The Collaborative Assessment and Management of Suicidality (CAMS): An Evolving Evidence-Based Clinical Approach to Suicidal Risk

ERIC Educational Resources Information Center

Jobes, David A.

2012-01-01

The Collaborative Assessment and Management of Suicidality (CAMS) is an evidence-based clinical intervention that has significantly evolved over 25 years of clinical research. CAMS is best understood as a therapeutic framework that emphasizes a unique collaborative assessment and treatment planning process between the suicidal patient and…

Therapeutic Mechanisms of Bile Acids and Nor-Ursodeoxycholic Acid in Non-Alcoholic Fatty Liver Disease.

PubMed

Steinacher, Daniel; Claudel, Thierry; Trauner, Michael

2017-01-01

Non-alcoholic fatty liver disease is one of the most rapidly rising clinical problems in the 21st century. So far no effective drug treatment has been established to cure this disease. Bile acids (BAs) have a variety of signaling properties, which can be used therapeutically for modulating hepatic metabolism and inflammation. A side-chain shorted derivative of ursodeoxycholic acid (UDCA) is 24 nor-ursodeoxycholic acid (NorUDCA) and it represents a new class of drugs for treatment of liver diseases. NorUDCA has unique biochemical and therapeutic properties, since it is relatively resistant to conjugation with glycine or taurine compared to UDCA. NorUDCA undergoes cholehepatic shunting, resulting in ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection. Furthermore, it showed anti-fibrotic, anti-inflammatory, and anti-lipotoxic properties in several animal models. As such, NorUDCA is a promising new approach in the treatment of cholestatic and metabolic liver diseases. This review is a summary of current BA-based therapeutic approaches in the treatment of the fatty liver disease. © 2017 S. Karger AG, Basel.

Oncolytic Viruses: Therapeutics With an Identity Crisis.

PubMed

Breitbach, Caroline J; Lichty, Brian D; Bell, John C

2016-07-01

Oncolytic viruses (OV) are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a "one-size fits all" approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Glioblastoma: new therapeutic strategies to address cellular and genomic complexity

PubMed Central

Cai, Xue; Sughrue, Michael E.

2018-01-01

Glioblastoma (GBM) is the most invasive and devastating primary brain tumor with a median overall survival rate about 18 months with aggressive multimodality therapy. Its unique characteristics of heterogeneity, invasion, clonal populations maintaining stem cell-like cells and recurrence, have limited responses to a variety of therapeutic approaches, and have made GBM the most difficult brain cancer to treat. A great effort and progress has been made to reveal promising molecular mechanisms to target therapeutically. Especially with the emerging of new technologies, the mechanisms underlying the pathology of GBM are becoming more clear. The purpose of this review is to summarize the current knowledge of molecular mechanisms of GBM and highlight the novel strategies and concepts for the treatment of GBM. PMID:29507709

Reconciling the Structural Attributes of Avian Antibodies*

PubMed Central

Conroy, Paul J.; Law, Ruby H. P.; Gilgunn, Sarah; Hearty, Stephen; Caradoc-Davies, Tom T.; Lloyd, Gordon; O'Kennedy, Richard J.; Whisstock, James C.

2014-01-01

Antibodies are high value therapeutic, diagnostic, biotechnological, and research tools. Combinatorial approaches to antibody discovery have facilitated access to unique antibodies by surpassing the diversity limitations of the natural repertoire, exploitation of immune repertoires from multiple species, and tailoring selections to isolate antibodies with desirable biophysical attributes. The V-gene repertoire of the chicken does not utilize highly diverse sequence and structures, which is in stark contrast to the mechanism employed by humans, mice, and primates. Recent exploitation of the avian immune system has generated high quality, high affinity antibodies to a wide range of antigens for a number of therapeutic, diagnostic and biotechnological applications. Furthermore, extensive examination of the amino acid characteristics of the chicken repertoire has provided significant insight into mechanisms employed by the avian immune system. A paucity of avian antibody crystal structures has limited our understanding of the structural consequences of these uniquely chicken features. This paper presents the crystal structure of two chicken single chain fragment variable (scFv) antibodies generated from large libraries by phage display against important human antigen targets, which capture two unique CDRL1 canonical classes in the presence and absence of a non-canonical disulfide constrained CDRH3. These structures cast light on the unique structural features of chicken antibodies and contribute further to our collective understanding of the unique mechanisms of diversity and biochemical attributes that render the chicken repertoire of particular value for antibody generation. PMID:24737329

Psychologically informed physiotherapy for chronic pain: patient experiences of treatment and therapeutic process.

