novel potential biomarkers and therapeutic targets. We used genome-wide alternative splicing screening to investigate alternative splicing abnormalities in two independent AML patient cohorts [Dana-Farber Cancer Institute (DFCI) (Boston, MA) and University Hospital de Nantes (UHN) (Nantes, France)] and normal donors. Selected splicing events were confirmed through cloning and sequencing analysis, and than validated in 193 patients with AML. Our results show that approximately 29% of expressed genes genome-wide were differentially and recurrently spliced in patients with AML compared with normal donors bone marrow CD34(+) cells. Results were reproducible in two independent AML cohorts. In both cohorts, annotation analyses indicated similar proportions of differentially spliced genes encoding several oncogenes, tumor suppressor proteins, splicing factors, and heterogeneous-nuclear-ribonucleoproteins, proteins involved in apoptosis, cell proliferation, and spliceosome assembly. Our findings are consistent with reports for other malignances and indicate that AML-specific aberrations in splicing mechanisms are a hallmark of AML pathogenesis. Overall, our results suggest that aberrant splicing is a common characteristic for AML. Our findings also suggest that splice variant transcripts that are the result of splicing aberrations create novel disease markers and provide potential targets for small molecules or antibody therapeutics for this disease. ©2013 AACR

Therapeutic drug monitoring of antimetabolic cytotoxic drugs

PubMed Central

Lennard, L

1999-01-01

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs. PMID:10190647

Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma.

PubMed

Chow, Yock Ping; Tan, Lu Ping; Chai, San Jiun; Abdul Aziz, Norazlin; Choo, Siew Woh; Lim, Paul Vey Hong; Pathmanathan, Rajadurai; Mohd Kornain, Noor Kaslina; Lum, Chee Lun; Pua, Kin Choo; Yap, Yoke Yeow; Tan, Tee Yong; Teo, Soo Hwang; Khoo, Alan Soo-Beng; Patel, Vyomesh

2017-03-03

In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that ~72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.

Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma

PubMed Central

Chow, Yock Ping; Tan, Lu Ping; Chai, San Jiun; Abdul Aziz, Norazlin; Choo, Siew Woh; Lim, Paul Vey Hong; Pathmanathan, Rajadurai; Mohd Kornain, Noor Kaslina; Lum, Chee Lun; Pua, Kin Choo; Yap, Yoke Yeow; Tan, Tee Yong; Teo, Soo Hwang; Khoo, Alan Soo-Beng; Patel, Vyomesh

2017-01-01

In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that ~72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies. PMID:28256603

Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis

PubMed Central

Xie, Jiangan; Codd, Christopher; Mo, Kevin; He, Yongqun

2016-01-01

M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death

Current Status of Gene Engineering Cell Therapeutics

PubMed Central

Saudemont, Aurore; Jespers, Laurent; Clay, Timothy

2018-01-01

Ex vivo manipulations of autologous patient’s cells or gene-engineered cell therapeutics have allowed the development of cell and gene therapy approaches to treat otherwise incurable diseases. These modalities of personalized medicine have already shown great promises including product commercialization for some rare diseases. The transfer of a chimeric antigen receptor or T cell receptor genes into autologous T cells has led to very promising outcomes for some cancers, and particularly for hematological malignancies. In addition, gene-engineered cell therapeutics are also being explored to induce tolerance and regulate inflammation. Here, we review the latest gene-engineered cell therapeutic approaches being currently explored to induce an efficient immune response against cancer cells or viruses by engineering T cells, natural killer cells, gamma delta T cells, or cytokine-induced killer cells and to modulate inflammation using regulatory T cells. PMID:29459866

Discovery, clinical development, and therapeutic uses of bisphosphonates.

PubMed

Licata, Angelo A

2005-04-01

To review the literature concerning the history, development, and therapeutic uses of bisphosphonates. English-language articles were identified through a search of MEDLINE (through December 2004) using the key word bisphosphonate. Reference lists of pivotal studies, reviews, and full prescribing information for the approved agents were also examined. Selected studies included those that discussed the discovery and initial applications of bisphosphonates, as well as their historical development, pharmacokinetic and pharmacodynamic properties, and current therapeutic uses. Bisphosphonates structurally resemble pyrophosphates (naturally occurring polyphosphates) and have demonstrated similar physicochemical effects to pyrophosphates. In addition, bisphosphonates reduce bone turnover and resist hydrolysis when administered orally. The information gained from initial work with etidronate generated a considerable scientific effort to design new and more effective bisphosphonates. The PCP moiety in the general bisphosphonate structure is essential for binding to hydroxyapatite and allows for a number of chemical variations by changing the 2 lateral side chains (designated R(1) and R(2)). The R(1) side chain determines binding affinity to hydroxyapatite, and the R(2) side chain determines antiresorptive potency. Accordingly, each bisphosphonate has its own characteristic profile of activity. The bisphosphonates reduce bone turnover, increase bone mass, and decrease fracture risk and therefore have a significant place in the management of skeletal disorders including osteoporosis, Paget's disease, bone metastases, osteogenesis imperfecta, and heterotopic ossification.

Study Identifies New Lymphoma Treatment Target

Cancer.gov

NCI researchers have identified new therapeutic targets for diffuse large B-cell lymphoma. Drugs that hit these targets are under clinical development and the researchers hope to begin testing them in clinical trials of patients with DLBCL.

Therapeutic Uses of Triphala in Ayurvedic Medicine.

PubMed

Peterson, Christine Tara; Denniston, Kate; Chopra, Deepak

2017-08-01

The aim of this article is to review the current literature on the therapeutic uses and efficacy of Triphala. Herbal remedies are among the most ancient medicines used in traditional systems of healthcare such as Ayurveda. Triphala, a well-recognized and highly efficacious polyherbal Ayurvedic medicine consisting of fruits of the plant species Emblica officinalis (Amalaki), Terminalia bellerica (Bibhitaki), and Terminalia chebula (Haritaki), is a cornerstone of gastrointestinal and rejuvenative treatment. A search of the PubMed database was conducted. In addition, numerous additional therapeutic uses described both in the Ayurvedic medical literature and anecdotally are being validated scientifically. In addition to laxative action, Triphala research has found the formula to be potentially effective for several clinical uses such as appetite stimulation, reduction of hyperacidity, antioxidant, anti-inflammatory, immunomodulating, antibacterial, antimutagenic, adaptogenic, hypoglycemic, antineoplastic, chemoprotective, and radioprotective effects, and prevention of dental caries. Polyphenols in Triphala modulate the human gut microbiome and thereby promote the growth of beneficial Bifidobacteria and Lactobacillus while inhibiting the growth of undesirable gut microbes. The bioactivity of Triphala is elicited by gut microbiota to generate a variety of anti-inflammatory compounds. This review summarizes recent data on pharmacological properties and clinical effects of Triphala while highlighting areas in need of additional investigation and clinical development.

Enlight: A Comprehensive Quality and Therapeutic Potential Evaluation Tool for Mobile and Web-Based eHealth Interventions

PubMed Central

Faber, Keren; Mathur, Nandita; Kane, John M; Muench, Fred

2017-01-01

Background Studies of criteria-based assessment tools have demonstrated the feasibility of objectively evaluating eHealth interventions independent of empirical testing. However, current tools have not included some quality constructs associated with intervention outcome, such as persuasive design, behavior change, or therapeutic alliance. In addition, the generalizability of such tools has not been explicitly examined. Objective The aim is to introduce the development and further analysis of the Enlight suite of measures, developed to incorporate the aforementioned concepts and address generalizability aspects. Methods As a first step, a comprehensive systematic review was performed to identify relevant quality rating criteria in line with the PRISMA statement. These criteria were then categorized to create Enlight. The second step involved testing Enlight on 42 mobile apps and 42 Web-based programs (delivery mediums) targeting modifiable behaviors related to medical illness or mental health (clinical aims). Results A total of 476 criteria from 99 identified sources were used to build Enlight. The rating measures were divided into two sections: quality assessments and checklists. Quality assessments included usability, visual design, user engagement, content, therapeutic persuasiveness, therapeutic alliance, and general subjective evaluation. The checklists included credibility, privacy explanation, basic security, and evidence-based program ranking. The quality constructs exhibited excellent interrater reliability (intraclass correlations=.77-.98, median .91) and internal consistency (Cronbach alphas=.83-.90, median .88), with similar results when separated into delivery mediums or clinical aims. Conditional probability analysis revealed that 100% of the programs that received a score of fair or above (≥3.0) in therapeutic persuasiveness or therapeutic alliance received the same range of scores in user engagement and content—a pattern that did not appear in

Molecular genetics and targeted therapeutics in biliary tract carcinoma

PubMed Central

Marks, Eric I; Yee, Nelson S

2016-01-01

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract. PMID:26819503

Molecular genetics and targeted therapeutics in biliary tract carcinoma.

PubMed

Marks, Eric I; Yee, Nelson S

2016-01-28

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

Novel therapeutic uses and formulations of botulinum neurotoxins: a patent review (2012 - 2014).

PubMed

Kane, Christopher D; Nuss, Jonathan E; Bavari, Sina

2015-06-01

Botulinum neurotoxins (BoNTs) are among the most toxic of known biological molecules and function as acetylcholine release inhibitors and neuromuscular blocking agents. Paradoxically, these properties also make them valuable therapeutic agents for the treatment of movement disorders, urological conditions and hypersecretory disorders. Greater understanding of their molecular mechanism of action and advances in protein engineering has led to significant efforts to improve and expand their function with a view towards broadening their therapeutic potential. Searches of Espacenet and Google Patent have revealed a number of patents related to BoNTs. This review will focus on novel therapeutic uses and formulations disclosed during 2012 - 2014. The seven patents discussed will include nanoformulations of FDA-approved BoNTs, additional BoNT subtypes and novel BoNT variants and chimeras created through protein engineering. Supporting patents and related publications are also briefly discussed. The clinical and commercial success of BoNTs has prompted investigation into novel BoNTs or BoNT-mediated chimeras with promising in vitro results. Distinct strategies including the use of nanoformulations and targeted delivery have been implemented to identify new indication and improved functionality. Greater understanding of their systemic exposure, efficacy and safety profiles will be required for further development.

Prioritizing therapeutic targets using patient-derived xenograft models

PubMed Central

Lodhia, K.A; Hadley, A; Haluska, P; Scott, C.L

2015-01-01

Effective systemic treatment of cancer relies on the delivery of agents with optimal therapeutic potential. The molecular age of medicine has provided genomic tools that can identify a large number of potential therapeutic targets in individual patients, heralding the promise of personalized treatment. However, determining which potential targets actually drive tumor growth and should be prioritized for therapy is challenging. Indeed, reliable molecular matches of target and therapeutic agent have been stringently validated in the clinic for only a small number of targets. Patient-derived xenografts (PDX) are tumor models developed in immunocompromised mice using tumor procured directly from the patient. As patient surrogates, PDX models represent a powerful tool for addressing individualized therapy. Challenges include humanizing the immune system of PDX models and ensuring high quality molecular annotation, in order to maximise insights for the clinic. Importantly, PDX can be sampled repeatedly and in parallel, to reveal clonal evolution, which may predict mechanisms of drug resistance and inform therapeutic strategy design. PMID:25783201

Identifying additional studies for a systematic review of retention strategies in randomised controlled trials: making contact with trials units and trial methodologists.

PubMed

Brueton, Valerie; Tierney, Jayne F; Stenning, Sally; Rait, Greta

2017-08-22

Search strategies for systematic reviews aim to identify all evidence relevant to the research question posed. Reports of methodological research can be difficult to find leading to biased results in systematic reviews of research methodology. Evidence suggests that contact with investigators can help to identify unpublished research. To identify additional eligible randomised controlled trials (RCTs) for a Cochrane systematic review of strategies to improve retention in RCTs, we conducted a survey of UK clinical trials units (CTUs) and made contact with RCT methodologists. Key contacts for all UK CTUs were sent a personalised email with a short questionnaire and summary protocol of the Cochrane methodology review. The questionnaire asked whether a RCT evaluating strategies to improve retention embedded in a RCT had ever been conducted by the CTU. Questions about the stage of completion and publication of such RCTs were included. The summary protocol outlined the aims, eligibility criteria, examples of types of retention strategies, and the primary outcome for the systematic review. Personal communication with RCT methodologists and presentations of preliminary results of the review at conferences were also used to identify additional eligible RCTs. We checked the results of our standard searches to see if eligible studies identified through these additional methods were also found using our standard searches. We identified 14 of the 38 RCTs included in the Cochrane methodology review by contacting trials units and methodologists. Eleven of the 14 RCTs identified by these methods were either published in grey literature, in press or unpublished. Three remaining RCTs were fully published at the time. Six of the RCTs identified were not found through any other searches. The RCTs identified represented data for 6 of 14 RCTs of incentive strategies (52% of randomised participants included in the review), and 6 of 14 RCTs of communication strategies (52% of randomised

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

PubMed Central

Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.; Hogervorst, Frans B.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Gibson, Lorna; Aitken, Zoe; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Benitez, Javier; Zamora, Maria Pilar; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Hamann, Ute; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Beesley, Jonathan; Lambrechts, Diether; Moisse, Matthieu; Floris, Guiseppe; Beuselinck, Benoit; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Pensotti, Valeria; Couch, Fergus J.; Olson, Janet E.; Slettedahl, Seth; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robertus A. E. M.; Seynaeve, Caroline M.; Van Asperen, Christi J.; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Hooning, Maartje J.; Hollestelle, Antoinette; van Deurzen, Carolien H. M.; Kriege, Mieke; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Perkins, Barbara J.; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J.; Meindl, Alfons; Schmutzler, Rita K.; Olswold, Curtis; Slager, Susan; Toland, Amanda E.; Yannoukakos, Drakoulis; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Matsuo, Keitaro; Ito, Hidema; Iwata, Hiroji; Ishiguro, Junko; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Teo, Soo Hwang; Yip, Cheng Har; Kang, Peter; Ikram, Mohammad Kamran; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Lee, Soo Chin; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Wu, Pei-Ei; Hou, Ming-Feng; Yu, Jyh-Cherng; Shen, Chen-Yang; Blot, William; Cai, Qiuyin; Signorello, Lisa B.; Luccarini, Craig; Bayes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Hunter, David J.; Lindstrom, Sara; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K.; Easton, Douglas F.; dos Santos Silva, Isabel; Fletcher, Olivia; Peto, Julian

2015-01-01

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. PMID:25652398

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

PubMed

Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K; Broeks, Annegien; Van't Veer, Laura J; Hogervorst, Frans B; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Gibson, Lorna; Aitken, Zoe; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, Maria Pilar; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Hamann, Ute; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Beesley, Jonathan; Lambrechts, Diether; Moisse, Matthieu; Floris, Guiseppe; Beuselinck, Benoit; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Pensotti, Valeria; Couch, Fergus J; Olson, Janet E; Slettedahl, Seth; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Van Asperen, Christi J; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Hooning, Maartje J; Hollestelle, Antoinette; van Deurzen, Carolien H M; Kriege, Mieke; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Pharoah, Paul D P; Dunning, Alison M; Shah, Mitul; Perkins, Barbara J; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J; Meindl, Alfons; Schmutzler, Rita K; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Matsuo, Keitaro; Ito, Hidema; Iwata, Hiroji; Ishiguro, Junko; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Teo, Soo Hwang; Yip, Cheng Har; Kang, Peter; Ikram, Mohammad Kamran; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Lee, Soo Chin; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Wu, Pei-Ei; Hou, Ming-Feng; Yu, Jyh-Cherng; Shen, Chen-Yang; Blot, William; Cai, Qiuyin; Signorello, Lisa B; Luccarini, Craig; Bayes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Hunter, David J; Lindstrom, Sara; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K; Easton, Douglas F; dos Santos Silva, Isabel; Fletcher, Olivia; Peto, Julian

2015-05-15

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. © The Author 2015. Published by Oxford University Press.

Therapeutic lighting design for the elderly: a review.

PubMed

Shikder, Shariful; Mourshed, Monjur; Price, Andrew

2012-11-01

Research suggests that specialised lighting design is essential to cater for the elderly users of a building because of reduced visual performance with increased age. This review aims to document what is known of the physical and psychological aspects of lighting and their role in promoting a healthy and safe environment for the elderly. A methodical review was carried out of published literature on the physical and psychological impacts of light on the elderly. Design standards and guides from professional organizations were evaluated to identify synergies and gaps between the evidence base and current practice. Lighting has been identified as a significant environmental attribute responsible for promoting physical and mental health of the elderly. The evidence related to visual performance was found to be robust. However, guides and standards appeared to have focused mostly on illumination requirements for specific tasks and have lacked detailed guidelines on vertical lighting and luminance design. This review has identified a growing body of evidence on the therapeutic benefits of lighting and its use in treating psychological disorders among the elderly. The experiments using light as a therapy have improved our understanding of the underlying principles, but the integration of therapeutic aspects of lighting in design practice and guidelines is lacking. While design guidelines discuss the physical needs of lighting for the elderly fairly well, they lack incorporation of photobiological impacts. Despite positive outcomes from research, the implementation of therapeutic aspects of lighting in buildings is still debatable due to insufficient relevant investigations and robustness of their findings. Collaborations between designers and physicians can contribute in delivering customised lighting solutions by considering disease types and needs. Further investigation needs to be carried out for translating therapeutic benefits to photometric units to implement them

Computationally identified novel agonists for GPRC6A

PubMed Central

Ye, Ruisong; Hwang, Dong-Jin; Miller, Duane D.; Smith, Jeremy C.; Baudry, Jerome; Quarles, L. Darryl

2018-01-01

New insights into G protein coupled receptor regulation of glucose metabolism by β-cells, skeletal muscle and liver hepatocytes identify GPRC6A as a potential therapeutic target for treating type 2 diabetes mellitus (T2D). Activating GPRC6A with a small molecule drug represents a potential paradigm-shifting opportunity to make significant strides in regulating glucose homeostasis by simultaneously correcting multiple metabolic derangements that underlie T2D, including abnormalities in β-cell proliferation and insulin secretion and peripheral insulin resistance. Using a computational, structure-based high-throughput screening approach, we identified novel tri-phenyl compounds predicted to bind to the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A. Experimental testing found that these compounds dose-dependently stimulated GPRC6A signaling in a heterologous cell expression system. Additional chemical modifications and functional analysis identified one tri-phenyl lead compound, DJ-V-159 that demonstrated the greatest potency in stimulating insulin secretion in β-cells and lowering serum glucose in wild-type mice. Collectively, these studies show that GPRC6A is a “druggable” target for developing chemical probes to treat T2DM. PMID:29684031

Homozygosity Mapping Identifies an Additional Locus for Wolfram Syndrome on Chromosome 4q

PubMed Central

El-Shanti, Hatem; Lidral, Andrew C.; Jarrah, Nadim; Druhan, Lawrence; Ajlouni, Kamel

2000-01-01

Wolfram syndrome, which is sometimes referred to as “DIDMOAD” (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an autosomal recessive neurodegenerative disorder for which only insulin-dependent diabetes mellitus and optic atrophy are necessary to make the diagnosis. Researchers have mapped Wolfram syndrome to chromosome 4p16.1, and, recently, a gene encoding a putative transmembrane protein has been cloned and mutations have been identified in patients. To pursue the possibility of locus heterogeneity, 16 patients from four different families were recruited. These patients, who have the Wolfram syndrome phenotype, also have additional features that have not previously been reported. There is an absence of diabetes insipidus in all affected family members. In addition, several patients have profound upper gastrointestinal ulceration and bleeding. With the use of three microsatellite markers (D4S432, D4S3023, and D4S2366) reported to be linked to the chromosome 4p16.1 locus, we significantly excluded linkage in three of the four families. The two affected individuals in one family showed homozygosity for all three markers from the region of linkage on chromosome 4p16.1. For the other three families, genetic heterogeneity for Wolfram syndrome was verified by demonstration of linkage to chromosome 4q22-24. In conclusion, we report the unique clinical findings and linkage-analysis results of 16 patients with Wolfram syndrome and provide further evidence for the genetic heterogeneity of this disorder. We also provide data on a new locus that plays a role in the etiology of insulin-dependent diabetes mellitus. PMID:10739754

Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling

PubMed Central

Kuusanmäki, Heikki; Dufva, Olli; Parri, Elina; van Adrichem, Arjan J.; Rajala, Hanna; Majumder, Muntasir M.; Yadav, Bhagwan; Parsons, Alun; Chan, Wing C.; Wennerberg, Krister; Mustjoki, Satu; Heckman, Caroline A.

2017-01-01

Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability. We identified JAK, mTOR, Hsp90 and CDK inhibitors as potent inhibitors of both WT and mutant STAT3 activity. The Hsp90 inhibitor luminespib was highly effective at reducing the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples. Luminespib decreased the phosphorylation of mutant STAT3 at Y705, whereas JAK1/JAK2 inhibitor ruxolitinib had reduced efficacy on mutant STAT3 phosphorylation. Additionally, combinations involving Hsp90, JAK and mTOR inhibitors were more effective at reducing cell viability than single agents. Our findings show alternative approaches to inhibit STAT3 activity and suggest Hsp90 as a therapeutic target in lymphoproliferative disorders with constitutively active STAT3. PMID:29228628

Current progress on aptamer-targeted oligonucleotide therapeutics

PubMed Central

Dassie, Justin P; Giangrande, Paloma H

2014-01-01

Exploiting the power of the RNAi pathway through the use of therapeutic siRNA drugs has remarkable potential for treating a vast array of human disease conditions. However, difficulties in delivery of these and similar nucleic acid-based pharmacological agents to appropriate organs or tissues, remains a major impediment to their broad clinical application. Synthetic nucleic acid ligands (aptamers) have emerged as effective delivery vehicles for therapeutic oligonucleotides, including siRNAs. In this review, we summarize recent attractive developments in creatively employing cell-internalizing aptamers to deliver therapeutic oligonucleotides (e.g., siRNAs, miRNAs, anti-miRs and antisense oligos) to target cells. We also discuss advancements in aptamer-siRNA chimera technology, as well as, aptamer-functionalized nanoparticles for siRNA delivery. In addition, the challenges and future prospects of aptamer-targeted oligonucleotide drugs for clinical translation are further highlighted. PMID:24304250

Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics.

PubMed

Shah, Dhaval K

2015-10-01

Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biological molecules. Consequently, in order to support the discovery and development of these next generation molecules, it becomes important to understand the determinants controlling their PK/PD. This review discusses the determinants that a PK/PD scientist should consider during the design and development of next generation protein therapeutics. In addition, the role of systems PK/PD models in enabling rational development of the next generation protein therapeutics is emphasized.

Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics

PubMed Central

Shah, Dhaval K.

2015-01-01

Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biological molecules. Consequently, in order to support the discovery and development of these next generation molecules, it becomes important to understand the determinants controlling their PK/PD. This review discusses the determinants that a PK/PD scientist should consider during the design and development of next generation protein therapeutics. In addition, the role of systems PK/PD models in enabling rational development of the next generation protein therapeutics is emphasized. PMID:26373957

Therapeutic strategy for hair regeneration: Hair cycle activation, niche environment modulation, wound-induced follicle neogenesis and stem cell engineering

PubMed Central

Chueh, Shan-Chang; Lin, Sung-Jan; Chen, Chih-Chiang; Lei, Mingxing; Wang, Ling Mei; Widelitz, Randall B.; Hughes, Michael W.; Jiang, Ting-Xing; Chuong, Cheng Ming

2013-01-01

Introduction There are major new advancements in the fields of stem cell biology, developmental biology, regenerative hair cycling, and tissue engineering. The time is ripe to integrate, translate and apply these findings to tissue engineering and regenerative medicine. Readers will learn about new progress in cellular and molecular aspects of hair follicle development, regeneration and potential therapeutic opportunities these advances may offer. Areas covered Here we use hair follicle formation to illustrate this progress and to identify targets for potential strategies in therapeutics. Hair regeneration is discussed in four different categories. (1) Intra-follicle regeneration (or renewal) is the basic production of hair fibers from hair stem cells and dermal papillae in existing follicles. (2) Chimeric follicles via epithelial-mesenchymal recombination to identify stem cells and signaling centers. (3) Extra-follicular factors including local dermal and systemic factors can modulate the regenerative behavior of hair follicles, and may be relatively easy therapeutic targets. (4) Follicular neogenesis means the de novo formation of new follicles. In addition, scientists are working to engineer hair follicles, which require hair forming competent epidermal cells and hair inducing dermal cells. Expert opinion Ideally self-organizing processes similar to those occurring during embryonic development should be elicited with some help from biomaterials. PMID:23289545

Therapeutic spaces of care farming: Transformative or ameliorating?

PubMed

Kaley, Alexandra; Hatton, Chris; Milligan, Christine

2018-05-04

Since Wil Gesler's earliest articulation (Gesler, 1992; Gesler, 1996) key thinkers in the field of therapeutic landscapes have sought to emphasise the embodied, contextual and wholly relational nature of the relationship that exists between people and place. However, the extant research has tended to focus on the relational healing experience as this occurs 'in the moment' and with reference to a specific location or site of healing, with less attention being paid to what happens to people when they return to their ordinary or everyday places. In this paper, we reflect on findings from visual ethnographic work (including photography and film) that explored the therapeutic landscape experiences of people with intellectual disabilities engaged in care farming interventions for health and wellbeing. The study also recruited farm staff and family members or carers to take part, and comprised 20 participants in total. Having identified a gap in our understanding, consideration is given to wider impact that engaging in these sorts of activities had on the everyday lives of the participants in this study. We argue that this study has identified two types of therapeutic journey that broadly fit the experiences of study participants. The first type of journey denotes landscape experiences that are transformative. Here the therapeutic power of the care farm landscape resides in the ability of activities conducted on care farms to influence other aspects of participants' lives in ways that promote wellbeing. By contrast, there is another type of journey where the therapeutic power of the care farm resides in its ability to ameliorate challenging or harmful life situations, thus offering people a temporary site of respite or refuge. We conclude that these findings denote an important development for this sub-field of health geography, not only because they draw attention to the transformative power of the therapeutic encounter, but also the broader socio-spatial environments

A confidence building exercise in data and identifiability: Modeling cancer chemotherapy as a case study.

PubMed

Eisenberg, Marisa C; Jain, Harsh V

2017-10-27

Mathematical modeling has a long history in the field of cancer therapeutics, and there is increasing recognition that it can help uncover the mechanisms that underlie tumor response to treatment. However, making quantitative predictions with such models often requires parameter estimation from data, raising questions of parameter identifiability and estimability. Even in the case of structural (theoretical) identifiability, imperfect data and the resulting practical unidentifiability of model parameters can make it difficult to infer the desired information, and in some cases, to yield biologically correct inferences and predictions. Here, we examine parameter identifiability and estimability using a case study of two compartmental, ordinary differential equation models of cancer treatment with drugs that are cell cycle-specific (taxol) as well as non-specific (oxaliplatin). We proceed through model building, structural identifiability analysis, parameter estimation, practical identifiability analysis and its biological implications, as well as alternative data collection protocols and experimental designs that render the model identifiable. We use the differential algebra/input-output relationship approach for structural identifiability, and primarily the profile likelihood approach for practical identifiability. Despite the models being structurally identifiable, we show that without consideration of practical identifiability, incorrect cell cycle distributions can be inferred, that would result in suboptimal therapeutic choices. We illustrate the usefulness of estimating practically identifiable combinations (in addition to the more typically considered structurally identifiable combinations) in generating biologically meaningful insights. We also use simulated data to evaluate how the practical identifiability of the model would change under alternative experimental designs. These results highlight the importance of understanding the underlying mechanisms

Putting Meaning Back Into the Mean: A Comment on the Misuse of Elementary Statistics in a Sample of Manuscripts Submitted to Clinical Therapeutics.

PubMed

Forrester, Janet E

2015-12-01

Errors in the statistical presentation and analyses of data in the medical literature remain common despite efforts to improve the review process, including the creation of guidelines for authors and the use of statistical reviewers. This article discusses common elementary statistical errors seen in manuscripts recently submitted to Clinical Therapeutics and describes some ways in which authors and reviewers can identify errors and thus correct them before publication. A nonsystematic sample of manuscripts submitted to Clinical Therapeutics over the past year was examined for elementary statistical errors. Clinical Therapeutics has many of the same errors that reportedly exist in other journals. Authors require additional guidance to avoid elementary statistical errors and incentives to use the guidance. Implementation of reporting guidelines for authors and reviewers by journals such as Clinical Therapeutics may be a good approach to reduce the rate of statistical errors. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Anaplastic Thyroid Carcinoma: Current Treatments and Potential New Therapeutic Options with Emphasis on TfR1/CD71

PubMed Central

Salvatorelli, Lucia; Magro, Gaetano

2014-01-01

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers. Actually, ATC is refractory to conventional therapies, including surgery, chemotherapy, radiotherapy, and radioiodine (131I) therapy. Accordingly, genetic and molecular characterizations of ATC have been frequently and periodically reviewed in order to identify potential biological markers exploitable for target therapy. This review briefly focuses on main molecular events that characterize ATC and provides an update about preclinical studies. In addition, the overexpression of transferrin receptor 1 (TfR1/CD71) by neoplastic cells of ATC is emphasized in that it could represent a potential therapeutic target. In this regard, new therapeutic approaches based on the use of monoclonal or recombinant antibodies, or transferrin-gallium-TfR1/CD71 molecular complexes, or lastly small interfering RNAs (siRNAs) are proposed. PMID:25097549

Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches.

PubMed

Hajishengallis, George; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Lambris, John D

2015-01-01

The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis.

Health care provider communication: an empirical model of therapeutic effectiveness.

PubMed

Chochinov, Harvey M; McClement, Susan E; Hack, Thomas F; McKeen, Nancy A; Rach, Amanda M; Gagnon, Pierre; Sinclair, Shane; Taylor-Brown, Jill

2013-05-01

Patients who are facing life-threatening and life-limiting cancer almost invariably experience psychological distress. Responding effectively requires therapeutic sensitivity and skill. In this study, we examined therapeutic effectiveness within the setting of cancer-related distress with the objective of understanding its constituent parts. Seventy-eight experienced psychosocial oncology clinicians from 24 health care centers across Canada were invited to participate in 3 focus groups each. In total, 29 focus groups were held over 2 years, during which clinicians articulated the therapeutic factors deemed most helpful in mitigating patient psychosocial distress. The content of each focus group was summarized into major themes and was reviewed with participants to confirm their accuracy. Upon completion of the focus groups, workshops were held in various centers, eliciting participant feedback on an empirical model of therapeutic effectiveness based on the qualitative analysis of focus group data. Three primary, interrelated therapeutic domains emerged from the data, forming a model of optimal therapeutic effectiveness: 1) personal growth and self-care (domain A), 2) therapeutic approaches (domain B), and 3) creation of a safe space (domain C). Areas of domain overlap were identified and labeled accordingly: domain AB, therapeutic humility; domain BC, therapeutic pacing; and domain AC, therapeutic presence. This empirical model provides detailed insights regarding the elements and pedagogy of effective communication and psychosocial care for patients who are experiencing cancer-related distress. Copyright © 2012 American Cancer Society.

Therapeutic Uses of Triphala in Ayurvedic Medicine

PubMed Central

Denniston, Kate; Chopra, Deepak

2017-01-01

Abstract Aim: The aim of this article is to review the current literature on the therapeutic uses and efficacy of Triphala. Herbal remedies are among the most ancient medicines used in traditional systems of healthcare such as Ayurveda. Triphala, a well-recognized and highly efficacious polyherbal Ayurvedic medicine consisting of fruits of the plant species Emblica officinalis (Amalaki), Terminalia bellerica (Bibhitaki), and Terminalia chebula (Haritaki), is a cornerstone of gastrointestinal and rejuvenative treatment. Methods: A search of the PubMed database was conducted. Results: In addition, numerous additional therapeutic uses described both in the Ayurvedic medical literature and anecdotally are being validated scientifically. In addition to laxative action, Triphala research has found the formula to be potentially effective for several clinical uses such as appetite stimulation, reduction of hyperacidity, antioxidant, anti-inflammatory, immunomodulating, antibacterial, antimutagenic, adaptogenic, hypoglycemic, antineoplastic, chemoprotective, and radioprotective effects, and prevention of dental caries. Polyphenols in Triphala modulate the human gut microbiome and thereby promote the growth of beneficial Bifidobacteria and Lactobacillus while inhibiting the growth of undesirable gut microbes. The bioactivity of Triphala is elicited by gut microbiota to generate a variety of anti-inflammatory compounds. Conclusions: This review summarizes recent data on pharmacological properties and clinical effects of Triphala while highlighting areas in need of additional investigation and clinical development. PMID:28696777

Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization.

PubMed

Ramirez, Ursula D; Nikonova, Anna S; Liu, Hanqing; Pecherskaya, Anna; Lawrence, Sarah H; Serebriiskii, Ilya G; Zhou, Yan; Robinson, Matthew K; Einarson, Margret B; Golemis, Erica A; Jaffe, Eileen K

2015-05-28

Overexpression or mutation of the epidermal growth factor receptor (EGFR) potently enhances the growth of many solid tumors. Tumor cells frequently display resistance to mechanistically-distinct EGFR-directed therapeutic agents, making it valuable to develop therapeutics that work by additional mechanisms. Current EGFR-targeting therapeutics include antibodies targeting the extracellular domains, and small molecules inhibiting the intracellular kinase domain. Recent studies have identified a novel prone extracellular tetrameric EGFR configuration, which we identify as a potential target for drug discovery. Our focus is on the prone EGFR tetramer, which contains a novel protein-protein interface involving extracellular domain III. This EGFR tetramer is computationally targeted for stabilization by small molecule ligand binding. This study performed virtual screening of a Life Chemicals, Inc. small molecule library of 345,232 drug-like compounds against a molecular dynamics simulation of protein-protein interfaces distinct to the novel tetramer. One hundred nine chemically diverse candidate molecules were selected and evaluated using a cell-based high-content imaging screen that directly assessed induced internalization of the EGFR effector protein Grb2. Positive hits were further evaluated for influence on phosphorylation of EGFR and its effector ERK1/2. Fourteen hit compounds affected internalization of Grb2, an adaptor responsive to EGFR activation. Most hits had limited effect on cell viability, and minimally influenced EGFR and ERK1/2 phosphorylation. Docked hit compound poses generally include Arg270 or neighboring residues, which are also involved in binding the effective therapeutic cetuximab, guiding further chemical optimization. These data suggest that the EGFR tetrameric configuration offers a novel cancer drug target.

Identifying problem and compulsive gamblers.

PubMed Central

van Es, R.

2000-01-01

OBJECTIVE: To present a meta-analysis of current research on the prevalence, identification, and treatment of problem and compulsive gamblers. QUALITY OF EVIDENCE: Problem and compulsive gambling was not a socio-scientific concern until the last two decades. Hence research on this topic is limited. The summary and analysis for this paper relied on computer searches of journal and news abstracts in addition to direct contact with organizations addressing the identification and treatment of compulsive gamblers. MAIN MESSAGE: An estimated 5% of those who gamble run into problems. About 1% of those who gamble are predicted to experience serious problems. Successful treatment of problem and compulsive gambling continues to be a challenge. Although cognitive therapy has been the favoured approach, a combination of several therapeutic approaches is advocated. CONCLUSIONS: Problem and compulsive gambling can present a real health threat. As with other addictions, treatment strategies continue to be a baffling social problem. Aware and informed physicians can have a pivotal role in the difficult process of identifying, acknowledging, and remediating problem and compulsive gambling. PMID:10907572

Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma.

PubMed

Reznik, Robert; Hendifar, Andrew E; Tuli, Richard

2014-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided.

Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma

PubMed Central

Reznik, Robert; Hendifar, Andrew E.; Tuli, Richard

2014-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided. PMID:24624093

A systematic review and meta-analysis of self-help therapeutic interventions for obsessive-compulsive disorder: Is therapeutic contact key to overall improvement?

PubMed

Pearcy, Caitlin P; Anderson, Rebecca A; Egan, Sarah J; Rees, Clare S

2016-06-01

The presence of obsessive-compulsive disorder (OCD) can result in low quality of life, with significant impairments in social and occupational functioning. An increase in the dissemination of self-help programs has been observed in the treatment of OCD, and has provided improved accessibility to treatment. The present study examined the efficacy of self-help interventions for OCD in the context of therapeutic contact. Randomised controlled trials and quasi-experimental studies were identified through computerised database searches. Self-help format (bibliotherapy, internet-based, computerised), and therapeutic contact were examined for their effect on treatment outcomes. Eighteen studies targeting self-help for OCD met inclusion criteria with 1570 participants. The average post-treatment effect size (Hedges' g) of self-help interventions on primary outcomes was .51 (95% CI: .41 to 0.61). Subgroup analysis revealed large effect sizes for minimal-contact self-help (g = 0.91, 95% CI: 0.66 to 1.17), moderate effect sizes for predominantly self-help (g = 0.68, 95% CI: 0.40 to 0.96), and small effect sizes for self-administered self-help (g = 0.33, 95% CI: .18 to 0.47). A large variation of treatment approaches, amount of therapeutic contact, and risk of bias within each study may account for the large magnitude in effect sizes across studies. Additionally, the long-term follow-up effects of treatment approaches were not examined. A growing body of literature supporting to the use of self-help treatments for OCD is evident, however, further investigation through use of randomised controlled trials is required, particularly the use of stepped care and long-term effectiveness. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mental Health Disorder Therapeutic Modalities Modified for the GMS.

PubMed

Sumneangsanor, Tipsuda; Vuthiarpa, Sararud; Somprasert, Chomchueun

2017-12-01

Mental health disorders can affect physical and psychological behaviors. The people of the Greater Mekong Subregion (GMS) have a high risk of mental health disorders, such as depression, stress, and substance abuse be-cause the people in this region are trafficked for forced sex work and various forms of forced labor. In these situations, vic-tims often endure violence and abuse from trafficking recruiters, employers, and other individuals. The purposes of this study were to identify the elements characterizing mental health disorders, especially in terms of depression, stress, and sub-stance abuse, and to identify the treatment modalities for mental health disorders in the GMS. The researcher undertook a comparative analysis of the literature, reviews of epidemiological studies and mental disorder therapies, and overviews of previous research studies, were used to generate a synthesis of the existing knowledge of the mental disorder therapeutic modalities. Regarding the search methods, the data from the electronic databases PubMed, PsycINFO, Dynamed and ScienceDirect were supplemented with a manual reference search covering relevant studies from 2005 to 2016. Thirty-one papers were included in the review of elements characterizing mental health disorders, especially in terms of depression, stress, and substance abuse, and to identify the treatment modalities for mental health disorders in the GMS. Nine papers defined characterizing mental health disorders, in terms of depression, stress, and substance abuse. Twenty-two papers showed the treatment modalities for mental health disorders that the treatment was effective, these in-cluded pharmacological treatments and psychological treatments, such as mindfulness-based cognitive therapy, biofeedback, and music therapy. Useful guidance can be provided for the prevention and treatment of mental health disorders, and for the care of people in the Greater Mekong Subregion. The finding of this review confirms the

Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics

PubMed Central

Chi, Jen-Tsan; Thrall, Donald E.; Jiang, Chen; Snyder, Stacey; Fels, Diane; Landon, Chelsea; McCall, Linda; Lan, Lan; Hauck, Marlene; MacFall, James R.; Viglianti, Benjamin L.; Dewhirst, Mark W.

2011-01-01

Purpose While hyperthermia is an effective adjuvant treatment to radiotherapy, we don’t completely understand the nature of the response heterogeneity. Experimental Design We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. Results From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair and inflammation. The treatment-induced changes in gene expression identified two distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The two tumor subtypes could also be readily identified by pre-treatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of hsp70, POT1 and centrosomal proteins and lower levels of CD31, vWF and transferrin. Such differential gene expression between the two subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays. Conclusions To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors. PMID:21292819

Laparoscopic surgery for trauma: the realm of therapeutic management.

PubMed

Zafar, Syed N; Onwugbufor, Michael T; Hughes, Kakra; Greene, Wendy R; Cornwell, Edward E; Fullum, Terrence M; Tran, Daniel D

2015-04-01

The use of laparoscopy in trauma is, in general, limited for diagnostic purposes. We aim to evaluate the therapeutic role of laparoscopic surgery in trauma patients. We analyzed the National Trauma Data Bank (2007 to 2010) for all patients undergoing diagnostic laparoscopy. Patients undergoing a therapeutic laparoscopic surgical procedure were identified and tabulated. Mortality and hospital length of stay for patients with isolated abdominal injuries were compared between the open and laparoscopic groups. Of a total of 2,539,818 trauma visits in the National Trauma Data Bank, 4,755 patients underwent a diagnostic laparoscopy at 467 trauma centers. Of these, 916 (19.3%) patients underwent a therapeutic laparoscopic intervention. Common laparoscopic operations included diaphragm repair, bowel repair or resection, and splenectomy. Patients undergoing laparoscopic surgery had a significantly shorter length of stay than the open group (5 vs 6 days; P < .001). Therapeutic laparoscopic surgery for trauma is feasible and may provide better outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.