PubMed

Wilson, S; Chaloner, N; Osborn, M; Gauntlett-Gilbert, J

2017-03-01

Psychologically informed physiotherapy is used widely with patients with chronic pain. This study aimed to investigate patients' beliefs about, and experiences of, this type of treatment, and helpful and unhelpful experiences. A qualitative study using Interpretative Phenomenological Analysis of semi-structured interviews. Participants (n=8) were recruited within a national specialist pain centre following a residential pain management programme including 2.25hours of physiotherapy each day. Participants were eligible for inclusion if they had achieved clinically reliable improvements in physical functioning during treatment. Interviews were conducted 3 months post-treatment. Participants reported differing experiences of physiotherapy interventions and differences in the therapeutic relationship, valuing a more individualised approach. The themes of 'working with the whole of me', 'more than just a professional', 'awareness' and 'working through challenges in the therapeutic relationship' emerged as central to behavioural change, together with promotion of perceptions of improved capability and physical capacity. Psychologically informed physiotherapy is an effective treatment for some patients with chronic pain. Participants experienced this approach as uniquely different from non-psychologically informed physiotherapy approaches due to its focus on working with the patient's whole experience. Therapeutic alliance and management of relationship ruptures may have more importance than previously appreciated in physiotherapy. Copyright © 2016 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

The Effects of Curriculum in Motion on Reading Scores for Male Students with Attention Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Pritchard, Jan Teena

2013-01-01

The most basic and fundamental skill for academic success is the ability to read. The purpose of this 1-group pretest and posttest pre-experimental quantitative study was to investigate how a unique instructional approach, called "curriculum in motion" with an emphasis on therapeutic martial arts and Brain Gym exercises influenced…

Molecular Approaches to Sarcoma Therapy

PubMed Central

Olsen, R. J.; Tarantolo, S. R.

2002-01-01

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed. PMID:18521343

Gingival Mesenchymal Stem/Progenitor Cells: A Unique Tissue Engineering Gem

PubMed Central

Fawzy El-Sayed, Karim M.; Dörfer, Christof E.

2016-01-01

The human gingiva, characterized by its outstanding scarless wound healing properties, is a unique tissue and a pivotal component of the periodontal apparatus, investing and surrounding the teeth in their sockets in the alveolar bone. In the last years gingival mesenchymal stem/progenitor cells (G-MSCs), with promising regenerative and immunomodulatory properties, have been isolated and characterized from the gingival lamina propria. These cells, in contrast to other mesenchymal stem/progenitor cell sources, are abundant, readily accessible, and easily obtainable via minimally invasive cell isolation techniques. The present review summarizes the current scientific evidence on G-MSCs' isolation, their characterization, the investigated subpopulations, the generated induced pluripotent stem cells- (iPSC-) like G-MSCs, their regenerative properties, and current approaches for G-MSCs' delivery. The review further demonstrates their immunomodulatory properties, the transplantation preconditioning attempts via multiple biomolecules to enhance their attributes, and the experimental therapeutic applications conducted to treat multiple diseases in experimental animal models in vivo. G-MSCs show remarkable tissue reparative/regenerative potential, noteworthy immunomodulatory properties, and primary experimental therapeutic applications of G-MSCs are very promising, pointing at future biologically based therapeutic techniques, being potentially superior to conventional clinical treatment modalities. PMID:27313628

Exploring 'new' bioactivities of polymers at the nano-bio interface.

PubMed

Wang, Chunming; Dong, Lei

2015-01-01

A biological system is essentially an elegant assembly of polymeric nanostructures. The polymers in the body, biomacromolecules, are both building blocks and versatile messengers. We propose that non-biologically derived polymers can be potential therapeutic candidates with unique advantages. Emerging findings about polycations, polysaccharides, immobilised multivalent ligands, and biomolecular coronas provide evidence that polymers are activated at the nano-bio interface, while emphasising the current theoretical and practical challenges. Our increasing understanding of the nano-bio interface and evolving approaches to establish the therapeutic potential of polymers enable the development of polymer drugs with high specificities for broad applications. Copyright © 2014 Elsevier Ltd. All rights reserved.

Targeting therapeutics to the glomerulus with nanoparticles.

PubMed

Zuckerman, Jonathan E; Davis, Mark E

2013-11-01

Nanoparticles are an enabling technology for the creation of tissue-/cell-specific therapeutics that have been investigated extensively as targeted therapeutics for cancer. The kidney, specifically the glomerulus, is another accessible site for nanoparticle delivery that has been relatively overlooked as a target organ. Given the medical need for the development of more potent, kidney-targeted therapies, the use of nanoparticle-based therapeutics may be one such solution to this problem. Here, we review the literature on nanoparticle targeting of the glomerulus. Specifically, we provide a broad overview of nanoparticle-based therapeutics and how the unique structural characteristics of the glomerulus allow for selective, nanoparticle targeting of this area of the kidney. We then summarize literature examples of nanoparticle delivery to the glomerulus and elaborate on the appropriate nanoparticle design criteria for glomerular targeting. Finally, we discuss the behavior of nanoparticles in animal models of diseased glomeruli and review examples of nanoparticle therapeutic approaches that have shown promise in animal models of glomerulonephritic disease. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Supporting families of parents with mental illness in general practice.

PubMed

Baulderstone, Michaela J; Morgan, Bradley S; Fudge, Elizabeth A

2013-08-05

The general-practice setting provides a unique opportunity to positively influence the impact of mental illness on individuals and families. Intervention can begin from the moment an individual seeks professional help. Using a family-focused approach, and supporting parents to develop practical strategies to promote resilience in their children, can aid parents' recovery and promote the optimal emotional wellbeing of their children. We suggest a family-orientated therapeutic approach relevant to the general-practice setting, with particular consideration of the value of communicating with children according to the child's stage of emotional development.

HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression.

PubMed

Keith, Brian; Johnson, Randall S; Simon, M Celeste

2011-12-15

Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.

Antioxidant gene therapy against neuronal cell death

PubMed Central

Navarro-Yepes, Juliana; Zavala-Flores, Laura; Annadurai, Anandhan; Wang, Fang; Skotak, Maciej; Chandra, Namas; Li, Ming; Pappa, Aglaia; Martinez-Fong, Daniel; Razo, Luz Maria Del; Quintanilla-Vega, Betzabet; Franco, Rodrigo

2014-01-01

Oxidative stress is a common hallmark of neuronal cell death associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, as well as brain stroke/ischemia and traumatic brain injury. Increased accumulation of reactive species of both oxygen (ROS) and nitrogen (RNS) has been implicated in mitochondrial dysfunction, energy impairment, alterations in metal homeostasis and accumulation of aggregated proteins observed in neurodegenerative disorders, which lead to the activation/modulation of cell death mechanisms that include apoptotic, necrotic and autophagic pathways. Thus, the design of novel antioxidant strategies to selectively target oxidative stress and redox imbalance might represent important therapeutic approaches against neurological disorders. This work reviews the evidence demonstrating the ability of genetically encoded antioxidant systems to selectively counteract neuronal cell loss in neurodegenerative diseases and ischemic brain damage. Because gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches, we discussed basic research/clinical evidence and the potential of virus-mediated gene delivery techniques for antioxidant gene therapy. PMID:24333264