Molecular Chaperone Hsp90 Is a Therapeutic Target for Noroviruses

PubMed Central

Urena, Luis; Gonzalez-Hernandez, Mariam B.; Choi, Jayoung; de Rougemont, Alexis; Rocha-Pereira, Joana; Neyts, Johan; Hwang, Seungmin; Wobus, Christiane E.

2015-01-01

ABSTRACT Human noroviruses (HuNoV) are a significant cause of acute gastroenteritis in the developed world, and yet our understanding of the molecular pathways involved in norovirus replication and pathogenesis has been limited by the inability to efficiently culture these viruses in the laboratory. Using the murine norovirus (MNV) model, we have recently identified a network of host factors that interact with the 5′ and 3′ extremities of the norovirus RNA genome. In addition to a number of well-known cellular RNA binding proteins, the molecular chaperone Hsp90 was identified as a component of the ribonucleoprotein complex. Here, we show that the inhibition of Hsp90 activity negatively impacts norovirus replication in cell culture. Small-molecule-mediated inhibition of Hsp90 activity using 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) revealed that Hsp90 plays a pleiotropic role in the norovirus life cycle but that the stability of the viral capsid protein is integrally linked to Hsp90 activity. Furthermore, we demonstrate that both the MNV-1 and the HuNoV capsid proteins require Hsp90 activity for their stability and that targeting Hsp90 in vivo can significantly reduce virus replication. In summary, we demonstrate that targeting cellular proteostasis can inhibit norovirus replication, identifying a potential novel therapeutic target for the treatment of norovirus infections. IMPORTANCE HuNoV are a major cause of acute gastroenteritis around the world. RNA viruses, including noroviruses, rely heavily on host cell proteins and pathways for all aspects of their life cycle. Here, we identify one such protein, the molecular chaperone Hsp90, as an important factor required during the norovirus life cycle. We demonstrate that both murine and human noroviruses require the activity of Hsp90 for the stability of their capsid proteins. Furthermore, we demonstrate that targeting Hsp90 activity in vivo using small molecule inhibitors also reduces

Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke.

PubMed

Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

2010-07-08

Cannabis contains the psychoactive component delta⁸-tetrahydrocannabinol (delta⁸-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta⁸-THC and other cannabinoid CB₁ receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta⁸-THC also mediates psychological effects through the activation of the CB₁ receptor in the central nervous system. In addition to the CB₁ receptor agonists, cannabis also contains therapeutically active components which are CB₁ receptor independent. Of the CB₁ receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson's disease, Alzheimer's disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB₁ receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.

Enlight: A Comprehensive Quality and Therapeutic Potential Evaluation Tool for Mobile and Web-Based eHealth Interventions.

PubMed

Baumel, Amit; Faber, Keren; Mathur, Nandita; Kane, John M; Muench, Fred

2017-03-21

Studies of criteria-based assessment tools have demonstrated the feasibility of objectively evaluating eHealth interventions independent of empirical testing. However, current tools have not included some quality constructs associated with intervention outcome, such as persuasive design, behavior change, or therapeutic alliance. In addition, the generalizability of such tools has not been explicitly examined. The aim is to introduce the development and further analysis of the Enlight suite of measures, developed to incorporate the aforementioned concepts and address generalizability aspects. As a first step, a comprehensive systematic review was performed to identify relevant quality rating criteria in line with the PRISMA statement. These criteria were then categorized to create Enlight. The second step involved testing Enlight on 42 mobile apps and 42 Web-based programs (delivery mediums) targeting modifiable behaviors related to medical illness or mental health (clinical aims). A total of 476 criteria from 99 identified sources were used to build Enlight. The rating measures were divided into two sections: quality assessments and checklists. Quality assessments included usability, visual design, user engagement, content, therapeutic persuasiveness, therapeutic alliance, and general subjective evaluation. The checklists included credibility, privacy explanation, basic security, and evidence-based program ranking. The quality constructs exhibited excellent interrater reliability (intraclass correlations=.77-.98, median .91) and internal consistency (Cronbach alphas=.83-.90, median .88), with similar results when separated into delivery mediums or clinical aims. Conditional probability analysis revealed that 100% of the programs that received a score of fair or above (≥3.0) in therapeutic persuasiveness or therapeutic alliance received the same range of scores in user engagement and content-a pattern that did not appear in the opposite direction. Preliminary

Vocational Education and Training and the Therapeutic Turn

ERIC Educational Resources Information Center

Hyland, Terry

2006-01-01

The concept of "therapeutic education" is being increasingly used in contemporary education policy studies to identify learning initiatives which are dominated by objectives linked to personal and social skills, emotional intelligence and building self-esteem. Contemporary educational goals connected with such strategies have been…

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma.

PubMed

Hanes, Robert; Grad, Iwona; Lorenz, Susanne; Stratford, Eva W; Munthe, Else; Reddy, Chilamakuri Chandra Sekhar; Meza-Zepeda, Leonardo A; Myklebost, Ola

2016-08-23

Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines. We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma (DDLPS) by exome and transcriptome sequencing as well as DNA copy number analysis. Genomic aberrations of several potentially targetable genes, including amplification of KITLG and FRS2, in addition to amplification of CDK4 and MDM2, characteristic of this disease, were identified. We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a cell line derived from the patient. Interestingly, the pan-FGFR inhibitor NVP-BGJ398, which targets FGFR upstream of FRS2, strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G0 phase of the cell cycle. This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2.

Determinants of immunogenic response to protein therapeutics.

PubMed

Singh, Satish K; Cousens, Leslie P; Alvarez, David; Mahajan, Pramod B

2012-09-01

Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation. Copyright © 2012. Published by Elsevier Ltd.. All rights reserved.

Characteristics of therapeutic alliance in musculoskeletal physiotherapy and occupational therapy practice: a scoping review of the literature.

PubMed

Babatunde, Folarin; MacDermid, Joy; MacIntyre, Norma

2017-05-30

Most conventional treatment for musculoskeletal conditions continue to show moderate effects, prompting calls for ways to increase effectiveness, including drawing from strategies used across other health conditions. Therapeutic alliance refers to the relational processes at play in treatment which can act in combination or independently of specific interventions. Current evidence guiding the use of therapeutic alliance in health care arises largely from psychotherapy and medicine literature. The objective of this review was to map out the available literature on therapeutic alliance conceptual frameworks, themes, measures and determinants in musculoskeletal rehabilitation across physiotherapy and occupational therapy disciplines. A scoping review of the literature published in English since inception to July 2015 was conducted using Medline, EMBASE, PsychINFO, PEDro, SportDISCUS, AMED, OTSeeker, AMED and the grey literature. A key search term strategy was employed using "physiotherapy", "occupational therapy", "therapeutic alliance", and "musculoskeletal" to identify relevant studies. All searches were performed between December 2014 and July 2015 with an updated search on January 2017. Two investigators screened article title, abstract and full text review for articles meeting the inclusion criteria and extracted therapeutic alliance data and details of each study. One hundred and thirty articles met the inclusion criteria including quantitative (33%), qualitative (39%), mixed methods (7%) and reviews and discussions (23%) and most data came from the USA (23%). Randomized trials and systematic reviews were 4.6 and 2.3% respectively. Low back pain condition (22%) and primary care (30.7%) were the most reported condition and setting respectively. One theory, 9 frameworks, 26 models, 8 themes and 42 subthemes of therapeutic alliance were identified. Twenty-six measures were identified; the Working Alliance Inventory (WAI) was the most utilized measure (13%). Most of

A gene-signature progression approach to identifying candidate small-molecule cancer therapeutics with connectivity mapping.

PubMed

Wen, Qing; Kim, Chang-Sik; Hamilton, Peter W; Zhang, Shu-Dong

2016-05-11

Gene expression connectivity mapping has gained much popularity recently with a number of successful applications in biomedical research testifying its utility and promise. Previously methodological research in connectivity mapping mainly focused on two of the key components in the framework, namely, the reference gene expression profiles and the connectivity mapping algorithms. The other key component in this framework, the query gene signature, has been left to users to construct without much consensus on how this should be done, albeit it has been an issue most relevant to end users. As a key input to the connectivity mapping process, gene signature is crucially important in returning biologically meaningful and relevant results. This paper intends to formulate a standardized procedure for constructing high quality gene signatures from a user's perspective. We describe a two-stage process for making quality gene signatures using gene expression data as initial inputs. First, a differential gene expression analysis comparing two distinct biological states; only the genes that have passed stringent statistical criteria are considered in the second stage of the process, which involves ranking genes based on statistical as well as biological significance. We introduce a "gene signature progression" method as a standard procedure in connectivity mapping. Starting from the highest ranked gene, we progressively determine the minimum length of the gene signature that allows connections to the reference profiles (drugs) being established with a preset target false discovery rate. We use a lung cancer dataset and a breast cancer dataset as two case studies to demonstrate how this standardized procedure works, and we show that highly relevant and interesting biological connections are returned. Of particular note is gefitinib, identified as among the candidate therapeutics in our lung cancer case study. Our gene signature was based on gene expression data from Taiwan

Healing Classrooms: Therapeutic Possibilities in Academic Writing

ERIC Educational Resources Information Center

Batzer, Benjamin

2016-01-01

This article asks us to consider what the process of healing and composition pedagogy have to learn from each other. More specifically, it identifies how the therapeutic potential of writing, which has been largely neglected in the academy in recent years, can influence the ways we teach transferable writing skills. The article considers how…

Update on Huntington's disease: advances in care and emerging therapeutic options.

PubMed

Zielonka, Daniel; Mielcarek, Michal; Landwehrmeyer, G Bernhard

2015-03-01

Huntington's disease (HD) is the most common hereditary neurodegenerative disorder. Despite the fact that both the gene and the mutation causing this monogenetic disorder were identified more than 20 years ago, disease-modifying therapies for HD have not yet been established. While intense preclinical research and large cohort studies in HD have laid foundations for tangible improvements in understanding HD and caring for HD patients, identifying targets for therapeutic interventions and developing novel therapeutic modalities (new chemical entities and advanced therapies using DNA and RNA molecules as therapeutic agents) continues to be an ongoing process. The authors review recent achievements in HD research and focus on approaches towards disease-modifying therapies, ranging from huntingtin-lowering strategies to improving huntingtin clearance that may be promoted by posttranslational HTT modifications. The nature and number of upcoming clinical studies/trials in HD is a reason for hope for HD patients and their families. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer.

PubMed

Brägelmann, Johannes; Klümper, Niklas; Offermann, Anne; von Mässenhausen, Anne; Böhm, Diana; Deng, Mario; Queisser, Angela; Sanders, Christine; Syring, Isabella; Merseburger, Axel S; Vogel, Wenzel; Sievers, Elisabeth; Vlasic, Ignacija; Carlsson, Jessica; Andrén, Ove; Brossart, Peter; Duensing, Stefan; Svensson, Maria A; Shaikhibrahim, Zaki; Kirfel, Jutta; Perner, Sven

2017-04-01

Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches. Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities ( n = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer ( n = 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq. Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancer was marked by high expression of CDK19 In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8 were present in metastases. In vitro , inhibition of CDK19 and CDK8 by knockdown or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion. Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer. Clin Cancer Res; 23(7); 1829-40. ©2016 AACR . ©2016 American Association for Cancer Research.

Component resolution reveals additional major allergens in patients with honeybee venom allergy.

PubMed

Köhler, Julian; Blank, Simon; Müller, Sabine; Bantleon, Frank; Frick, Marcel; Huss-Marp, Johannes; Lidholm, Jonas; Spillner, Edzard; Jakob, Thilo

2014-05-01

Detection of IgE to recombinant Hymenoptera venom allergens has been suggested to improve the diagnostic precision in Hymenoptera venom allergy. However, the frequency of sensitization to the only available recombinant honeybee venom (HBV) allergen, rApi m 1, in patients with HBV allergy is limited, suggesting that additional HBV allergens might be of relevance. We performed an analysis of sensitization profiles of patients with HBV allergy to a panel of HBV allergens. Diagnosis of HBV allergy (n = 144) was based on history, skin test results, and allergen-specific IgE levels to HBV. IgE reactivity to 6 HBV allergens devoid of cross-reactive carbohydrate determinants (CCD) was analyzed by ImmunoCAP. IgE reactivity to rApi m 1, rApi m 2, rApi m 3, nApi m 4, rApi m 5, and rApi m 10 was detected in 72.2%, 47.9%, 50.0%, 22.9%, 58.3%, and 61.8% of the patients with HBV allergy, respectively. Positive results to at least 1 HBV allergen were detected in 94.4%. IgE reactivity to Api m 3, Api m 10, or both was detected in 68.0% and represented the only HBV allergen-specific IgE in 5% of the patients. Limited inhibition of IgE binding by therapeutic HBV and limited induction of Api m 3- and Api m 10-specific IgG4 in patients obtaining immunotherapy supports recent reports on the underrepresentation of these allergens in therapeutic HBV preparations. Analysis of a panel of CCD-free HBV allergens improved diagnostic sensitivity compared with use of rApi m 1 alone, identified additional major allergens, and revealed sensitizations to allergens that have been reported to be absent or underrepresented in therapeutic HBV preparations. Copyright © 2014 The Authors. Published by Mosby, Inc. All rights reserved.

Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery.

PubMed

Qu, Ying; Chu, BingYang; Shi, Kun; Peng, JinRong; Qian, ZhiYong

2017-12-01

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.

An assessment of the factors affecting the commercialization of cell-based therapeutics: a systematic review protocol.

PubMed

Pettitt, David; Arshad, Zeeshaan; Davies, Benjamin; Smith, James; French, Anna; Cole, Doug; Bure, Kim; Dopson, Sue; DiGiusto, David; Karp, Jeff; Reeve, Brock; Barker, Richard; Holländer, Georg; Brindley, David

2017-06-26

Cellular-based therapies represent a platform technology within the rapidly expanding field of regenerative medicine and are distinct from conventional therapeutics-offering a unique approach to managing what were once considered untreatable diseases. Despite a significant increase in basic science activity within the cell therapy arena, alongside a growing portfolio of cell therapy trials and promising investment, the translation of cellular-based therapeutics from "bench to bedside" remains challenging, and the number of industry products available for widespread clinical use remains comparatively low. This systematic review identifies unique intrinsic and extrinsic barriers in the cell-based therapy domain. Eight electronic databases will be searched, specifically Medline, EMBASE (OvidSP), BIOSIS & Web of Science, Cochrane Library & HEED, EconLit (ProQuest), WHOLIS WHO Library Database, PAIS International (ProQuest), and Scopus. Addition to this gray literature was searched by manually reviewing relevant work. All identified articles will be subjected for review by two authors who will decide whether or not each article passes our inclusion/exclusion criteria. Eligible papers will subsequently be reviewed, and key data extracted into a pre-designed data extraction scorecard. An assessment of the perceived impact of broad commercial barriers to the adoption of cell-based therapies will be conducted. These broad categories will include manufacturing, regulation and intellectual property, reimbursement, clinical trials, clinical adoption, ethics, and business models. This will inform further discussion in the review. There is no PROSPERO registration number. Through a systematic search and appraisal of available literature, this review will identify key challenges in the commercialization pathway of cellular-based therapeutics and highlights significant barriers impeding successful clinical adoption. This will aid in creating an adaptable, acceptable, and

Using generalized additive modeling to empirically identify thresholds within the ITERS in relation to toddlers' cognitive development.

PubMed

Setodji, Claude Messan; Le, Vi-Nhuan; Schaack, Diana

2013-04-01

Research linking high-quality child care programs and children's cognitive development has contributed to the growing popularity of child care quality benchmarking efforts such as quality rating and improvement systems (QRIS). Consequently, there has been an increased interest in and a need for approaches to identifying thresholds, or cutpoints, in the child care quality measures used in these benchmarking efforts that differentiate between different levels of children's cognitive functioning. To date, research has provided little guidance to policymakers as to where these thresholds should be set. Using the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) data set, this study explores the use of generalized additive modeling (GAM) as a method of identifying thresholds on the Infant/Toddler Environment Rating Scale (ITERS) in relation to toddlers' performance on the Mental Development subscale of the Bayley Scales of Infant Development (the Bayley Mental Development Scale Short Form-Research Edition, or BMDSF-R). The present findings suggest that simple linear models do not always correctly depict the relationships between ITERS scores and BMDSF-R scores and that GAM-derived thresholds were more effective at differentiating among children's performance levels on the BMDSF-R. Additionally, the present findings suggest that there is a minimum threshold on the ITERS that must be exceeded before significant improvements in children's cognitive development can be expected. There may also be a ceiling threshold on the ITERS, such that beyond a certain level, only marginal increases in children's BMDSF-R scores are observed. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Autoimmune therapies targeting costimulation and emerging trends in multivalent therapeutics.

PubMed

Chittasupho, Chuda; Siahaan, Teruna J; Vines, Charlotte M; Berkland, Cory

2011-07-01

Proteins participating in immunological signaling have emerged as important targets for controlling the immune response. A multitude of receptor-ligand pairs that regulate signaling pathways of the immune response have been identified. In the complex milieu of immune signaling, therapeutic agents targeting mediators of cellular signaling often either activate an inflammatory immune response or induce tolerance. This review is primarily focused on therapeutics that inhibit the inflammatory immune response by targeting membrane-bound proteins regulating costimulation or mediating immune-cell adhesion. Many of these signals participate in larger, organized structures such as the immunological synapse. Receptor clustering and arrangement into organized structures is also reviewed and emerging trends implicating a potential role for multivalent therapeutics is posited.

Therapeutic gold, silver, and platinum nanoparticles.

PubMed

Yamada, Miko; Foote, Matthew; Prow, Tarl W

2015-01-01

There are an abundance of nanoparticle technologies being developed for use as part of therapeutic strategies. This review focuses on a narrow class of metal nanoparticles that have therapeutic potential that is a consequence of elemental composition and size. The most widely known of these are gold nanoshells that have been developed over the last two decades for photothermal ablation in superficial cancers. The therapeutic effect is the outcome of the thickness and diameter of the gold shell that enables fine tuning of the plasmon resonance. When these metal nanoparticles are exposed to the relevant wavelength of light, their temperature rapidly increases. This in turn induces a localized photothermal ablation that kills the surrounding tumor tissue. Similarly, gold nanoparticles have been developed to enhance radiotherapy. The high-Z nature of gold dramatically increases the photoelectric cross-section. Thus, the photoelectric effects are significantly increased. The outcome of these interactions is enhanced tumor killing with lower doses of radiation, all while sparing tissue without gold nanoparticles. Silver nanoparticles have been used for their wound healing properties in addition to enhancing the tumor-killing effects of anticancer drugs. Finally, platinum nanoparticles are thought to serve as a reservoir for platinum ions that can induce DNA damage in cancer cells. The future is bright with the path to clinical trials is largely cleared for some of the less complex therapeutic metal nanoparticle systems. © 2014 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.

Therapeutic bond judgments: Congruence and incongruence.

PubMed

Atzil-Slonim, Dana; Bar-Kalifa, Eran; Rafaeli, Eshkol; Lutz, Wolfgang; Rubel, Julian; Schiefele, Ann-Kathrin; Peri, Tuvia

2015-08-01

The present study had 2 aims: (a) to implement West and Kenny's (2011) Truth-and-Bias model to simultaneously assess the temporal congruence and directional discrepancy between clients' and therapists' ratings of the bond facet of the therapeutic alliance, as they cofluctuate from session to session; and (b) to examine whether symptom severity and a personality disorder (PD) diagnosis moderate congruence and/or discrepancy. Participants included 213 clients treated by 49 therapists. At pretreatment, clients were assessed for a PD diagnosis and completed symptom measures. Symptom severity was also assessed at the beginning of each session, using client self-reports. Both clients and therapists rated the therapeutic bond at the end of each session. Therapists and clients exhibited substantial temporal congruence in their session-by-session bond ratings, but therapists' ratings tended to be lower than their clients' across sessions. Additionally, therapeutic dyads whose session-by-session ratings were more congruent also tended to have a larger directional discrepancy (clients' ratings being higher). Pretreatment symptom severity and PD diagnosis did not moderate either temporal congruence or discrepancy at the dyad level; however, during sessions when clients were more symptomatic, therapist and client ratings were both farther apart and tracked each other less closely. Our findings are consistent with a "better safe than sorry" pattern, which suggests that therapists are motivated to take a vigilant approach that may lead both to underestimation and to attunement to fluctuations in the therapeutic bond. (c) 2015 APA, all rights reserved).

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed

Straube, Andreas; Aicher, Bernhard; Fiebich, Bernd L; Haag, Gunther

2011-03-31

Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixed-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed Central

2011-01-01

Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic

MicroRNAs as Therapeutic Targets and Colorectal Cancer Therapeutics.

PubMed

Yamamoto, Hirofumi; Mori, Masaki

The diagnosis and treatment of colorectal cancer (CRC) have improved greatly over recent years; however, CRC is still one of the most common cancers and a major cause of cancer death worldwide. Several recently developed drugs and treatment strategies are currently in clinical trials; however, there is still a compelling need for novel, highly efficacious therapies. MicroRNAs (miRNAs) are short non-coding RNAs consisting of 20-25 nucleotides that regulate post-transcriptional gene expression by binding to the 3'-untranslated region of mRNAs. miRNAs are known to regulate cancer pathways and to be expressed aberrantly in cancer. Since their initial discovery, a large number of miRNAs have been identified as oncogenes, whereas others function as tumor suppressors. Furthermore, signaling pathways that are important in CRC (e.g. the WNT, MAPK, TGF-β, TP53 and PI3K pathways) are regulated by miRNAs. A single miRNA can simultaneously regulate several target genes and pathways, indicating the therapeutic potential of miRNAs in CRC. However, significant obstacles remain to be overcome, such as an efficient miRNA delivery system, and the assessment of safety and side effects. Thus, miRNA therapy is still developing and possesses great potential for the treatment of CRC. In this chapter, we focus on miRNAs related to CRC and summarize previous studies that emphasize the therapeutic aspects of miRNAs in CRC.

Therapeutic Change in Group Therapy For Interpersonal Trauma: A Relational Framework for Research and Clinical Practice.

PubMed

Chouliara, Zoë; Karatzias, Thanos; Gullone, Angela; Ferguson, Sandra; Cosgrove, Katie; Burke Draucker, Claire

2017-04-01

Our understanding of therapeutic change processes in group therapy for complex interpersonal trauma has been limited. The present study aimed at addressing this gap by developing a framework of therapeutic change in this field from a survivor and therapist perspective. This is a qualitative study, which utilized semistructured individual interviews. Transcripts were analyzed using interpretative phenomenological analysis (IPA) to identify recurrent themes. A final sample of n = 16 patients and n = 5 facilitators completed the interview. Main change processes identified by survivors were as follows: self versus others, trust versus threat, confrontation versus avoidance, and "patching up" versus true healing. Therapeutic processes identified by therapist facilitators included managing group dynamics, unpredictability and uncertainty, and process versus content. The proposed framework explains therapeutic change in group therapy in relational terms, that is, therapeutic dissonance, the dynamic interaction of self and experience as well as building empathic trusting relations. The importance of managing dissonance to aid personally meaningful recovery was highlighted. These findings have implications for the usefulness of relational and person-centered approaches to clinical practice in the area of interpersonal and complex trauma, especially in the early identification, prevention, and management of dropouts.

Microglia activation in Niemann-Pick disease, type C1 is amendable to therapeutic intervention.

PubMed

Cougnoux, Antony; Drummond, Rebecca A; Collar, Amanda L; Iben, James R; Salman, Alexander; Westgarth, Harrison; Wassif, Christopher A; Cawley, Niamh X; Farhat, Nicole Y; Ozato, Keiko; Lionakis, Michail S; Porter, Forbes D

2018-06-15

Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 is associated with neuroinflammation; however, attempts to therapeutically target neuroinflammation in NPC1 have had mixed success. We show here that NPC1 neuroinflammation is characterized by an atypical microglia activation phenotype. Specifically, Npc1-/- microglia demonstrated altered morphology, reduced levels of lineage markers and a shift toward glycolytic metabolism. Treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a drug currently being studied in a phase 2b/3 clinical trial, reversed all microglia-associated defects in Npc1-/- animals. In addition, impairing microglia mediated neuroinflammation by genetic deletion of IRF8 led to decreased symptoms and increased lifespan. We identified CD22 as a marker of dysregulated microglia in Npc1 mutant mice and subsequently demonstrated that elevated cerebrospinal fluid levels of CD22 in NPC1 patients responds to HPβCD administration. Collectively, these data provide the first in-depth analysis of microglia function in NPC1 and suggest possible new therapeutic approaches.

The Role of Chromosomal Instability in Cancer and Therapeutic Responses

PubMed Central

Vargas-Rondón, Natalia

2017-01-01

Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses. PMID:29283387

CONVERGENT TRANSCRIPTOMICS AND PROTEOMICS OF ENVIRONMENTAL ENRICHMENT AND COCAINE IDENTIFIES NOVEL THERAPEUTIC STRATEGIES FOR ADDICTION

PubMed Central

ZHANG, YAFANG; CROFTON, ELIZABETH J.; FAN, XIUZHEN; LI, DINGGE; KONG, FANPING; SINHA, MALA; LUXON, BRUCE A.; SPRATT, HEIDI M.; LICHTI, CHERYL F.; GREEN, THOMAS A.

2016-01-01

Transcriptomic and proteomic approaches have separately proven effective at identifying novel mechanisms affecting addiction-related behavior; however, it is difficult to prioritize the many promising leads from each approach. A convergent secondary analysis of proteomic and transcriptomic results can glean additional information to help prioritize promising leads. The current study is a secondary analysis of the convergence of recently published separate transcriptomic and proteomic analyses of nucleus accumbens (NAc) tissue from rats subjected to environmental enrichment vs. isolation and cocaine self-administration vs. saline. Multiple bioinformatics approaches (e.g. Gene Ontology (GO) analysis, Ingenuity Pathway Analysis (IPA), and Gene Set Enrichment Analysis (GSEA)) were used to interrogate these rich data sets. Although there was little correspondence between mRNA vs. protein at the individual target level, good correspondence was found at the level of gene/protein sets, particularly for the environmental enrichment manipulation. These data identify gene sets where there is a positive relationship between changes in mRNA and protein (e.g. glycolysis, ATP synthesis, translation elongation factor activity, etc.) and gene sets where there is an inverse relationship (e.g. ribosomes, Rho GTPase signaling, protein ubiquitination, etc.). Overall environmental enrichment produced better correspondence than cocaine self-administration. The individual targets contributing to mRNA and protein effects were largely not overlapping. As a whole, these results confirm that robust transcriptomic and proteomic data sets can provide similar results at the gene/protein set level even when there is little correspondence at the individual target level and little overlap in the targets contributing to the effects. PMID:27717806

Menstrual Migraine: Therapeutic Approaches

PubMed Central

2009-01-01

The development of diagnostic criteria has enabled greater recognition of menstrual migraine as a highly prevalent and disabling condition meriting specific treatment. Although few therapeutic trials have yet been undertaken in accordance with the criteria, the results of those published to date confirm the efficacy of acute migraine drugs for symptomatic treatment. If this approach is insufficient, the predictability of attacks provides the opportunity for perimenstrual prophylaxis. Continuous contraceptive strategies provide an additional option for management, although clinical trial data are limited. Future approaches to treatment could explore the genomic and nongenomic actions of sex steroids. PMID:21180623

Therapeutic Substance Abuse Treatment for Incarcerated Women

PubMed Central

Finfgeld-Connett, Deborah; Johnson, E. Diane

2011-01-01

The purpose of this qualitative systematic review was to explicate attributes of optimal therapeutic strategies for treating incarcerated women who have a history of substance abuse. An expansive search of electronic databases for qualitative research reports relating to substance abuse treatment for incarcerated women was conducted. Nine qualitative research reports comprised the sample for this review. Findings from these reports were extracted, placed into a data analysis matrix, coded, and categorized. Memos were written, and strategies for treating incarcerated women with alcohol problems were identified. Therapeutic effects of treatment programs for incarcerated women with substance-abuse problems appear to be enhanced when trust-based relationships are established, individualized and just care is provided, and treatment facilities are separate from the general prison environment. PMID:21771929

Differential activation of an identified motor neuron and neuromodulation provide Aplysia's retractor muscle an additional function.

PubMed

McManus, Jeffrey M; Lu, Hui; Cullins, Miranda J; Chiel, Hillel J

2014-08-15

To survive, animals must use the same peripheral structures to perform a variety of tasks. How does a nervous system employ one muscle to perform multiple functions? We addressed this question through work on the I3 jaw muscle of the marine mollusk Aplysia californica's feeding system. This muscle mediates retraction of Aplysia's food grasper in multiple feeding responses and is innervated by a pool of identified neurons that activate different muscle regions. One I3 motor neuron, B38, is active in the protraction phase, rather than the retraction phase, suggesting the muscle has an additional function. We used intracellular, extracellular, and muscle force recordings in several in vitro preparations as well as recordings of nerve and muscle activity from intact, behaving animals to characterize B38's activation of the muscle and its activity in different behavior types. We show that B38 specifically activates the anterior region of I3 and is specifically recruited during one behavior, swallowing. The function of this protraction-phase jaw muscle contraction is to hold food; thus the I3 muscle has an additional function beyond mediating retraction. We additionally show that B38's typical activity during in vivo swallowing is insufficient to generate force in an unmodulated muscle and that intrinsic and extrinsic modulation shift the force-frequency relationship to allow contraction. Using methods that traverse levels from individual neuron to muscle to intact animal, we show how regional muscle activation, differential motor neuron recruitment, and neuromodulation are key components in Aplysia's generation of multifunctionality. Copyright © 2014 the American Physiological Society.

Identification of the APC/C co-factor FZR1 as a novel therapeutic target for multiple myeloma.

PubMed

Crawford, Lisa J; Anderson, Gordon; Johnston, Cliona K; Irvine, Alexandra E

2016-10-25

Multiple Myeloma (MM) is a haematological neoplasm characterised by the clonal proliferation of malignant plasma cells in the bone marrow. The success of proteasome inhibitors in the treatment of MM has highlighted the importance of the ubiquitin proteasome system (UPS) in the pathogenesis of this disease. In this study, we analysed gene expression of UPS components to identify novel therapeutic targets within this pathway in MM. Here we demonstrate how this approach identified previously validated and novel therapeutic targets. In addition we show that FZR1 (Fzr), a cofactor of the multi-subunit E3 ligase complex anaphase-promoting complex/cyclosome (APC/C), represents a novel therapeutic target in myeloma. The APC/C associates independently with two cofactors, Fzr and Cdc20, to control cell cycle progression. We found high levels of FZR1 in MM primary cells and cell lines and demonstrate that expression is further increased on adhesion to bone marrow stromal cells (BMSCs). Specific knockdown of either FZR1 or CDC20 reduced viability and induced growth arrest of MM cell lines, and resulted in accumulation of APC/CFzr substrate Topoisomerase IIα (TOPIIα) or APC/CCdc20 substrate Cyclin B. Similar effects were observed following treatment with proTAME, an inhibitor of both APC/CFzr and APC/CCdc20. Combinations of proTAME with topoisomerase inhibitors, etoposide and doxorubicin, significantly increased cell death in MM cell lines and primary cells, particularly if TOPIIα levels were first increased through pre-treatment with proTAME. Similarly, combinations of proTAME with the microtubule inhibitor vincristine resulted in enhanced cell death. This study demonstrates the potential of targeting the APC/C and its cofactors as a therapeutic approach in MM.

[Epilepsy-new diagnostic tools, old drugs? : Therapeutic consequences of epilepsy genetics].

PubMed

Tacke, M; Neubauer, B A; Gerstl, L; Roser, T; Rémi, J; Borggraefe, I

2017-12-01

Recent advances in the field of epilepsy genetics have led to an increased fraction of patients with epilepsies where the etiology of the disease could be identified. Nevertheless, there is some criticism regarding the use of epilepsy genetics because in many cases the identification of a pathogenetic mutation does not lead to an adaptation of therapy or to an improved prognosis. In addition, the interpretation of genetic results might be complicated due to the considerable numbers of variants of unclear significance. This publication presents the arguments in favour of a broad use of genetic investigations for children with epilepsies. Several diseases where a genetic diagnosis does in fact have direct therapeutic consequences are mentioned. In addition, the indirect impact of an established etiology, encompassing the avoidance of unnecessary diagnostic measures, possibility of genetic counselling, and the easing of the psychologic burden for the caregivers, should not be underestimated. The arguments in favour of broad genetic diagnostics prevail notwithstanding the lack of relevant new developments regarding the therapy.

Towards new uses of botulinum toxin as a novel therapeutic tool.

PubMed

Pickett, Andy; Perrow, Karen

2011-01-01

The uses of botulinum toxin in the fields of neurology, ophthalmology, urology, rehabilitation medicine and aesthetic applications have been revolutionary for the treatment of patients. This non-invasive therapeutic has continually been developed since first discovered in the 1970s as a new approach to what were previously surgical treatments. As these applications develop, so also the molecules are developing into tools with new therapeutic properties in specific clinical areas. This review examines how the botulinum toxin molecule is being adapted to new therapeutic uses and also how new areas of use for the existing molecules are being identified. Prospects for future developments are also considered.

Synergizing vaccinations with therapeutics for measles eradication.

PubMed

Plemper, Richard K; Hammond, Anthea L

2014-02-01

The measles virus is a major human pathogen responsible for approximately 150,000 deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible, in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence, combined with public anxiety over the vaccination's safety, has led to increased vaccine refusal, especially in Europe. This has led to the resurgence of measles in some areas. This article discusses whether synergizing effective measles therapeutics with the measles vaccination could contribute to finally eradicating measles. The authors identify key elements in a desirable drug profile and review current disease management strategies and the state of experimental inhibitor candidates. The authors also evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics in the management of persistent central nervous system (CNS) viral infection. Finally, the authors contemplate the possible impact of therapeutics in controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles. Efficacious therapeutics used for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps; this is due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent population, dictates the drug profile. It also has to be safe and efficacious, orally available, shelf-stable at ambient temperature and amenable to cost-effective manufacturing.

Structurally Based Therapeutic Evaluation: A Therapeutic and Practical Approach to Teaching Medicinal Chemistry.

ERIC Educational Resources Information Center

Alsharif, Naser Z.; And Others

1997-01-01

Explains structurally based therapeutic evaluation of drugs, which uses seven therapeutic criteria in translating chemical and structural knowledge into therapeutic decision making in pharmaceutical care. In a Creighton University (Nebraska) medicinal chemistry course, students apply the approach to solve patient-related therapeutic problems in…

Cyclic peptides as potential therapeutic agents for skin disorders.

PubMed

Namjoshi, Sarika; Benson, Heather A E

2010-01-01

There is an increasing understanding of the role of peptides in normal skin function and skin disease. With this knowledge, there is significant interest in the application of peptides as therapeutics in skin disease or as cosmeceuticals to enhance skin appearance. In particular, antimicrobial peptides and those involved in inflammatory processes provide options for the development of new therapeutic directions in chronic skin conditions such as psoriasis and dermatitis. To exploit their potential, it is essential that these peptides are delivered to their site of action in active form and in sufficient quantity to provide the desired effect. Many polymers permeate the skin poorly and are vulnerable to enzymatic degradation. Synthesis of cyclic peptide derivatives can substantially alter the physicochemical characteristics of the peptide with the potential to improve its skin permeation. In addition, cyclization can stabilize the peptide structure and thereby increase its stability. This review describes the role of cyclic peptides in the skin, examples of current cyclic peptide therapeutic products, and the potential for cyclic peptides as dermatological therapeutics and cosmeceuticals.

HER2-positive breast cancer: Current and new therapeutic strategies.

PubMed

Escrivá-de-Romaní, Santiago; Arumí, Miriam; Bellet, Meritxell; Saura, Cristina

2018-06-01

Since the identification of the HER2 receptor amplification as an adverse prognostic factor that defined a special subtype of metastatic breast cancer, there has been a substantial improvement in survival of patients affected with this disease due to the development of anti-HER2 targeted therapies. The approval of trastuzumab and pertuzumab associated to a taxane in first line and subsequent treatment with the antibody-drug conjugate T-DM1 has certainly contributed to achieve these outcomes. The Tyrosine Kinase Inhibitor lapatinib was also approved in the basis of an improvement in progression free survival, becoming another commonly used treatment in combination with capecitabine. Inevitably, despite these therapeutic advances most patients progress on therapy due to primary or acquired resistance or because of an incorrect HER2 positivity assessment. Hence, it is crucial to correctly categorize HER2 amplified tumors and define mechanisms of resistance to design effective new treatment approaches. In addition, identifying biomarkers of response or resistance permits to tailor the therapeutic options for each patient sparing them from unnecessary toxicity as well as improving their outcomes. The aim of this review is to examine new strategies in development to treat HER2-positive metastatic breast cancer referring to the mechanisms of action of new drugs and new combinations including results reported so far. Copyright © 2018 Elsevier Ltd. All rights reserved.

Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke

PubMed Central

Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

2010-01-01

Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke. PMID:27713349

Mechanisms of Plasma Therapeutics

NASA Astrophysics Data System (ADS)

Graves, David

2015-09-01

In this talk, I address research directed towards biomedical applications of atmospheric pressure plasma such as sterilization, surgery, wound healing and anti-cancer therapy. The field has seen remarkable growth in the last 3-5 years, but the mechanisms responsible for the biomedical effects have remained mysterious. It is known that plasmas readily create reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS (or RONS), in addition to a suite of other radical and non-radical reactive species, are essential actors in an important sub-field of aerobic biology termed ``redox'' (or oxidation-reduction) biology. It is postulated that cold atmospheric plasma (CAP) can trigger a therapeutic shielding response in tissue in part by creating a time- and space-localized, burst-like form of oxy-nitrosative stress on near-surface exposed cells through the flux of plasma-generated RONS. RONS-exposed surface layers of cells communicate to the deeper levels of tissue via a form of the ``bystander effect,'' similar to responses to other forms of cell stress. In this proposed model of CAP therapeutics, the plasma stimulates a cellular survival mechanism through which aerobic organisms shield themselves from infection and other challenges.

Physical dose of therapeutic exercises in institutional neck rehabilitation.

PubMed

Wasenius, Niko; Karapalo, Teppo; Sjögren, Tuulikki; Pekkonen, Mika; Mälkiä, Esko

2013-03-01

To determine the intensity and volume of therapeutic exercises during a standard 13-day inpatient neck rehabilitation course in relation to overall physical activity in rehabilitation and everyday life. Cross-sectional study. Subjects (n = 19; 16 women and 3 men; mean age 48.6 years, standard deviation (SD) 6.6) with chronic non-specific neck pain were recruited from two inpatient neck rehabilitation courses. Intensity and volume of therapeutic exercises and physical activity were measured in metabolic equivalents (METs) with an objective measurement device and all-time recall questionnaire. Maximum oxygen uptake was determined in METs (METc) by direct maximal cycle ergometer. Subjects' mean METc was 7.2 METs (SD 1.4) or 25.3 ml/kg/min (SD 4.8). Intensity of all therapeutic exercises was 1.9 METs or 27 %METc (SD 5.1) and volume 7.7 MET-hours/week. Intensity of specific neck and shoulder exercises was 2.0 METs or 28 %METc (SD 5.4) and volume 2.5 MET-hours/week. In addition, subjects were more active in everyday life than in inpatient rehabilitation. The therapeutic exercise dose failed to reach previously reported target values for pain relief. The dose of therapeutic exercises and confounding physical activity should be carefully controlled in pain rehabilitation programmes.

Using a Stem Cell-Based Signature to Guide Therapeutic Selection in Cancer

PubMed Central

Shats, Igor; Gatza, Michael L.; Chang, Jeffrey T.; Mori, Seiichi; Wang, Jialiang; Rich, Jeremy; Nevins, Joseph R.

2010-01-01

Given the very substantial heterogeneity of most human cancers, it is likely that most cancer therapeutics will be active in only a small fraction of any population of patients. As such, the development of new therapeutics, coupled with methods to match a therapy with the individual patient, will be critical to achieving significant gains in disease outcome. One such opportunity is the use of expression signatures to identify key oncogenic phenotypes that can serve not only as biomarkers but also as a means of identifying therapeutic compounds that might specifically target these phenotypes. Given the potential importance of targeting tumors exhibiting a stem-like phenotype, we have developed an expression signature that reflects common biological aspects of various stem-like characteristics. The Consensus Stemness Ranking (CSR) signature is upregulated in cancer stem cell enriched samples, at advanced tumor stages and is associated with poor prognosis in multiple cancer types. Using two independent computational approaches we utilized the CSR signature to identify clinically useful compounds that could target the CSR phenotype. In vitro assays confirmed selectivity of several predicted compounds including topoisomerase inhibitors and resveratrol towards breast cancer cell lines that exhibit a high-CSR phenotype. Importantly, the CSR signature could predict clinical response of breast cancer patients to a neoadjuvant regimen that included a CSR-specific agent. Collectively, these results suggest therapeutic opportunities to target the CSR phenotype in a relevant cohort of cancer patients. PMID:21169407

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

DOE PAGES

Schulze, Kornelius; Imbeaud, Sandrine; Letouzé, Eric; ...