Non-Duality, Simplicity and the Chong Mai

PubMed Central

2018-01-01

Abstract Chinese Medicine (CM) suggests that the root of all disease lies in separation from the Tao, which occurs when Yin and Yang differentiate. Chong Mai–focused acupuncture can theoretically address this level, but an adjusted therapeutic approach could be necessary to produce the best results. In this article, the author explores some context and needling strategies used to work effectively with the Chong Mai in a unique way. PMID:29410715

Recent Development of Anticancer Therapeutics Targeting Akt

PubMed Central

Morrow, John K.; Du-Cuny, Lei; Chen, Lu; Meuillet, Emmanuelle J.; Mash, Eugene A.; Powis, Garth; Zhang, Shuxing

2013-01-01

The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellular translocation, a kinase domain with serine/threonine specificity, and a C-terminal extension domain. These well defined regions have been targeted, and various approaches, including in silico methods, have been implemented to develop Akt inhibitors. In spite of unique techniques and a prolific body of knowledge surrounding Akt, no targeted Akt therapeutics have reached the market yet. Here we will highlight successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents as well as discuss the methods employed for this task. Special attention will be given to patents with focus on those discoveries using computer-aided drug design approaches. PMID:21110830

Hyperthyroidism and pregnancy.

PubMed

Gargallo Fernández, Manuel

2013-11-01

Association of hyperthyroidism and pregnancy is not an unusual event, and has an impact on both the mother and fetus. After delivery, it may also affect the newborn and the nursing mother. Clinical management of this situation is quite different from that required by non-pregnant hyperthyroid women and poses significant diagnostic and therapeutic challenges. This review addresses aspects related to the unique characteristics of biochemical assessment of thyroid function in pregnancy, the potential causes of hyperthyroidism in pregnancy, and the clinical and therapeutic approach in each case. Special attention is paid to pregnancy complicated with Graves' disease and its different the maternal, fetal, neonatal, and postnatal consequences. Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.

Therapeutic interventions for hypertension in metabolic syndrome: a comprehensive approach.

PubMed

Ganne, Sudha; Arora, Surender; Karam, Jocelyne; McFarlane, Samy I

2007-03-01

Hypertension is a major component of the metabolic syndrome and a major cardiovascular risk factor. Both disorders are rapidly increasing in frequency, with hypertension affecting nearly 60 million Americans and over 1 billion people worldwide, and metabolic syndrome affecting 44% of the US population above the age of 60 years. Sedentary lifestyle, together with obesity and aging of the population, are the major contributing factors for this growing epidemic. Hypertension in metabolic syndrome possesses unique pathophysiological aspects that have considerable implications on therapy of this disease. In this article, we review the pathophysiology and provide a rationale for the current therapeutic options in light of the most recent clinical trials in the field.

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development.

PubMed

Burt, T; Yoshida, K; Lappin, G; Vuong, L; John, C; de Wildt, S N; Sugiyama, Y; Rowland, M

2016-04-01

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. All phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.

Nanoparticle agglomerates of fluticasone propionate in combination with albuterol sulfate as dry powder aerosols

PubMed Central

El-Gendy, Nashwa; Pornputtapitak, Warangkana; Berkland, Cory

2015-01-01

Particle engineering strategies remain at the forefront of aerosol research for localized treatment of lung diseases and represent an alternative for systemic drug therapy. With the hastily growing popularity and complexity of inhalation therapy, there is a rising demand for tailor-made inhalable drug particles capable of affording the most proficient delivery to the lungs and the most advantageous therapeutic outcomes. To address this formulation demand, nanoparticle agglomeration was used to develop aerosols of the asthma therapeutics, fluticasone or albuterol. In addition, a combination aerosol was formed by drying agglomerates of fluticasone nanoparticles in the presence of albuterol in solution. Powders of the single drug nanoparticle agglomerates or of the combined therapeutics possessed desirable aerodynamic properties for inhalation. Powders were efficiently aerosolized (~75% deposition determined by cascade impaction) with high fine particle fraction and rapid dissolution. Nanoparticle agglomeration offers a unique approach to obtain high performance aerosols from combinations of asthma therapeutics. PMID:21964203

State-of-the-art considerations in small cell lung cancer brain metastases

PubMed Central

Lukas, Rimas V.; Gondi, Vinai; Kamson, David O.; Kumthekar, Priya; Salgia, Ravi

2017-01-01

Background Small cell lung cancer (SCLC) frequently leads to development of brain metastases. These unfortunately continue to be associated with short survival. Substantial advances have been made in our understanding of the underlying biology of disease. This understanding on the background of previously evaluated and currently utilized therapeutic treatments can help guide the next steps in investigations into this disease with the potential to influence future treatments. Design A comprehensive review of the literature covering epidemiology, pathophysiology, imaging characteristics, prognosis, and therapeutic management of SCLC brain metastases was performed. Results SCLC brain metastases continue to have a poor prognosis. Both unique aspects of SCLC brain metastases as well as features seen more universally across other solid tumor brain metastases are discussed. Systemic therapeutic studies and radiotherapeutic approaches are reviewed. Conclusions A clearer understanding of SCLC brain metastases will help lay the framework for studies which will hopefully translate into meaningful therapeutic options for these patients. PMID:29050358

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 harmonized approach supported by apposite regulatory frameworks and pertinent expertise throughout the respective stages of the adoption cycle to facilitate the adoption of new products and technologies in the industry.

Biophotonic techniques for manipulation and characterization of drug delivery nanosystems in cancer therapy.

PubMed

Spyratou, E; Makropoulou, M; Mourelatou, E A; Demetzos, C

2012-12-31

Reactive oxygen species (ROS) are usually involved in two opposite procedures related to cancer: initiation, progression and metastasis of cancer, as well as in all non-surgical therapeutic approaches for cancer, including chemotherapy, radiotherapy and photodynamic therapy. This review is concentrated in new therapeutic strategies that take advantage of increased ROS in cancer cells to enhance therapeutic activity and selectivity. Novel biophotonic techniques for manipulation and characterization of drug delivery nanosystems in cancer therapy are discussed, including optical tweezers and atomic force microscopy. This review highlights how these techniques are playing a critical role in recent and future cancer fighting applications. We can conclude that Biophotonics and nanomedicine are the future for cancer biology and disease management, possessing unique potential for early detection, accurate diagnosis, dosimetry and personalized treatment of biomedical applications targeting cancer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

"What Do You Think We Should Do?": Relationship and Reflexivity in Participant Observation.

PubMed

Elliot, Michelle L

2015-07-01

This article uses three concepts as a framework by which to examine how the interrelational elements of ethnographic approaches to qualitative inquiry reflect dimensions of therapeutic engagement. Participant observation, reflexivity, and context are all widely and routinely included within research methods; however, they are less frequently attended to directly in their experiential capacity through the lens of the researcher, clinician turned investigator. A unique study design will be profiled to reflect the complicated juxtaposition between methods, questions, sample population, time, space, and identity. Studying occupational therapy students traveling abroad for a short-term immersion experience, this narrative study called on a necessary and attentive awareness of locality as the researcher traveled with the group. Conducting ethnographic research where the researcher's therapeutic skills aided and constrained relationships resulted in rich, guarded, and relevant insights that parallel the therapeutic use of self in occupational therapy practice.

[Psychoanalysis and Side Effect].