2015-03-30

Our genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, FGF4, FGF19 or CCND1more » amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. Finally, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.« less

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

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

Schulze, Kornelius; Imbeaud, Sandrine; Letouzé, Eric

Our genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, FGF4, FGF19 or CCND1more » amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. Finally, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.« less

[The nurses involved in therapeutic innovation].

PubMed

Cheron, Coralie

2016-03-01

Clinical research nurses (CRNs) play an important role within the teams involved in the fight against cancer and in therapeutic innovation. In the dermatology department of the Gustave-Roussy Institute, patients treated for melanoma and taking part in clinical trials are supported along their care pathway by a CRN who, in addition to her clinical expertise, acts as a link between the different players concerned. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

New approaches for identifying and testing potential new anti-asthma agents.

PubMed

Licari, Amelia; Castagnoli, Riccardo; Brambilla, Ilaria; Marseglia, Alessia; Tosca, Maria Angela; Marseglia, Gian Luigi; Ciprandi, Giorgio

2018-01-01

Asthma is a chronic disease with significant heterogeneity in clinical features, disease severity, pattern of underlying disease mechanisms, and responsiveness to specific treatments. While the majority of asthmatic patients are controlled by standard pharmacological strategies, a significant subgroup has limited therapeutic options representing a major unmet need. Ongoing asthma research aims to better characterize distinct clinical phenotypes, molecular endotypes, associated reliable biomarkers, and also to develop a series of new effective targeted treatment modalities. Areas covered: The expanding knowledge on the pathogenetic mechanisms of asthma has allowed researchers to investigate a range of new treatment options matched to patient profiles. The aim of this review is to provide a comprehensive and updated overview of the currently available, new and developing approaches for identifying and testing potential treatment options for asthma management. Expert opinion: Future therapeutic strategies for asthma require the identification of reliable biomarkers that can help with diagnosis and endotyping, in order to determine the most effective drug for the right patient phenotype. Furthermore, in addition to the identification of clinical and inflammatory phenotypes, it is expected that a better understanding of the mechanisms of airway remodeling will likely optimize asthma targeted treatment.

Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics.

PubMed

ElRakaiby, Marwa; Dutilh, Bas E; Rizkallah, Mariam R; Boleij, Annemarie; Cole, Jason N; Aziz, Ramy K

2014-07-01

The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug-microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed.

Dispositional Optimism and Therapeutic Expectations in Early Phase Oncology Trials

PubMed Central

Jansen, Lynn A.; Mahadevan, Daruka; Appelbaum, Paul S.; Klein, William MP; Weinstein, Neil D.; Mori, Motomi; Daffé, Racky; Sulmasy, Daniel P.

2016-01-01

Purpose Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early phase oncology trials. Optimism, however, is not a unitary construct – it can also be defined as a general disposition, or what is called dispositional optimism. We assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. We also assessed how dispositional optimism related to unrealistic optimism. Methods Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. Results Dispositional optimism was significantly associated with higher expectations for personal therapeutic benefit (Spearman r=0.333, p<0.0001), but was not associated with the therapeutic misconception. (Spearman r=−0.075, p=0.329). Dispositional optimism was weakly associated with unrealistic optimism (Spearman r=0.215, p=0.005). In multivariate analysis, both dispositional optimism (p=0.02) and unrealistic optimism (p<0.0001) were independently associated with high expectations for personal therapeutic benefit. Unrealistic optimism (p=.0001), but not dispositional optimism, was independently associated with the therapeutic misconception. Conclusion High expectations for therapeutic benefit among patient-subjects in early phase oncology trials should not be assumed to result from misunderstanding of specific information about the trials. Our data reveal that these expectations are associated with either a dispositionally positive outlook on life or biased expectations about specific aspects of trial participation. Not all manifestations of optimism are the same, and different types of optimism likely have different consequences for informed consent in early phase oncology research. PMID:26882017

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

PubMed

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

2015-12-29

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

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

PubMed Central

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

2015-01-01

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

Next-Generation Therapeutics for Inflammatory Bowel Disease.

PubMed

Dulai, Parambir S; Sandborn, William J

2016-09-01

Tumor necrosis factor (TNF) antagonists are the cornerstone of therapy for moderately to severely active inflammatory bowel disease (IBD). Although our understanding of pharmacokinetics, pharmacodynamics, and treatment optimization for these agents has evolved considerably over the past decade, a substantial majority of individuals fail to respond or lose response to TNF-antagonists over time. A need therefore remains for efficacious treatment options in these patients. Alternative immunological targets have now been identified, and several novel therapeutic agents are in development for IBD. In this review article, we discuss these novel therapeutic agents, with a particular focus on those demonstrated to be efficacious in phase 2 and 3 clinical trials. We further discuss considerations to be made when integrating these agents into routine practice over the next decade.

Next generation therapeutics for inflammatory bowel disease

PubMed Central

Dulai, Parambir S.; Sandborn, William J.

2018-01-01

Tumor necrosis factor (TNF)-antagonists are the cornerstone of therapy for moderately-severely active inflammatory bowel disease (IBD). Although our understanding of pharmacokinetics, pharmacodynamics, and treatment optimization for these agents has evolved considerably over the past decade, a substantial majority of individuals fail to respond or lose response to TNF-antagonists over time. A need therefore remains for efficacious treatment options in these patients. Alternative immunological targets have now been identified, and several novel therapeutic agents are in development for IBD. In this review article we discuss these novel therapeutic agents, with a particular focus on those demonstrated to be efficacious in phase 2 and 3 clinical trials. We further discuss considerations to be made when integrating these agents into routine practice over the next decade. PMID:27461274

DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics

NASA Astrophysics Data System (ADS)

Latorre, Alfonso; Posch, Christian; Garcimartín, Yolanda; Celli, Anna; Sanlorenzo, Martina; Vujic, Igor; Ma, Jeffrey; Zekhtser, Mitchell; Rappersberger, Klemens; Ortiz-Urda, Susana; Somoza, Álvaro

2014-06-01

Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further reduce toxicity by increasing targeted delivery towards malignant cells.Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further

Thiol–ene click hydrogels for therapeutic delivery

PubMed Central

Kharkar, Prathamesh M.; Rehmann, Matthew S.; Skeens, Kelsi M.; Maverakis, Emanual; Kloxin, April M.

2016-01-01

Hydrogels are of growing interest for the delivery of therapeutics to specific sites in the body. For use as a delivery vehicle, hydrophilic precursors are usually laden with bioactive moieties and then directly injected to the site of interest for in situ gel formation and controlled release dictated by precursor design. Hydrogels formed by thiol–ene click reactions are attractive for local controlled release of therapeutics owing to their rapid reaction rate and efficiency under mild aqueous conditions, enabling in situ formation of gels with tunable properties often responsive to environmental cues. Herein, we will review the wide range of applications for thiol–ene hydrogels, from the prolonged release of anti-inflammatory drugs in the spine to the release of protein-based therapeutics in response to cell-secreted enzymes, with a focus on their clinical relevance. We will also provide a brief overview of thiol–ene click chemistry and discuss the available alkene chemistries pertinent to macromolecule functionalization and hydrogel formation. These chemistries include functional groups susceptible to Michael type reactions relevant for injection and radically-mediated reactions for greater temporal control of formation at sites of interest using light. Additionally, mechanisms for the encapsulation and controlled release of therapeutic cargoes are reviewed, including i) tuning the mesh size of the hydrogel initially and temporally for cargo entrapment and release and ii) covalent tethering of the cargo with degradable linkers or affinity binding sequences to mediate release. Finally, myriad thiol–ene hydrogels and their specific applications also are discussed to give a sampling of the current and future utilization of this chemistry for delivery of therapeutics, such as small molecule drugs, peptides, and biologics. PMID:28361125

Statistical considerations for a trial of Ebola virus disease therapeutics.

PubMed

Proschan, Michael A; Dodd, Lori E; Price, Dionne

2016-02-01

The 2014 West African outbreak of Ebola virus ravaged Liberia, Sierra Leone, and Guinea, causing hemorrhagic fever and death. The need to identify effective therapeutics was acute. The usual drug development paradigm of phase I, followed by phase II, and then phase III trials would take too long. These and other factors led to the design of a clinical trial of Ebola virus disease therapeutics that differs from more conventional clinical trial designs. This article describes the Ebola virus disease medical countermeasures trial design and the thinking behind it. © The Author(s) 2016.

Enhancing adult therapeutic interpersonal relationships in the acute health care setting: an integrative review

PubMed Central

Kornhaber, Rachel; Walsh, Kenneth; Duff, Jed; Walker, Kim

2016-01-01

Therapeutic interpersonal relationships are the primary component of all health care interactions that facilitate the development of positive clinician–patient experiences. Therapeutic interpersonal relationships have the capacity to transform and enrich the patients’ experiences. Consequently, with an increasing necessity to focus on patient-centered care, it is imperative for health care professionals to therapeutically engage with patients to improve health-related outcomes. Studies were identified through an electronic search, using the PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO databases of peer-reviewed research, limited to the English language with search terms developed to reflect therapeutic interpersonal relationships between health care professionals and patients in the acute care setting. This study found that therapeutic listening, responding to patient emotions and unmet needs, and patient centeredness were key characteristics of strategies for improving therapeutic interpersonal relationships. PMID:27789958

Enhancing adult therapeutic interpersonal relationships in the acute health care setting: an integrative review.

PubMed

Kornhaber, Rachel; Walsh, Kenneth; Duff, Jed; Walker, Kim

2016-01-01

Therapeutic interpersonal relationships are the primary component of all health care interactions that facilitate the development of positive clinician-patient experiences. Therapeutic interpersonal relationships have the capacity to transform and enrich the patients' experiences. Consequently, with an increasing necessity to focus on patient-centered care, it is imperative for health care professionals to therapeutically engage with patients to improve health-related outcomes. Studies were identified through an electronic search, using the PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO databases of peer-reviewed research, limited to the English language with search terms developed to reflect therapeutic interpersonal relationships between health care professionals and patients in the acute care setting. This study found that therapeutic listening, responding to patient emotions and unmet needs, and patient centeredness were key characteristics of strategies for improving therapeutic interpersonal relationships.

The Therapeutic Roller Coaster

PubMed Central

CHU, JAMES A.

1992-01-01

Survivors of severe childhood abuse often encounter profound difficulties. In addition to posttraumatic and dissociative symptomatology, abuse survivors frequently have characterologic problems, particularly regarding self-care and maintaining relationships. Backgrounds of abuse, abandonment, and betrayal are often recapitulated and reenacted in therapy, making the therapeutic experience arduous and confusing for therapists and patients. Efforts must be directed at building an adequate psychotherapeutic foundation before undertaking exploration and abreaction of past traumatic experiences. This discussion sets out a model for treatment of childhood abuse survivors, describing stages of treatment and suggesting interventions. Common treatment dilemmas or "traps" are discussed, with recommendations for their resolution. PMID:22700116

On the advancement of therapeutic penality: therapeutic authority, personality science and the therapeutic community.

PubMed

McBride, Ruari-Santiago

2017-09-01

In this article I examine the advancement of therapeutic penality in the UK, a penal philosophy that reimagines prison policy, practices and environments utilising psychological knowledge. Adopting a historical approach, I show how modern therapeutic penality is linked to the emergence of personality science in the nineteenth century and the development of the democratic therapeutic community (DTC) model in the twentieth century. I outline how at the turn of the twenty-first century a catalytic event generated a moral panic that led the British government to mobilise psychological knowledge and technologies in an attempt to manage dangerous people with severe personality disorder. Tracing subsequent developments, I argue psychological ways of talking, thinking and acting have obtained unparalleled salience in domains of penality and, in turn, radically transformed the conditions of imprisonment. © 2017 Foundation for the Sociology of Health & Illness.

The Potential for Emerging Microbiome-Mediated Therapeutics in Asthma.

PubMed

Ozturk, Ayse Bilge; Turturice, Benjamin Arthur; Perkins, David L; Finn, Patricia W

2017-08-10

In terms of immune regulating functions, analysis of the microbiome has led the development of therapeutic strategies that may be applicable to asthma management. This review summarizes the current literature on the gut and lung microbiota in asthma pathogenesis with a focus on the roles of innate molecules and new microbiome-mediated therapeutics. Recent clinical and basic studies to date have identified several possible therapeutics that can target innate immunity and the microbiota in asthma. Some of these drugs have shown beneficial effects in the treatment of certain asthma phenotypes and for protection against asthma during early life. Current clinical evidence does not support the use of these therapies for effective treatment of asthma. The integration of the data regarding microbiota with technologic advances, such as next generation sequencing and omics offers promise. Combining comprehensive bioinformatics, new molecules and approaches may shape future asthma treatment.

A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

PubMed Central

Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A.; Gong, Yongquan; Fischbein, Michael P.; Robbins, Robert C.; Naesens, Maarten

2013-01-01

Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design. PMID:24127489

A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation.

PubMed

Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A; Gong, Yongquan; Fischbein, Michael P; Robbins, Robert C; Naesens, Maarten; Butte, Atul J; Sarwal, Minnie M

2013-10-21

Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

NASA Astrophysics Data System (ADS)

Manicke, Nicholas Edward; Abu-Rabie, Paul; Spooner, Neil; Ouyang, Zheng; Cooks, R. Graham

2011-09-01

A method is presented for the direct quantitative analysis of therapeutic drugs from dried blood spot samples by mass spectrometry. The method, paper spray mass spectrometry, generates gas phase ions directly from the blood card paper used to store dried blood samples without the need for complex sample preparation and separation; the entire time for preparation and analysis of blood samples is around 30 s. Limits of detection were investigated for a chemically diverse set of some 15 therapeutic drugs; hydrophobic and weakly basic drugs, such as sunitinib, citalopram, and verapamil, were found to be routinely detectable at approximately 1 ng/mL. Samples were prepared by addition of the drug to whole blood. Drug concentrations were measured quantitatively over several orders of magnitude, with accuracies within 10% of the expected value and relative standard deviation (RSD) of around 10% by prespotting an internal standard solution onto the paper prior to application of the blood sample. We have demonstrated that paper spray mass spectrometry can be used to quantitatively measure drug concentrations over the entire therapeutic range for a wide variety of drugs. The high quality analytical data obtained indicate that the technique may be a viable option for therapeutic drug monitoring.

Quantitative electroencephalograms and neuro-optometry: a case study that explores changes in electrophysiology while wearing therapeutic eyeglasses

PubMed Central

Zelinsky, Deborah; Feinberg, Corey

2017-01-01

Abstract. The brain is equipped with a complex system for processing sensory information, including retinal circuitry comprising part of the central nervous system. Retinal stimulation can influence brain function via customized eyeglasses at both subcortical and cortical levels. We investigated cortical effects from wearing therapeutic eyeglasses, hypothesizing that they can create measureable changes in electroencephalogram (EEG) tracings. A Z-BellSM test was performed on a participant to select optimal lenses. An EEG measurement was recorded before and after the participant wore the eyeglasses. Equivalent quantitative electroencephalography (QEEG) analyses (statistical analysis on raw EEG recordings) were performed and compared with baseline findings. With glasses on, the participant’s readings were found to be closer to the normed database. The original objective of our investigation was met, and additional findings were revealed. The Z-bellSM test identified lenses to influence neurotypical brain activity, supporting the paradigm that eyeglasses can be utilized as a therapeutic intervention. Also, EEG analysis demonstrated that encephalographic techniques can be used to identify channels through which neuro-optomertric treatments work. This case study’s preliminary exploration illustrates the potential role of QEEG analysis and EEG-derived brain imaging in neuro-optometric research endeavors to affect brain function. PMID:28386574

Mental Health Disorder Therapeutic Modalities Modified for the GMS

PubMed Central

Sumneangsanor, Tipsuda; Vuthiarpa, Sararud; Somprasert, Chomchueun

2017-01-01

Background: Mental health disorders can affect physical and psychological behaviors. The people of the Greater Mekong Subregion (GMS) have a high risk of mental health disorders, such as depression, stress, and substance abuse be-cause the people in this region are trafficked for forced sex work and various forms of forced labor. In these situations, vic-tims often endure violence and abuse from trafficking recruiters, employers, and other individuals. The purposes of this study were to identify the elements characterizing mental health disorders, especially in terms of depression, stress, and sub-stance abuse, and to identify the treatment modalities for mental health disorders in the GMS. Methods: The researcher undertook a comparative analysis of the literature, reviews of epidemiological studies and mental disorder therapies, and overviews of previous research studies, were used to generate a synthesis of the existing knowledge of the mental disorder therapeutic modalities. Regarding the search methods, the data from the electronic databases PubMed, PsycINFO, Dynamed and ScienceDirect were supplemented with a manual reference search covering relevant studies from 2005 to 2016. Results: Thirty-one papers were included in the review of elements characterizing mental health disorders, especially in terms of depression, stress, and substance abuse, and to identify the treatment modalities for mental health disorders in the GMS. Nine papers defined characterizing mental health disorders, in terms of depression, stress, and substance abuse. Twenty-two papers showed the treatment modalities for mental health disorders that the treatment was effective, these in-cluded pharmacological treatments and psychological treatments, such as mindfulness-based cognitive therapy, biofeedback, and music therapy. Useful guidance can be provided for the prevention and treatment of mental health disorders, and for the care of people in the Greater Mekong Subregion. Conclusion: The

Engineering responsive supramolecular biomaterials: Toward smart therapeutics.

PubMed

Webber, Matthew J

2016-09-01

Engineering materials using supramolecular principles enables generalizable and modular platforms that have tunable chemical, mechanical, and biological properties. Applying this bottom-up, molecular engineering-based approach to therapeutic design affords unmatched control of emergent properties and functionalities. In preparing responsive materials for biomedical applications, the dynamic character of typical supramolecular interactions facilitates systems that can more rapidly sense and respond to specific stimuli through a fundamental change in material properties or characteristics, as compared to cases where covalent bonds must be overcome. Several supramolecular motifs have been evaluated toward the preparation of "smart" materials capable of sensing and responding to stimuli. Triggers of interest in designing materials for therapeutic use include applied external fields, environmental changes, biological actuators, applied mechanical loading, and modulation of relative binding affinities. In addition, multistimuli-responsive routes can be realized that capture combinations of triggers for increased functionality. In sum, supramolecular engineering offers a highly functional strategy to prepare responsive materials. Future development and refinement of these approaches will improve precision in material formation and responsiveness, seek dynamic reciprocity in interactions with living biological systems, and improve spatiotemporal sensing of disease for better therapeutic deployment.

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

PubMed Central

Ku, Lawrence C.; Wu, Huali; Greenberg, Rachel G.; Hill, Kevin D.; Gonzalez, Daniel; Hornik, Christoph P.; Berezny, Alysha; Guptill, Jeffrey T.; Jiang, Wenlei; Zheng, Nan; Cohen-Wolkowiez, Michael; Melloni, Chiara

2016-01-01

Background Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Methods Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. Results For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 μg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7–1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. Conclusions This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration–response relationships

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine.

PubMed

Ku, Lawrence C; Wu, Huali; Greenberg, Rachel G; Hill, Kevin D; Gonzalez, Daniel; Hornik, Christoph P; Berezny, Alysha; Guptill, Jeffrey T; Jiang, Wenlei; Zheng, Nan; Cohen-Wolkowiez, Michael; Melloni, Chiara

2016-12-01

Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration-response relationships.

A new amoxicillin/clavulanate therapeutic system: preparation, in vitro and pharmacokinetic evaluation.

PubMed

Kerc, Janez; Opara, Jerneja

2007-04-20

A new peroral amoxicillin/clavulanate therapeutic system composed of immediate release tablet and controlled release floating capsule was developed and evaluated by in vivo bioavailability study. Pharmacokinetic (PK) parameters for amoxicillin and clavulanic acid of the new therapeutic systems: AUCt, AUCi, (AUCt/AUCi), Cmax, Tmax, kel, T(1/2) and additionally for amoxicillin T(4) and T(2) were calculated from the plasma levels. The study confirmed enhanced pharmacokinetic parameters of a newly developed therapeutic system containing 1500 mg of amoxicillin and 125 mg of clavulanic acid. Prolonged time over MIC of amoxicillin in relation to a regular immediate release amoxicillin/clavulanate formulation was confirmed.

Dispositional optimism and therapeutic expectations in early-phase oncology trials.

PubMed

Jansen, Lynn A; Mahadevan, Daruka; Appelbaum, Paul S; Klein, William M P; Weinstein, Neil D; Mori, Motomi; Daffé, Racky; Sulmasy, Daniel P

2016-04-15

Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early-phase oncology trials. However, optimism is not a unitary construct; it also can be defined as a general disposition, or what is called dispositional optimism. The authors assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. The authors also assessed how dispositional optimism related to unrealistic optimism. Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. Dispositional optimism was found to be significantly associated with higher expectations for personal therapeutic benefit (Spearman rank correlation coefficient [r], 0.333; P<.0001), but was not associated with the therapeutic misconception (Spearman r, -0.075; P = .329). Dispositional optimism was found to be weakly associated with unrealistic optimism (Spearman r, 0.215; P = .005). On multivariate analysis, both dispositional optimism (P = .02) and unrealistic optimism (P<.0001) were found to be independently associated with high expectations for personal therapeutic benefit. Unrealistic optimism (P = .0001), but not dispositional optimism, was found to be independently associated with the therapeutic misconception. High expectations for therapeutic benefit among patient-subjects in early-phase oncology trials should not be assumed to result from misunderstanding of specific information regarding the trials. The data from the current study indicate that these expectations are associated with either a dispositionally positive outlook on life or biased expectations concerning specific aspects of trial participation. Not all manifestations of optimism are the same, and different types of optimism likely have

A capillary zone electrophoresis method to detect conformers and dimers of antithrombin in therapeutic preparations.

PubMed

Marie, Anne-Lise; Tran, Nguyet Thuy; Saller, François; Abdou, Youmna Mohamed; Zeau, Pascal; Plantier, Jean-Luc; Urbain, Rémi; Borgel, Delphine; Taverna, Myriam

2016-07-01

Antithrombin (AT) is a human plasma glycoprotein that possesses anticoagulant and anti-inflammatory properties. However, the native (active) form of AT is unstable and undergoes conformational changes, leading to latent, cleaved, and heterodimeric forms. The presence of these alternative forms mostly inactive can highly impact the quality and therapeutic activity of pharmaceutical AT preparations. We developed a capillary zone electrophoresis method, based on a neutral polyethylene oxide-coated capillary and a buffer close to physiological conditions, enabling the separation of more than eight forms of AT. Several peaks were identified as native, latent, and heterodimeric forms. The CZE method was reproducible with intraday relative standard deviations less than 0.5 and 2% for migration times and peak areas, respectively. The method was applied to the comparison of AT preparations produced by five competitive pharmaceutical companies, and statistical tests were performed. Important differences in the proportion of each form were highlighted. In particular, one AT preparation was shown to contain a high quantity of heterodimer, and two preparations contained high quantities of latent form. In addition, one AT preparation exhibited additional forms, not yet identified. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of therapeutic class on counseling in community pharmacies.

PubMed

Vainio, Kirsti K; Airaksinen, Marja S A; Hyykky, Tarja T; Enlund, K Hannes

2002-05-01

To assess the effect and importance of the therapeutic class of a drug as a determinant for verbal counseling by community pharmacists. Direct external observations (n = 1431) of pharmacist-customer interactions at the point of delivery of prescription medicines were conducted in 7 community pharmacies in Finland. Trained observers noted whether the pharmacist provided information on directions for use, mode of action, and adverse effects. To examine factors associated with counseling, a multiple logistic regression analysis was constructed, with the dependent variable being counseling of any of the 3 observed topics. In addition to therapeutic class, other independent variables were the pharmacy; pharmacist's age, gender, and degree; and the customer's age, gender, previous use of medicine, and question asking. Provision of counseling differed significantly according to therapeutic classes. Counseling on any of the 3 observed topics was most likely to be provided for customers with antibiotics (80%) and least likely for customers with gynecologic preparations (18%). Differences between therapeutic classes remained statistically significant when the effects of the other variables were controlled for. Other significant predictors for any verbal counseling were the pharmacy, customer's previous use of the medicine, and question asking. Therapeutic class is an important variable that should be included in further studies and considered when comparing studies on patient counseling in community pharmacies.

Characterization of a Francisella tularensis-Caenorhabditis elegans Pathosystem for the Evaluation of Therapeutic Compounds

PubMed Central

Jayamani, Elamparithi; Tharmalingam, Nagendran; Rajamuthiah, Rajmohan; Kim, Wooseong; Okoli, Ikechukwu; Hernandez, Ana M.; Lee, Kiho; Nau, Gerard J.; Ausubel, Frederick M.

2017-01-01

ABSTRACT Francisella tularensis is a highly infectious Gram-negative intracellular pathogen that causes tularemia. Because of its potential as a bioterrorism agent, there is a need for new therapeutic agents. We therefore developed a whole-animal Caenorhabditis elegans-F. tularensis pathosystem for high-throughput screening to identify and characterize potential therapeutic compounds. We found that the C. elegans p38 mitogen-activate protein (MAP) kinase cascade is involved in the immune response to F. tularensis, and we developed a robust F. tularensis-mediated C. elegans killing assay with a Z′ factor consistently of >0.5, which was then utilized to screen a library of FDA-approved compounds that included 1,760 small molecules. In addition to clinically used antibiotics, five FDA-approved drugs were also identified as potential hits, including the anti-inflammatory drug diflunisal that showed anti-F. tularensis activity in vitro. Moreover, the nonsteroidal anti-inflammatory drug (NSAID) diflunisal, at 4× MIC, blocked the replication of an F. tularensis live vaccine strain (LVS) in primary human macrophages and nonphagocytic cells. Diflunisal was nontoxic to human erythrocytes and HepG2 human liver cells at concentrations of ≥32 μg/ml. Finally, diflunisal exhibited synergetic activity with the antibiotic ciprofloxacin in both a checkerboard assay and a macrophage infection assay. In conclusion, the liquid C. elegans-F. tularensis LVS assay described here allows screening for anti-F. tularensis compounds and suggests that diflunisal could potentially be repurposed for the management of tularemia. PMID:28652232

Therapeutic drug levels

MedlinePlus

... medlineplus.gov/ency/article/003430.htm Therapeutic drug levels To use the sharing features on this page, please enable JavaScript. Therapeutic drug levels are lab tests to look for the presence ...

The Molecular Phenotype of Endocapillary Proliferation: Novel Therapeutic Targets for IgA Nephropathy

PubMed Central

John, Rohan; Grone, Elisabeth; Porubsky, Stefan; Gröne, Hermann-Josef; Herzenberg, Andrew M.; Scholey, James W.; Hladunewich, Michelle; Cattran, Daniel C.

2014-01-01

IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN. PMID:25133636

Nanobubbles: a promising efficient tool for therapeutic delivery.

PubMed

Cavalli, Roberta; Soster, Marco; Argenziano, Monica

2016-01-01

In recent decades ultrasound-guided delivery of drugs loaded on nanocarriers has been the focus of increasing attention to improve therapeutic treatments. Ultrasound has often been used in combination with microbubbles, micron-sized spherical gas-filled structures stabilized by a shell, to amplify the biophysical effects of the ultrasonic field. Nanometer size bubbles are defined nanobubbles. They were designed to obtain more efficient drug delivery systems. Indeed, their small sizes allow extravasation from blood vessels into surrounding tissues and ultrasound-targeted site-specific release with minimal invasiveness. Additionally, nanobubbles might be endowed with improved stability and longer residence time in systemic circulation. This review will describe the physico-chemical properties of nanobubbles, the formulation parameters and the drug loading approaches, besides potential applications as a therapeutic tool.

Genome Editing in Stem Cells for Disease Therapeutics.

PubMed

Song, Minjung; Ramakrishna, Suresh

2018-04-01

Programmable nucleases including zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindrome repeats (CRISPR)/CRISPR-associated protein have tremendous potential biological and therapeutic applications as novel genome editing tools. These nucleases enable precise modification of the gene of interest by disruption, insertion, or correction. The application of genome editing technology to pluripotent stem cells or hematopoietic stem cells has the potential to remarkably advance the contribution of this technology to life sciences. Specifically, disease models can be generated and effective therapeutics can be developed with great efficiency and speed. Here we review the characteristics and mechanisms of each programmable nuclease. In addition, we review the applications of these nucleases to stem cells for disease therapies and summarize key studies of interest.

Therapeutic Alliance: A Concept for the Childbearing Season

PubMed Central

Doherty, Mary Ellen

2009-01-01

This analysis was conducted to describe the concept of therapeutic alliance and its appropriateness for health-care provider-client interactions during the childbearing season. The concept has been defined in other disciplines. A universal definition suggested a merging of efforts directed toward health. A simple and concise definition evolved, which is applicable to the childbearing season as well as to health-care encounters across the life span. This definition states: Therapeutic alliance is a process within a health-care provider-client interaction that is initiated by an identified need for positive client health-care behaviors, whereby both parties work together toward this goal with consideration of the client's current health status and developmental stage within the life span. PMID:20514120

Therapeutic targets and new directions for antibodies developed for ovarian cancer

PubMed Central

Bax, Heather J.; Josephs, Debra H.; Pellizzari, Giulia; Spicer, James F.; Montes, Ana; Karagiannis, Sophia N.

2016-01-01

ABSTRACT Antibody therapeutics against different target antigens are widely used in the treatment of different malignancies including ovarian carcinomas, but this disease still requires more effective agents. Improved understanding of the biological features, signaling pathways, and immunological escape mechanisms involved in ovarian cancer has emerged in the past few years. These advances, including an appreciation of the cross-talk between cancer cells and the patient's immune system, have led to the identification of new targets. In turn, potential antibody treatments with various mechanisms of action, including immune activation or toxin-delivery, that are directed at these targets have been developed. Here, we identify established as well as novel targets for antibodies in ovarian cancer, and discuss how they may provide fresh opportunities to identify interventions with enhanced therapeutic potential. PMID:27494775

Contamination of animal feedingstuffs with undeclared antimicrobial additives.

PubMed

Lynas, L; Currie, D; McCaughey, W J; McEvoy, J D; Kennedy, D G

1998-01-01

A study was carried out on 397 feedingstuffs and 11 premixes on which 161 (39.5%) were declared free of medication and 247 (60.5%) were medicated. These were subjected to analysis for the presence of antibiotics. Of the 247 medicated feeds 87 (35.2%) contained undeclared antimicrobials of which 59 (23.9%) were at a concentration sufficient to allow quantification by HPLC. Of the 161 unmedicated feeds 71 (44.1%) were shown to contain detectable antimicrobials of which 42 (26.1%) contained concentrations which could be quantified by HPLC. The most frequently identified contaminating antimicrobials were chlortetracycline (CTC) (15.2%), sulphonamides (6.9%), penicillin (3.4%) and ionophores (3.4%). Four samples (ionophores--3, sulphadimidine--1) contained therapeutic concentrations and one sample a supra-therapeutic concentration (monensin). The remainder were sub-therapeutic. All the contaminating concentrations of sulphadimidine detected were sufficient to cause violative tissue residues if fed to animals immediately prior to slaughter.

Intestinal ischemia-reperfusion injury in horses: pathogenesis and therapeutics.

PubMed

Wong, David M; Moore, Rustin M; Brockus, Charles W

2012-08-01

This article discusses the potential role of oxidative injury to the intestinal tract of horses and the therapeutic approaches that have been investigated to decrease cellular damage secondary to ischemia-reperfusion (IR) injury. Equine colic is a major concern for horse owners and veterinary practitioners. Strangulating and obstructive lesions of the small and large intestines commonly require intervention in patients via exploratory celiotomy. However, the application of information from experimentally induced IR injury in horses to clinical cases of naturally occurring equine colic is not clear. Thus, while the exact mechanisms and clinical significance of intestinal IR are being defined and may be matters of academic debate, a review of the available information may provide knowledge of potential underlying pathophysiologic mechanisms contributing to intestinal injury in equine colic. This information may allow clinicians to offer additional therapeutic strategies for horses with strangulating obstruction of the small or large intestine. Further clinical study of the therapeutic options for horses with naturally occurring disease is warranted.

Internalization, separation-individuation, and the nature of therapeutic action.

PubMed

Blatt, S J; Behrends, R S

1987-01-01

Based on the assumption that the mutative factors that facilitate growth in psychoanalysis involve the same fundamental mechanisms that lead to psychological growth in normal development, this paper considers the constant oscillation between gratification and deprivation leading to internalization as the central therapeutic mechanism of the psychoanalytic process. Patients experience the analytic process as a series of gratifying involvements and experienced incompatibilities that facilitate internalization, whereby the patient recovers lost or disrupted regulatory, gratifying interactions with the analyst, which are real or fantasied, by appropriating these interactions, transforming them into their own, enduring, self-generated functions and characteristics. Patients internalize not only the analyst's interpretive activity, but also the analyst's sensitivity, compassion and acceptance, and, in addition, their own activity in relation to the analyst such as free association. Both interpretation and the therapeutic relationship can contain elements of gratifying involvement and experienced incompatibility that lead to internalization and therefore both can be mutative factors in the therapeutic process.

Novel delivery approaches for cancer therapeutics.

PubMed

Mitra, Ashim K; Agrahari, Vibhuti; Mandal, Abhirup; Cholkar, Kishore; Natarajan, Chandramouli; Shah, Sujay; Joseph, Mary; Trinh, Hoang M; Vaishya, Ravi; Yang, Xiaoyan; Hao, Yi; Khurana, Varun; Pal, Dhananjay

2015-12-10

Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer. Copyright © 2015 Elsevier B.V. All rights reserved.

Functional correlates of the therapeutic and adverse effects evoked by thalamic stimulation for essential tremor

PubMed Central

Gibson, William S.; Jo, Hang Joon; Testini, Paola; Cho, Shinho; Felmlee, Joel P.; Welker, Kirk M.; Klassen, Bryan T.; Min, Hoon-Ki

2016-01-01

modelling revealed a correlation between therapeutic effectiveness and attenuated within-region inhibitory connectivity in cerebellum. Finally, specific subregions of sensorimotor cortex were identified in which deep brain stimulation-evoked activation correlated with the presence of unwanted paraesthesias. These results suggest that thalamic deep brain stimulation in tremor likely exerts its effects through modulation of both olivocerebellar and thalamocortical circuits. In addition, our findings indicate that deep brain stimulation-evoked functional activation maps obtained intraoperatively may contain predictive information pertaining to the therapeutic and adverse effects induced by deep brain stimulation. PMID:27329768

Adolescent depression: clinical features and therapeutic strategies.

PubMed

Nardi, B; Francesconi, G; Catena-Dell'osso, M; Bellantuono, C

2013-06-01

Major depressive disorder (MDD) is a common disorder during adolescence and it is associated with an increased risk of suicide, poor school performance, impaired social skills, social withdrawal and substance abuse. Further, as many depressive episode in adolescents do not reach the diagnostic threshold for MDD, the disorder remains undetected. This review aims to provide an update of clinical features of adolescent MDD and to focus on the most appropriate therapeutic strategies to adopt in clinical practice. We reviewed the international literature to identify studies focusing on clinical features and therapeutic options in adolescents affected by MDD. PubMed, Medline and Cochrane Library databases were searched for English language papers. The clinical picture of depression is variable with sex and age. Somatic complaints, particularly headache and fatigue, are a common presentation in adolescent MDD. Irritability is present most frequently in female and it is related to the severity of MDD. Adolescent MDD is also characterized by a high rates of suicides. The therapeutic strategy in adolescent depression includes psychotropic medications, psychotherapy or a combination of both treatments, with selection of the most appropriate strategy depending on symptom severity. As first-line treatment the traditional cognitive behavioural therapy (CBT), as well as the cognitive Post-Rationalist (PR) approach, are so far considered the goal standard. The therapeutic approach to the adolescent affected by MMD should respect the person in his/her psycho-physical entirety. The intervention may help the subject in seeking a more stable and adaptable identity. It is relevant to have a good knowledge of the peculiar clinical picture of adolescent MDD in order to make an early identification of the disorder and to define an appropriate personalized therapeutic program.

The Roman-Irish Bath: Medical/health history as therapeutic assemblage.

PubMed

Foley, Ronan

2014-04-01

The invention of a new form of hot-air bath in Blarney, Ireland in 1856, variously known in its lifetime as the Roman-Irish or Turkish Bath, acted as the starting point for a the production of a globalised therapeutic landscape. Tracking the diffusion of the Roman-Irish bath template from its local invention in Ireland to a global reach across the Victorian world and recognizing its place within a wider hydrotherapeutic history, this paper frames that diffusion as a valuable empirical addition to assemblage theory. The specific empirical history of the spread of the Roman-Irish/Turkish bath idea is drawn from primary archival and secondary historical sources. It is then discussed and, drawing from work on assemblage theory, analyzed against three broad themes: mobile networks, socio-material practices and contested emergence. The emergent relational geographies of the Roman-Irish Bath identify important roles for the diffusion and transformation of specific medical settings, identities and functions. These were linked in turn to competing social-healing pathways wherein bodies were technologically and morally managed, to produce a more inhabited form of therapeutic assemblage. In all cases the differential diffusion of the bath idea, it's shifting and fractured material forms and multiple inhabitations and discourses were contested and mobile and spoke to an assemblage approach which has ripe potential for exploration across a range of medical/health geography settings. Copyright © 2014 Elsevier Ltd. All rights reserved.

The therapeutic applications of antimicrobial peptides (AMPs): a patent review.

PubMed

Kang, Hee-Kyoung; Kim, Cheolmin; Seo, Chang Ho; Park, Yoonkyung

2017-01-01

Antimicrobial peptides (AMPs) are small molecules with a broad spectrum of antibiotic activities against bacteria, yeasts, fungi, and viruses and cytotoxic activity on cancer cells, in addition to anti-inflammatory and immunomodulatory activities. Therefore, AMPs have garnered interest as novel therapeutic agents. Because of the rapid increase in drug-resistant pathogenic microorganisms, AMPs from synthetic and natural sources have been developed using alternative antimicrobial strategies. This article presents a broad analysis of patents referring to the therapeutic applications of AMPs since 2009. The review focuses on the universal trends in the effective design, mechanism, and biological evolution of AMPs.

Acute Pulmonary Embolism in Emergency Department Patients Despite Therapeutic Anticoagulation.

PubMed

Liu, Michelle Y; Ballard, Dustin W; Huang, Jie; Rauchwerger, Adina S; Reed, Mary E; Bouvet, Sean C; Vinson, David R

2018-05-01

Emergency department (ED) patients with acute pulmonary embolism (PE) despite therapeutic anticoagulation at the time of diagnosis are uncommonly encountered and present a diagnostic and management challenge. Their characterization and outcomes are poorly described. We sought to describe the prevalence and characteristics of therapeutically anticoagulated patients among a population of patients with acute PE in a community setting and to describe treatment changes and 30-day outcomes. From a large retrospective cohort of adults with acute, objectively-confirmed PE across 21 EDs between 01/2013 and 04/2015, we identified patients who arrived on direct oral or injectable anticoagulants, or warfarin with an initial ED international normalized ratio (INR) value ≥2.0. Patients were excluded from the larger cohort if they had received a diagnosis of venous thromboembolism (VTE) in the prior 30 days. We gathered demographic and clinical variables from electronic health records and structured manual chart review. We report discharge anticoagulation regimens and major 30-day adverse outcomes. Among 2,996 PE patients, 36 (1.2%) met study criteria. Mean age was 63 years. Eleven patients (31%) had active cancer and 25 (69%) were high risk on the PE Severity Index (Classes III-V), comparable to the larger cohort (p>0.1). Reasons for pre-arrival anticoagulation were VTE treatment or prevention (n=21), and atrial fibrillation or flutter (n=15). All patients arrived on warfarin and one was also on enoxaparin: 32 had a therapeutic INR (2.0-3.0) and four had a supratherapeutic INR (>3.0). Fifteen patients (42%) had at least one subtherapeutic INR (<2.0) in the 14 days preceding their diagnostic visit. Two patients died during hospitalization. Of the 34 ultimately discharged, 22 underwent a change in anticoagulation drug or dosing, 19 of whom received injectables, either to replace or to supplement warfarin. Four patients also received inferior vena cava filters. Thirty

Irradiation-induced angiosarcoma and anti-angiogenic therapy: A therapeutic hope?

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

Azzariti, Amalia, E-mail: a.azzariti@oncologico.bari.it; Porcelli, Letizia; Mangia, Anita

2014-02-15

Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin. They can be sporadic or caused by therapeutic radiation, hence secondary breast angiosarcomas are an important subgroup of patients. Assessing the molecular biology of angiosarcomas and identify specific targets for treatment is challenging. There is currently great interest in the role of angiogenesis and of angiogenic factors associated with tumor pathogenesis and as targets for treatment of angiosarcomas. A primary cell line derived from a skin fragment of a irradiation-induced angiosarcoma patient was obtained and utilized to evaluate cell biomarkers CD31, CD34, HIF-1alpha and VEGFRs expression by immunocytochemistry and immunofluorescence, drugsmore » cytotoxicity by cell counting and VEGF release by ELISA immunoassay. In addition to previous biomarkers, FVIII and VEGF were also evaluated on tumor specimens by immunohistochemistry to further confirm the diagnosis. We targeted the VEGF–VEGFR-2 axis of tumor angiogenesis with two different class of vascular targeted drugs; caprelsa, the VEGFR-2/EGFR/RET inhibitor and bevacizumab the anti-VEGF monoclonal antibody. We found the same biomarkers expression either in tumor specimens and in the cell line derived from tumor. In vitro experiments demonstrated that angiogenesis plays a pivotal role in the progression of this tumor as cells displayed high level of VEGFR-2, HIF-1 alpha strongly accumulated into the nucleus and the pro-angiogenic factor VEGF was released by cells in culture medium. The evaluation of caprelsa and bevacizumab cytotoxicity demonstrated that both drugs were effective in inhibiting tumor proliferation. Due to these results, we started to treat the patient with pazopanib, which was the unique tyrosine kinase inhibitor available in Italy through a compassionate supply program, obtaining a long lasting partial response. Our data suggest that the study of the primary cell line could help physicians in choosing a therapeutic

The evolving landscape of therapeutic drug development for hepatocellular carcinoma.

PubMed

Chong, Dawn Qingqing; Tan, Iain Beehuat; Choo, Su-Pin; Toh, Han Chong

2013-11-01

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. Copyright © 2013 Elsevier Inc. All rights reserved.

Self-Identifying Emergency Radio Beacons

NASA Technical Reports Server (NTRS)

Friedman, Morton L.

1987-01-01

Rescue teams aided by knowledge of vehicle in distress. Similar to conventional emergency transmitters except contains additional timing and modulating circuits. Additions to standard emergency transmitter enable transmitter to send rescuers identifying signal in addition to conventional distress signal created by sweep generator. Data generator contains identifying code.

Sugar-based amphiphilic polymers for biomedical applications: from nanocarriers to therapeutics.

PubMed

Gu, Li; Faig, Allison; Abdelhamid, Dalia; Uhrich, Kathryn

2014-10-21

disease. The atherosclerotic cascade is usually triggered by the unregulated uptake of oxidized low-density lipoprotein, a cholesterol carrier, in macrophages of the blood vessel wall; SBAPs can significantly inhibit oxidized low-density lipoprotein uptake in macrophages and abrogate the atherosclerotic cascade. By modification of various functionalities (e.g., branching, stereochemistry, hydrophobicity, and charge) in the SBAP chemical structure, SBAP bioactivity was optimized, and influential structural components were identified. Despite the potential of SBAPs as atherosclerotic therapies, blood stability of the SBAP micelles was not ideal for in vivo applications, and means to stabilize them were pursued. Using kinetic entrapment via flash nanoprecipitation, SBAPs were formulated into nanoparticles with a hydrophobic solute core and SBAP shell. SBAP nanoparticles exhibited excellent physiological stability and enhanced bioactivity compared with SBAP micelles. Further, this method enables encapsulation of additional hydrophobic drugs (e.g., vitamin E) to yield a stable formulation that releases two bioactives. Both as nanoscale carriers and as polymer therapeutics, SBAPs are promising biomaterials for medical applications.

Therapeutic penetrating keratoplasty in severe fungal keratitis using cryopreserved donor corneas

PubMed Central

Yao, Y-F; Zhang, Y-M; Zhou, P; Zhang, B; Qiu, W-Y; Tseng, S C G

2003-01-01

Aims: To investigate whether cryopreserved donor cornea could be used for therapeutic penetrating keratoplasty (PKP) to eradicate the infection, obviate complications, and preserve anatomical integrity in severe fungal keratitis. Methods: In this retrospective, consecutive case series, 45 eyes of 45 patients with severe fungal keratitis, which exhibited anterior chamber collapse, corneal perforation, and/or large suppurative corneal infiltrate, received therapeutic PKP after removal of the infected corneal tissue, irrigation of the anterior chamber by 0.2% fluconazole solution, iris dissection of fibrinoid membrane, and iridectomy and therapeutic PKP using corneas cryopreserved at −20°C. Results: Among 45 eyes, 39 eyes (86.7%) were successfully eradicated the fungal infection without recurrence and maintained their anatomical integrity without any complication. Four of 45 eyes (8.9%) showed postoperative rise of intraocular pressure, of which three were controlled with subsequent antiglaucoma surgeries, whereas one eye needed additional antiglaucoma medications. Two of 45 eyes (4.4%) were enucleated because of uncontrollable fungal infection and secondary retinal detachment, respectively. 23 eyes received subsequent optical PKP and, among them, 21 maintained clear corneal grafts and two suffered from graft failure due to allograft rejections. Conclusion: Cryopreserved donor corneas are effective substitutes in therapeutic PKP to control severe fungal corneal infection and preserve the global integrity, and may offer additional advantages over conventional PKP in reducing allograft rejection, eradicating fungal infection during the postoperative period, and improving the success of optical PKP for visual rehabilitation. PMID:12714387

Biased and unbiased strategies to identify biologically active small molecules.

PubMed

Abet, Valentina; Mariani, Angelica; Truscott, Fiona R; Britton, Sébastien; Rodriguez, Raphaël

2014-08-15

Small molecules are central players in chemical biology studies. They promote the perturbation of cellular processes underlying diseases and enable the identification of biological targets that can be validated for therapeutic intervention. Small molecules have been shown to accurately tune a single function of pluripotent proteins in a reversible manner with exceptional temporal resolution. The identification of molecular probes and drugs remains a worthy challenge that can be addressed by the use of biased and unbiased strategies. Hypothesis-driven methodologies employs a known biological target to synthesize complementary hits while discovery-driven strategies offer the additional means of identifying previously unanticipated biological targets. This review article provides a general overview of recent synthetic frameworks that gave rise to an impressive arsenal of biologically active small molecules with unprecedented cellular mechanisms. Copyright © 2014. Published by Elsevier Ltd.

Introduction to current and future protein therapeutics: a protein engineering perspective.

PubMed

Carter, Paul J

2011-05-15

Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies to address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies. Copyright © 2011 Elsevier Inc. All rights reserved.

Introduction to current and future protein therapeutics: A protein engineering perspective

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

Carter, Paul J., E-mail: pjc@gene.com

2011-05-15

Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies tomore » address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies.« less

A therapeutic nanoparticle vaccine against Trypanosoma cruzi in a BALB/c mouse model of Chagas disease

PubMed Central

Barry, Meagan A.; Wang, Qian; Jones, Kathryn M.; Heffernan, Michael J.; Buhaya, Munir H.; Beaumier, Coreen M.; Keegan, Brian P.; Zhan, Bin; Dumonteil, Eric; Bottazzi, Maria Elena; Hotez, Peter J.

2016-01-01

ABSTRACT Chagas disease, caused by Trypanosoma cruzi, results in an acute febrile illness that progresses to chronic chagasic cardiomyopathy in 30% of patients. Current treatments have significant side effects and poor efficacy during the chronic phase; therefore, there is an urgent need for new treatment modalities. A robust TH1-mediated immune response correlates with favorable clinical outcomes. A therapeutic vaccine administered to infected individuals could bolster the immune response, thereby slowing or stopping the progression of chagasic cardiomyopathy. Prior work in mice has identified an efficacious T. cruzi DNA vaccine encoding Tc24. To elicit a similar protective cell-mediated immune response to a Tc24 recombinant protein, we utilized a poly(lactic-co-glycolic acid) nanoparticle delivery system in conjunction with CpG motif-containing oligodeoxynucleotides as an immunomodulatory adjuvant. In a BALB/c mouse model, the vaccine produced a TH1-biased immune response, as demonstrated by a significant increase in antigen-specific IFNγ-producing splenocytes, IgG2a titers, and proliferative capacity of CD8+ T cells. When tested for therapeutic efficacy, significantly reduced systemic parasitemia was seen during peak parasitemia. Additionally, there was a significant reduction in cardiac parasite burden and inflammatory cell infiltrate. This is the first study demonstrating immunogenicity and efficacy of a therapeutic Chagas vaccine using a nanoparticle delivery system. PMID:26890466

Therapeutic friendliness and the development of therapeutic leverage by mental health nurses in community rehabilitation settings.

PubMed

Gardner, Andrew

2010-01-01

In a world dominated by technology and driven by fiscal policy emphasis, the therapeutic relationship as a healing modality is still a central theme to mental health nurses (MHN) in their everyday work. This research, as part of a PhD program, used a constructivist grounded theory approach to explore the process of therapeutic relationships and professional boundaries. The current paper outlines how therapeutic friendliness provides a connection for the therapeutic relationship to develop but in doing so requires a balancing of the therapeutic relationship and constant maintenance of the professional boundary. The authors also discuss how community mental health nurses (CMHN) invest in the therapeutic relationship in order to develop a therapeutic alliance and how the alliance between the CMHN and the client facilitates the use of therapeutic leverage applied by the CMHN as part of the therapeutic process.

The current state of therapeutic and T cell-based vaccines against human papillomaviruses

PubMed Central

Yang, Andrew; Farmer, Emily; Lin, John; Wu, T-C.; Hung, Chien-Fu

2016-01-01

Human papillomavirus (HPV) is known to be a necessary factor for many gynecologic malignancies and is also associated with a subset of head and neck malignancies. This knowledge has created the opportunity to control these HPV-associated cancers through vaccination. However, despite the availability of prophylactic HPV vaccines, HPV infections remain extremely common worldwide. In addition, while prophylactic HPV vaccines have been effective in preventing infection, they are ineffective at clearing pre-existing HPV infections. Thus, there is an urgent need for therapeutic and T cell-based vaccines to treat existing HPV infections and HPV-associated lesions and cancers. Unlike prophylactic vaccines, which generate neutralizing antibodies, therapeutic, and T cell-based vaccines enhance cell-mediated immunity against HPV antigens. Our review will cover various therapeutic and T cell-based vaccines in development for the treatment of HPV-associated diseases. Furthermore, we review the strategies to enhance the efficacy of therapeutic vaccines and the latest clinical trials on therapeutic and T cell-based HPV vaccines. PMID:27932207

Pharmacomicrobiomics: The Impact of Human Microbiome Variations on Systems Pharmacology and Personalized Therapeutics

PubMed Central

ElRakaiby, Marwa; Dutilh, Bas E.; Rizkallah, Mariam R.; Boleij, Annemarie; Cole, Jason N.

2014-01-01

Abstract The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug–microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed. PMID:24785449

Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

PubMed

Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A

2016-09-01

Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function. Copyright © 2016 Elsevier Inc. All rights reserved.

Neurosteroids in Schizophrenia: Pathogenic and Therapeutic Implications

PubMed Central

Cai, HuaLin; Cao, Ting; Zhou, Xiang; Yao, Jeffrey K.

2018-01-01

Neurosteroids are a group of important endogenous molecules affecting many neural functions in the brain. Increasing evidence suggests a possible role of these neurosteroids in the pathology and symptomatology of schizophrenia (SZ) and other mental disorders. The aim of this review is to summarize the current knowledge about the neural functions of neurosteroids in the brain, and to evaluate the role of the key neurosteroids as candidate modulators in the etiology and therapeutics of SZ. The present paper provides a brief introduction of neurosteroid metabolism and distribution, followed by a discussion of the mechanisms underlying neurosteroid actions in the brain. The content regarding the modulation of the GABAA receptor is elaborated, given the considerable knowledge of its interactions with other neurotransmitter and neuroprotective systems, as well as its ameliorating effects on stress that may play a role in the SZ pathophysiology. In addition, several preclinical and clinical studies suggested a therapeutic benefit of neurosteroids in SZ patients, even though the presence of altered neurosteroid pathways in the circulating blood and/or brain remains debatable. Following treatment of antipsychotic drugs in SZ, therapeutic benefits have also been linked to the regulation of neurosteroid signaling. Specifically, the neurosteroids such as pregnenolone and dehydroepiandrosterone affect a broad spectrum of behavioral functions through their unique molecular characteristics and may represent innovative therapeutic targets for SZ. Future investigations in larger cohorts with long-term follow-ups will be required to ascertain the neuropsychopharmacological role of this yet unexploited class of neurosteroid agents. PMID:29568275

Absence of bacterial colonization of the airways after therapeutic rigid bronchoscopy without stenting.

PubMed

Noppen, M; Piérard, D; Meysman, M; Herreweghe, R V; Vincken, W

2000-12-01

Following airway stenting, bacterial colonization of the airways with potentially pathogenic micro-organisms occurs within 4 weeks after treatment in the majority of patients. The objective of this study was to prospectively investigate whether nonstenting therapeutic rigid bronchoscopy (using laser, cryotherapy, mechanical dilatation or debridement) is followed by airway colonization or infection. Protected specimen brush sampling of the central airways and quantitative culture were performed immediately prior to, and 4 weeks after nonstenting therapeutic rigid bronchoscopy in 20 consecutive patients with central airway lesions. Prior to therapeutic bronchoscopy, airway colonization/infection was present in nine of 20 (45%) patients. In these nine patients, 10 different potential pathogens were identified: Streptococcus pneumoniae (four cases), Pseudomonas aeruginosa (three), Haemophilus influenzae (two), and Serratia marcescens (one). Eight of these nine patients had a history of postobstructive infections, of which three were currently being treated with antibiotics. Four weeks following therapeutic bronchoscopy, airway colonization/infection was present in five of 20 (25%) patients, each of whom had airway colonization/infection prior to bronchoscopy. In three of these five patients, the same organisms were found 4 weeks after bronchoscopy as at baseline bronchoscopy. In two of five patients new organisms were identified: one case of Streptococcus viridans and one case of Haemophilus parainfluenzae, both considered to be nonpathogens. In four of nine patients with airway colonization/infection prior to bronchoscopy, the airways were clear of micro-organisms after the procedure. The authors conclude that: 1) nonstenting therapeutic rigid bronchoscopy is not complicated by airway colonization or infection by new potential pathogens; and 2) therapeutic rigid bronchoscopy led to clearing of airway colonization/infection in almost half of the patients studied.

Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes

PubMed Central

Phamduy, Theresa B.; Chrisey, Douglas B.

2017-01-01

Triple negative breast cancers (TNBCs) have high recurrence and metastasis rates. Acquisition of a mesenchymal morphology and phenotype in addition to driving migration is a consequential process that promotes metastasis. Although some kinases are known to regulate a mesenchymal phenotype, the role for a substantial portion of the human kinome remains uncharacterized. Here we evaluated the Published Kinase Inhibitor Set (PKIS) and screened a panel of TNBC cell lines to evaluate the compounds’ effects on a mesenchymal phenotype. Our screen identified 36 hits representative of twelve kinase inhibitor chemotypes based on reversal of the mesenchymal cell morphology, which was then prioritized to twelve compounds based on gene expression and migratory behavior analyses. We selected the most active compound and confirmed mesenchymal reversal on transcript and protein levels with qRT-PCR and Western Blot. Finally, we utilized a kinase array to identify candidate kinases responsible for the EMT reversal. This investigation shows the novel application to identify previously unrecognized kinase pathways and targets in acquisition of a mesenchymal TNBC phenotype that warrant further investigation. Future studies will examine specific roles of the kinases in mechanisms responsible for acquisition of the mesenchymal and/or migratory phenotype. PMID:28771473

Recommendations for research priorities in breast cancer by the Coalition of Cancer Cooperative Groups Scientific Leadership Council: systemic therapy and therapeutic individualization.

PubMed

Sparano, Joseph A; Hortobagyi, Gabriel N; Gralow, Julie R; Perez, Edith A; Comis, Robert L

2010-02-01

Over 9,000 women with breast cancer are enrolled annually on clinical trials sponsored by the National Cancer Institute (NCI), accounting for about one-third of all patients enrolled on NCI-sponsored trials. Thousands are also enrolled on pharmaceutical-sponsored studies. Although breast cancer mortality rates have recently declined for the first time in part due to systemic therapeutic advances, coordinated efforts will be necessary to maintain this trend. The Coalition of Cancer Cooperative Groups convened the Scientific Leadership Council in breast cancer (BC), an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for chemoprevention, development and application of molecular markers for predicting therapeutic benefit and toxicity, intermediate markers predictive of therapeutic effect, pathogenesis-based therapeutic approaches, utilization of adaptive designs requiring fewer patients to achieve objectives, special and minority populations, and effects of BC and treatment on patients and families. Panelists identified 13 ongoing studies as High Priority and identified gaps in the current trial portfolio. We propose priorities for current and future clinical breast cancer research evaluating systemic therapies that may serve to improve the efficiency of clinical trials, identify individuals most likely to derive therapeutic benefit, and prioritize therapeutic strategies.

Exploration of developmental approaches to companion animal antimicrobials: providing for the unmet therapeutic needs of dogs and cats.

PubMed

Apley, M; Claxton, R; Davis, C; DeVeau, I; Donecker, J; Lucas, A; Neal, A; Papich, M

2010-04-01

The American Academy of Veterinary Pharmacology and Therapeutics (AAVPT) and the United States Pharmacopeia (USP) co-sponsored a workshop to explore approaches for developing companion animal antimicrobials. This workshop was developed in response to the shortage of antimicrobials labeled for dogs and cats, as there is a shortage of approved antimicrobials for the range of infectious diseases commonly treated in small animal practice. The objective of the workshop was to identify alternative approaches to data development to support new indications consistent with the unmet therapeutic needs of dogs and cats. The indications for currently approved antimicrobials do not reflect the broader range of infectious diseases that are commonly diagnosed and treated by the veterinarian. Therefore, the labels for these approved antimicrobials provide limited information to the veterinarian for appropriate therapeutic decision-making beyond the few indications listed. Industry, veterinary practice, and regulatory challenges to the development of new antimicrobial indications were discussed. The workshop resulted in short- and long-term recommendations. Short-term recommendations focus on the use of additional data considerations for product labeling. Long-term recommendations center on legislative or regulatory legal initiatives. The workshop recommendations will need collaboration from industry, academia, and regulatory authorities and a legal shift in the drug approval and availability processes.

Toxicological perspectives of inhaled therapeutics and nanoparticles.

PubMed

Hayes, Amanda J; Bakand, Shahnaz

2014-07-01

The human respiratory system is an important route for the entry of inhaled therapeutics into the body to treat diseases. Inhaled materials may consist of gases, vapours, aerosols and particulates. In all cases, assessing the toxicological effect of inhaled therapeutics has many challenges. This article provides an overview of in vivo and in vitro models for testing the toxicity of inhaled therapeutics and nanoparticles implemented in drug delivery. Traditionally, inhalation toxicity has been performed on test animals to identify the median lethal concentration of airborne materials. Later maximum tolerable concentration denoted by LC0 has been introduced as a more ethically acceptable end point. More recently, in vitro methods have been developed, allowing the direct exposure of airborne material to cultured human target cells on permeable porous membranes at the air-liquid interface. Modifications of current inhalation therapies, new pulmonary medications for respiratory diseases and implementation of the respiratory tract for systemic drug delivery are providing new challenges when conducting well-designed inhalation toxicology studies. In particular, the area of nanoparticles and nanocarriers is of critical toxicological concern. There is a need to develop toxicological test models, which characterise the toxic response and cellular interaction between inhaled particles and the respiratory system.

RNAi therapeutics for brain cancer: current advancements in RNAi delivery strategies.

PubMed

Malhotra, Meenakshi; Toulouse, André; Godinho, Bruno M D C; Mc Carthy, David John; Cryan, John F; O'Driscoll, Caitriona M

2015-10-01

Malignant primary brain tumors are aggressive cancerous cells that invade the surrounding tissues of the central nervous system. The current treatment options for malignant brain tumors are limited due to the inability to cross the blood-brain barrier. The advancements in current research has identified and characterized certain molecular markers that are essential for tumor survival, progression, metastasis and angiogenesis. These molecular markers have served as therapeutic targets for the RNAi based therapies, which enable site-specific silencing of the gene responsible for tumor proliferation. However, to bring about therapeutic success, an efficient delivery carrier that can cross the blood-brain barrier and reach the targeted site is essential. The current review focuses on the potential of targeted, non-viral and viral particles containing RNAi therapeutic molecules as delivery strategies specifically for brain tumors.

Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer.

PubMed

Giamas, Georgios; Filipović, Aleksandra; Jacob, Jimmy; Messier, Walter; Zhang, Hua; Yang, Dongyun; Zhang, Wu; Shifa, Belul Assefa; Photiou, Andrew; Tralau-Stewart, Cathy; Castellano, Leandro; Green, Andrew R; Coombes, R Charles; Ellis, Ian O; Ali, Simak; Lenz, Heinz-Josef; Stebbing, Justin

2011-06-01

Therapies targeting estrogen receptor α (ERα, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERα pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERα activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERα activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERα+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERα+ but not ERα- cells, indicative of its role in ERα activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target.

Therapeutics of Ebola hemorrhagic fever: whole-genome transcriptional analysis of successful disease mitigation.

PubMed

Yen, Judy Y; Garamszegi, Sara; Geisbert, Joan B; Rubins, Kathleen H; Geisbert, Thomas W; Honko, Anna; Xia, Yu; Connor, John H; Hensley, Lisa E

2011-11-01

The mechanisms of Ebola (EBOV) pathogenesis are only partially understood, but the dysregulation of normal host immune responses (including destruction of lymphocytes, increases in circulating cytokine levels, and development of coagulation abnormalities) is thought to play a major role. Accumulating evidence suggests that much of the observed pathology is not the direct result of virus-induced structural damage but rather is due to the release of soluble immune mediators from EBOV-infected cells. It is therefore essential to understand how the candidate therapeutic may be interrupting the disease process and/or targeting the infectious agent. To identify genetic signatures that are correlates of protection, we used a DNA microarray-based approach to compare the host genome-wide responses of EBOV-infected nonhuman primates (NHPs) responding to candidate therapeutics. We observed that, although the overall circulating immune response was similar in the presence and absence of coagulation inhibitors, surviving NHPs clustered together. Noticeable differences in coagulation-associated genes appeared to correlate with survival, which revealed a subset of distinctly differentially expressed genes, including chemokine ligand 8 (CCL8/MCP-2), that may provide possible targets for early-stage diagnostics or future therapeutics. These analyses will assist us in understanding the pathogenic mechanisms of EBOV infection and in identifying improved therapeutic strategies.

[Nodular toxoplasmosis as a diagnostic and therapeutic problem].

PubMed

Zaorski, P; Kozłowski, J

1999-01-01

Enlargement of lymph nodes of the neck, slightly elevated body temperature and discomfort are symptoms characteristic of many illnesses. One of these can be toxoplasmosis. Because the rarity of its occurrence, sometimes toxoplasmosis may be last to be recognized. In many cases absence of specific additional examination guidelines can contribute to several problems with correct diagnosis. At the present time, the most reliable sample analysis methods are the examination of levels of antibodies IgG and IgM, and the histopathological verification. The authors also indicate that varying therapeutic effects using prophilactic treatment and insufficient additional examination could lead to diagnostic problems.

Therapeutic communication in nursing students: A Walker & Avant concept analysis

PubMed Central

Abdolrahimi, Mahbobeh; Ghiyasvandian, Shahrzad; Zakerimoghadam, Masoumeh; Ebadi, Abbas

2017-01-01

Background and aim Therapeutic communication, the fundamental component of nursing, is a complex concept. Furthermore, the poor encounters between nursing student and patient demonstrate the necessity of instruction regarding therapeutic communication. The aim of this study was to define and clarify this important concept for including this subject in the nursing curriculum with more emphasis. Methods A literature search was conducted using keywords such as “nursing student”, “patient” and “therapeutic communication” and Persian-equivalent words in Persian databases (including Magiran and Medlib) and English databases (including PubMed, ScienceDirect, Scopus and ProQuest) without time limitation. After extracting concept definitions and determining characteristic features, therapeutic communication in nursing students was defined. Then, sample cases, antecedents, consequences and empirical referents of concept were determined. Results After assessing 30 articles, therapeutic communication defining attributes were as follows: “an important means in building interpersonal relationships”, “a process of information transmission”, “an important clinical competency”, “a structure with two different sections” and “a significant tool in patient centered care”. Furthermore, theoretical and clinical education and receiving educators’ feedback regarding therapeutic communication were considered as antecedents of the concept. Improving physical and psychological health status of patient as well as professional development of nursing students were identified as consequences of the concept. Conclusion Nursing instructors can use these results in order to teach and evaluate therapeutic communication in nursing students and train qualified nurses. Also, nursing students may apply the results to improve the quality of their interactions with patients, perform their various duties and meet patients’ diverse needs. PMID:28979730

Molecular characterization of an unauthorized genetically modified Bacillus subtilis production strain identified in a vitamin B2 feed additive.

PubMed

Paracchini, Valentina; Petrillo, Mauro; Reiting, Ralf; Angers-Loustau, Alexandre; Wahler, Daniela; Stolz, Andrea; Schönig, Birgit; Matthies, Anastasia; Bendiek, Joachim; Meinel, Dominik M; Pecoraro, Sven; Busch, Ulrich; Patak, Alex; Kreysa, Joachim; Grohmann, Lutz

2017-09-01

Many food and feed additives result from fermentation of genetically modified (GM) microorganisms. For vitamin B2 (riboflavin), GM Bacillus subtilis production strains have been developed and are often used. The presence of neither the GM strain nor its recombinant DNA is allowed for fermentation products placed on the EU market as food or feed additive. A vitamin B 2 product (80% feed grade) imported from China was analysed. Viable B. subtilis cells were identified and DNAs of two bacterial isolates (LHL and LGL) were subjected to three whole genome sequencing (WGS) runs with different devices (MiSeq, 454 or HiSeq system). WGS data revealed the integration of a chloramphenicol resistance gene, the deletion of the endogenous riboflavin (rib) operon and presence of four putative plasmids harbouring rib operons. Event- and construct-specific real-time PCR methods for detection of the GM strain and its putative plasmids in food and feed products have been developed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Therapeutic approaches to preventing cell death in Huntington disease.

PubMed

Kaplan, Anna; Stockwell, Brent R

2012-12-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Therapeutic approaches to preventing cell death in Huntington disease

PubMed Central

Kaplan, Anna; Stockwell, Brent R.

2012-01-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors—fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. PMID:22967354

Integrality of the therapeutic and pharmaceutical care: a necessary debate

PubMed Central

Vieira, Fabiola Sulpino

2017-01-01

ABSTRACT The controversy surrounding the different interpretations on the integrality of therapeutic and pharmaceutical care has led to the delimitation of its scope by a law, but the issue has not been completely pacified. As a contribution to this debate, we aim to discuss the challenges to ensure the integrality of the therapeutic and pharmaceutical care, based on a conceptual approach on the meanings of integrality in the Brazilian Unified Health System (SUS). We identified important challenges to ensure the integrality of the therapeutic and pharmaceutical care in the SUS. These challenges are related to professional practices, the organization of actions and services, and the governmental response to health problems or to the treatment of specific population groups. For this end, governments need to carry out structuring actions and be efficient in using available resources so that existing problems can be overcome. PMID:29236879

Therapeutic abortion: the psychiatric nurse as therapist, liaison, and consultant.

PubMed

Zahourek, R; Tower, M

1971-01-01

It is noted that as abortion becomes an accepted medical practice, more nurses will be involved in the treatment and counseling of the therapeutic abortion patient. The authors, psychiatric nurses in a Colorado comprehensive urban mental health center, became involved in the treatment of the therapeutic abortion patient with the passing of the State's liberalized 1967 abortion law. As they became involved with all aspects of therapeutic abortion patients' care, they identified 3 specific roles for the psychiatric nurse: 1) providing direct They treatment, 2) providing liaison service and promoting continuity of care for the patient, and 3) providing consultation service to the staff involved with the patient. As the psychiatric nurses shared their own mixed feelings about abortion with the obstetrical staff, the staff began to feel less guilty and less alone with their feelings. The became more involved with the patients and benefited them more.

Advancing Biological Understanding and Therapeutics Discovery with Small Molecule Probes

PubMed Central

Schreiber, Stuart L.; Kotz, Joanne D.; Li, Min; Aubé, Jeffrey; Austin, Christopher P.; Reed, John C.; Rosen, Hugh; White, E. Lucile; Sklar, Larry A.; Lindsley, Craig W.; Alexander, Benjamin R.; Bittker, Joshua A.; Clemons, Paul A.; de Souza, Andrea; Foley, Michael A.; Palmer, Michelle; Shamji, Alykhan F.; Wawer, Mathias J.; McManus, Owen; Wu, Meng; Zou, Beiyan; Yu, Haibo; Golden, Jennifer E.; Schoenen, Frank J.; Simeonov, Anton; Jadhav, Ajit; Jackson, Michael R.; Pinkerton, Anthony B.; Chung, Thomas D.Y.; Griffin, Patrick R.; Cravatt, Benjamin F.; Hodder, Peter S.; Roush, William R.; Roberts, Edward; Chung, Dong-Hoon; Jonsson, Colleen B.; Noah, James W.; Severson, William E.; Ananthan, Subramaniam; Edwards, Bruce; Oprea, Tudor I.; Conn, P. Jeffrey; Hopkins, Corey R.; Wood, Michael R.; Stauffer, Shaun R.; Emmitte, Kyle A.

2015-01-01

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery. PMID:26046436

KRAS as a Therapeutic Target.

PubMed

McCormick, Frank

2015-04-15

KRAS proteins play a major role in human cancer, but have not yielded to therapeutic attack. New technologies in drug discovery and insights into signaling pathways that KRAS controls have promoted renewed efforts to develop therapies through direct targeting of KRAS itself, new ways of blocking KRAS processing, or by identifying targets that KRAS cancers depend on for survival. Although drugs that block the well-established downstream pathways, RAF-MAPK and PI3K, are being tested in the clinic, new efforts are under way to exploit previously unrecognized vulnerabilities, such as altered metabolic networks, or novel pathways identified through synthetic lethal screens. Furthermore, new ways of suppressing KRAS gene expression and of harnessing the immune system offer further hope that new ways of treating KRAS are finally coming into view. These issues are discussed in this edition of CCR Focus. ©2015 American Association for Cancer Research.

Biomarkers in mood disorders research: developing new and improved therapeutics

PubMed Central

Niciu, Mark J.; Mathews, Daniel C.; Ionescu, Dawn F.; Richards, Erica M.; Furey, Maura L.; Yuan, Peixiong; Nugent, Allison C.; Henter, Ioline D.; Machado-Vieira, Rodrigo; Zarate, Carlos A.

2015-01-01

Background Recently, surrogate neurobiological biomarkers that correlate with target engagement and therapeutic response have been developed and tested in early phase studies of mood disorders. Objective The identification of biomarkers could help develop personalized psychiatric treatments that may impact public health. Methods These biomarkers, which are associated with clinical response post-treatment, can be directly validated using multimodal approaches including genetic tools, proteomics/metabolomics, peripheral measures, neuroimaging, biostatistical predictors, and clinical predictors. Results To date, early phase biomarker studies have sought to identify measures that can serve as “biosignatures”, or biological patterns of clinical response. These studies have also sought to identify clinical predictors and surrogate outcomes associated with pathophysiological domains consistently described in the National Institute of Mental Health’s (NIMH) new Research Domain Criteria (RDoC). Using the N-methyl-D-aspartate (NMDA) antagonist ketamine as an example, we identified changes in several domains (clinical, cognitive, and neurophysiological) that predicted ketamine’s rapid and sustained antidepressant effects in individuals with treatment-resistant major depressive disorder (MDD) or bipolar depression. Discussion These approaches may ultimately provide clues into the neurobiology of psychiatric disorders and may have enormous impact Backon the development of novel therapeutics. PMID:26082563

Novel therapeutic strategies in myelodysplastic syndromes: do molecular genetics help?

PubMed

Chung, Stephen S

2016-03-01

Many studies over the past decade have together identified genes that are recurrently mutated in the myelodysplastic syndromes (MDS). We will summarize how this information has informed our understanding of disease pathogenesis and behavior, with an emphasis on how this information may inform therapeutic strategies. Genomic sequencing techniques have allowed for the identification of many recurrently mutated genes in MDS, with the most common mutations being found in epigenetic modifiers and components of the splicing machinery. Although many mutations are associated with clinical outcomes and disease phenotypes, at the current time they add relatively little to already robust clinical prognostic algorithms. However, as molecular genetic data are accumulated in larger numbers of patients, it is likely that the clinical significance of co-occurring mutations and less common mutations will come to light. Finally, mutated genes may identify biologically distinct subgroups of MDS that may benefit from novel therapies, and a subset of these genes may themselves serve as therapeutic targets. Advances in our knowledge of the molecular genetics of MDS have significantly improved our understanding of disease biology and promise to improve tools for clinical decision-making and identify new therapies for patients.

Issues in formulary management: therapeutic interchange. The value, cost, and quality of therapeutic interchange.

PubMed

Mahoney, C D

1992-10-01

Therapeutic interchange is a process of substituting a prescribed medication with one that offers therapeutic and cost benefits. The practice not only provides short-term savings but also is associated with decreases in lengths of stay in hospitals and total hospital drug expenses. There may be medicolegal implications when FDA-approved indications differ for interchanged drugs. The potential for liability is decreased when a standard of care is met, but since standards can change, guidelines should be reviewed regularly. High-tech, high-cost drugs are sometimes appropriate for therapeutic interchange. Pharmacy and therapeutics committees should assure best value by considering indirect expenses, quality, and therapeutic outcome, as well as product cost. Therapeutic interchange programs enable pharmacy managers to neutralize or at least slow the rate of drug cost increases, ensuring appropriate utilization of resources and more favorable patient outcomes.

Therapeutic hypothermia in patients following traumatic brain injury: a systematic review.

PubMed

Dunkley, Steven; McLeod, Anne

2017-05-01

The efficacy of therapeutic hypothermia in adult patients with traumatic brain injury is not fully understood. The historical use of therapeutic hypothermia at extreme temperatures was associated with severe complications and led to it being discredited. Positive results from animal studies using milder temperatures led to renewed interest. However, recent studies have not convincingly demonstrated the beneficial effects of therapeutic hypothermia in practice. This review aims to answer the question: in adults with a severe traumatic brain injury (TBI), does the use of therapeutic hypothermia compared with normothermia affect neurological outcome? Systematic review. Four major electronic databases were searched, and a hand search was undertaken using selected key search terms. Inclusion and exclusion criteria were applied. The studies were appraised using a systematic approach, and four themes addressing the research question were identified and critically evaluated. A total of eight peer-reviewed studies were found, and the results show there is some evidence that therapeutic hypothermia may be effective in improving neurological outcome in adult patients with traumatic brain injury. However, the majority of the trials report conflicting results. Therapeutic hypothermia is reported to be effective at lowering intracranial pressure; however, its efficacy in improving neurological outcome is not fully demonstrated. This review suggests that therapeutic hypothermia had increased benefits in patients with haematoma-type injuries as opposed to those with diffuse injury and contusions. It also suggests that cooling should recommence if rebound intracranial hypertension is observed. Although the data indicates a trend towards better neurological outcome and reduced mortality rates, higher quality multi-centred randomized controlled trials are required before therapeutic hypothermia is implemented as a standard adjuvant therapy for treating traumatic brain injury

Obesity, Inflammation, and Postmenopausal Breast Cancer: Therapeutic Implications

PubMed Central

Macciò, Antonio; Madeddu, Clelia

2011-01-01

Breast cancer is the female malignant neoplasia with the highest incidence in the industrialized world. Although early diagnosis has contributed to therapeutic success, breast cancer remains a major health issue. In the last few year the hormone therapy for estrogen-dependent breast cancer has evolved achieving significant clinical results; at the same time, it has enabled us to better define the role of estrogens in the etiopathogenesis of this tumour. Weight increase and obesity have been identified as the most important risk and prognostic factors for breast cancer in postmenopausal women. Several hypotheses have been proposed to explain the association of obesity with postmenopausal breast cancer. Specific obesity-associated factors, including leptin, insulin and inflammatory mediators, seem to influence breast cancer growth and prognosis independently of estrogens and at least in part by interacting with estrogen signalling at a cellular level. Therefore, a careful assessment of the nutritional status and body composition is paramount for a proper therapeutic approach for postmenopausal breast carcinoma. The use of antidiabetic and anti-inflammatory drugs associated with conventional hormone therapies and dietary/physical interventions could offer a new therapeutic approach for breast carcinoma that develops in the context of adiposity. PMID:22125453

The therapeutic potential of cell cycle targeting in multiple myeloma.

PubMed

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

2017-10-27

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

Contraindications for superficial heat and therapeutic ultrasound: do sources agree?

PubMed

Batavia, Mitchell

2004-06-01

To determine the amount of agreement among general rehabilitation sources for both superficial heating and therapeutic ultrasound contraindications. English-language textbook and peer-reviewed journal sources, from January 1992 to July 2002. Searches of computerized databases (HealthSTAR, CINAHL, MEDLINE, Embase) as well as Library of Congress Online Catalogs, Books in Print, and AcqWeb's Directory of Publishers and Venders. Sources were excluded if they (1) were published before 1992, (2) failed to address general rehabilitation audiences, or (3) were identified as a researcher's related publication with similar information on the topic. Type and number of contraindications, type of audience, year of publication, number of references, rationales, and alternative treatment strategies. Eighteen superficial heat and 20 ultrasound sources identified anywhere from 5 to 22 and 9 to 36 contraindications/precautions, respectively. Agreement among sources was generally high but ranged from 11% to 95%, with lower agreement noted for pregnancy, metal implants, edema, skin integrity, and cognitive/communicative concerns. Seventy-two percent of superficial heat sources and 25% of ultrasound sources failed to reference at least 1 contraindication claim. Agreement among contraindication sources was generally good for both superficial heat and therapeutic ultrasound. Sources varied with regard to the number of contraindications, references, and rationales cited. Greater reliance on objective data and standardized classification systems may serve to develop more uniform guidelines for superficial heat and therapeutic ultrasound.

Therapeutic micro-environments in the Edgelands: A thematic analysis of Richard Mabey's The Unofficial Countryside.

PubMed

Houghton, Frank; Houghton, Sharon

2015-05-01

The concept of therapeutic landscapes, as introduced by Gesler, has had a significant impact on what has become a reformed geography (or geographies) of health. Research in this field has developed the number and type of sites that have been characterised as therapeutic landscapes. A wide range of environments have now been explored through the analytical lens of the 'therapeutic landscape'. This research further expands current descriptions of such environments by exploring Edgelands as therapeutic micro landscapes. Edgelands refer to the neglected and routinely ignored interfacial zone between urban and rural that are a routine characteristic of the urban fringe resulting from dynamic cycles of urban development and decay. Using a hybrid method of thematic analysis incorporating both inductive and deductive approaches, this research explores Richard Mabey's seminal work on this topic, The Unofficial Countryside. Previous examinations of the features of therapeutic environments are therefore scrutinised to explore both scale and the possibility of further extending the kind of environments that may be described as therapeutic to include Edgelands. This approach is informed, in part, by principles of mindfulness, a historically Eastern, but increasingly Western approach to exploring oneself and the environment. This research identifies that these overlooked and neglected landscapes are in fact vibrant, resilient and enthralling environments teeming with life, renewal and re-birth. Examination reveals that there are three crucial outcomes of this research. The first relates to the issue of scale. Mabey's book provides evidence of the importance of micro environments in providing a therapeutic environmental focus. Secondly, this research explores the potential of mindfulness as an approach in Geography. Lastly, this research also identifies Edgelands as therapeutic sites and calls for an increased understanding and appreciation of their potential. Copyright © 2014

Patient-centred communication is associated with positive therapeutic alliance: a systematic review.

PubMed

Pinto, Rafael Zambelli; Ferreira, Manuela L; Oliveira, Vinicius C; Franco, Marcia R; Adams, Roger; Maher, Christopher G; Ferreira, Paulo H

2012-01-01

During the patient-therapist encounter, which communication factors correlate with constructs of therapeutic alliance? Systematic review. Clinicians and patients in primary, secondary or tertiary care settings. Studies had to investigate the association between communication factors (interaction styles, verbal factors or non-verbal factors) and constructs of the therapeutic alliance (collaboration, affective bond, agreement, trust, or empathy), measured during encounters between health practitioners and patients. Among the twelve studies that met the inclusion criteria, 67 communication factors were identified (36 interaction styles, 17 verbal factors and 14 non-verbal factors). The constructs of therapeutic alliance in the included studies were rapport, trust, communicative success and agreement. Interaction styles that showed positive large correlations with therapeutic alliance were those factors that help clinicians to engage more with patients by listening to what they have to say, asking questions and showing sensitivity to their emotional concerns. Studies of verbal and non-verbal factors were scarce and inconclusive. The limited evidence suggests patient-centred interaction styles related to the provision of emotional support and allowing patient involvement in the consultation process enhance the therapeutic alliance. Clinicians can use this evidence to adjust their interactions with patients to include communication strategies that strengthen the therapeutic alliance. Copyright © 2012 Australian Physiotherapy Association. Published by .. All rights reserved.

HAMLET: functional properties and therapeutic potential.

PubMed

Ho C S, James; Rydström, Anna; Trulsson, Maria; Bålfors, Johannes; Storm, Petter; Puthia, Manoj; Nadeem, Aftab; Svanborg, Catharina

2012-10-01

Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells.

RNA interference-based therapeutics for inherited long QT syndrome.

PubMed

Li, Guoliang; Ma, Shuting; Sun, Chaofeng

2015-08-01

Inherited long QT syndrome (LQTS) is an electrical heart disorder that manifests with syncope, seizures, and increased risk of torsades de pointes and sudden cardiac death. Dominant-negative current suppression is a mechanism by which pathogenic proteins disrupt the function of ion channels in inherited LQTS. However, current approaches for the management of inherited LQTS are inadequate. RNA interference (RNAi) is a powerful technique that is able to suppress or silence the expression of mutant genes. RNAi may be harnessed to knock out mRNAs that code for toxic proteins, and has been increasingly recognized as a potential therapeutic intervention for a range of conditions. The present study reviews the literature for RNAi-based therapeutics in the treatment of inherited LQTS. Furthermore, this review discusses the combined use of RNAi with the emerging technology of induced pluripotent stem cells for the treatment of inherited LQTS. In addition, key challenges that must be overcome prior to RNAi-based therapies becoming clinically applicable are addressed. In summary, RNAi-based therapy is potentially a powerful therapeutic intervention, although a number of difficulties remain unresolved.

RNA interference-based therapeutics for inherited long QT syndrome

PubMed Central

LI, GUOLIANG; MA, SHUTING; SUN, CHAOFENG

2015-01-01

Inherited long QT syndrome (LQTS) is an electrical heart disorder that manifests with syncope, seizures, and increased risk of torsades de pointes and sudden cardiac death. Dominant-negative current suppression is a mechanism by which pathogenic proteins disrupt the function of ion channels in inherited LQTS. However, current approaches for the management of inherited LQTS are inadequate. RNA interference (RNAi) is a powerful technique that is able to suppress or silence the expression of mutant genes. RNAi may be harnessed to knock out mRNAs that code for toxic proteins, and has been increasingly recognized as a potential therapeutic intervention for a range of conditions. The present study reviews the literature for RNAi-based therapeutics in the treatment of inherited LQTS. Furthermore, this review discusses the combined use of RNAi with the emerging technology of induced pluripotent stem cells for the treatment of inherited LQTS. In addition, key challenges that must be overcome prior to RNAi-based therapies becoming clinically applicable are addressed. In summary, RNAi-based therapy is potentially a powerful therapeutic intervention, although a number of difficulties remain unresolved. PMID:26622327

Clinical differences among nonsteroidal antiinflammatory drugs: implications for therapeutic substitution in ambulatory patients.

PubMed

Levy, R A; Smith, D L

1989-01-01

The practice of therapeutic substitution, i.e., replacing one drug with another chemically different drug from the same therapeutic class, represents an important therapeutic modification with potential clinical significance far beyond that of generic substitution. Adverse consequences following therapeutic substitution of nonsteroidal antiinflammatory drugs (NSAID) is of special concern because of substantial differences among these agents in pharmacokinetic, pharmacological, and clinical properties. Therapeutic substitution of NSAID for ambulatory patients may result in compromised clinical outcome because (1) patient response is unpredictable and selection of the optimal agent must be tailored for each patient; (2) substantial differences exist in adverse reaction profiles; (3) drug interaction studies are lacking; and (4) selection of an agent must be individualized to ensure compliance with the dosing regimen. Cost savings achieved through therapeutic substitution of NSAID may be lost by additional overall treatment costs due to adverse reactions or suboptimal therapy. The occurrence of adverse or suboptimal effects in ambulatory patients is more likely if NSAID are substituted without full knowledge of the patient's medical history and clinical status. Communication between the pharmacy and prescribing physician regarding a patient's specific needs is essential for rational substitution among NSAID.

FGFR-targeted therapeutics for the treatment of breast cancer.

PubMed

De Luca, Antonella; Frezzetti, Daniela; Gallo, Marianna; Normanno, Nicola

2017-03-01

Breast cancer is a complex disease and several molecular drivers regulate its progression. Fibroblast growth factor receptor (FGFR) signaling is frequently deregulated in many cancers, including breast cancer. Due the involvement of the FGFR/FGF axis in the pathogenesis and progression of tumors, FGFR-targeted agents might represent a potential therapeutic option for breast cancer patients. Areas covered: This review offers an overview of targeted agents against FGFRs and their clinical development in breast cancer. The most relevant literature and the latest studies in the Clinicaltrial.com database have been discussed. Expert opinion: FGFR inhibition has been recently considered as a promising therapeutic option for different tumor types. However, preliminary results of clinical trials of FGFR inhibitors in breast cancer have been quite disappointing. In order to increase the clinical benefit of FGFR therapies in breast cancer, future studies should focus on: understanding the role of the various FGFR aberrations in cancer progression; identifying potential biomarkers to select patients that could benefit of FGFR inhibitors and developing therapeutic strategies that improve the efficacy of these agents and minimize toxicities.

A novel method for detecting neutralizing antibodies against therapeutic proteins by measuring gene expression.

PubMed

Yu, Yanbin; Piddington, Christopher; Fitzpatrick, Dan; Twomey, Brian; Xu, Ren; Swanson, Steven J; Jing, Shuqian

2006-10-20

The presence of neutralizing antibodies against protein therapeutics is a concern in the biomedical field. Such antibodies not only reduce the efficacy of protein therapeutics, but also impose potential dangers to the patients receiving them. To date, a small number of in vitro cell-based bioassays for detecting neutralizing antibodies against therapeutic proteins have been developed. Most of the existing assays, however, either involve the use of radioactive materials or have limited sensitivities and/or poor specificities. With advances in mRNA profiling and detection techniques, we have established a novel and non-radioactive bioassay system using branched DNA (bDNA) technology for detecting protein-therapeutic neutralizing antibodies in patient serum. Our assay measures the variations of target gene expression that reflect the biologic effect of the therapeutic agent and the capability of the antibodies, if present, to neutralize the therapeutics. Compared with most existing assays, the new assay is more sensitive and specific, and completely eliminates the use of radioactive materials. Application of the new assay system can be widely expanded if new target genes and responding cell lines for other therapeutics are identified or engineered.

GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics.

PubMed

Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C; Souza, Milena M; Cirillo, Cintia A; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K

2014-01-01

Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88- 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10(-13), r(2) = 8.9%, β = -0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with-but is statistically distinct from-the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10(-37), r(2) = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception.

Eosinophilic pustular folliculitis: A proposal of diagnostic and therapeutic algorithms.

PubMed

Nomura, Takashi; Katoh, Mayumi; Yamamoto, Yosuke; Miyachi, Yoshiki; Kabashima, Kenji

2016-11-01

Eosinophilic pustular folliculitis (EPF) is a sterile inflammatory dermatosis of unknown etiology. In addition to classic EPF, which affects otherwise healthy individuals, an immunocompromised state can cause immunosuppression-associated EPF (IS-EPF), which may be referred to dermatologists in inpatient services for assessments. Infancy-associated EPF (I-EPF) is the least characterized subtype, being observed mainly in non-Japanese infants. Diagnosis of EPF is challenging because its lesions mimic those of other common diseases, such as acne and dermatomycosis. Furthermore, there is no consensus regarding the treatment for each subtype of EPF. Here, we created procedure algorithms that facilitate the diagnosis and selection of therapeutic options on the basis of published work available in the public domain. Our diagnostic algorithm comprised a simple flowchart to direct physicians toward proper diagnosis. Recommended regimens were summarized in an easy-to-comprehend therapeutic algorithm for each subtype of EPF. These algorithms would facilitate the diagnostic and therapeutic procedure of EPF. © 2016 Japanese Dermatological Association.

Versican is a potential therapeutic target in docetaxel-resistant prostate cancer

PubMed Central

Arichi, Naoko; Mitsui, Yozo; Hiraki, Miho; Nakamura, Sigenobu; Hiraoka, Takeo; Sumura, Masahiro; Hirata, Hiroshi; Tanaka, Yuichiro; Dahiya, Rajvir; Yasumoto, Hiroaki; Shiina, Hiroaki

2015-01-01

In the current study, we investigated a combination of docetaxel and thalidomide (DT therapy) in castration-resistant prostate cancer (CRPC) patients. We identified marker genes that predict the effect of DT therapy. Using an androgen-insensitive PC3 cell line, we established a docetaxel-resistant PC-3 cell line (DR-PC3). In DR-PC3 cells, DT therapy stronger inhibited proliferation/viability than docetaxel alone. Based on gene ontology analysis, we found versican as a selective gene. This result with the findings of cDNA microarray and validated by quantitative RT-PCR. In addition, the effect of DT therapy on cell viability was the same as the effect of docetaxel plus versican siRNA. In other words, silencing of versican can substitute for thalidomide. In the clinical setting, versican expression in prostate biopsy samples (before DT therapy) correlated with PSA reduction after DT therapy (p<0.05). Thus targeting versican is a potential therapeutic strategy in docetaxel-resistant prostate cancer. PMID:25859560

The state-of-play and future of antibody therapeutics.

PubMed

Elgundi, Zehra; Reslan, Mouhamad; Cruz, Esteban; Sifniotis, Vicki; Kayser, Veysel

2017-12-01

It has been over four decades since the development of monoclonal antibodies (mAbs) using a hybridoma cell line was first reported. Since then more than thirty therapeutic antibodies have been marketed, mostly as oncology, autoimmune and inflammatory therapeutics. While antibodies are very efficient, their cost-effectiveness has always been discussed owing to their high costs, accumulating to more than one billion dollars from preclinical development through to market approval. Because of this, therapeutic antibodies are inaccessible to some patients in both developed and developing countries. The growing interest in biosimilar antibodies as affordable versions of therapeutic antibodies may provide alternative treatment options as well potentially decreasing costs. As certain markets begin to capitalize on this opportunity, regulatory authorities continue to refine the requirements for demonstrating quality, efficacy and safety of biosimilar compared to originator products. In addition to biosimilars, innovations in antibody engineering are providing the opportunity to design biobetter antibodies with improved properties to maximize efficacy. Enhancing effector function, antibody drug conjugates (ADC) or targeting multiple disease pathways via multi-specific antibodies are being explored. The manufacturing process of antibodies is also moving forward with advancements relating to host cell production and purification processes. Studies into the physical and chemical degradation pathways of antibodies are contributing to the design of more stable proteins guided by computational tools. Moreover, the delivery and pharmacokinetics of antibody-based therapeutics are improving as optimized formulations are pursued through the implementation of recent innovations in the field. Copyright © 2016 Elsevier B.V. All rights reserved.

Improving Lithium Therapeutics by Crystal Engineering of Novel Ionic Cocrystals

PubMed Central

2013-01-01

Current United States Food and Drug Administration (FDA)-approved lithium salts are plagued with a narrow therapeutic window. Recent attempts to find alternative drugs have identified new chemical entities, but lithium’s polypharmacological mechanisms for treating neuropsychiatric disorders are highly debated and are not yet matched. Thus, re-engineering current lithium solid forms in order to optimize performance represents a low cost and low risk approach to the desired therapeutic outcome. In this contribution, we employed a crystal engineering strategy to synthesize the first ionic cocrystals (ICCs) of lithium salts with organic anions. We are unaware of any previous studies that have assessed the biological efficacy of any ICCs, and encouragingly we found that the new speciation did not negatively affect established bioactivities of lithium. We also observed that lithium ICCs exhibit modulated pharmacokinetics compared to lithium carbonate. Indeed, the studies detailed herein represent an important advancement in a crystal engineering approach to a new generation of lithium therapeutics. PMID:24191685

Improving lithium therapeutics by crystal engineering of novel ionic cocrystals.

PubMed

Smith, Adam J; Kim, Seol-Hee; Duggirala, Naga K; Jin, Jingji; Wojtas, Lukasz; Ehrhart, Jared; Giunta, Brian; Tan, Jun; Zaworotko, Michael J; Shytle, R Douglas

2013-12-02

Current United States Food and Drug Administration (FDA)-approved lithium salts are plagued with a narrow therapeutic window. Recent attempts to find alternative drugs have identified new chemical entities, but lithium's polypharmacological mechanisms for treating neuropsychiatric disorders are highly debated and are not yet matched. Thus, re-engineering current lithium solid forms in order to optimize performance represents a low cost and low risk approach to the desired therapeutic outcome. In this contribution, we employed a crystal engineering strategy to synthesize the first ionic cocrystals (ICCs) of lithium salts with organic anions. We are unaware of any previous studies that have assessed the biological efficacy of any ICCs, and encouragingly we found that the new speciation did not negatively affect established bioactivities of lithium. We also observed that lithium ICCs exhibit modulated pharmacokinetics compared to lithium carbonate. Indeed, the studies detailed herein represent an important advancement in a crystal engineering approach to a new generation of lithium therapeutics.

Activin in acute pancreatitis: Potential risk-stratifying marker and novel therapeutic target.

PubMed

Staudacher, Jonas J; Yazici, Cemal; Carroll, Timothy; Bauer, Jessica; Pang, Jingbo; Krett, Nancy; Xia, Yinglin; Wilson, Annette; Papachristou, Georgios; Dirmeier, Andrea; Kunst, Claudia; Whitcomb, David C; Fantuzzi, Giamila; Jung, Barbara

2017-10-06

Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. Currently, no reliable predictive marker to identify patients at risk for severe disease exists. Treatment is limited to rehydration and supporting care suggesting an urgent need to develop novel approaches to improve standard care. Activin is a critical modulator of inflammatory responses, but has not been assessed in pancreatitis. Here, we demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Furthermore, in mice, inhibition of activin conveys survival benefits in pancreatitis. In addition, serum activin levels were measured from a retrospective clinical cohort of pancreatitis patients and high activin levels in patients at admission are predictive of worse outcomes, indicated by longer overall hospital and intensive care unit stays. Taken together, activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis.

Therapeutic play: preparing the child for the vaccine

PubMed Central

Pontes, Jéssica Etienne Dourado; Tabet, Elaine; Folkmann, Maria Áurea dos Santos; Cunha, Mariana Lucas da Rocha; Almeida, Fabiane de Amorim

2015-01-01

ABSTRACT Objective: To identify and compare behaviors of children during vaccination, who were prepared or not for the procedure using an instructional therapeutic play. Methods: A quasi experimental study, with quantitative approach of 60 children aged 3 to 6 years. The child's reactions were recorded in a checklist. Data were analyzed using descriptive and inferential statistics and Fisher's test. Results: The main reactions in the experimental group were stay still (25;83%) and spontaneously collaborate (24;80%). In the control group, the main reactions were cries and cling to parents (15; 50%), flushing (11;36.67%) and moving the body/agitated (10;33.3%). Conclusion: The reactions of cooperation were more frequent in the experimental group, while low acceptance was observed only in the control group. Therapeutic play has proved an important tool in preparing for the vaccine. PMID:26154545

MACROMOLECULAR THERAPEUTICS

PubMed Central

Yang, Jiyuan; Kopeček, Jindřich

2014-01-01

This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines – (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. PMID:24747162

Additive manufactured serialization

DOEpatents

Bobbitt, III, John T.

2017-04-18

Methods for forming an identifying mark in a structure are described. The method is used in conjunction with an additive manufacturing method and includes the alteration of a process parameter during the manufacturing process. The method can form in a unique identifying mark within or on the surface of a structure that is virtually impossible to be replicated. Methods can provide a high level of confidence that the identifying mark will remain unaltered on the formed structure.

Patients' experiences with technology during inpatient rehabilitation: opportunities to support independence and therapeutic engagement.

PubMed

Fager, Susan Koch; Burnfield, Judith M

2014-03-01

To understand individuals' perceptions of technology use during inpatient rehabilitation. A qualitative phenomenological study using semi-structured interviews of 10 individuals with diverse underlying diagnoses and/or a close family member who participated in inpatient rehabilitation. Core themes focused on assistive technology usage (equipment set-up, reliability and fragility of equipment, expertise required to use assistive technology and use of mainstream technologies) and opportunities for using technology to increase therapeutic engagement (opportunities for practice outside of therapy, goals for therapeutic exercises and technology for therapeutic exercises: motivation and social interaction). Interviews revealed the need for durable, reliable and intuitive technology without requiring a high level of expertise to install and implement. A strong desire for the continued use of mainstream devices (e.g. cell phones, tablet computers) reinforces the need for a wider range of access options for those with limited physical function. Finally, opportunities to engage in therapeutically meaningful activities beyond the traditional treatment hours were identified as valuable for patients to not only improve function but to also promote social interaction. Assistive technology increases functional independence of severely disabled individuals. End-users (patients and families) identified a need for designs that are durable, reliable, intuitive, easy to consistently install and use. Technology use (adaptive or commercially available) provides a mechanism to extend therapeutic practice beyond the traditional therapy day. Adapting skeletal tracking technology used in gaming software could automate exercise tracking, documentation and feedback for patient motivation and clinical treatment planning and interventions.

Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request.

PubMed

Hogan, William R; Hanna, Josh; Hicks, Amanda; Amirova, Samira; Bramblett, Baxter; Diller, Matthew; Enderez, Rodel; Modzelewski, Timothy; Vasconcelos, Mirela; Delcher, Chris

2017-03-03

The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outset to carefully distinguish those entities that have a therapeutic indication from those entities that have a molecular mechanism of action, we had not previously represented in DrOn any particular therapeutic indication. In this work, we add therapeutic indications for three research use cases: resistant hypertension, malaria, and opioid abuse research. We also added mechanisms of action for opioid analgesics and added 108 classes representing drug products in response to a large term request from the Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) project. The net result is a new version of DrOn, current to May 2016, that represents three major therapeutic classes of drugs and six new mechanisms of action. A therapeutic indication of a drug product is represented as a therapeutic function in DrOn. Adverse effects of drug products, as well as other therapeutic uses for which the drug product was not designed are dispositions. Our work provides a framework for representing additional therapeutic indications, adverse effects, and uses of drug products beyond their design. Our work also validated our past modeling decisions for specific types of mechanisms of action, namely effects mediated via receptor and/or enzyme binding. DrOn is available at: http://purl.obolibrary.org/obo/dron.owl . A smaller version without NDCs is available at: http://purl.obolibrary.org/obo/dron/dron-lite.owl.

The Therapeutic Potential of Anti-Inflammatory Exerkines in the Treatment of Atherosclerosis

PubMed Central

Yu, Megan; Tsai, Sheng-Feng; Kuo, Yu-Min

2017-01-01

Although many cardiovascular (CVD) medications, such as antithrombotics, statins, and antihypertensives, have been identified to treat atherosclerosis, at most, many of these therapeutic agents only delay its progression. A growing body of evidence suggests physical exercise could be implemented as a non-pharmacologic treatment due to its pro-metabolic, multisystemic, and anti-inflammatory benefits. Specifically, it has been discovered that certain anti-inflammatory peptides, metabolites, and RNA species (collectively termed “exerkines”) are released in response to exercise that could facilitate these benefits and could serve as potential therapeutic targets for atherosclerosis. However, much of the relationship between exercise and these exerkines remains unanswered, and there are several challenges in the discovery and validation of these exerkines. This review primarily highlights major anti-inflammatory exerkines that could serve as potential therapeutic targets for atherosclerosis. To provide some context and comparison for the therapeutic potential of exerkines, the anti-inflammatory, multisystemic benefits of exercise, the basic mechanisms of atherosclerosis, and the limited efficacies of current anti-inflammatory therapeutics for atherosclerosis are briefly summarized. Finally, key challenges and future directions for exploiting these exerkines in the treatment of atherosclerosis are discussed. PMID:28608819

The current state of therapeutic and T cell-based vaccines against human papillomaviruses.

PubMed

Yang, Andrew; Farmer, Emily; Lin, John; Wu, T-C; Hung, Chien-Fu

2017-03-02

Human papillomavirus (HPV) is known to be a necessary factor for many gynecologic malignancies and is also associated with a subset of head and neck malignancies. This knowledge has created the opportunity to control these HPV-associated cancers through vaccination. However, despite the availability of prophylactic HPV vaccines, HPV infections remain extremely common worldwide. In addition, while prophylactic HPV vaccines have been effective in preventing infection, they are ineffective at clearing pre-existing HPV infections. Thus, there is an urgent need for therapeutic and T cell-based vaccines to treat existing HPV infections and HPV-associated lesions and cancers. Unlike prophylactic vaccines, which generate neutralizing antibodies, therapeutic, and T cell-based vaccines enhance cell-mediated immunity against HPV antigens. Our review will cover various therapeutic and T cell-based vaccines in development for the treatment of HPV-associated diseases. Furthermore, we review the strategies to enhance the efficacy of therapeutic vaccines and the latest clinical trials on therapeutic and T cell-based HPV vaccines. Copyright © 2016 Elsevier B.V. All rights reserved.

Therapeutic Nanodevices

NASA Astrophysics Data System (ADS)

Lee, Stephen C.; Ruegsegger, Mark; Barnes, Philip D.; Smith, Bryan R.; Ferrari, Mauro

Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'etre of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multi-step work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

Therapeutic Nanodevices

NASA Astrophysics Data System (ADS)

Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

State of the art of the therapeutic perspective of sorafenib against hematological malignancies.

PubMed

Zauli, G; Voltan, R; Tisato, V; Secchiero, P

2012-01-01

The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti-neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the

Image Guidance in Stem Cell Therapeutics: Unfolding the Blindfold.

PubMed

Bukhari, Amirali B; Dutta, Shruti; De, Abhijit

2015-01-01

Stem cell therapeutics is the future of regenerative medicine in the modern world. Many studies have been instigated with the hope of translating the outcome for the treatment of several disease conditions ranging from heart and neuronal disease to malignancies as grave as cancers. Stem cell therapeutics undoubtedly holds great promise on the front of regenerative medicine, however, the correct distribution and homing of these stem cells to the host site remained blinded until the recent advances in the discipline of molecular imaging. Herein, we discuss the various imaging guidance applied for determination of the proper delivery of various types of stem cell used as therapeutics for various maladies. Additionally, we scrutinize the use of several indirect labeling mechanisms for efficient tagging of the reporter entity for image guidance. Further, the promise of improving patient healthcare has led to the initiation of several clinical trials worldwide. However, in number of the cases, the benefits arrive with a price heavy enough to pose a serious health risk, one such being formation of teratomas. Thus numerous challenges and methodological obstacles must be overcome before their eloquent clinical impact can be realized. Therefore, we also discuss several clinical trials that have taken into consideration the various imaging guided protocols to monitor correct delivery and understand the distribution of therapeutic stem cells in real time.

The therapeutic alliance in internet interventions: A narrative review and suggestions for future research.

PubMed

Berger, Thomas

2017-09-01

Research on Internet interventions has grown rapidly over the recent years and evidence is growing that Internet-based treatments often result in similar outcomes as conventional face-to-face psychotherapy. Yet there are still unanswered concerns such as whether a therapeutic alliance can be established over the Internet and whether the alliance is important in this new treatment format. A narrative review of studies formally assessing the therapeutic alliance in Internet interventions was conducted. It is the first review summarizing findings on the therapeutic alliance that (i) distinguishes between different forms of Internet interventions and (ii) does not restrict itself to specific Internet-based treatment formats such as guided self-help treatments, e-mail or videoconferencing therapies. Independent of communication modalities, diagnostic groups and amount of contact between clients and therapists, client-rated alliance scores were high, roughly equivalent to alliance ratings found in studies on face-to-face therapy. Mixed results were found regarding the therapist-rated alliance and alliance-outcome associations. The review points to the limitations of the available evidence and identifies unanswered questions. It is concluded that one of the major tasks for future research is to identify unique characteristics of the therapeutic alliance in the different treatment formats.

Evaluation of Therapeutics for Advanced-Stage Heart Failure and Other Severely-Debilitating or Life-Threatening Diseases.

PubMed

Prescott, J S; Andrews, P A; Baker, R W; Bogdanffy, M S; Fields, F O; Keller, D A; Lapadula, D M; Mahoney, N M; Paul, D E; Platz, S J; Reese, D M; Stoch, S A; DeGeorge, J J

2017-08-01

Severely-debilitating or life-threatening (SDLT) diseases include conditions in which life expectancy is short or quality of life is greatly diminished despite available therapies. As such, the medical context for SDLT diseases is comparable to advanced cancer and the benefit vs. risk assessment and development of SDLT disease therapeutics should be similar to that of advanced cancer therapeutics. A streamlined development approach would allow patients with SDLT conditions earlier access to therapeutics and increase the speed of progression through development. In addition, this will likely increase the SDLT disease therapeutic pipeline, directly benefiting patients and reducing the economic and societal burden of SDLT conditions. Using advanced-stage heart failure (HF) as an example that illustrates the concepts applicable to other SDLT indications, this article proposes a streamlined development paradigm for SDLT disease therapeutics and recommends development of aligned global regulatory guidance. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Macromolecular therapeutics.

PubMed

Yang, Jiyuan; Kopeček, Jindřich

2014-09-28

This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.

[Therapeutic cloning in debate].

PubMed

de Wert, G

2001-11-03

Human embryos can be conceived by cell nuclear transfer in order to isolate human embryonic stem cells (hES cells) for research into autologous cell therapy (therapeutic cloning). However, this technique broaches the major ethical problem concerning the instrumental use of human preimplantation embryos. From the viewpoint of subsidiarity, it is argued that various potential alternatives for therapeutic cloning should first be investigated further. The question as to whether therapeutic cloning should be allowed only becomes apparent when research with surplus embryos obtained in the course of in-vitro fertilization suggests that usable transplants can be obtained in vitro from hES cells, and when the potential alternatives for therapeutic cloning are either less promising or need more time for development than is currently expected.

Uncovering the Rosetta Stone: Report from the First Annual Conference on Key Elements in Translating Stroke Therapeutics from Pre-Clinical to Clinical.

PubMed

Bix, Gregory J; Fraser, Justin F; Mack, William J; Carmichael, S Thomas; Perez-Pinzon, Miguel; Offner, Halina; Sansing, Lauren; Bosetti, Francesca; Ayata, Cenk; Pennypacker, Keith R

2018-06-01

The first annual Stroke Translational Research Advancement Workshop (STRAW), entitled "Uncovering the Rosetta Stone: Key Elements in Translating Stroke Therapeutics from Pre-Clinical to Clinical" was held at the University of Kentucky on October 4-5, 2017. This workshop was organized by the Center for Advanced Translational Stroke Science. The workshop consisted of 2 days of activities. These included three presentations establishing the areas of research in stroke therapeutics, discussing the routes for translation from bench to bedside, and identifying successes and failures in the field. On day 2, grant funding opportunities and goals for the National Institute for Neurological Diseases and Stroke were presented. In addition, the meeting also included break-out sessions designed to connect researchers in areas of stroke, and to foster potential collaborations. Finally, the meeting concluded with an open discussion among attendees led by a panel of experts.

Blood-Brain Barrier Integrity and Glial Support: Mechanisms that can be targeted for Novel Therapeutic Approaches in Stroke

PubMed Central

Ronaldson, Patrick T.; Davis, Thomas P.

2014-01-01

The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics (i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this “barrier,” brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a “neurovascular unit.” Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB in an effort to identify novel targets for optimization of CNS delivery of therapeutics in the setting of ischemic stroke. PMID:22574987

Therapeutic action of ghrelin in a mouse model of colitis.

PubMed

Gonzalez-Rey, Elena; Chorny, Alejo; Delgado, Mario

2006-05-01

Ghrelin is a novel growth hormone-releasing peptide with potential endogenous anti-inflammatory activities ameliorating some pathologic inflammatory conditions. Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon. The aim of this study was to investigate the therapeutic effect of ghrelin in a murine model of colitis. We examined the anti-inflammatory action of ghrelin in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid. Diverse clinical signs of the disease were evaluated, including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of ghrelin, such as inflammatory cytokines and chemokines, Th1-type response, and regulatory factors. Ghrelin ameliorated significantly the clinical and histopathologic severity of the trinitrobenzene sulfonic acid-induced colitis; abrogating body weight loss, diarrhea, and inflammation; and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response through the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of interluekin-10/transforming growth factor-beta1-secreting regulatory T cells in this therapeutic effect was demonstrated. Importantly, the ghrelin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. Our data demonstrate novel anti-inflammatory actions for ghrelin in the gastrointestinal tract, ie, the capacity to deactivate the intestinal inflammatory response and to restore mucosal immune tolerance at multiple levels. Consequently, ghrelin administration represents a novel possible therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.

Acute Pulmonary Embolism in Emergency Department Patients Despite Therapeutic Anticoagulation

PubMed Central

Liu, Michelle Y.; Ballard, Dustin W.; Huang, Jie; Rauchwerger, Adina S.; Reed, Mary E.; Bouvet, Sean C.

2018-01-01

Introduction Emergency department (ED) patients with acute pulmonary embolism (PE) despite therapeutic anticoagulation at the time of diagnosis are uncommonly encountered and present a diagnostic and management challenge. Their characterization and outcomes are poorly described. We sought to describe the prevalence and characteristics of therapeutically anticoagulated patients among a population of patients with acute PE in a community setting and to describe treatment changes and 30-day outcomes. Methods From a large retrospective cohort of adults with acute, objectively-confirmed PE across 21 EDs between 01/2013 and 04/2015, we identified patients who arrived on direct oral or injectable anticoagulants, or warfarin with an initial ED international normalized ratio (INR) value ≥2.0. Patients were excluded from the larger cohort if they had received a diagnosis of venous thromboembolism (VTE) in the prior 30 days. We gathered demographic and clinical variables from electronic health records and structured manual chart review. We report discharge anticoagulation regimens and major 30-day adverse outcomes. Results Among 2,996 PE patients, 36 (1.2%) met study criteria. Mean age was 63 years. Eleven patients (31%) had active cancer and 25 (69%) were high risk on the PE Severity Index (Classes III–V), comparable to the larger cohort (p>0.1). Reasons for pre-arrival anticoagulation were VTE treatment or prevention (n=21), and atrial fibrillation or flutter (n=15). All patients arrived on warfarin and one was also on enoxaparin: 32 had a therapeutic INR (2.0–3.0) and four had a supratherapeutic INR (>3.0). Fifteen patients (42%) had at least one subtherapeutic INR (<2.0) in the 14 days preceding their diagnostic visit. Two patients died during hospitalization. Of the 34 ultimately discharged, 22 underwent a change in anticoagulation drug or dosing, 19 of whom received injectables, either to replace or to supplement warfarin. Four patients also received inferior vena

Psychodynamic Perspective on Therapeutic Boundaries

PubMed Central

Bridges, Nancy A.

1999-01-01

Discussion of boundaries in therapeutic work most often focuses on boundary maintenance, risk management factors, and boundary violations. The psychodynamic meaning and clinical management of boundaries in therapeutic relationships remains a neglected area of discourse. Clinical vignettes will illustrate a psychodynamic, developmental-relational perspective using boundary dilemmas to deepen and advance the therapeutic process. This article contributes to the dialogue about the process of making meaning and constructing therapeutically useful and creative boundaries that further the psychotherapeutic process. PMID:10523432

[Nuclear transfer and therapeutic cloning].

PubMed

Xu, Xiao-Ming; Lei, An-Min; Hua, Jin-Lian; Dou, Zhong-Ying

2005-03-01

Nuclear transfer and therapeutic cloning have widespread and attractive prospects in animal agriculture and biomedical applications. We reviewed that the quality of oocytes and nuclear reprogramming of somatic donor cells were the main reasons of the common abnormalities in cloned animals and the low efficiency of cloning and showed the problems and outlets in therapeutic cloning, such as some basic problems in nuclear transfer affected clinical applications of therapeutic cloning. Study on isolation and culture of nuclear transfer embryonic stem (ntES) cells and specific differentiation of ntES cells into important functional cells should be emphasized and could enhance the efficiency. Adult stem cells could help to cure some great diseases, but could not replace therapeutic cloning. Ethics also impeded the development of therapeutic cloning. It is necessary to improve many techniques and reinforce the research of some basic theories, then somatic nuclear transfer and therapeutic cloning may apply to agriculture reproduction and benefit to human life better.

Adenosine Kinase: Exploitation for Therapeutic Gain

PubMed Central

2013-01-01

Adenosine kinase (ADK; EC 2.7.1.20) is an evolutionarily conserved phosphotransferase that converts the purine ribonucleoside adenosine into 5′-adenosine-monophosphate. This enzymatic reaction plays a fundamental role in determining the tone of adenosine, which fulfills essential functions as a homeostatic and metabolic regulator in all living systems. Adenosine not only activates specific signaling pathways by activation of four types of adenosine receptors but it is also a primordial metabolite and regulator of biochemical enzyme reactions that couple to bioenergetic and epigenetic functions. By regulating adenosine, ADK can thus be identified as an upstream regulator of complex homeostatic and metabolic networks. Not surprisingly, ADK dysfunction is involved in several pathologies, including diabetes, epilepsy, and cancer. Consequently, ADK emerges as a rational therapeutic target, and adenosine-regulating drugs have been tested extensively. In recent attempts to improve specificity of treatment, localized therapies have been developed to augment adenosine signaling at sites of injury or pathology; those approaches include transplantation of stem cells with deletions of ADK or the use of gene therapy vectors to downregulate ADK expression. More recently, the first human mutations in ADK have been described, and novel findings suggest an unexpected role of ADK in a wider range of pathologies. ADK-regulating strategies thus represent innovative therapeutic opportunities to reconstruct network homeostasis in a multitude of conditions. This review will provide a comprehensive overview of the genetics, biochemistry, and pharmacology of ADK and will then focus on pathologies and therapeutic interventions. Challenges to translate ADK-based therapies into clinical use will be discussed critically. PMID:23592612

c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

PubMed

Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo J A; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

2015-06-03

c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.

Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer*

PubMed Central

Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh; Nirujogi, Raja Sekhar; Kim, Min-Sik; Manda, Srikanth S.; Stearns, Vered; Gabrielson, Edward; Sukumar, Saraswati; Pandey, Akhilesh

2015-01-01

Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers. PMID:26330541

GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics

PubMed Central

Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C.; Souza, Milena M.; Cirillo, Cintia A.; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S.; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K.

2014-01-01

Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88– 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10−13, r2 = 8.9%, β = −0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with—but is statistically distinct from—the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10−37, r2 = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception. PMID:23966204

Applications of Metal Additive Manufacturing in Veterinary Orthopedic Surgery

NASA Astrophysics Data System (ADS)

Harrysson, Ola L. A.; Marcellin-Little, Denis J.; Horn, Timothy J.

2015-03-01

Veterinary medicine has undergone a rapid increase in specialization over the last three decades. Veterinarians now routinely perform joint replacement, neurosurgery, limb-sparing surgery, interventional radiology, radiation therapy, and other complex medical procedures. Many procedures involve advanced imaging and surgical planning. Evidence-based medicine has also become part of the modus operandi of veterinary clinicians. Modeling and additive manufacturing can provide individualized or customized therapeutic solutions to support the management of companion animals with complex medical problems. The use of metal additive manufacturing is increasing in veterinary orthopedic surgery. This review describes and discusses current and potential applications of metal additive manufacturing in veterinary orthopedic surgery.

Therapeutic Inertia and Treatment Intensification.

PubMed

Josiah Willock, Robina; Miller, Joseph B; Mohyi, Michelle; Abuzaanona, Ahmed; Muminovic, Meri; Levy, Phillip D

2018-01-29

This review aims to emphasize how therapeutic inertia, the failure of clinicians to intensify treatment when blood pressure rises or remains above therapeutic goals, contributes to suboptimal blood pressure control in hypertensive populations. Studies reveal that the therapeutic inertia is quite common and contributes to suboptimal blood pressure control. Quality improvement programs and standardized approaches to support antihypertensive treatment intensification are ways to combat therapeutic inertia. Furthermore, programs that utilize non-physician medical professionals such as pharmacists and nurses demonstrate promise in mitigating the effects of this important problem. Therapeutic inertia impedes antihypertensive management and requires a broad effort to reduce its effects. There is an ongoing need for renewed focus and research in this area to improve hypertension control.

Translational research in addiction: toward a framework for the development of novel therapeutics.

PubMed

Paterson, Neil E

2011-06-15

The development of novel substance use disorder (SUD) therapeutics is insufficient to meet the medical needs of a growing SUD patient population. The identification of translatable SUD models and tests is a crucial step in establishing a framework for SUD therapeutic development programs. The present review begins by identifying the clinical features of SUDs and highlights the narrow regulatory end-point required for approval of a novel SUD therapeutic. A conceptual overview of dependence is provided, followed by identification of potential intervention targets in the addiction cycle. The main components of the addiction cycle provide the framework for a discussion of preclinical models and their clinical analogs, all of which are focused on isolated behavioral end-points thought to be relevant to the persistence of compulsive drug use. Thus, the greatest obstacle to successful development is the gap between the multiplicity of preclinical and early clinical end-points and the regulatory end-point of sustained abstinence. This review proposes two pathways to bridging this gap: further development and validation of the preclinical extended access self-administration model; inclusion of secondary end-points comprising all of the measures highlighted in the present discussion in Phase 3 trials. Further, completion of the postdictive validation of analogous preclinical and clinical assays is of high priority. Ultimately, demonstration of the relevance and validity of a variety of end-points to the ultimate goal of abstinence will allow researchers to identify truly relevant therapeutic mechanisms and intervention targets, and establish a framework for SUD therapeutic development that allows optimal decision-making and resource allocation. 2011 Elsevier Inc. All rights reserved.

[Multiple myeloma: current therapeutic approaches].

PubMed

Troussard, X; Bauduer, F; Leporrier, M

1992-01-01

The therapeutic strategy in multiple myeloma depends on age and tumor mass. Stage I must not be treated. The Melphalan Prednisone regimen is the reference for induction therapy because polychemotherapies are generally not superior. At this phase, the addition of Interferon alpha seems to be interesting. This drug has an important role during the steady-state phase. VAD represents the most efficient chemotherapy. Body hemi-irradiation is also useful. The analgesic effect and the decrease in the tumoral mass are the striking effects of this treatment. In young patients, high dose chemotherapy with bone marrow transplantation is proposed. Verapamil and anti-IL6 antibodies are currently being evaluated. Symptomatic treatment is essential in this non curable disease.

Carrier Mediated Systemic Delivery of Protein and Peptide Therapeutics.

PubMed

Zaman, Rahela; Othman, Iekhan; Chowdhury, Ezharul Hoque

2016-01-01

Over the last few decades proteins and peptide therapeutics have occupied an enormous fraction of pharmaceutical industry. Despite their high potential as therapeutics, the big challenge often encountered is the effective administration and bioavailability of protein therapeutics in vivo system. Peptide molecules are well known for their in vivo short half-lives. In addition, due to high molecular weight and susceptibility to enzymatic degradation, often it is not easy to administer peptides and proteins orally or through any other noninvasive routes. Conventional drug management system often demands for frequent and regular interval intravenous/subcutaneous administration, which decreases overall patient compliance and increases chances of side-effects related to dose-fluctuation in systemic circulation. A controlled mode of delivery system could address all these short-comings at a time. Therefore, long-acting sustained release formulations for both invasive and noninvasive routes are under rigorous study currently. Long-acting formulations through invasive routes can address patient compliance and dose-fluctuation issues by less frequent administration. Also, any new route of administration other than invasive routes will address cost-effectiveness of the therapeutic by lessening the need to deal with health professional and health care facility. Although a vast number of studies are dealing with novel drug delivery systems, till now only a handful of controlled release formulations for proteins and peptides have been approved by FDA. This study therefore focuses on current and perspective controlled release formulations of existing and novel protein/peptide therapeutics via conventional invasive routes as well as potential novel non-invasive routes of administration, e.g., oral, buccal, sublingual, nasal, ocular, rectal, vaginal and pulmonary.

Biomanufacturing of Therapeutic Cells: State of the Art, Current Challenges, and Future Perspectives.

PubMed

Roh, Kyung-Ho; Nerem, Robert M; Roy, Krishnendu

2016-06-07

Stem cells and other functionally defined therapeutic cells (e.g., T cells) are promising to bring hope of a permanent cure for diseases and disorders that currently cannot be cured by conventional drugs or biological molecules. This paradigm shift in modern medicine of using cells as novel therapeutics can be realized only if suitable manufacturing technologies for large-scale, cost-effective, reproducible production of high-quality cells can be developed. Here we review the state of the art in therapeutic cell manufacturing, including cell purification and isolation, activation and differentiation, genetic modification, expansion, packaging, and preservation. We identify current challenges and discuss opportunities to overcome them such that cell therapies become highly effective, safe, and predictively reproducible while at the same time becoming affordable and widely available.

Challenges and new strategies for therapeutic peptide delivery to the CNS.

PubMed

McGowan, Jeremy Wd; Bidwell, Gene L; Vig, Parminder Js

2015-07-01

Therapeutic peptides represent a largely untapped resource in medicine today, especially in the central nervous system. Despite their ease of design and remarkably high target specificity, it is difficult to deliver them beyond the blood-brain barrier or into the required intracellular compartments. In addition, the instability of these peptides in vivo precludes their use to combat the symptoms of numerous neurological disorders including Alzheimer's disease and spinocerebellar ataxia. In this review, we aim to characterize recent advances in the delivery of therapeutic peptides to the central nervous system past the blood-brain barrier and discuss the advantages and disadvantages of the examined methods as well as explore new potential directions.

Somatic mutations in salivary duct carcinoma and potential therapeutic targets

PubMed Central

Smith, Joel A.; Clarke, Angus J.; Luk, Peter P.; Selinger, Christina I.; Mahon, Kate L.; Kraitsek, Spiridoula; Palme, Carsten; Boyer, Michael J.; Dinger, Marcel E.; Cowley, Mark J.; O’Toole, Sandra A.

2017-01-01

Background Salivary duct carcinomas (SDCa) are rare highly aggressive malignancies. Most patients die from distant metastatic disease within three years of diagnosis. There are limited therapeutic options for disseminated disease. Results 11 cases showed androgen receptor expression and 6 cases showed HER2 amplification. 6 Somatic mutations with additional available targeted therapies were identified: EGFR (p.G721A: Gefitinib), PDGFRA (p.H845Y: Imatinib and Crenolanib), PIK3CA (p.H1047R: Everolimus), ERBB2 (p.V842I: Lapatinib), HRAS (p.Q61R: Selumetinib) and KIT (p.T670I: Sorafenib). Furthermore, alterations in PTEN, PIK3CA and HRAS that alter response to androgen deprivation therapy and HER2 inhibition were also seen. Materials and Methods Somatic mutation analysis was performed on DNA extracted from 15 archival cases of SDCa using the targeted Illumina TruSeq Amplicon Cancer Panel. Potential targetable genetic alterations were identified using extensive literature and international somatic mutation database (COSMIC, KEGG) search. Immunohistochemistry for androgen receptor and immunohistochemistry and fluorescent in situ hybridization for HER2 were also performed. Conclusions SDCa show multiple somatic mutations, some that are amenable to pharmacologic manipulation and others that confer resistance to treatments currently under investigation. These findings emphasize the need to develop testing and treatment strategies for SDCa. PMID:29100278

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics.

PubMed

Huang, Wenwen; Rollett, Alexandra; Kaplan, David L

2015-05-01

Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure-function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release. An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence-structure-function relationships, stimuli-responsive features and current and potential drug delivery applications. The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.

Evaluation of Two Dry Commercial Therapeutic Diets for the Management of Feline Chronic Gastroenteropathy

PubMed Central

Perea, Sally C.; Marks, Stanley L.; Daristotle, Leighann; Koochaki, Patricia E.; Haydock, Richard

2017-01-01

Management of feline chronic gastroenteropathies has included intervention with both veterinary therapeutic formulas designed to manage non-specific gastrointestinal disorders and those designed with limited novel or hydrolyzed ingredients for management of food-responsive enteropathies and steroid-responsive enteropathies (inflammatory bowel disease). There have been few studies evaluating the use of dietary intervention for the management of feline chronic gastroenteropathy. This prospective, multi-center study evaluated the use of two commercially available feline veterinary therapeutic dry diets designed to manage non-specific gastrointestinal disorders in 28 cats with a history of chronic vomiting and/or diarrhea. The majority of cats enrolled in the study had a history of vomiting (n = 25), with a smaller number having a history of concurrent diarrhea (n = 2) or diarrhea alone (n = 3). Cats were excluded if diagnostic tests identified any systemic or infectious disease that could be associated with the clinical signs of vomiting or diarrhea, and if they were panhypoproteinemic, hypoalbuminemic, hypocobalaminemic, or had a Spec fPL ≥5.4 µg/L. Cats were randomized to one of two veterinary therapeutic diets for 4 weeks. Feeding of both therapeutic diets resulted in a numeric reduction in the number of vomiting episodes over the 4-week period, but no significant differences were seen between dietary interventions. When looking within dietary groups, significant differences were seen in cats fed Diet A with reductions of 69.1, 73.3, and 63.2% (p values of 0.008, 0.003, and 0.029) in weeks 2, 3, and 4, respectively, when compared to week 0. The probability of vomiting also showed significant reductions in cats fed Diet A between weeks 0 and 2, 3, and 4, with odds ratios of 0.008, 0.005, and 0.005, respectively (p values of 0.038, 0.23, and 0.23). Results of this study demonstrate that a veterinary therapeutic gastrointestinal formula can be

[Gradual effects of therapeutic touch in reducing anxiety in university students].

PubMed

Gomes, Vanessa Miranda; Silva, Maria Júlia Paes da; Araújo, Eutália Aparecida Cândido

2008-01-01

This is quantitative research conducted with 42 students of a public university using the Therapeutic Touch - Krieger-Kunz Method and the application of a questionnaire validated in Brazil to assess anxiety in three sessions. Subjects were divided into two groups: experimental (1), in which the complementary therapy was used; and control (2), in which a mock of the technique, with no therapeutic intention, was applied. The objective was to identify the gradual influence of that health complementary therapy upon the students' state of anxiety. The analysis of the data showed a statistically significant reduction of the state of anxiety in both groups, with pd' 0.05.

The impact of online therapeutic feedback on outcome measures in Internet-CBTI for adolescents with insomnia.

PubMed

de Bruin, Eduard Jan; Meijer, Anne Marie

2017-01-01

Guided Internet cognitive behavioral therapy for insomnia (CBTI) offers an effective treatment for adolescents, but little is known about the active ingredients of therapeutic feedback on outcomes. This study aims to identify which factors can be distinguished in written therapeutic feedback in Internet CBTI, and examine whether these factors and participation in a chat session contribute to sleep outcomes. Internet CBTI was applied to 57 adolescents (mean age 15.43 years, SD 1.74, 82.5% girls). Symptoms of insomnia and chronic sleep reduction, and total sleep time, time in bed, and sleep efficiency from seven day sleep logs were measured at baseline, post-treatment, and at two month follow-up. With a coding instrument developed for this study, two independent researchers coded transcripts of the written therapeutic feedback of the Internet CBTI sessions with an event sampling method. Principal component analysis of the initial 17 items from the coding instrument yielded four distinct factors of therapeutic feedback, of which only Sleep expertise seemed to contribute to improvements after Internet CBTI. The other factors, indicating forms of encouragement, and participation in a chat session seemed counterproductive. This first longitudinal study into effects of therapeutic feedback in adolescent Internet CBTI indicated that emphasizing knowledge about sleep might contribute to insomnia improvement. The structured nature of the preprogrammed treatment content, delay of therapeutic feedback due to standardized timing, and unintentional reinforcement of undesirable behavior by giving attention to failures might explain the negative results of encouraging behavior. Further research to identify effective therapeutic factors in Internet therapy is warranted. Copyright © 2016 Elsevier B.V. All rights reserved.

Combining Immune Checkpoint Inhibitors and Kinase-Inhibiting Supramolecular Therapeutics for Enhanced Anticancer Efficacy.

PubMed

Kulkarni, Ashish; Natarajan, Siva Kumar; Chandrasekar, Vineethkrishna; Pandey, Prithvi Raj; Sengupta, Shiladitya

2016-09-29

A major limitation of immune checkpoint inhibitors is that only a small subset of patients achieve durable clinical responses. This necessitates the development of combinatorial regimens with immunotherapy. However, some combinations, such as MEK- or PI3K-inhibitors with a PD1-PDL1 checkpoint inhibitor, are pharmacologically challenging to implement. We rationalized that such combinations can be enabled using nanoscale supramolecular targeted therapeutics, which spatially home into tumors and exert temporally sustained inhibition of the target. Here we describe two case studies where nanoscale MEK- and PI3K-targeting supramolecular therapeutics were engineered using a quantum mechanical all-atomistic simulation-based approach. The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively. Additionally, the temporal sequence of administration impacts the outcome. The combination of supramolecular therapeutics and immunotherapy could emerge as a paradigm shift in the treatment of cancer.

Measuring Therapeutic Alliance with Children in Residential Treatment and Therapeutic Day Care

ERIC Educational Resources Information Center

Roest, Jesse; van der Helm, Peer; Strijbosch, Eefje; van Brandenburg, Mariëtte; Stams, Geert Jan

2016-01-01

Purpose: This study examined the construct validity and reliability of a therapeutic alliance measure (Children's Alliance Questionnaire [CAQ]) for children with psychosocial and/or behavioral problems, receiving therapeutic residential care or day care in the Netherlands. Methods: Confirmatory factor analysis of a one-factor model ''therapeutic…

Precision medicine and precision therapeutics: hedgehog signaling pathway, basal cell carcinoma and beyond.

PubMed

Mohan, Shalini V; Chang, Anne Lynn S

2014-06-01

Precision medicine and precision therapeutics is currently in its infancy with tremendous potential to improve patient care by better identifying individuals at risk for skin cancer and predict tumor responses to treatment. This review focuses on the Hedgehog signaling pathway, its critical role in the pathogenesis of basal cell carcinoma, and the emergence of targeted treatments for advanced basal cell carcinoma. Opportunities to utilize precision medicine are outlined, such as molecular profiling to predict basal cell carcinoma response to targeted therapy and to inform therapeutic decisions.

Affinity Maturation of a Cyclic Peptide Handle for Therapeutic Antibodies Using Deep Mutational Scanning*

PubMed Central

van Rosmalen, Martijn; Janssen, Brian M. G.; Hendrikse, Natalie M.; van der Linden, Ardjan J.; Pieters, Pascal A.; Wanders, Dave; de Greef, Tom F. A.; Merkx, Maarten

2017-01-01

Meditopes are cyclic peptides that bind in a specific pocket in the antigen-binding fragment of a therapeutic antibody such as cetuximab. Provided their moderate affinity can be enhanced, meditope peptides could be used as specific non-covalent and paratope-independent handles in targeted drug delivery, molecular imaging, and therapeutic drug monitoring. Here we show that the affinity of a recently reported meditope for cetuximab can be substantially enhanced using a combination of yeast display and deep mutational scanning. Deep sequencing was used to construct a fitness landscape of this protein-peptide interaction, and four mutations were identified that together improved the affinity for cetuximab 10-fold to 15 nm. Importantly, the increased affinity translated into enhanced cetuximab-mediated recruitment to EGF receptor-overexpressing cancer cells. Although in silico Rosetta simulations correctly identified positions that were tolerant to mutation, modeling did not accurately predict the affinity-enhancing mutations. The experimental approach reported here should be generally applicable and could be used to develop meditope peptides with low nanomolar affinity for other therapeutic antibodies. PMID:27974464

Impact of a pharmacist-driven warfarin management protocol on achieving therapeutic International Normalized Ratios.

PubMed

Downing, Amanda; Mortimer, Molly; Hiers, Jill

2016-03-01

Warfarin is a high alert medication and a challenge to dose and monitor. Pharmacist-driven warfarin management has been shown to decrease the time international normalized ratio (INR) is out of range, which may reduce undesired outcomes. The purpose of this study is to assess the effect of the implementation of a pharmacist-driven warfarin management protocol on the achievement of therapeutic INRs. A warfarin management protocol was developed using evidence based literature and similar protocols from other institutions. Pharmacists utilized the protocol to provide patient specific warfarin dosing upon provider referral. To evaluate the protocol's impact, a retrospective chart review pre- and post-implementation was completed for admitted patients receiving warfarin. Three hundred twenty-seven charts were reviewed for pre- and post-implementation data. INRs within therapeutic range increased from 27.8% before protocol implementation to 38.5% after implementation. There was also a reduction in subtherapeutic INRs (55.3% pre to 39% post) and supratherapeutic INRs 5 or above (3.7% pre to 2.6% post). Supratherapeutic INRs between 3 and 5 did increase from 13.2% before protocol implementation to 19.9% in the pharmacist managed group. In addition to reducing the time to achievement of therapeutic INRs by 0.5 days, implementation of the protocol resulted in an increased the number of patients with at least one therapeutic INR during admission (35% pre to 40% post). The implementation of a pharmacist-driven warfarin dosing protocol increased therapeutic INRs, and decreased the time to therapeutic range, as well as the proportion of subtherapeutic INRs and supratherapeutic INRs 5 or greater. Additional benefits of the protocol include documentation of Joint Commission National Patient Safety Goal compliance, promotion of interdisciplinary collaboration and increased continuity of care. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights

RNA-Targeted Therapeutics.

PubMed

Crooke, Stanley T; Witztum, Joseph L; Bennett, C Frank; Baker, Brenda F

2018-04-03

RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform. Copyright © 2018 Elsevier Inc. All rights reserved.

GPs' role security and therapeutic commitment in managing alcohol problems: a randomised controlled trial of a tailored improvement programme.

PubMed

Keurhorst, Myrna; van Beurden, Ivonne; Anderson, Peter; Heinen, Maud; Akkermans, Reinier; Wensing, Michel; Laurant, Miranda

2014-04-17

General practitioners with more positive role security and therapeutic commitment towards patients with hazardous or harmful alcohol consumption are more involved and manage more alcohol-related problems than others. In this study we evaluated the effects of our tailored multi-faceted improvement implementation programme on GPs' role security and therapeutic commitment and, in addition, which professional related factors influenced the impact of the implementation programme. In a cluster randomised controlled trial, 124 GPs from 82 Dutch general practices were randomised to either the intervention or control group. The tailored, multi-faceted programme included combined physician, organisation, and patient directed alcohol-specific implementation strategies to increase role security and therapeutic commitment in GPs. The control group was mailed the national guideline and patients received feedback letters. Questionnaires were completed before and 12 months after start of the programme. We performed linear multilevel regression analysis to evaluate effects of the implementation programme. Participating GPs were predominantly male (63%) and had received very low levels of alcohol related education before start of the study (0.4 h). The programme increased therapeutic commitment (p = 0.005; 95%-CI 0.13 - 0.73) but not role security (p = 0.58; 95%-CI -0.31 - 0.54). How important GPs thought it was to improve their care for problematic alcohol consumption, and the GPs' reported proportion of patients asked about alcohol consumption at baseline, contributed to the effect of the programme on therapeutic commitment. A tailored, multi-faceted programme aimed at improving GP management of patients with hazardous and harmful alcohol consumption improved GPs' therapeutic commitment towards patients with alcohol-related problems, but failed to improve GPs' role security. How important GPs thought it was to improve their care for problematic alcohol consumption, and the GPs

Therapeutic Duplicates in a Cohort of Hospitalized Elderly Patients: Results from the REPOSI Study.

PubMed

Pasina, Luca; Astuto, Sarah; Cortesi, Laura; Tettamanti, Mauro; Franchi, Carlotta; Marengoni, Alessandra; Mannucci, Pier Mannuccio; Nobili, Alessandro

2016-09-01

Explicit criteria for potentially inappropriate prescriptions in the elderly are recommended to avoid prescriptions of duplicate drug classes and to optimize monotherapy within a single drug class before a new agent is considered. Duplicate drug class prescription (or therapeutic duplicates) puts the patient at increased risk of adverse drug reactions with no additional therapeutic benefits. To our knowledge, the prevalence of elderly inpatients receiving therapeutic duplicates has never been studied. Our objective was to assess the prevalence of therapeutic duplicates at admission, discharge, and 3-month follow-up of hospitalized elderly patients. This cross-sectional prospective study was conducted in 97 Italian internal medicine and geriatric wards. Therapeutic duplicates were defined as at least two drugs of the same therapeutic class prescribed simultaneously to a patient. A patient's drug therapy at admission relates to prescriptions from general practitioners, whereas prescriptions at discharge are those from hospital internists or geriatricians. The study sample comprised 5821 admitted and 4983 discharged patients. In all, 143 therapeutic duplicates were found at admission and 170 at discharge. The prevalence of patients exposed to at least one therapeutic duplicate rose significantly from hospital admission (2.5 %) to discharge (3.4 %; p = 0.0032). Psychotropic drugs and drugs for peptic ulcer or gastroesophageal reflux disease were the most frequently involved. A total of 86.8 % of patients discharged with at least one therapeutic duplicate were still receiving them at 3-month follow-up. Hospitalization and drugs prescribed by internists and geriatricians are both factors associated with a small but definite increase in overall therapeutic duplicates in elderly patients admitted to internal medicine and geriatric wards. More attention should be paid to the indications for each drug prescribed, because therapeutic duplicates are not supported by evidence

The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs.

PubMed

Hudson, Brian D; Ulven, Trond; Milligan, Graeme

2013-01-01

G protein coupled receptors (GPCRs) are the most historically successful therapeutic targets. Despite this success there are many important aspects of GPCR pharmacology and function that have yet to be exploited to their full therapeutic potential. One in particular that has been gaining attention in recent times is that of GPCR ligands that bind to allosteric sites on the receptor distinct from the orthosteric site of the endogenous ligand. As therapeutics, allosteric ligands possess many theoretical advantages over their orthosteric counterparts, including more complex modes of action, improved safety, more physiologically appropriate responses, better target selectivity, and reduced likelihood of desensitisation and tachyphylaxis. Despite these advantages, the development of allosteric ligands is often difficult from a medicinal chemistry standpoint due to the more complex challenge of identifying allosteric leads and their often flat or confusing SAR. The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid sensitive GPCRs.

Therapeutic microRNAs targeting the NF-kappa B Signaling Circuits of Cancers

PubMed Central

Tong, Lingying; Yuan, Ye; Wu, Shiyong

2014-01-01

MicroRNAs (miRNAs) not only directly regulate NF-κB expression, but also up- or down-regulate NF-κB activity via upstream and downstream signaling pathways of NF-κB. In many cancer cells, miRNA expressions are altered accompanied with an elevation of NF-κB, which often plays a role in promoting cancer development and progression as well as hindering the effectiveness of chemo and radiation therapies. Thus NF-κB-targeting miRNAs have been identified and characterized as potential therapeutics for cancer treatment and sensitizers of chemo and radiotherapies. However, due to cross-targeting and instability of miRNAs, some limitations of using miRNA as cancer therapeutics still exist. In this review, the mechanisms for miRNA-mediated alteration of NF-κB expression and activation in different types of cancers will be discussed. The results of therapeutic use of NF-κB-targeting miRNA for cancer treatment will be examined. Some limitations, challenges and potential strategies in future development of miRNA as cancer therapeutics are also assessed. PMID:25220353

Kidney disease models: tools to identify mechanisms and potential therapeutic targets

PubMed Central

Bao, Yin-Wu; Yuan, Yuan; Chen, Jiang-Hua; Lin, Wei-Qiang

2018-01-01

Acute kidney injury (AKI) and chronic kidney disease (CKD) are worldwide public health problems affecting millions of people and have rapidly increased in prevalence in recent years. Due to the multiple causes of renal failure, many animal models have been developed to advance our understanding of human nephropathy. Among these experimental models, rodents have been extensively used to enable mechanistic understanding of kidney disease induction and progression, as well as to identify potential targets for therapy. In this review, we discuss AKI models induced by surgical operation and drugs or toxins, as well as a variety of CKD models (mainly genetically modified mouse models). Results from recent and ongoing clinical trials and conceptual advances derived from animal models are also explored. PMID:29515089

Significance of Antioxidant Potential of Plants and its Relevance to Therapeutic Applications

PubMed Central

Kasote, Deepak M.; Katyare, Surendra S.; Hegde, Mahabaleshwar V.; Bae, Hanhong

2015-01-01

Oxidative stress has been identified as the root cause of the development and progression of several diseases. Supplementation of exogenous antioxidants or boosting endogenous antioxidant defenses of the body is a promising way of combating the undesirable effects of reactive oxygen species (ROS) induced oxidative damage. Plants have an innate ability to biosynthesize a wide range of non-enzymatic antioxidants capable of attenuating ROS- induced oxidative damage. Several in vitro methods have been used to screen plants for their antioxidant potential, and in most of these assays they revealed potent antioxidant activity. However, prior to confirming their in vivo therapeutic efficacy, plant antioxidants have to pass through several physiopharmacological processes. Consequently, the findings of in vitro and in vivo antioxidant potential assessment studies are not always the same. Nevertheless, the results of in vitro assays have been irrelevantly extrapolated to the therapeutic application of plant antioxidants without undertaking sufficient in vivo studies. Therefore, we have briefly reviewed the physiology and redox biology of both plants and humans to improve our understanding of plant antioxidants as therapeutic entities. The applications and limitations of antioxidant activity measurement assays were also highlighted to identify the precise path to be followed for future research in the area of plant antioxidants. PMID:26157352

Therapeutic HPV vaccines.

PubMed

Hancock, Gemma; Hellner, Karin; Dorrell, Lucy

2018-02-01

High-risk human papillomavirus (HPV) infection is known to be a necessary factor for cervical and anogenital malignancies. Cervical cancers account for over a quarter of a million deaths annually. Despite the availability of prophylactic vaccines, HPV infections remain extremely common worldwide. Furthermore, these vaccines are ineffective at clearing pre-existing infections and associated preinvasive lesions. As cervical dysplasia can regress spontaneously, a therapeutic HPV vaccine that boosts host immunity could have a significant impact on the morbidity and mortality associated with HPV. Therapeutic vaccines differ from prophylactic vaccines in that they are aimed at generating cell-mediated immunity rather than neutralising antibodies. This review will cover various therapeutic vaccine strategies in development for the treatment of HPV-associated lesions and cancers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer.

PubMed

Harada, Koji; Ferdous, Tarannum; Ueyama, Yoshiya

2017-08-01

Oral cancer has been recognized as a tumor with low sensitivity to anticancer agents. However, introduction of S-1, an oral cancer agent is improving treatment outcome for patients with oral cancer. In addition, S-1, as a main drug for oral cancer treatment in Japan can be easily available for outpatients. In fact, S-1 exerts high therapeutic effects with acceptable side effects. Moreover, combined chemotherapy with S-1 shows higher efficacy than S-1 alone, and combined chemo-radiotherapy with S-1 exerts remarkable therapeutic effects. Furthermore, we should consider the combined therapy of S-1 and molecular targeting agents right now as these combinations were reportedly useful for oral cancer treatment. Here, we describe our findings related to S-1 that were obtained experimentally and clinically, and favorable therapeutic strategies with S-1 against oral cancer with bibliographic considerations.

SCIRehab Project Series: The Therapeutic Recreation Taxonomy

PubMed Central

Cahow, Claire; Skolnick, Susan; Joyce, Joan; Jug, Julie; Dragon, Charlotte; Gassaway, Julie

2009-01-01

Background/Objective: Outcomes research of therapeutic recreation (TR) activities and interventions for spinal cord injury (SCI) rehabilitation is made more difficult by a lack of uniform descriptions and the absence of a formal treatments classification system (taxonomy). The objective of this study was to describe a taxonomy developed by Certified Therapeutic Recreation Specialists. Methods: TR lead clinicians and researchers from 6 SCI rehabilitation centers developed a TR documentation system to describe the details of each TR session involving patients with SCI enrolled in the SCIRehab study. The SCIRehab study uses the practice-based evidence methodology, a rigorous observational methodology that examines current practice without introducing additional treatments, to capture details of each TR session for 1,500 SCI rehabilitation patients at 6 US inpatient SCI rehabilitation facilities. This may be the first attempt to document the many details of the TR rehabilitation process for patients with SCI. Results: The TR taxonomy consists of 6 activities (eg, leisure education and counseling, outings, and leisure skill work in center) and activity-specific interventions, as well as time spent on each activity. Activity descriptions are enhanced with additional details that focus on assistance needs for each activity, patient ability to direct care, and patient/family involvement, which may help to determine TR activity selection. Conclusion: Development and application of a TR taxonomy, which is comprehensive for patients with SCI and efficient to use, are feasible despite significantly different TR programs at the 6 SCIRehab centers. PMID:19810631

Engineering Neprilysin Activity and Specificity to Create a Novel Therapeutic for Alzheimer’s Disease

PubMed Central

Webster, Carl I.; Burrell, Matthew; Olsson, Lise-Lotte; Fowler, Susan B.; Digby, Sarah; Sandercock, Alan; Snijder, Arjan; Tebbe, Jan; Haupts, Ulrich; Grudzinska, Joanna; Jermutus, Lutz; Andersson, Christin

2014-01-01

Neprilysin is a transmembrane zinc metallopeptidase that degrades a wide range of peptide substrates. It has received attention as a potential therapy for Alzheimer’s disease due to its ability to degrade the peptide amyloid beta. However, its broad range of peptide substrates has the potential to limit its therapeutic use due to degradation of additional peptides substrates that tightly regulate many physiological processes. We sought to generate a soluble version of the ectodomain of neprilysin with improved activity and specificity towards amyloid beta as a potential therapeutic for Alzheimer’s disease. Extensive amino acid substitutions were performed at positions surrounding the active site and inner surface of the enzyme and variants screened for activity on amyloid beta 1–40, 1–42 and a variety of other physiologically relevant peptides. We identified several mutations that modulated and improved both enzyme selectivity and intrinsic activity. Neprilysin variant G399V/G714K displayed an approximately 20-fold improved activity on amyloid beta 1–40 and up to a 3,200-fold reduction in activity on other peptides. Along with the altered peptide substrate specificity, the mutant enzyme produced a markedly altered series of amyloid beta cleavage products compared to the wild-type enzyme. Crystallisation of the mutant enzyme revealed that the amino acid substitutions result in alteration of the shape and size of the pocket containing the active site compared to the wild-type enzyme. The mutant enzyme offers the potential for the more efficient degradation of amyloid beta in vivo as a therapeutic for the treatment of Alzheimer’s disease. PMID:25089527

Comparative analysis of success of psoriasis treatment with standard therapeutic modalities and balneotherapy.

PubMed

Baros, Duka Ninković; Gajanin, Vesna S; Gajanin, Radoslav B; Zrnić, Bogdan

2014-01-01

Psoriasis is a chronic, inflammatory, immune-mediated skin disease. In addition to standard therapeutic modalities (antibiotics, cytostatics, phototherapy, photochemotherapy and retinoids), nonstandard methods can be used in the treatment of psoriasis. This includes balneotherapy which is most commonly used in combination with therapeutic resources. The aim of this research was to determine the length of remission of psoriasis in patients treated with standard therapeutic modalities, balneotherapy, and combined treatment (standard therapeutic modalities and balneotherapy). The study analyzed 60 adult patients, of both sexes, with different clinical forms of psoriasis, who were divided into three groups according to the applied therapeutic modalities: the first group (treated with standard therapeutic modalities), the second group (treated with balneotherapy) and the third group (treated with combined therapy-standard methods therapy and balneotherapy). The Psoriasis Area and Severity Index was determined in first, third and sixth week of treatment for all patients. The following laboratory analysis were performed and monitored: C reactive protein, iron with total iron binding capacity, unsaturated iron binding capacity and ferritin, uric acid, rheumatoid factors and antibodies to streptolysin O in the first and sixth week of treatment. The average length of remission in patients treated with standard therapeutic modalities and in those treated with balneotherapy was 1.77 +/- 0.951 months and 1.79 +/- 0.918 months, respectively. There was a statistically significant difference in the duration of remission between the patients treated with combination therapy and patients treated with standard therapeutic modalities (p = 0.019) and balneotherapy (p = 0.032). The best results have been achieved when the combination therapy was administered.

Past Strategies and Future Directions for Identifying AMP-Activated Protein Kinase (AMPK) Modulators

PubMed Central

Sinnett, Sarah E.; Brenman, Jay E.

2014-01-01

AMP-activated protein kinase (AMPK) is a promising therapeutic target for cancer, type II diabetes, and other illnesses characterized by abnormal energy utilization. During the last decade, numerous labs have published a range of methods for identifying novel AMPK modulators. The current understanding of AMPK structure and regulation, however, has propelled a paradigm shift in which many researchers now consider ADP to be an additional regulatory nucleotide of AMPK. How can the AMPK community apply this new understanding of AMPK signaling to translational research? Recent insights into AMPK structure, regulation, and holoenzyme-sensitive signaling may provide the hindsight needed to clearly evaluate the strengths and weaknesses of past AMPK drug discovery efforts. Improving future strategies for AMPK drug discovery will require pairing the current understanding of AMPK signaling with improved experimental designs. PMID:24583089

Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

PubMed Central

Scott, Robert A.; Freitag, Daniel F.; Li, Li; Chu, Audrey Y.; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning; V.Varga, Tibor; Yaghootkar, Hanieh; Luan, Jian'an; Zhao, Jing Hua; Willems, Sara M.; Wessel, Jennifer; Wang, Shuai; Maruthur, Nisa; Michailidou, Kyriaki; Pirie, Ailith; van der Lee, Sven J.; Gillson, Christopher; Olama, Ali Amin Al; Amouyel, Philippe; Arriola, Larraitz; Arveiler, Dominique; Aviles-Olmos, Iciar; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Garcia, Sara Benlloch; Bis, Joshua C.; Blankenberg, Stefan; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Borecki, Ingrid B.; Bork-Jensen, Jette; Bowden, Sarah; Caldas, Carlos; Caslake, Muriel; Cupples, L. Adrienne; Cruchaga, Carlos; Czajkowski, Jacek; den Hoed, Marcel; Dunn, Janet A.; Earl, Helena M.; Ehret, Georg B.; Ferrannini, Ele; Ferrieres, Jean; Foltynie, Thomas; Ford, Ian; Forouhi, Nita G.; Gianfagna, Francesco; Gonzalez, Carlos; Grioni, Sara; Hiller, Louise; Jansson, Jan-Håkan; Jørgensen, Marit E.; Jukema, J. Wouter; Kaaks, Rudolf; Kee, Frank; Kerrison, Nicola D.; Key, Timothy J.; Kontto, Jukka; Kote-Jarai, Zsofia; Kraja, Aldi T.; Kuulasmaa, Kari; Kuusisto, Johanna; Linneberg, Allan; Liu, Chunyu; Marenne, Gaëlle; Mohlke, Karen L.; Morris, Andrew P.; Muir, Kenneth; Müller-Nurasyid, Martina; Munroe, Patricia B.; Navarro, Carmen; Nielsen, Sune F.; Nilsson, Peter M.; Nordestgaard, Børge G.; Packard, Chris J.; Palli, Domenico; Panico, Salvatore; Peloso, Gina M.; Perola, Markus; Peters, Annette; Poole, Christopher J.; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Salomaa, Veikko; Sánchez, María-José; Sattar, Naveed; Sharp, Stephen J.; Sims, Rebecca; Slimani, Nadia; Smith, Jennifer A.; Thompson, Deborah J.; Trompet, Stella; Tumino, Rosario; van der A, Daphne L.; van der Schouw, Yvonne T.; Virtamo, Jarmo; Walker, Mark; Walter, Klaudia; Abraham, Jean E.; Amundadottir, Laufey T.; Aponte, Jennifer L.; Butterworth, Adam S.; Dupuis, Josée; Easton, Douglas F.; Eeles, Rosalind A.; Erdmann, Jeanette; Franks, Paul W.; Frayling, Timothy M.; Hansen, Torben; Howson, Joanna M. M.; Jørgensen, Torben; Kooner, Jaspal; Laakso, Markku; Langenberg, Claudia; McCarthy, Mark I.; Pankow, James S.; Pedersen, Oluf; Riboli, Elio; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schunkert, Heribert; Vollenweider, Peter; O'Rahilly, Stephen; Deloukas, Panos; Danesh, John; Goodarzi, Mark O.; Kathiresan, Sekar; Meigs, James B.; Ehm, Margaret G.; Wareham, Nicholas J.; Waterworth, Dawn M.

2016-01-01

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. PMID:27252175

Use of Targeted Therapeutics in Epithelial Ovarian Cancer: A Review of Current Literature and Future Directions.

PubMed

Vetter, Monica Hagan; Hays, John L

2018-03-01

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions. A literature search of Medline and PubMed was conducted (January 2000-October 2017) to identify recent reports of targeted drugs in EOC. A wide range of targeted therapeutics is currently being used as both monotherapy and in combination in the treatment of EOC. Clinically, the most commonly used classes of drugs currently are antiangiogenics and poly (ADP-ribose) polymerase inhibitors. However, a number of drugs in varying stages in development target a wide range of biochemical pathways. Activity and response rates of these drugs vary greatly. Questions continue about combination drug therapy and appropriate patient selection. The use of targeted therapeutics in the treatment of EOC, both as monotherapy and in combination, will continue to expand as more mechanisms of tumorigenesis are identified. Multiple clinical trials of a wide range of targeted therapeutics are currently ongoing. Evidence-based selection of drug targets and appropriate patient populations will allow strategic application of targeted therapeutics. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

Improving therapeutic outcomes in autism spectrum disorders: Enhancing social communication and sensory processing through the use of interactive robots.

PubMed

Sartorato, Felippe; Przybylowski, Leon; Sarko, Diana K

2017-07-01

For children with autism spectrum disorders (ASDs), social robots are increasingly utilized as therapeutic tools in order to enhance social skills and communication. Robots have been shown to generate a number of social and behavioral benefits in children with ASD including heightened engagement, increased attention, and decreased social anxiety. Although social robots appear to be effective social reinforcement tools in assistive therapies, the perceptual mechanism underlying these benefits remains unknown. To date, social robot studies have primarily relied on expertise in fields such as engineering and clinical psychology, with measures of social robot efficacy principally limited to qualitative observational assessments of children's interactions with robots. In this review, we examine a range of socially interactive robots that currently have the most widespread use as well as the utility of these robots and their therapeutic effects. In addition, given that social interactions rely on audiovisual communication, we discuss how enhanced sensory processing and integration of robotic social cues may underlie the perceptual and behavioral benefits that social robots confer. Although overall multisensory processing (including audiovisual integration) is impaired in individuals with ASD, social robot interactions may provide therapeutic benefits by allowing audiovisual social cues to be experienced through a simplified version of a human interaction. By applying systems neuroscience tools to identify, analyze, and extend the multisensory perceptual substrates that may underlie the therapeutic benefits of social robots, future studies have the potential to strengthen the clinical utility of social robots for individuals with ASD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Endoscopy and polyps-diagnostic and therapeutic advances in management

PubMed Central

Steele, Scott R; Johnson, Eric K; Champagne, Bradley; Davis, Brad; Lee, Sang; Rivadeneira, David; Ross, Howard; Hayden, Dana A; Maykel, Justin A

2013-01-01

Despite multiple efforts aimed at early detection through screening, colon cancer remains the third leading cause of cancer-related deaths in the United States, with an estimated 51000 deaths during 2013 alone. The goal remains to identify and remove benign neoplastic polyps prior to becoming invasive cancers. Polypoid lesions of the colon vary widely from hyperplastic, hamartomatous and inflammatory to neoplastic adenomatous growths. Although these lesions are all benign, they are common, with up to one-quarter of patients over 60 years old will develop pre-malignant adenomatous polyps. Colonoscopy is the most effective screening tool to detect polyps and colon cancer, although several studies have demonstrated missed polyp rates from 6%-29%, largely due to variations in polyp size. This number can be as high as 40%, even with advanced (> 1 cm) adenomas. Other factors including sub-optimal bowel preparation, experience of the endoscopist, and patient anatomical variations all affect the detection rate. Additional challenges in decision-making exist when dealing with more advanced, and typically larger, polyps that have traditionally required formal resection. In this brief review, we will explore the recent advances in polyp detection and therapeutic options. PMID:23885138

Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response

PubMed Central

Pondugula, Satyanarayana R.; Mani, Sridhar

2012-01-01

Pregnane xenobiotic receptor (PXR) is an orphan nuclear receptor that regulates the metabolism of endobiotics and xenobiotics. PXR is promiscuous and unique in that it is activated by a diverse group of xenochemicals, including therapeutic anticancer drugs and naturally-occurring endocrine disruptors. PXR has been predominantly studied to understand its regulatory role in xenobiotic clearance in liver and intestine via induction of drug metabolizing enzymes and drug transporters. PXR, however, is widely expressed and has functional implications in other normal and malignant tissues, including breast, prostate, ovary, endometrium and bone. The differential expression of PXR and its target genes in cancer tissues has been suggested to determine the prognosis of chemotherapeutic outcome. In addition, the emerging evidence points to the implications of PXR in regulating apoptotic and antiapoptotic as well as growth factor signaling that promote tumor proliferation and metastasis. In this review, we highlight the recent progress made in understanding the role of PXR in cancer, discuss the future directions to further understand the mechanistic role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators. PMID:22939994

Functional Nanostructures for Effective Delivery of Small Interfering RNA Therapeutics

PubMed Central

Hong, Cheol Am; Nam, Yoon Sung

2014-01-01

Small interfering RNA (siRNA) has proved to be a powerful tool for target-specific gene silencing via RNA interference (RNAi). Its ability to control targeted gene expression gives new hope to gene therapy as a treatment for cancers and genetic diseases. However, siRNA shows poor pharmacological properties, such as low serum stability, off-targeting, and innate immune responses, which present a significant challenge for clinical applications. In addition, siRNA cannot cross the cell membrane for RNAi activity because of its anionic property and stiff structure. Therefore, the development of a safe, stable, and efficient system for the delivery of siRNA therapeutics into the cytoplasm of targeted cells is crucial. Several nanoparticle platforms for siRNA delivery have been developed to overcome the major hurdles facing the therapeutic uses of siRNA. This review covers a broad spectrum of non-viral siRNA delivery systems developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and discusses their characteristics and opportunities for clinical applications of therapeutic siRNA. PMID:25285170

Acquired thrombotic thrombocytopenic purpura: new therapeutic options and their optimal use.

PubMed

Cataland, S R; Wu, H M

2015-06-01

Advances in our understanding of the pathophysiology of both congenital and acquired thrombotic thrombocytopenic purpura (TTP) have led to both an increased understanding of the disease and novel approaches to therapy. The efficacy of rituximab in acquired TTP has led to consideration of rituximab as a prophylactic therapy to prevent relapse of TTP. Novel therapies that target the A1 domain of von Willebrand factor (VWF) to block the formation of microthrombotic disease have also entered clinical study and have demonstrated promise as potential therapeutic options. Additionally, a recombinant ADAMTS13 protease has been developed which may be an important therapeutic option for both congenital and acquired TTP. The development of these new therapeutic options for patients diagnosed with TTP has increased the importance of conducting prospective, randomized studies with these agents to both confirm their efficacy and more importantly understand their most appropriate role in the treatment of patients with TTP. © 2015 International Society on Thrombosis and Haemostasis.

Therapeutic target discovery using Boolean network attractors: improvements of kali

PubMed Central

Guziolowski, Carito

2018-01-01

In a previous article, an algorithm for identifying therapeutic targets in Boolean networks modelling pathological mechanisms was introduced. In the present article, the improvements made on this algorithm, named kali, are described. These improvements are (i) the possibility to work on asynchronous Boolean networks, (ii) a finer assessment of therapeutic targets and (iii) the possibility to use multivalued logic. kali assumes that the attractors of a dynamical system, such as a Boolean network, are associated with the phenotypes of the modelled biological system. Given a logic-based model of pathological mechanisms, kali searches for therapeutic targets able to reduce the reachability of the attractors associated with pathological phenotypes, thus reducing their likeliness. kali is illustrated on an example network and used on a biological case study. The case study is a published logic-based model of bladder tumorigenesis from which kali returns consistent results. However, like any computational tool, kali can predict but cannot replace human expertise: it is a supporting tool for coping with the complexity of biological systems in the field of drug discovery. PMID:29515890

Words matter: distinguishing "personalized medicine" and "biologically personalized therapeutics".

PubMed

Cherny, Nathan I; de Vries, Elisabeth G E; Emanuel, Linda; Fallowfield, Lesley; Francis, Prudence A; Gabizon, Alberto; Piccart, Martine J; Sidransky, David; Soussan-Gutman, Lior; Tziraki, Chariklia

2014-12-01

"Personalized medicine" has become a generic term referring to techniques that evaluate either the host or the disease to enhance the likelihood of beneficial patient outcomes from treatment interventions. There is, however, much more to personalization of care than just identifying the biotherapeutic strategy with the highest likelihood of benefit. In its new meaning, "personalized medicine" could overshadow the individually tailored, whole-person care that is at the bedrock of what people need and want when they are ill. Since names and definitional terms set the scope of the discourse, they have the power to define what personalized medicine includes or does not include, thus influencing the scope of the professional purview regarding the delivery of personalized care. Taxonomic accuracy is important in understanding the differences between therapeutic interventions that are distinguishable in their aims, indications, scope, benefits, and risks. In order to restore the due emphasis to the patient and his or her needs, we assert that it is necessary, albeit belated, to deconflate the contemporary term "personalized medicine" by taxonomizing this therapeutic strategy more accurately as "biologically personalized therapeutics" (BPT). The scope of truly personalized medicine and its relationship to biologically personalized therapeutics is described, emphasizing that the best of care must give due recognition and emphasis to both BPT and truly personalized medicine. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Myasthenia gravis: subgroup classification and therapeutic strategies.

PubMed

Gilhus, Nils Erik; Verschuuren, Jan J

2015-10-01

Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Optometrists Association Australia Universal (entry-level) and Therapeutic Competency Standards for Optometry 2008.

PubMed

Kiely, Patricia M

2009-07-01

Competency standards for entry-level to the profession of optometry in Australia were first developed in 1993, revised in 1997 and expanded in 2000 to include therapeutic competency standards. The entry-level standards cover the competencies required by a person entering the profession without therapeutic endorsement of their registration. The therapeutic competency standards address the additional competencies required for therapeutic endorsement of registration. This paper presents a revised version of the universal (entry-level) and therapeutic competency standards for the profession of optometry in Australia in 2008. Expert members of the profession and representatives from schools of optometry, registration boards in Australia, state divisions of Optometrists Association Australia and the New Zealand Association of Optometrists were consulted in the process of updating the standards. Three new elements of competency have been added to the standards. Twenty-three new performance criteria with associated indicators have been added. Some performance criteria from the earlier document have been combined. Substantial alterations were made to the presentation of indicators throughout the document. The updated entry-level (universal) and therapeutic competency standards were adopted on behalf of the profession by the National Council of Optometrists Association Australia in November 2008. Competency standards are used by Australian and New Zealand registration authorities for the purposes of registration and therapeutic endorsement of registration via the Optometry Council of Australia and New Zealand accreditation and assessment processes. They have also been used as the basis of the World Council of Optometry Global Competency-Based Model.

Therapeutic intraspinal microstimulation improves forelimb function after cervical contusion injury

NASA Astrophysics Data System (ADS)

Kasten, M. R.; Sunshine, M. D.; Secrist, E. S.; Horner, P. J.; Moritz, C. T.

2013-08-01

Objective. Intraspinal microstimulation (ISMS) is a promising method for activating the spinal cord distal to an injury. The objectives of this study were to examine the ability of chronically implanted stimulating wires within the cervical spinal cord to (1) directly produce forelimb movements, and (2) assess whether ISMS stimulation could improve subsequent volitional control of paretic extremities following injury. Approach. We developed a technique for implanting intraspinal stimulating electrodes within the cervical spinal cord segments C6-T1 of Long-Evans rats. Beginning 4 weeks after a severe cervical contusion injury at C4-C5, animals in the treatment condition received therapeutic ISMS 7 hours/day, 5 days/week for the following 12 weeks. Main results. Over 12 weeks of therapeutic ISMS, stimulus-evoked forelimb movements were relatively stable. We also explored whether therapeutic ISMS promoted recovery of forelimb reaching movements. Animals receiving daily therapeutic ISMS performed significantly better than unstimulated animals during behavioural tests conducted without stimulation. Quantitative video analysis of forelimb movements showed that stimulated animals performed better in the movements reinforced by stimulation, including extending the elbow to advance the forelimb and opening the digits. While threshold current to elicit forelimb movement gradually increased over time, no differences were observed between chronically stimulated and unstimulated electrodes suggesting that no additional tissue damage was produced by the electrical stimulation. Significance. The results indicate that therapeutic intraspinal stimulation delivered via chronic microwire implants within the cervical spinal cord confers benefits extending beyond the period of stimulation, suggesting future strategies for neural devices to promote sustained recovery after injury.

Therapeutic intraspinal microstimulation improves forelimb function after cervical contusion injury

PubMed Central

Kasten, M.R.; Sunshine, M.D.; Secrist, E.S.; Horner, P.J.; Moritz, C.T.

2013-01-01

Objective Intraspinal microstimulation (ISMS) is a promising method for activating the spinal cord distal to an injury. The objectives of this study were to examine the ability of chronically implanted stimulating wires within the cervical spinal cord to (1) directly produce forelimb movements, and (2) assess whether ISMS stimulation improved subsequent volitional control of paretic extremities following injury. Approach We developed a technique for implanting intraspinal stimulating electrodes within the cervical spinal cord segments C6-T1 of Long-Evans rats. Beginning 4 weeks after a severe cervical contusion injury at C4–C5, animals in the treatment condition received therapeutic ISMS 7 hours/day, 5 days/week for the following 12 weeks. Main Results Over 12 weeks of therapeutic ISMS, stimulus-evoked forelimb movements were relatively stable. We also explored whether therapeutic ISMS promotes recovery of forelimb reaching movements. Animals receiving daily therapeutic ISMS performed significantly better than unstimulated animals during behavioral tests conducted without stimulation. Quantitative video analysis of forelimb movements showed that stimulated animals performed better in the movements reinforced by stimulation, including extending the elbow to advance the forelimb and opening the digits. While threshold current to elicit forelimb movement gradually increased over time, no differences were observed between chronically stimulated and unstimulated electrodes suggesting that no additional tissue damage was produced by the electrical stimulation. Significance The results indicate that therapeutic intraspinal stimulation delivered via chronic microwire implants within the cervical spinal cord confers benefits extending beyond the period of stimulation, suggesting future strategies for neural devices to promote sustained recovery after injury. PMID:23715242

[Anal fissure of cryptoglandular origin. Therapeutic options].

PubMed

Casal, Enrique; de San Ildefonso, Alberto; Sánchez, Juan; Facal, Cristina; Pampin, José

2005-12-01

Anal fistula is a frequent condition. The most commonly accepted origin is infectious. The most widely used classification is based on cryptoglandular theory and on the position of the fistulous tract in relation to the anal sphincter. Physical examination will help to identify the type of fistula and allow its treatment to be planned. The most widely used complementary tests are endoanal ultrasound and magnetic resonance imaging. We review the various therapeutic options and their results, especially fistulotomy, endorectal advancement flap, use of sedal, anodermal advancement flap, sphincterorrhaphy with sphincter repair, and fibrin glue.

Recruiting terminally ill patients into non-therapeutic oncology studies: views of health professionals.

PubMed

Kleiderman, Erika; Avard, Denise; Black, Lee; Diaz, Zuanel; Rousseau, Caroline; Knoppers, Bartha Maria

2012-12-05

Non-therapeutic trials in which terminally ill cancer patients are asked to undergo procedures such as biopsies or venipunctures for research purposes, have become increasingly important to learn more about how cancer cells work and to realize the full potential of clinical research. Considering that implementing non-therapeutic studies is not likely to result in direct benefits for the patient, some authors are concerned that involving patients in such research may be exploitive of vulnerable patients and should not occur at all, or should be greatly restricted, while some proponents doubt whether such restrictions are appropriate. Our objective was to explore clinician-researcher attitudes and concerns when recruiting patients who are in advanced stages of cancer into non-therapeutic research. We conducted a qualitative exploratory study by carrying out open-ended interviews with health professionals, including physicians, research nurses, and study coordinators. Interviews were audio-recorded and transcribed. Analysis was carried out using grounded theory. The analysis of the interviews unveiled three prominent themes: 1) ethical considerations; 2) patient-centered issues; 3) health professional issues. Respondents identified ethical issues surrounding autonomy, respect for persons, beneficence, non-maleficence, discrimination, and confidentiality; bringing to light that patients contribute to science because of a sense of altruism and that they want reassurance before consenting. Several patient-centered and health professional issues are having an impact on the recruitment of patients for non-therapeutic research. Facilitators were most commonly associated with patient-centered issues enhancing communication, whereas barriers in non-therapeutic research were most often professionally based, including the doctor-patient relationship, time constraints, and a lack of education and training in research. This paper aims to contribute to debates on the overall

[Is there a German history of evidence-based medicine? Methodic standards of therapeutic research in the early 20th century and Paul Martini's "Methodology of therapeutic investigation" (1932)].

PubMed

Stoll, S; Roelcke, V; Raspe, H

2005-07-29

The article addresses the history of evidence-based medicine in Germany. Its aim was to reconstruct the standard of clinical-therapeutic investigation in Germany at the beginning of the 20 (th) century. By a historical investigation of five important German general medical journals for the time between 1918 and 1932 an overview of the situation of clinical investigation is given. 268 clinical trails are identified, and are analysed in view of their methodological design. Heterogeneous results are found: While few examples of sophisticated methodology exist, the design of the majority of the studies is poor. A response to the situation described can be seen in Paul Martini's book "Methodology of Therapeutic Investigation", first published in 1932. Paul Martini's biography, his criticism of the situation of clinical-therapeutic investigation of his time, the major points of his methodology and the reception of the book in Germany and abroad are described.

Emerging therapeutic targets for treatment of leishmaniasis.

PubMed

Sundar, Shyam; Singh, Bhawana

2018-06-01

Parasitic diseases that pose a threat to human life include leishmaniasis - caused by protozoan parasite Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity, high cost and drug resistance. This calls for the need to have an insight into therapeutic aspects of disease. Areas covered: We have identified different drug targets via. molecular, imuunological, metabolic as well as by system biology approaches. We bring these promising drug targets into light so that they can be explored to their maximum. In an effort to bridge the gaps between existing knowledge and prospects of drug discovery, we have compiled interesting studies on drug targets, thereby paving the way for establishment of better therapeutic aspects. Expert opinion: Advancements in technology shed light on many unexplored pathways. Further probing of well established pathways led to the discovery of new drug targets. This review is a comprehensive report on current and emerging drug targets, with emphasis on several metabolic targets, organellar biochemistry, salvage pathways, epigenetics, kinome and more. Identification of new targets can contribute significantly towards strengthening the pipeline for disease elimination.

Clinical decision-making and therapeutic approaches in osteopathy - a qualitative grounded theory study.

PubMed

Thomson, Oliver P; Petty, Nicola J; Moore, Ann P

2014-02-01

There is limited understanding of how osteopaths make decisions in relation to clinical practice. The aim of this research was to construct an explanatory theory of the clinical decision-making and therapeutic approaches of experienced osteopaths in the UK. Twelve UK registered osteopaths participated in this constructivist grounded theory qualitative study. Purposive and theoretical sampling was used to select participants. Data was collected using semi-structured interviews which were audio-recorded and transcribed. As the study approached theoretical sufficiency, participants were observed and video-recorded during a patient appointment, which was followed by a video-prompted interview. Constant comparative analysis was used to analyse and code data. Data analysis resulted in the construction of three qualitatively different therapeutic approaches which characterised participants and their clinical practice, termed; Treater, Communicator and Educator. Participants' therapeutic approach influenced their approach to clinical decision-making, the level of patient involvement, their interaction with patients, and therapeutic goals. Participants' overall conception of practice lay on a continuum ranging from technical rationality to professional artistry, and contributed to their therapeutic approach. A range of factors were identified which influenced participants' conception of practice. The findings indicate that there is variation in osteopaths' therapeutic approaches to practice and clinical decision-making, which are influenced by their overall conception of practice. This study provides the first explanatory theory of the clinical decision-making and therapeutic approaches of osteopaths. Copyright © 2013 Elsevier Ltd. All rights reserved.

New therapeutic solutions for Behçet's syndrome.

PubMed

Vitale, Antonio; Rigante, Donato; Lopalco, Giuseppe; Emmi, Giacomo; Bianco, Maria Teresa; Galeazzi, Mauro; Iannone, Florenzo; Cantarini, Luca

2016-07-01

Behçet's syndrome (BS) is a systemic inflammatory disorder characterized by a wide range of potential clinical manifestations with no gold-standard therapy. However, the recent classification of BS at a crossroads between autoimmune and autoinflammatory syndromes has paved the way to new further therapeutic opportunities in addition to anti-tumor necrosis factor agents. This review provides a digest of all current experience and evidence about pharmacological agents recently described as having a role in the treatment of BS, including interleukin (IL)-1 inhibitors, tocilizumab, rituximab, alemtuzumab, ustekinumab, interferon-alpha-2a, and apremilast. IL-1 inhibitors currently represent the most studied agents among the latest treatment options for BS, proving to be effective, safe and with an acceptable retention on treatment. However, since BS is a peculiar disorder with clinical features responding to certain treatments that in turn can worsen other manifestations, identifying new treatment options for patients unresponsive to the current drug armamentarium is of great relevance. A number of agents have been studied in the last decade showing changing fortunes in some cases and promising results in others. The latter will potentially provide their contribution for better clinical management of BS, improving patients' quality of life and long-term outcome.

Therapeutic potential of natural products in Parkinson's disease.

PubMed

Mythri, Rajeswara B; Harish, Gangadharappa; Bharath, M M

2012-09-01

The central objective in treating patients with Parkinson's disease (PD) is two-fold (i) to increase the striatal dopamine content and (ii) to prevent further degeneration of the surviving dopaminergic neurons in the substantia nigra region of the ventral midbrain. Most of the current PD drugs contribute to the former and provide symptomatic relief. Although compounds such as Levodopa (L-DOPA) improve the striatal dopamine content, their long-term usage is associated with progressive decrease in drug response, motor fluctuations, dyskinesias and drug-induced toxicity. In addition, these drugs fail to prevent the progression of the degenerative process. This has shifted the focus onto alternative therapeutic approaches involving natural products that could provide independent therapy or offer neuroprotective support to the existing drugs. The current review describes the neuroprotective and therapeutic utility of such natural products including herbal extracts, phytochemicals and bioactive ingredients from other natural sources either in isolation or in combination, with potential application in PD, highlighting the relevant patents.

Therapeutic targeting of RNA splicing in myelodysplasia.

PubMed

Kim, Young Joon; Abdel-Wahab, Omar

2017-07-01

Genomic analysis of patients with myelodysplastic syndromes (MDS) has identified that mutations within genes encoding RNA splicing factors represent the most common class of genetic alterations in MDS. These mutations primarily affect SF3B1, SRSF2, U2AF1, and ZRSR2. Current data suggest that these mutations perturb RNA splicing catalysis in a manner distinct from loss of function but how exactly the global changes in RNA splicing imparted by these mutations result in MDS is not well delineated. At the same time, cells bearing mutations in RNA splicing factors are exquisitely dependent on the presence of the remaining wild-type (WT) allele to maintain residual normal splicing for cell survival. The high frequency of these mutations in MDS, combined with their mutual exclusivity and noteworthy dependence on the WT allele, make targeting RNA splicing attractive in MDS. To this end, two promising therapeutic approaches targeting RNA splicing are being tested clinically currently. These include molecules targeting core RNA splicing catalysis by interfering with the ability of the SF3b complex to interact with RNA, as well as molecules degrading the auxiliary RNA splicing factor RBM39. The preclinical and clinical evaluation of these compounds are discussed here in addition to their potential as therapies for spliceosomal mutant MDS. Copyright © 2017 Elsevier Inc. All rights reserved.

Therapeutic Engagement as a Predictor of Retention in Adolescent Therapeutic Community Treatment

ERIC Educational Resources Information Center

Abdel-Salam, Sami; Gunter, Whitney D.

2014-01-01

The adolescent drug problem places a huge toll on society and a heavy burden on the criminal justice system. Research regarding the benefits of therapeutic community (TC) treatment for adolescents has shown it to be effective. Despite the ability of therapeutic communities to lower drug relapse and reduce criminality, a great deal remains unknown…

Leveraging biodiversity knowledge for potential phyto-therapeutic applications

PubMed Central

Sharma, Vivekanand; Sarkar, Indra Neil

2013-01-01

Objective To identify and highlight the feasibility, challenges, and advantages of providing a cross-domain pipeline that can link relevant biodiversity information for phyto-therapeutic assessment. Materials and methods A public repository of clinical trials information (ClinicalTrials.gov) was explored to determine the state of plant-based interventions under investigation. Results The results showed that ∼15% of drug interventions in ClinicalTrials.gov were potentially plant related, with about 60% of them clustered within 10 taxonomic families. Further analysis of these plant-based interventions identified ∼3.7% of associated plant species as endangered as determined from the International Union for the Conservation of Nature Red List. Discussion The diversity of the plant kingdom has provided human civilization with life-sustaining food and medicine for centuries. There has been renewed interest in the investigation of botanicals as sources of new drugs, building on traditional knowledge about plant-based medicines. However, data about the plant-based biodiversity potential for therapeutics (eg, based on genetic or chemical information) are generally scattered across a range of sources and isolated from contemporary pharmacological resources. This study explored the potential to bridge biodiversity and biomedical knowledge sources. Conclusions The findings from this feasibility study suggest that there is an opportunity for developing plant-based drugs and further highlight taxonomic relationships between plants that may be rich sources for bioprospecting. PMID:23518859

[Health security--GMOs in therapeutics].

PubMed

Trouvin, J-H

2003-03-01

The recent progress in human therapeutics has been made possible thanks to molecular biology and its use in producing proteins having the same sequence and structure as that of human proteins. The use of GMOs allows production of proteins with high added value in therapeutics, which are of satisfactory quality. GMOs may also be directly administered to patients as gene therapy vectors. However, the use of GMOs in therapeutics must take into consideration some risks, particularly those of microbiological contamination, of neo-antigenicity as well as environmental risks with regard to the way of use of the GMO. Nevertheless, those risks are taken in due consideration in the development of these new medicinal products; solutions have been found to allow their use in therapeutics with a very positive benefit/risk ratio. Medicinal products from biotechnology have enabled considerable therapeutic progress without compromising health security.

Therapeutic cloning in the mouse

PubMed Central

Mombaerts, Peter

2003-01-01

Nuclear transfer technology can be applied to produce autologous differentiated cells for therapeutic purposes, a concept termed therapeutic cloning. Countless articles have been published on the ethics and politics of human therapeutic cloning, reflecting the high expectations from this new opportunity for rejuvenation of the aging or diseased body. Yet the research literature on therapeutic cloning, strictly speaking, is comprised of only four articles, all in the mouse. The efficiency of derivation of embryonic stem cell lines via nuclear transfer is remarkably consistent among these reports. However, the efficiency is so low that, in its present form, the concept is unlikely to become widespread in clinical practice. PMID:12949262

Chemical modifications of therapeutic proteins induced by residual ethylene oxide.

PubMed

Chen, Louise; Sloey, Christopher; Zhang, Zhongqi; Bondarenko, Pavel V; Kim, Hyojin; Ren, Da; Kanapuram, Sekhar

2015-02-01

Ethylene oxide (EtO) is widely used in sterilization of drug product primary containers and medical devices. The impact of residual EtO on protein therapeutics is of significant interest in the biopharmaceutical industry. The potential for EtO to modify individual amino acids in proteins has been previously reported. However, specific identification of EtO adducts in proteins and the effect of residual EtO on the stability of therapeutic proteins has not been reported to date. This paper describes studies of residual EtO with two therapeutic proteins, a PEGylated form of the recombinant human granulocyte colony-stimulating factor (Peg-GCSF) and recombinant human erythropoietin (EPO) formulated with human serum albumin (HSA). Peg-GCSF was filled in an EtO sterilized delivery device and incubated at accelerated stress conditions. Glu-C peptide mapping and LC-MS analyses revealed residual EtO reacted with Peg-GCSF and resulted in EtO modifications at two methionine residues (Met-127 and Met-138). In addition, tryptic peptide mapping and LC-MS analyses revealed residual EtO in plastic vials reacted with HSA in EPO formulation at Met-328 and Cys-34. This paper details the work conducted to understand the effects of residual EtO on the chemical stability of protein therapeutics. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Will Synergizing Vaccination with Therapeutics Boost Measles Virus Eradication?

PubMed Central

Plemper, Richard K; Hammond, Anthea L

2014-01-01

Introduction Measles virus is a major human pathogen responsible for approximately 150,000 measles deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence combined with public anxieties about vaccination safety has increased vaccine refusal especially in the European region, which has resulted in measles resurgence in some areas. Areas covered Here, we discuss whether synergizing effective measles therapeutics with vaccination could contribute to solving an endgame conundrum of measles elimination by accelerating the eradication effort. Based on an anticipated use for protection of high-risk contacts of confirmed measles cases through post-exposure prophylaxis, we identify key elements of the desirable drug profile, review current disease management strategies and the state of experimental inhibitor candidates, evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics for the management of persistent viral infection of the CNS. Assuming a post-measles world with waning measles immunity, we contemplate the possible impact of therapeutics on controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles virus. Expert opinion Efficacious therapeutics given for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent patient population dictates the drug profile; the article must be safe and efficacious, orally available, shelf-stable at ambient temperature, and amenable to cost-effective manufacture

77 FR 13009 - Regulation of Fuels and Fuel Additives: Identification of Additional Qualifying Renewable Fuel...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-05

... ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 80 [EPA-HQ-OAR-2011-0542; FRL-9642-3] RIN 2060-AR07 Regulation of Fuels and Fuel Additives: Identification of Additional Qualifying Renewable Fuel Pathways Under... of Sec. 80.1426 to identify additional renewable fuel production pathways and pathway components that...

Urinary tract infections: treatment/comparative therapeutics.

PubMed

Olin, Shelly J; Bartges, Joseph W

2015-07-01

Urinary tract infection (UTI) occurs when there is compromise of host defense mechanisms and a virulent microbe adheres, multiplies, and persists in a portion of the urinary tract. Most commonly, UTI is caused by bacteria, but fungi and viruses are possible. Urine culture and sensitivity are the gold standards for diagnosis of bacterial UTI. Identifying the location of infection (eg, bladder, kidney, prostate) as well as comorbidities (eg, diabetes mellitus, immunosuppression) is essential to guide the diagnostic and therapeutic plan. Antimicrobial agents are the mainstay of therapy for bacterial UTI and selected ideally based on culture and sensitivity. Copyright © 2015 Elsevier Inc. All rights reserved.

A systematic evaluation of the therapeutic effectiveness of sacroiliac joint interventions.

PubMed

Hansen, Hans; Manchikanti, Laxmaiah; Simopoulos, Thomas T; Christo, Paul J; Gupta, Sanjeeva; Smith, Howard S; Hameed, Haroon; Cohen, Steven P

2012-01-01

The contribution of the sacroiliac joint to low back and lower extremity pain has been a subject of debate with extensive research. It is generally accepted that approximately 10% to 25% of patients with persistent low back pain may have pain arising from the sacroiliac joints. In spite of this, there are currently no definite conservative, interventional, or surgical management options for managing sacroiliac joint pain. In addition, there continue to be significant variations in the application of various techniques as well as a paucity of literature. A systematic review of therapeutic sacroiliac joint interventions. To evaluate the accuracy of therapeutic sacroiliac joint interventions. The available literature on therapeutic sacroiliac joint interventions in managing chronic low back and lower extremity pain was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria for randomized trials of interventional techniques and the criteria developed by the Newcastle-Ottawa Scale for observational studies. The level of evidence was classified as good, fair, or poor based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature published from 1966 through December 2011 that was identified through searches of PubMed and EMBASE, and manual searches of the bibliographies of known primary and review articles. The primary outcome measure was pain relief (short-term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. For this systematic review, 56 studies were considered for inclusion. Of these, 45 studies were excluded and a total of 11 studies met inclusion criteria for methodological quality assessment with 6 randomized trials and 5 non-randomized studies. The evidence for cooled

Improving Antibody-Based Cancer Therapeutics Through Glycan Engineering.

PubMed

Yu, Xiaojie; Marshall, Michael J E; Cragg, Mark S; Crispin, Max

2017-06-01

Antibody-based therapeutics has emerged as a major tool in cancer treatment. Guided by the superb specificity of the antibody variable domain, it allows the precise targeting of tumour markers. Recently, eliciting cellular effector functions, mediated by the Fc domain, has gained traction as a means by which to generate more potent antibody therapeutics. Extensive mutagenesis studies of the Fc protein backbone has enabled the generation of Fc variants that more optimally engage the Fcγ receptors known to mediate cellular effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and cellular phagocytosis. In addition to the protein backbone, the homodimeric Fc domain contains two opposing N-linked glycans, which represent a further point of potential immunomodulation, independent of the Fc protein backbone. For example, a lack of core fucose usually attached to the IgG Fc glycan leads to enhanced ADCC activity, whereas a high level of terminal sialylation is associated with reduced inflammation. Significant growth in knowledge of Fc glycosylation over the last decade, combined with advancement in genetic engineering, has empowered glyco-engineering to fine-tune antibody therapeutics. This has culminated in the approval of two glyco-engineered antibodies for cancer therapy: the anti-CCR4 mogamulizumab approved in 2012 and the anti-CD20 obinutuzumab in 2013. We discuss here the technological platforms for antibody glyco-engineering and review the current clinical landscape of glyco-engineered antibodies.

Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma

PubMed Central

Li, Qi; Wang, Wei; Machino, Yusuke; Yamada, Tadaaki; Kita, Kenji; Oshima, Masanobu; Sekido, Yoshitaka; Tsuchiya, Mami; Suzuki, Yui; Nan-ya, Ken-ichiro; Iida, Shigeru; Nakamura, Kazuyasu; Iwakiri, Shotaro; Itoi, Kazumi; Yano, Seiji

2015-01-01

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial, or peritoneal lining. Although surgery, chemotherapy, radiotherapy, and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there are no published reports regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant antibody-dependent cellular cytotoxicity activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients. PMID:25421609

[Eye contact effects: A therapeutic issue?

PubMed

Baltazar, M; Conty, L

2016-12-01

following the view that people with autism are not interested in processing social signals such as gaze but could do so efficiently if properly motivated. For each pathology we emphasize that eye contact could be used, for example, to enhance sensitivity to bodily states, thus improving emotional decision making (in autism); to lead to more positive appraisal of the self and others (in depression); to improve memory performances (in Alzheimer disease) and, more generally, to motivate the recipient to engage in the therapeutic process. (3) Finally we propose two concrete ways to employ eye contact effects as a therapeutic tool. The first is to develop cognitive-behavioral tools to learn and/or motivate the recipient to create frequent and prolonged eye contact periods. The second is to raise awareness among caregivers of the beneficial effects of eye contact and to teach them the way to use eye contact to reach its optimum effects. Future investigations are however needed to explore the ways in which eye contact effects can be efficiently integrated in therapeutic strategies, as well as to identify the clinical populations that can benefit from such therapeutic interventions. Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

The Therapeutic Relationship: Enhancing Referrals.

PubMed

Coyle, Mary Kathleen

2018-05-19

This article focuses on the ways rehabilitation nurses use the therapeutic relationship to lessen barriers some veterans experience when a referral to mental health treatment is recommended. Veterans presenting with posttraumatic stress symptoms are discussed, and possible interventions within the therapeutic relationship are proposed. Veterans' perception of mental health stigma, building a collaborative therapeutic relationship, recommending a referral and assessments of stress responses, posttraumatic stress symptoms, suicide risk, and intervention strategies are proposed. When changes in functioning and suicidality occur in veterans with posttraumatic stress disorder symptoms, it is important to screen and engage veterans at risk. When veterans in the rehabilitation process present with a need for mental health referral, barriers to treatment may include the stigma of mental health treatment. Rehabilitation nurses using the therapeutic relationship act as change agents to assist veterans in overcoming these barriers to treatment. The therapeutic relationship provides nurses with a foundation to provide opportunities for veterans to be supported and to seek treatment.

Bacteriophage Procurement for Therapeutic Purposes

PubMed Central

Weber-Dąbrowska, Beata; Jończyk-Matysiak, Ewa; Żaczek, Maciej; Łobocka, Małgorzata; Łusiak-Szelachowska, Marzanna; Górski, Andrzej

2016-01-01

Bacteriophages (phages), discovered 100 years ago, are able to infect and destroy only bacterial cells. In the current crisis of antibiotic efficacy, phage therapy is considered as a supplementary or even alternative therapeutic approach. Evolution of multidrug-resistant and pandrug-resistant bacterial strains poses a real threat, so it is extremely important to have the possibility to isolate new phages for therapeutic purposes. Our phage laboratory and therapy center has extensive experience with phage isolation, characterization, and therapeutic application. In this article we present current progress in bacteriophages isolation and use for therapeutic purposes, our experience in this field and its practical implications for phage therapy. We attempt to summarize the state of the art: properties of phages, the methods for their isolation, criteria of phage selection for therapeutic purposes and limitations of their use. Perspectives for the use of genetically engineered phages to specifically target bacterial virulence-associated genes are also briefly presented. PMID:27570518

A physarum-inspired prize-collecting steiner tree approach to identify subnetworks for drug repositioning.

PubMed

Sun, Yahui; Hameed, Pathima Nusrath; Verspoor, Karin; Halgamuge, Saman

2016-12-05

Drug repositioning can reduce the time, costs and risks of drug development by identifying new therapeutic effects for known drugs. It is challenging to reposition drugs as pharmacological data is large and complex. Subnetwork identification has already been used to simplify the visualization and interpretation of biological data, but it has not been applied to drug repositioning so far. In this paper, we fill this gap by proposing a new Physarum-inspired Prize-Collecting Steiner Tree algorithm to identify subnetworks for drug repositioning. Drug Similarity Networks (DSN) are generated using the chemical, therapeutic, protein, and phenotype features of drugs. In DSNs, vertex prizes and edge costs represent the similarities and dissimilarities between drugs respectively, and terminals represent drugs in the cardiovascular class, as defined in the Anatomical Therapeutic Chemical classification system. A new Physarum-inspired Prize-Collecting Steiner Tree algorithm is proposed in this paper to identify subnetworks. We apply both the proposed algorithm and the widely-used GW algorithm to identify subnetworks in our 18 generated DSNs. In these DSNs, our proposed algorithm identifies subnetworks with an average Rand Index of 81.1%, while the GW algorithm can only identify subnetworks with an average Rand Index of 64.1%. We select 9 subnetworks with high Rand Index to find drug repositioning opportunities. 10 frequently occurring drugs in these subnetworks are identified as candidates to be repositioned for cardiovascular diseases. We find evidence to support previous discoveries that nitroglycerin, theophylline and acarbose may be able to be repositioned for cardiovascular diseases. Moreover, we identify seven previously unknown drug candidates that also may interact with the biological cardiovascular system. These discoveries show our proposed Prize-Collecting Steiner Tree approach as a promising strategy for drug repositioning.

Therapeutic decision making in a new drug era in multiple sclerosis.

PubMed

Keegan, B Mark

2013-02-01

Multiple sclerosis is a presumed autoimmune, inflammatory disease of the central nervous system. Since the early 1990s, medications have been devised, tested, and approved for relapsing forms of multiple sclerosis (MS). MS treatments work by altering the immune system to reduce inflammatory MS activity, thus curtailing clinical relapses (attacks), thereby reducing short-term disability related to the MS attacks. The promise of long-term improvement in MS-related disability remains the most desirable therapeutic goal; to what degree current MS therapies are effective in reducing this is controversial. Recent years have seen a surge in novel MS therapies delivered both parenterally and orally that offer new therapeutic alternatives to MS patients and their treating providers. It remains essential to make an unequivocal diagnosis of MS and identify its clinical course prior to initiating therapies. Switching and altering MS therapies can now be done by rational approaches based on therapeutic efficacy and tolerability; however, these remain nonevidence-based for the most part. The high cost of MS therapies remains a significant concern. A new therapeutic era is at hand offering new hope for patients affected by this chronic, frequently disabling disease. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The role of the therapeutic alliance on pain relief in musculoskeletal rehabilitation: A systematic review.

PubMed

Taccolini Manzoni, Ana Carolina; Bastos de Oliveira, Naiane Teixeira; Nunes Cabral, Cristina Maria; Aquaroni Ricci, Natalia

2018-02-05

The aim of this systematic review was to investigate the role of therapeutic alliance in pain relief in patients with musculoskeletal disorders treated by physiotherapy. Manual and database searches (Medline, Embase, ISI Web of Knowledge, CINAHL, PEDro, Lilacs, Cochrane Library, and PsycINFO) were performed with no restrictions of language and publication date. We included prospective studies with samples of patients undergoing physiotherapy for musculoskeletal conditions, with one measure of therapeutic alliance and the outcome pain. Methodological quality was assessed by the Methodological Index for Nonrandomized Studies and the Cochrane tool for risk of bias. Six articles from four studies were included out of the 936 manuscripts identified. All studies used samples composed of patients with chronic low back pain. Two studies applied therapeutic alliance incentive measures during treatment and reported significant improvement in pain. The remaining studies, without alliance incentives, showed divergence regarding the relationship between the therapeutic alliance and pain. Methodological quality analysis determined low risk of bias of the studies. A lack of studies on the therapeutic alliance regarding musculoskeletal physiotherapy was verified. Existing studies fail to provide evidence of a strong relationship between the therapeutic alliance and pain relief.

Addressing clients' racism and racial prejudice in individual psychotherapy: Therapeutic considerations.

PubMed

Bartoli, Eleonora; Pyati, Aarti

2009-06-01

Psychotherapists lack clear guidelines regarding how to address clients' racist and prejudicial comments in clinical work. The authors explore the contributions of multicultural, social justice, feminist, and ethical theories to the field of psychotherapy and apply these theories to 2 clinical vignettes in which clients made racially charged statements. These clinical examples highlight the importance of using racial, in addition to traditional, theories to decipher the clinical meanings of racial comments and dynamics in clinical work. The article provides therapeutic conceptualizations regarding how to address clients' racist and prejudicial comments in psychotherapy and elaborates on the complex meanings that might arise from engaging in racially charged discussions with clients depending on the racial composition of the therapeutic dyad. In addition to highlighting how social justice, multicultural, and feminist lenses are necessary to fully understand the meaning of clients' comments, the argument is made that addressing clients' racist and prejudicial comments is at once a clinical and a social justice issue. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

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.

Additive Manufactured Product Integrity

NASA Technical Reports Server (NTRS)

Waller, Jess; Wells, Doug; James, Steve; Nichols, Charles

2017-01-01

NASA is providing key leadership in an international effort linking NASA and non-NASA resources to speed adoption of additive manufacturing (AM) to meet NASA's mission goals. Participants include industry, NASA's space partners, other government agencies, standards organizations and academia. Nondestructive Evaluation (NDE) is identified as a universal need for all aspects of additive manufacturing.

Evaluation of MicroRNAs Regulating Anoikis Pathways and Its Therapeutic Potential

PubMed Central

Malagobadan, Sharan

2015-01-01

Dysregulation of microRNAs (miRNAs) has been implicated in almost every known survival mechanisms utilized by cancer cells. One of such mechanisms, anoikis resistance, plays a pivotal role in enabling metastasis by allowing cancer cells to circumvent cell death induced by lack of attachment. Understanding how miRNAs regulate the various anoikis pathways has become the research question of increasing number of studies published in the past years. Through these studies, a growing list of miRNAs has been identified to be important players in promoting either anoikis or resistance to anoikis. In this review, we will be focusing on these miRNAs and how the findings from those studies can contribute to novel therapeutic strategies against cancer progression. We will be examining miRNAs that have been found to promote anoikis sensitivity in numerous cancer types followed by miRNAs that inhibit anoikis. In addition, we will also be taking a look at major signaling pathways involved in the action of the each of these miRNAs to gain a better understanding on how miRNAs regulate anoikis. PMID:26587543

Chicanoizing the Therapeutic Community

ERIC Educational Resources Information Center

Aron, William S.; And Others

1974-01-01

Focusing on the drug addiction problem and its antecedent conditions in a Chicano population, the article examines several therapeutic interventions suggested by these conditions and indicates how they might be incorporated into a drug addiction Therapeutic Community treatment program designed to meet the needs of Chicano drug addicts. (Author/NQ)

MIGS: therapeutic success of combined Xen Gel Stent implantation with cataract surgery.

PubMed

Hohberger, Bettina; Welge-Lüßen, Ulrich-Christoph; Lämmer, Robert

2018-03-01

Glaucoma, a common disease in the elderly population, is frequently coexistent with cataract. While the combination of filtration surgery and cataract surgery is a challenging topic with limited success, minimal invasive glaucoma surgery (MIGS), such as Xen Gel Stents, seems to provide promising results. The aim of this study was to investigate the complete and qualified therapeutic success of Xen Gel Stent implantation with (XenPhaco) and without cataract surgery. One hundred and eleven open-angle glaucoma eyes underwent implantation of Xen45 Gel Stent (AqueSys, Inc.) with or without cataract operation. Complete therapeutic success was defined as target intraocular pressure (IOP) < 18 mmHg at any time point within 6 months of follow-up without local antiglaucomatous therapy or further surgical interventions. Qualified success was defined as target IOP <18 mmHg with additional 1-2 local antiglaucomatous eye drops. Failure included all cases with the necessity of at least three local antiglaucomatous eye drops or additional glaucoma surgery. Combined implantation of Xen Gel Stent with cataract surgery was performed in 30 eyes and stand-alone Xen Gel Stent implantation was performed in 81 eyes. A complete therapeutic success was achieved in 46.9% of single Xen Gel Stent implantation, whereas 53.3% was reached with combined XenPhaco. Qualified success was seen in 2.5% in the eyes of the single Xen Gel Stent implantation group and in 3.3% of the combined surgery group. Therapeutic failure rate was 49.4% in the stand-alone group vs 46.7% in the combined group. Data were not significantly different for group and subgroup analyses. Complete and qualified therapeutic success is similar for the combination of Xen Gel Stent implantation with and without cataract surgery in open-angle glaucoma patients. MIGS using Xen Gel Stent can be recommended in situations if glaucoma surgery is indicated besides coexisting cataract.

Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics

PubMed Central

Jelveh, Salomeh; Chithrani, Devika B.

2011-01-01

The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. PMID:24212654

Constraint based modeling of metabolism allows finding metabolic cancer hallmarks and identifying personalized therapeutic windows.

PubMed

Bordel, Sergio

2018-04-13

In order to choose optimal personalized anticancer treatments, transcriptomic data should be analyzed within the frame of biological networks. The best known human biological network (in terms of the interactions between its different components) is metabolism. Cancer cells have been known to have specific metabolic features for a long time and currently there is a growing interest in characterizing new cancer specific metabolic hallmarks. In this article it is presented a method to find personalized therapeutic windows using RNA-seq data and Genome Scale Metabolic Models. This method is implemented in the python library, pyTARG. Our predictions showed that the most anticancer selective (affecting 27 out of 34 considered cancer cell lines and only 1 out of 6 healthy mesenchymal stem cell lines) single metabolic reactions are those involved in cholesterol biosynthesis. Excluding cholesterol biosynthesis, all the considered cell lines can be selectively affected by targeting different combinations (from 1 to 5 reactions) of only 18 metabolic reactions, which suggests that a small subset of drugs or siRNAs combined in patient specific manners could be at the core of metabolism based personalized treatments.

Structured Therapeutic Games for Nonoffending Caregivers of Children Who Have Experienced Sexual Abuse.

PubMed

Springer, Craig I; Colorado, Giselle; Misurell, Justin R

2015-01-01

Game-based cognitive-behavioral therapy group model for nonoffending caregivers utilizes structured therapeutic games to assist parents following child sexual abuse. Game-based cognitive-behavioral therapy group model is a manualized group treatment approach that integrates evidence-based cognitive-behavioral therapy components with structured play therapy to teach parenting and coping skills, provide psychoeducation, and process trauma. Structured therapeutic games were designed to allow nonoffending caregivers to process their children's abuse experiences and learn skills necessary to overcome trauma in a nonthreatening, fun, and engaging manner. The implementation of these techniques allow clinicians to address a variety of psychosocial difficulties that are commonly found among nonoffending caregivers of children who have experienced sexual abuse. In addition, structured therapeutic games help caregivers develop strengths and abilities that they can use to help their children cope with abuse and trauma and facilitates the development of positive posttraumatic growth. Techniques and procedures for treatment delivery along with a description of core components and therapeutic modules are discussed. An illustrative case study is provided.

Therapeutic efficacy of equine botulism antitoxin in Rhesus macaques

PubMed Central

Emanuel, Andrew; Takla, Teresa; Hua, Yi; Hobbs, Charles; LeClaire, Ross; O’Donnell, Denise C.

2017-01-01

Background There are currently no licensed vaccines available for prevention of botulism in humans. The vaccination is not desirable due to expanding therapeutic indications of botulinum toxins. The only available specific treatment for botulism is antitoxin to remove circulating toxin, thus, preventing further neuronal damage. BAT® (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)—(Equine)) has been developed and its therapeutic efficacy evaluated against botulinum neurotoxin serotype A (BoNT/A) in Rhesus macaques. Methods and findings In a post-exposure prophylaxis (PEP) study, animals were exposed to 4x LD50/kg of BoNT/A and administered intravenously with either BAT (1x or 0.1x scaled human dose), or placebo at 4 hours post-exposure. The animals were monitored for 14 days. For the therapeutic intervention studies, animals were exposed to a 1.7x LD50/kg of BoNT/A and treated intravenously with either placebo or BAT at a 1x scaled human dose at the onset of clinical signs. Animals were monitored on an hourly basis for 14 or 21 days. In the PEP study, all animals tolerated equine based antitoxin without any adverse clinical signs. A 100% survival was observed in groups treated with the BAT compared to 0% survival in those treated with the placebo (p<0.001, Fisher’s exact test). BAT antitoxin prevented the development of signs of neurotoxicity of botulinum toxin. In a therapeutic study, treatment with the BAT at scaled 1x human dose after the onset of clinical signs significantly enhanced survival compared to the placebo (46.6% vs. 0%, p<0.0001, Fisher’s exact test). Additionally, treatment with the BAT delayed the progression of signs (muscular weakness, respiratory distress, oral/nasal discharge) of toxin intoxication and reduced the severity of the disease. Conclusions A single dose of BAT, when administered to symptomatic monkeys, resulted in a statistically significant survival benefit compared to the placebo. Additionally, BAT completely protected

Therapeutic efficacy of equine botulism antitoxin in Rhesus macaques.

PubMed

Kodihalli, Shantha; Emanuel, Andrew; Takla, Teresa; Hua, Yi; Hobbs, Charles; LeClaire, Ross; O'Donnell, Denise C

2017-01-01

There are currently no licensed vaccines available for prevention of botulism in humans. The vaccination is not desirable due to expanding therapeutic indications of botulinum toxins. The only available specific treatment for botulism is antitoxin to remove circulating toxin, thus, preventing further neuronal damage. BAT® (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine)) has been developed and its therapeutic efficacy evaluated against botulinum neurotoxin serotype A (BoNT/A) in Rhesus macaques. In a post-exposure prophylaxis (PEP) study, animals were exposed to 4x LD50/kg of BoNT/A and administered intravenously with either BAT (1x or 0.1x scaled human dose), or placebo at 4 hours post-exposure. The animals were monitored for 14 days. For the therapeutic intervention studies, animals were exposed to a 1.7x LD50/kg of BoNT/A and treated intravenously with either placebo or BAT at a 1x scaled human dose at the onset of clinical signs. Animals were monitored on an hourly basis for 14 or 21 days. In the PEP study, all animals tolerated equine based antitoxin without any adverse clinical signs. A 100% survival was observed in groups treated with the BAT compared to 0% survival in those treated with the placebo (p<0.001, Fisher's exact test). BAT antitoxin prevented the development of signs of neurotoxicity of botulinum toxin. In a therapeutic study, treatment with the BAT at scaled 1x human dose after the onset of clinical signs significantly enhanced survival compared to the placebo (46.6% vs. 0%, p<0.0001, Fisher's exact test). Additionally, treatment with the BAT delayed the progression of signs (muscular weakness, respiratory distress, oral/nasal discharge) of toxin intoxication and reduced the severity of the disease. A single dose of BAT, when administered to symptomatic monkeys, resulted in a statistically significant survival benefit compared to the placebo. Additionally, BAT completely protected monkeys from the clinical signs of intoxication

A High-throughput Assay for mRNA Silencing in Primary Cortical Neurons in vitro with Oligonucleotide Therapeutics.

PubMed

Alterman, Julia F; Coles, Andrew H; Hall, Lauren M; Aronin, Neil; Khvorova, Anastasia; Didiot, Marie-Cécile

2017-08-20

Primary neurons represent an ideal cellular system for the identification of therapeutic oligonucleotides for the treatment of neurodegenerative diseases. However, due to the sensitive nature of primary cells, the transfection of small interfering RNAs (siRNA) using classical methods is laborious and often shows low efficiency. Recent progress in oligonucleotide chemistry has enabled the development of stabilized and hydrophobically modified small interfering RNAs (hsiRNAs). This new class of oligonucleotide therapeutics shows extremely efficient self-delivery properties and supports potent and durable effects in vitro and in vivo . We have developed a high-throughput in vitro assay to identify and test hsiRNAs in primary neuronal cultures. To simply, rapidly, and accurately quantify the mRNA silencing of hundreds of hsiRNAs, we use the QuantiGene 2.0 quantitative gene expression assay. This high-throughput, 96-well plate-based assay can quantify mRNA levels directly from sample lysate. Here, we describe a method to prepare short-term cultures of mouse primary cortical neurons in a 96-well plate format for high-throughput testing of oligonucleotide therapeutics. This method supports the testing of hsiRNA libraries and the identification of potential therapeutics within just two weeks. We detail methodologies of our high throughput assay workflow from primary neuron preparation to data analysis. This method can help identify oligonucleotide therapeutics for treatment of various neurological diseases.

A study of the differential effects of Tomm's questioning styles on therapeutic alliance.

PubMed

Ryan, D; Carr, A

2001-01-01

To replicate and extend Dozier's (1992) test of Tomm's hypothesis about the differential effects of questioning styles on therapeutic alliance, an analogue study was conducted. Twenty-eight family triads, each including a son and his parents, viewed four videotaped, simulated family therapy scenarios in which Tomm's four questioning styles were separately portrayed. Participants were asked to identify with the client whose role corresponded to theirs (that is, father, mother, or son) and, on the basis of this, to rate the client's alliance with the therapist. They were also asked to rate the overall alliance between the family and the therapist. Finally, having viewed all four scenarios, they were invited to rate comparatively the quality of the therapeutic alliance across the four questioning styles. Compared with strategic and lineal questioning styles, circular and reflexive questions led to higher ratings of therapeutic alliance on all three measures. The results of this study support Tomm's hypothesis that questioning styles based on circular assumptions lead to a better therapeutic alliance at an individual and systemic level than do questions based on lineal assumptions.

Therapeutic Outcome of Achalasia Based on High-Resolution Manometry: A Korean Multicenter Study.

PubMed

Lee, Hyuk; Chung, Hyunsoo; Lee, Tae Hee; Hong, Kyoung Sup; Youn, Young Hoon; Park, Jung Ho; Park, Hyung Seok; Park, Hyojin

2017-09-11

Because achalasia subtype is associated with therapeutic response, it is possible that regional differences in subtype distribution could lead to differences in therapeutic outcomes. We aimed to evaluate and compare high-resolution manometry (HRM) profiles among the different subtypes of achalasia and to elucidate predictive factors associated with treatment outcomes. Patients who were diagnosed with achalasia using HRM at 4 Korean university hospitals were retrospectively identified and analyzed. Sixty-four patients with untreated achalasia were divided into 3 subtypes using the Chicago classification system. Clinical characteristics, manometric features, and treatment outcomes were compared. Among 64 patients diagnosed with achalasia, 31 patients were classified as type I, 27 as type II, and 6 as type III. Regarding HRM parameters, there were statistically significant differences in basal lower esophageal sphincter pressure, 4-second-integrated relaxation pressure, residual upper esophageal sphincter pressure, body amplitude, and maximal intrabolus pressure between subtypes. Regarding therapeutic outcome, type II patients (overall success rate of 80.0%) were more likely to respond than type I (55.2%) or type III (33.2%) patients. Multivariate analysis demonstrated that achalasia subtype (type I vs. III, P = 0.072; type II vs. III, P = 0.005), therapeutic modality (dilation vs. pharmacologic, P = 0.013; laparoscopic Heller's myotomy vs. pharmacologic, P = 0.006), and HRM-measured esophageal length (<27.5 vs. ≥27.5 cm, P = 0.014) are independent predictive factors for therapeutic failure. Patients with type II achalasia had better treatment outcomes than patients with other achalasia subtypes. Achalasia subtype, therapeutic modality, and esophageal length are independent predictive factors of therapeutic outcome.

Therapeutic Potential of Targeting PAK Signaling.

PubMed

Senapedis, William; Crochiere, Marsha; Baloglu, Erkan; Landesman, Yosef

2016-01-01

The therapeutic potential of targeting p21-Activated Kinases (PAK1 - 6) for the treatment of cancer has recently gained traction in the biotech industry. Many pharmaceutically-viable ATP competitive inhibitors have been through different stages of pre-clinical development with only a single compound evaluated in human trails (PF-3758309). The best studied functional roles of PAK proteins are control of cell adhesion and migration. PAK proteins are known downstream effectors of Ras signaling with PAK expression elevated in cancer (pancreatic, colon, breast, lung and other solid tumors). In addition altered PAK expression is a confirmed driver of this disease, especially in tumors harboring oncogenic Ras. However, there are very few examples of gain-of-function PAK mutations, as a majority of the cancer types have elevated PAK expression due to gene amplification or transcriptional modifications. There is a substantial number of known substrates affected by this aberrant PAK activity. One particular substrate, β-catenin, has garnered interest given its importance in both normal and cancer cell development. These data place PAK proteins between two major signaling pathways in cancer (Ras and β -catenin), making therapeutic targeting of PAKs an intriguing approach for the treatment of a broad array of oncological malignancies.

Molecular engineering of proteins and polymers for targeting and intracellular delivery of therapeutics.

PubMed

Stayton, P S; Hoffman, A S; Murthy, N; Lackey, C; Cheung, C; Tan, P; Klumb, L A; Chilkoti, A; Wilbur, F S; Press, O W

2000-03-01

There are many protein and DNA based therapeutics under development in the biotechnology and pharmaceutical industries. Key delivery challenges remain before many of these biomolecular therapeutics reach the clinic. Two important barriers are the effective targeting of drugs to specific tissues and cells and the subsequent intracellular delivery to appropriate cellular compartments. In this review, we summarize protein engineering work aimed at improving the stability and refolding efficiency of antibody fragments used in targeting, and at constructing new streptavidin variants which may offer improved performance in pre-targeting delivery strategies. In addition, we review recent work with pH-responsive polymers that mimic the membrane disruptive properties of viruses and toxins. These polymers could serve as alternatives to fusogenic peptides in gene therapy formulations and to enhance the intracellular delivery of protein therapeutics that function in the cytoplasm.

THPdb: Database of FDA-approved peptide and protein therapeutics.

PubMed

Usmani, Salman Sadullah; Bedi, Gursimran; Samuel, Jesse S; Singh, Sandeep; Kalra, Sourav; Kumar, Pawan; Ahuja, Anjuman Arora; Sharma, Meenu; Gautam, Ankur; Raghava, Gajendra P S

2017-01-01

THPdb (http://crdd.osdd.net/raghava/thpdb/) is a manually curated repository of Food and Drug Administration (FDA) approved therapeutic peptides and proteins. The information in THPdb has been compiled from 985 research publications, 70 patents and other resources like DrugBank. The current version of the database holds a total of 852 entries, providing comprehensive information on 239 US-FDA approved therapeutic peptides and proteins and their 380 drug variants. The information on each peptide and protein includes their sequences, chemical properties, composition, disease area, mode of activity, physical appearance, category or pharmacological class, pharmacodynamics, route of administration, toxicity, target of activity, etc. In addition, we have annotated the structure of most of the protein and peptides. A number of user-friendly tools have been integrated to facilitate easy browsing and data analysis. To assist scientific community, a web interface and mobile App have also been developed.

Biological and therapeutic activities, and anticancer properties of curcumin.

PubMed

Perrone, Donatella; Ardito, Fatima; Giannatempo, Giovanni; Dioguardi, Mario; Troiano, Giuseppe; Lo Russo, Lucio; DE Lillo, Alfredo; Laino, Luigi; Lo Muzio, Lorenzo

2015-11-01

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Curcumin has been used extensively in Ayurvedic medicine, as it is nontoxic and exhibits a variety of therapeutic properties, including antioxidant, analgesic, anti-inflammatory and antiseptic activities. Recently, certain studies have indicated that curcumin may exert anticancer effects in a variety of biological pathways involved in mutagenesis, apoptosis, tumorigenesis, cell cycle regulation and metastasis. The present study reviewed previous studies in the literature, which support the therapeutic activity of curcumin in cancer. In addition, the present study elucidated a number of the challenges concerning the use of curcumin as an adjuvant chemotherapeutic agent. All the studies reviewed herein suggest that curcumin is able to exert anti-inflammatory, antiplatelet, antioxidative, hepatoprotective and antitumor activities, particularly against cancers of the liver, skin, pancreas, prostate, ovary, lung and head neck, as well as having a positive effect in the treatment of arthritis.

Therapeutic patient education in adrenal insufficiency.

PubMed

Guignat, Laurence

2018-06-01

It is essential to encourage patient autonomy in the management of their illness, and notably their participation in treatment education programs; specific programs target avoidance or early preventive treatment of acute adrenal insufficiency, which is a life-threatening complication. Therapeutic patient education is recommended by the two international consensus statements on the management of primary adrenal insufficiency and the French consensus on adrenal insufficiency. Although there is no common international reference framework to date, the objective of the French consensus was to provide a frame of reference to facilitate the development of therapeutic education for patients with adrenal insufficiency. The principal educational objectives were: for the patient to always carry the necessary emergency equipment; be able to identify situations of increased risk and the early signs of adrenal crisis; know how to adjust oral glucocorticoid treatment; be capable of administering hydrocortisone by subcutaneous injection; be able to adjust treatment to different situations (heat, physical exercise, travel); and be able to appropriately use the resources of the healthcare services. Other programs could also be developed to respond to patients' needs and expectations, notably concerning hydrocortisone dose adjustment to avoid overdose in the context of chronic fatigue syndrome. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The social dimensions of therapeutic horticulture.

PubMed

Harris, Holly

2017-07-01

Harnessing nature to promote mental health is increasingly seen as a sustainable solution to healthcare across the industrialised world. The benefits of these approaches to well-being include reduced symptoms of anxiety, depression and improved social functioning. Many studies assume that contact with nature is the main therapeutic component of these interventions yet 'green care' programmes typically include activities not based on 'nature' that may contribute to positive outcomes. This study explored the views of service users participating in a Therapeutic Horticultural programme on what factors promoted their engagement in the project, to identify variables other than 'nature' that may be responsible for successful engagement in these programmes. A secondary aim was to assess the significance 'nature' plays including, for example whether a prior interest in horticultural-related activities, such as gardening, is significant. Two focus groups were held with mental health service users (n = 15) attending a gardening project in south-east England. Findings revealed that the social element of the project was the key facilitator to engagement; the flexible structure of the gardening project was also significant and allowed service users to feel empowered. 'Nature' evoked a sense of calm and provided participants with a non-threatening space that was engaging. © 2017 John Wiley & Sons Ltd.

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

PubMed Central

Gu, Zhaohui; Churchman, Michelle; Roberts, Kathryn; Li, Yongjin; Liu, Yu; Harvey, Richard C.; McCastlain, Kelly; Reshmi, Shalini C.; Payne-Turner, Debbie; Iacobucci, Ilaria; Shao, Ying; Chen, I-Ming; Valentine, Marcus; Pei, Deqing; Mungall, Karen L.; Mungall, Andrew J.; Ma, Yussanne; Moore, Richard; Marra, Marco; Stonerock, Eileen; Gastier-Foster, Julie M.; Devidas, Meenakshi; Dai, Yunfeng; Wood, Brent; Borowitz, Michael; Larsen, Eric E.; Maloney, Kelly; Mattano Jr, Leonard A.; Angiolillo, Anne; Salzer, Wanda L.; Burke, Michael J.; Gianni, Francesca; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Moorman, Anthony V.; Patel, Bella; Fielding, Adele K.; Rowe, Jacob M.; Luger, Selina M.; Bhatia, Ravi; Aldoss, Ibrahim; Forman, Stephen J.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Marcucci, Guido; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Steven; Kantarjian, Hagop M.; Konopleva, Marina; Paietta, Elisabeth; Willman, Cheryl L.; L. Loh, Mignon; P. Hunger, Stephen; Mullighan, Charles G.

2016-01-01

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered. PMID:27824051

Dance is more than therapy: Qualitative analysis on therapeutic dancing classes for Parkinson's.

PubMed

Rocha, Priscila A; Slade, Susan C; McClelland, Jodie; Morris, Meg E

2017-10-01

To understand the benefits and limitations of therapeutic dancing classes for people with Parkinson's disease (PD) and how best to design and implement classes. A stakeholder forum explored the opinions of 18 allied health clinicians, dance instructors, people with PD and caregivers. Data were thematically analysed and interpreted within a grounded theory framework. Four main themes were identified: (1) the need to consider the stage of disease progression when designing classes; (2) recognition that dance is more than just therapy; (3) the benefits of carefully selecting music to move by; (4) ways to design classes that are both feasible and engaging. These themes give rise to the theory that dancing classes can provide more than just therapeutic benefits. Dance affords creative expression and enables people to immerse themselves in the art-form, rather than focussing on the disease. The results highlight the benefits of enabling individuals with PD to be able to express themselves in a supportive environment that does not see them solely through the lens of Parkinson's. The feasibility of dance programs can be increased by educating dancing teachers about PD and the unique needs of people living with this condition. Well-structured dance classes can promote social-connectedness and joy, in addition to facilitating movement to music and physical activity. Consumers advised that careful planning of the classes and tailoring them to participant needs optimizes outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

ROCK in CNS: Different Roles of Isoforms and Therapeutic Target for Neurodegenerative Disorders.

PubMed

Chong, Cheong-Meng; Ai, Nana; Lee, Simon Ming-Yuen

2017-01-01

Rho-associated protein kinase (ROCK) is a serine-threonine kinase originally identified as a crucial regulator of actin cytoskeleton. Recent studies have defined new functions of ROCK as a critical component of diverse signaling pathways in neurons. In addition, inhibition of ROCK causes several biological events such as increase of neurite outgrowth, axonal regeneration, and activation of prosurvival Akt. Thus, it has attracted scientist's strong attentions and considered ROCK as a promising therapeutic target for the treatment of neurodegenerative disorders including Alzheimer disease, Parkinson's disease, Huntington';s disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, ROCK has two highly homologous isoforms, ROCK1 and ROCK2. Accumulated evidences indicate that ROCK1 and ROCK2 might involve in distinct cellular functions in central nervous system (CNS) and neurodegenerative processes. This review summarizes recent updates regarding ROCK isoformspecific functions in CNS and the progress of ROCK inhibitors in preclinical studies for neurodegenerative diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Therapeutic recreation treatment time during inpatient rehabilitation

PubMed Central

Gassaway, Julie; Dijkers, Marcel; Rider, Cecelia; Edens, Kelly; Cahow, Claire; Joyce, Joan

2011-01-01

Objective Following spinal cord injury (SCI), certified therapeutic recreation specialists (CTRSs) work with patients during rehabilitation to re-create leisure lifestyles. Although there is much literature available to describe the benefits of recreation, little has been written about the process of inpatient or outpatient rehabilitation therapeutic recreation (TR) programs or the effectiveness of such programs. To delineate how TR time is used during inpatient rehabilitation for SCI. Methods Six rehabilitation centers enrolled 600 patients with traumatic SCI for an observational study. CTRSs documented time spent on each of a set of specific TR activities during each patient encounter. Patterns of time use are described, for all patients and by neurologic category. Ordinary least-squares stepwise regression models are used to identify patient and injury characteristics predictive of total treatment time (overall and average per week) and time spent in TR activities. Results Ninety-four percent of patients enrolled in the SCIRehab study participated in TR. Patients received a mean total of 17.5 hours of TR; significant differences were seen in the amount of time spent in each activity among and within neurologic groups. The majority (76%) of patients participated in at least one structured therapeutic outing. Patient and injury characteristics explained little of the variation in time spent within activities. Conclusion The large amount of variability seen in TR treatment time within and among injury group categories, which is not explained well by patient and injury characteristics, sets the stage for future analyses to associate treatments with outcomes. PMID:21675356

[Therapeutic restraint and freedom of movement, changing practices].

PubMed

Perrin-Niquet, Annick

From confinement to the philosophy of care in the community, the history of psychiatry testifies to the evolution of practices in the matter of the restriction of freedom. The French National Health Authority still too often recommends practices based on restraint. Caregivers, in relation to the clinical aspect of the patients, need clearly identified therapeutic projects. While training can be vital for them, risk management policies can prove to be a hindrance to patients' freedom. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Corrective interpersonal experience in psychodrama group therapy: a comprehensive process analysis of significant therapeutic events.

PubMed

McVea, Charmaine S; Gow, Kathryn; Lowe, Roger

2011-07-01

This study investigated the process of resolving painful emotional experience during psychodrama group therapy, by examining significant therapeutic events within seven psychodrama enactments. A comprehensive process analysis of four resolved and three not-resolved cases identified five meta-processes which were linked to in-session resolution. One was a readiness to engage in the therapeutic process, which was influenced by client characteristics and the client's experience of the group; and four were therapeutic events: (1) re-experiencing with insight; (2) activating resourcefulness; (3) social atom repair with emotional release; and (4) integration. A corrective interpersonal experience (social atom repair) healed the sense of fragmentation and interpersonal disconnection associated with unresolved emotional pain, and emotional release was therapeutically helpful when located within the enactment of this new role relationship. Protagonists who experienced resolution reported important improvements in interpersonal functioning and sense of self which they attributed to this experience.

Nanoparticles for Imaging, Sensing, and Therapeutic Intervention

PubMed Central

2014-01-01

Nanoparticles have the potential to contribute to new modalities in molecular imaging and sensing as well as in therapeutic interventions. In this Nano Focus article, we identify some of the current challenges and knowledge gaps that need to be confronted to accelerate the developments of various applications. Using specific examples, we journey from the characterization of these complex hybrid nanomaterials; continue with surface design and (bio)physicochemical properties, their fate in biological media and cells, and their potential for cancer treatment; and finally reflect on the role of animal models to predict their behavior in humans. PMID:24641589

Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer.

PubMed

Chong, Irene Yushing; Aronson, Lauren; Bryant, Hanna; Gulati, Aditi; Campbell, James; Elliott, Richard; Pettitt, Stephen; Wilkerson, Paul; Lambros, Maryou B; Reis-Filho, Jorge S; Ramessur, Anisha; Davidson, Michael; Chau, Ian; Cunningham, David; Ashworth, Alan; Lord, Christopher J

2017-08-22

Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets. By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G 1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer. BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453). NCT02884453; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

EXETRA Perspectives: Concepts in Therapeutic Recreation.

ERIC Educational Resources Information Center

Neal, Larry L.; Edginton, Christopher R.

Fifteen papers address issues in therapeutic recreation for disabled persons from the perspectives of practitioners, educators, and students. The following papers are presented. "Therapeutic Recreation Service: The Past and Challenging Present" (H. Sessoms); "Therapeutic Recreatiion in an Era of Limits: A Crisis...A Challenge... An Opportunity"…

21 CFR 890.5975 - Therapeutic vibrator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Therapeutic vibrator. 890.5975 Section 890.5975 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5975 Therapeutic...

21 CFR 890.5975 - Therapeutic vibrator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Therapeutic vibrator. 890.5975 Section 890.5975 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5975 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

WINCS Harmoni: Closed-loop dynamic neurochemical control of therapeutic interventions

NASA Astrophysics Data System (ADS)

Lee, Kendall H.; Lujan, J. Luis; Trevathan, James K.; Ross, Erika K.; Bartoletta, John J.; Park, Hyung Ook; Paek, Seungleal Brian; Nicolai, Evan N.; Lee, Jannifer H.; Min, Hoon-Ki; Kimble, Christopher J.; Blaha, Charles D.; Bennet, Kevin E.

2017-04-01

There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.

The patient relationship and therapeutic techniques of the South Sotho traditional healer.

PubMed

Pinkoane, M G; Greeff, M; Williams, M J S

2005-11-01

Until 1996 the practice of traditional healers was outlawed in South Africa and not afforded a legal position in the community of health care providers. In 1978 the World Health Organization (WHO) identified traditional healers as those people forming an essential core of primary health care workers for rural people in the Third World Countries. However in 1994 the new South African government identified traditional healers as forming an essential element of primary health care workers. It is estimated that 80% of the black population uses traditional medicine because it is deeply rooted in their culture, which is linked to their religion. The traditional healer shares with the patient a world view which is completely alien to biomedical personnel. Therapeutic techniques typically used in traditional healing conflict with the therapeutic techniques used in biomedicine. The patients' perceptions of traditional healing, their needs and expectations, may be the driving force behind their continuous persistence to consult a traditional healer, even after these patients may have sought the therapeutic techniques of biomedical personnel. The operation of both systems in the same society creates a problem to both providers and recipients of health care. Confusion then arises and the consumer consequently chooses the services closer to her. The researcher aimed at investigating the characteristics of the relationship between the traditional healers and the patients, explored the therapeutic techniques that are used in the South Sotho traditional healing process, and investigated the views of both the traditional healers and the patients about the South -Sotho traditional healing process, to facilitate incorporation of the traditional healers in the National Health Care Delivery System. A qualitative research design was followed. Participants were identified by means of a non-probable, purposive voluntary sample. Data was collected by means of a video camera and semi

Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.

PubMed

Parker, Nicole R; Hudson, Amanda L; Khong, Peter; Parkinson, Jonathon F; Dwight, Trisha; Ikin, Rowan J; Zhu, Ying; Cheng, Zhangkai Jason; Vafaee, Fatemeh; Chen, Jason; Wheeler, Helen R; Howell, Viive M

2016-03-04

Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies.

Chaperoning G Protein-Coupled Receptors: From Cell Biology to Therapeutics

PubMed Central

Conn, P. Michael

2014-01-01

G protein-coupled receptors (GPCRs) are membrane proteins that traverse the plasma membrane seven times (hence, are also called 7TM receptors). The polytopic structure of GPCRs makes the folding of GPCRs difficult and complex. Indeed, many wild-type GPCRs are not folded optimally, and defects in folding are the most common cause of genetic diseases due to GPCR mutations. Both general and receptor-specific molecular chaperones aid the folding of GPCRs. Chemical chaperones have been shown to be able to correct the misfolding in mutant GPCRs, proving to be important tools for studying the structure-function relationship of GPCRs. However, their potential therapeutic value is very limited. Pharmacological chaperones (pharmacoperones) are potentially important novel therapeutics for treating genetic diseases caused by mutations in GPCR genes that resulted in misfolded mutant proteins. Pharmacoperones also increase cell surface expression of wild-type GPCRs; therefore, they could be used to treat diseases that do not harbor mutations in GPCRs. Recent studies have shown that indeed pharmacoperones work in both experimental animals and patients. High-throughput assays have been developed to identify new pharmacoperones that could be used as therapeutics for a number of endocrine and other genetic diseases. PMID:24661201

Juxtapapillary duodenal diverticula early and late clinical and therapeutical implications.

PubMed

Straja, D; Marincaş, M; Alecu, M; Boroghina, G; Simion, L; Stanescu, A; Drilea, E; Brătucu, E

2009-01-01

The aim of this paper is to identify the early and late implications of JPDD for biliary pathology, as well as for endoscopic therapy and classical surgery dealing mainly with lithiasis. This paper is based on a retrospective study comprising a number of 675 ERCP performed on 601 patients between 1997-2007, out of which 399 cases were followed by therapeutic measures. A total of 79 procedures were performed on 65 cases with JPDD. The main criteria were: gender, age, indications regarding the performance of ERCP+/-ES, complications that occurred while carrying out these procedures. In all the cases examined (601) the percentage of JPDD reported was of 10.81%. The rate of complications in the sphincterotomized patients without JPDD was 5.75% and the rate in the sphincterotomized patients with JPDD was 14.89%. In conclusion, the paper discusses the clinical and therapeutic implications of JPDD in biliary pathology. It has been found that JPDD is an important etiological cause for the late diseases occurring after cholelithiasis surgery. JPDD also leads to immediate therapeutic implications such as: difficult cannulation and high incidence of ERCP+/-ES complications.

ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents.

PubMed

Agnihotri, Sameer; Burrell, Kelly; Buczkowicz, Pawel; Remke, Marc; Golbourn, Brian; Chornenkyy, Yevgen; Gajadhar, Aaron; Fernandez, Nestor A; Clarke, Ian D; Barszczyk, Mark S; Pajovic, Sanja; Ternamian, Christian; Head, Renee; Sabha, Nesrin; Sobol, Robert W; Taylor, Michael D; Rutka, James T; Jones, Chris; Dirks, Peter B; Zadeh, Gelareh; Hawkins, Cynthia

2014-10-01

Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window. ©2014 American Association for Cancer Research.

21 CFR 880.5160 - Therapeutic medical binder.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Therapeutic medical binder. 880.5160 Section 880...) MEDICAL DEVICES GENERAL HOSPITAL AND PERSONAL USE DEVICES General Hospital and Personal Use Therapeutic Devices § 880.5160 Therapeutic medical binder. (a) Identification. A therapeutic medical binder is a...

21 CFR 880.5160 - Therapeutic medical binder.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Therapeutic medical binder. 880.5160 Section 880...) MEDICAL DEVICES GENERAL HOSPITAL AND PERSONAL USE DEVICES General Hospital and Personal Use Therapeutic Devices § 880.5160 Therapeutic medical binder. (a) Identification. A therapeutic medical binder is a...

Bulky Polar Additives That Greatly Reduce the Viscosity of Concentrated Solutions of Therapeutic Monoclonal Antibodies.

PubMed

Larson, Alyssa M; Weight, Alisha K; Love, Kevin; Bonificio, Amanda; Wescott, Charles R; Klibanov, Alexander M

2017-05-01

The viscosity of concentrated aqueous solutions of 3 clinical monoclonal antibodies (mAbs), Erbitux®, Herceptin®, and Rituxan®, has been reduced up to over 10-fold by adding certain bulky polar additives instead of saline at isotonic levels. Because these additives are also found not to compromise mAbs' stability against aggregation induced by stresses, a drug-delivery modality switch from intravenous infusions to more convenient and inexpensive parenteral options like subcutaneous injections may become possible. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Therapeutic Fc-fusion proteins and peptides as successful alternatives to antibodies.

PubMed

Beck, Alain; Reichert, Janice M

2011-01-01

Therapeutic antibodies have captured substantial attention due to the relatively high rate at which these products reach marketing approval, and the subsequent commercial success they frequently achieve. In the 2000s, a total of 20 antibodies (18 full-length IgG and 2 Fab) were approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA). In the 2010s to date, an additional 3 antibodies (denosumab, belimumab, ipilimumab) have been approved and one antibody-drug conjugate (brentuximab vedotin) is undergoing regulatory review and may be approved in the US by August 30, 2011. However, a less heralded group of antibody-based therapeutics comprising proteins or peptides fused with an Fc is following the success of classical antibodies.

Integration of a Community Pharmacy Simulation Program into a Therapeutics Course.

PubMed

Shin, Jaekyu; Tabatabai, Daryush; Boscardin, Christy; Ferrone, Marcus; Brock, Tina

2018-02-01

Objective. To demonstrate the feasibility of integrating the computer simulation, MyDispense, into a therapeutics course and to measure its effects on student perception and learning. Methods. We conducted a prospective study with an experimental phase and an implementation phase. In the first phase, students were randomized to complete a therapeutics case using MyDispense or traditional paper methods in class. In the second phase, all students completed two therapeutic cases using MyDispense in class with the option to complete four additional outside-of-class cases using MyDispense. Students completed pre- and post-tests in class and three surveys. Results. In the experimental phase, mean test scores increased from pre- to post-test for both MyDispense and traditional paper groups, but the difference between the groups was not statistically significant. Students in the traditional paper group reported statistically significant gains in confidence compared to the MyDispense group. In the implementation phase, mean test scores again increased, however, student perception of the use of MyDispense for therapeutics was negative. Completing the optional outside-of-class cases, however, was positively and significantly correlated with the midterm and final examination scores. Conclusion. Implementation of MyDispense in therapeutics may be feasible and has positive effects (eg, correlation with exam scores, capacity for immediate feedback, and potential for effective self-study). With short-term use and in the absence of assessment methods that also require seeking information from patients, students prefer to learn via traditional paper cases.

Extracellular Vesicles as Therapeutic Tools in Cardiovascular Diseases

PubMed Central

Fleury, Audrey; Martinez, Maria Carmen; Le Lay, Soazig

2014-01-01

Extracellular vesicles (EVs), including microvesicles (MVs) and exosomes, are small vesicles secreted from a wide variety of cells. Whereas MVs are particles released by the outward budding of the plasma membrane, exosomes are derived from endocytic compartments. Secretion of EVs can be enhanced by specific stimuli, and increased plasma circulating levels of EVs have been correlated with pathophysiological situations. MVs, already present in the blood of healthy individuals, are considerably elevated in several cardiovascular diseases associated with inflammation, suggesting that they can mediate deleterious effects such as endothelial dysfunction or thrombosis. Nonetheless, very recent studies also demonstrate that MVs may act as biological information vectors transferring proteins or genetic material to maintain cell homeostasis, favor cell repair, or even promote angiogenesis. Additionally, exosomes have also been shown to have pro-angiogenic and cardio-protective properties. These beneficial effects, therefore, reveal the potential therapeutical use of EVs in the field of cardiovascular medicine and regenerative therapy. In this review, we will provide an update of cellular processes modulated by EVs of specific interest in the treatment of cardiovascular pathologies. A special focus will be made on the morphogen sonic hedgehog (Shh) associated with EVs (EVsShh+), which have been shown to mediate many pro-angiogenic effects. In addition to offer a potential source of cardiovascular markers, therapeutical potential of EVs reveal exciting opportunities to deliver specific agents by non-immunogenic means to cardiovascular system. PMID:25136343

Pathology Dynamics Predict Spinal Cord Injury Therapeutic Success

PubMed Central

Mitchell, Cassie S.

2008-01-01

Abstract Secondary injury, the complex cascade of cellular events following spinal cord injury (SCI), is a major source of post-insult neuron death. Experimental work has focused on the details of individual factors or mechanisms that contribute to secondary injury, but little is known about the interactions among factors leading to the overall pathology dynamics that underlie its propagation. Prior hypotheses suggest that the pathology is dominated by interactions, with therapeutic success lying in combinations of neuroprotective treatments. In this study, we provide the first comprehensive, system-level characterization of the entire secondary injury process using a novel relational model methodology that aggregates the findings of ~250 experimental studies. Our quantitative examination of the overall pathology dynamics suggests that, while the pathology is initially dominated by “fire-like,” rate-dependent interactions, it quickly switches to a “flood-like,” accumulation-dependent process with contributing factors being largely independent. Our evaluation of ~20,000 potential single and combinatorial treatments indicates this flood-like pathology results in few highly influential factors at clinically realistic treatment time frames, with multi-factor treatments being merely additive rather than synergistic in reducing neuron death. Our findings give new fundamental insight into the understanding of the secondary injury pathology as a whole, provide direction for alternative therapeutic strategies, and suggest that ultimate success in treating SCI lies in the pursuit of pathology dynamics in addition to individually involved factors. PMID:19125684

A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs

PubMed Central

Karlas, Alexander; Berre, Stefano; Couderc, Thérèse; Varjak, Margus; Braun, Peter; Meyer, Michael; Gangneux, Nicolas; Karo-Astover, Liis; Weege, Friderike; Raftery, Martin; Schönrich, Günther; Klemm, Uwe; Wurzlbauer, Anne; Bracher, Franz; Merits, Andres; Meyer, Thomas F.; Lecuit, Marc

2016-01-01

Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents. PMID:27177310

A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.

PubMed

Karlas, Alexander; Berre, Stefano; Couderc, Thérèse; Varjak, Margus; Braun, Peter; Meyer, Michael; Gangneux, Nicolas; Karo-Astover, Liis; Weege, Friderike; Raftery, Martin; Schönrich, Günther; Klemm, Uwe; Wurzlbauer, Anne; Bracher, Franz; Merits, Andres; Meyer, Thomas F; Lecuit, Marc

2016-05-12

Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents.

Salmonella and cancer: from pathogens to therapeutics.

PubMed

Chorobik, Paulina; Czaplicki, Dominik; Ossysek, Karolina; Bereta, Joanna

2013-01-01

Bacterial cancer therapy is a concept more than 100 years old - yet, all things considered, it is still in early development. While the use of many passive therapeutics is hindered by the complexity of tumor biology, bacteria offer unique features that can overcome these limitations. Microbial metabolism, motility and sensitivity can lead to site-specific treatment, highly focused on the tumor and safe to other tissues. Activation of tumor-specific immunity is another important mechanism of such therapies. Several bacterial strains have been evaluated as cancer therapeutics so far, Salmonella Typhimurium being one of the most promising. S. Typhimurium and its derivatives have been used both as direct tumoricidal agents and as cancer vaccine vectors. VNP20009, an attenuated mutant of S. Typhimurium, shows significant native toxicity against murine tumors and was studied in a first-in-man phase I clinical trial for toxicity and anticancer activity. While proved to be safe in cancer patients, insufficient tumor colonization of VNP20009 was identified as a major limitation for further clinical development. Antibody-fragment-based targeting of cancer cells is one of the few approaches proposed to overcome this drawback.

Rheumatoid arthritis patients' experiences of wearing therapeutic footwear - A qualitative investigation

PubMed Central

Williams, Anita E; Nester, Christopher J; Ravey, Michael I

2007-01-01

Background Specialist 'therapeutic' footwear is recommended for patients with diseases such as rheumatoid arthritis (RA) as a beneficial intervention for reducing foot pain, improving foot health, and increasing general mobility. However, many patients choose not to wear this footwear. Recommendations from previous studies have been implemented but have had little impact in improving this situation. The aim of this study was to explore RA patients' experiences of this footwear to ascertain the factors which influence their choice to wear it or not. Method Ten females and three males with RA and experience of wearing specialist footwear were recruited from four National Health Service orthotic services. Semi-structured interviews were carried out in the participants own homes. A hermeneutic phenomenological analysis of the transcripts was carried out to identify themes. Results The analysis revealed two main themes from both the female and male groups. These were the participants' feelings about their footwear and their experiences of the practitioner/s involved in providing the footwear. In addition, further themes were revealed from the female participants. These were feelings about their feet, behaviour associated with the footwear, and their feelings about what would have improved their experience. Conclusion Unlike any other intervention specialist therapeutic footwear replaces something that is normally worn and is part of an individual's body image. It has much more of a negative impact on the female patients' emotions and activities than previously acknowledged and this influences their behaviour with it. The patients' consultations with the referring and dispensing practitioners are pivotal moments within the patient/practitioner relationship that have the potential to influence whether patients choose to wear the footwear or not. PMID:17976235

New ways to analyze word generation performance in brain injury: A systematic review and meta-analysis of additional performance measures.

PubMed

Thiele, Kristina; Quinting, Jana Marie; Stenneken, Prisca

2016-09-01

The investigation of word generation performance is an accepted, widely used, and well-established method for examining cognitive, language, or communication impairment due to brain damage. The performance measure traditionally applied in the investigation of word generation is the number of correct responses. Previous studies, however, have suggested that this measure does not capture all potentially relevant aspects of word generation performance and hence its underlying processes, so that its analytical and explanatory power of word generation performance might be rather limited. Therefore, additional qualitative or quantitative performance measures have been introduced to gain information that goes beyond the deficit and allows for therapeutic implications. We undertook a systematic review and meta-analysis of original research that focused on the application of additional measures of word generation performance in adult clinical populations with acquired brain injury. Word generation tasks are an integral part of many different tests, but only few use additional performance measures in addition to the number of correct responses in the analysis of word generation performance. Additional measures, which showed increased or similar diagnostic utility relative to the traditional performance measure, regarded clustering and switching, error types, and temporal characteristics. The potential of additional performance measures is not yet fully exhausted in patients with brain injury. The temporal measure of response latencies in particular is not adequately represented, though it may be a reliable measure especially for identifying subtle impairments. Unfortunately, there is no general consensus as of yet on which additional measures are best suited to characterizing word generation performance. Further research is needed to specify the additional parameters that are best qualified for identifying and characterizing impaired word generation performance.

Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma.

PubMed

Li, Qi; Wang, Wei; Machino, Yusuke; Yamada, Tadaaki; Kita, Kenji; Oshima, Masanobu; Sekido, Yoshitaka; Tsuchiya, Mami; Suzuki, Yui; Nan-Ya, Ken-ichiro; Iida, Shigeru; Nakamura, Kazuyasu; Iwakiri, Shotaro; Itoi, Kazumi; Yano, Seiji

2015-01-01

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial, or peritoneal lining. Although surgery, chemotherapy, radiotherapy, and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there are no published reports regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant antibody-dependent cellular cytotoxicity activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Virtual High-Throughput Screening To Identify Novel Activin Antagonists

PubMed Central