PubMed

Shirahase, Joichiro

2015-01-01

A study of psychoanalysis from the perspective of side effects reveals that its history was a succession of measures to deal with its own side effects. This, however, does not merely suggest that, as a treatment method, psychoanalysis is incomplete and weak: rather, its history is a record of the growth and development of psychoanalysis that discovered therapeutic significance from phenomena that were initially regarded as side effects, made use of these discoveries, and elaborated them as a treatment method. The approach of research seen during the course of these developments is linked to the basic therapeutic approach of psychoanalysis. A therapist therefore does not draw conclusions about a patient's words and behaviors from a single aspect, but continues to make efforts to actively discover a variety of meanings and values from them, and to make the patient's life richer and more productive. This therapeutic approach is undoubtedly one of the unique aspects of psychoanalysis. I discuss the issue of psychoanalysis and side effects with the aim of clarifying this unique characteristic of psychoanalysis. The phenomenon called resistance inevitably emerges during the process of psychoanalytic treatment. Resistance can not only obstruct the progress of therapy; it also carries the risk of causing a variety of disadvantages to the patient. It can therefore be seen as an adverse effect. However, if we re-examine this phenomenon from the perspective of transference, we find that resistance is in fact a crucial tool in psychoanalysis, and included in its main effect, rather than a side effect. From the perspective of minimizing the character of resistance as a side effect and maximizing its character as a main effect, I have reviewed logical organization, dynamic evaluation, the structuring of treatment, the therapist's attitudes, and the training of therapists. I conclude by stating that psychoanalysis has aspects that do not match the perspective known as a side effect.

Brain Metastasis: Unique Challenges and Open Opportunities

PubMed Central

Lowery, Frank J.; Yu, Dihua

2016-01-01

The metastasis of cancer to the central nervous system (CNS) remains a devastating clinical reality, carrying an estimated survival time of less than one year in spite of recent therapeutic breakthroughs for other disease contexts. Advances in brain metastasis research are hindered by a number of reasons, including its complicated nature and the difficulty of modeling metastatic cancer growth in the unique brain microenvironment. In this review, we will discuss the clinical challenge, and compare the values and limitations of the available models for brain metastasis research. Additionally, we will specifically address current knowledge on how brain metastases take advantage of the unique brain environment to benefit their own growth. Finally, we will explore the distinctive metabolic and nutrient characteristics of the brain; how these paradoxically represent barriers to establishment of brain metastasis, but also provide ample supplies for metastatic cells’ growth in the brain. We envision that multi-disciplinary innovative approaches will open opportunities for the field to make breakthroughs in tackling unique challenges of brain metastasis. PMID:27939792

Protein and peptide-based therapeutics in periodontal regeneration.

PubMed

Reynolds, Mark A; Aichelmann-Reidy, Mary E

2012-09-01

Protein and peptide-based therapeutics provide a unique strategy for controlling highly specific and complex biologic actions that cannot be accomplished by simple devices or chemical compounds. This article reviews some of the key characteristics and summarizes the clinical effectiveness of protein and peptide-based therapeutics targeting periodontal regeneration. A literature search was conducted of randomized clinical trials and systematic reviews evaluating protein and peptide-based therapeutics for the regeneration of periodontal tissues of at least 6 months duration. Data sources included PubMed and Embase electronic databases, hand-searched journals, and the ClinicalTrials.gov registry. Commercially marketed protein and peptide-based therapeutics for periodontal regeneration provide gains in clinical attachment level and bone formation that are comparable or superior to other regenerative approaches. Results from several clinical trials indicate that protein and peptide-based therapies can accelerate repair and regeneration when compared with other treatments and that improvements in clinical parameters continue beyond 12 months. Protein and peptide-based therapies also exhibit the capacity to increase the predictability of treatment outcomes. Clinical and histologic studies support the effectiveness of protein- and peptide-based therapeutics for periodontal regeneration. Emerging evidence suggests that the delivery devices/scaffolds play a critical role in determining the effectiveness of this class of therapeutics. Copyright © 2012 Elsevier Inc. All rights reserved.

Role of Transient Receptor Potential Channels in Heart Transplantation: A Potential Novel Therapeutic Target for Cardiac Allograft Vasculopathy.

PubMed

Ma, Shuo; Jiang, Yue; Huang, Weiting; Li, Xintao; Li, Shuzhuang

2017-05-18

Heart transplantation has evolved as the criterion standard therapy for end-stage heart failure, but its efficacy is limited by the development of cardiac allograft vasculopathy (CAV), a unique and rapidly progressive form of atherosclerosis in heart transplant recipients. Here, we briefly review the key processes in the development of CAV during heart transplantation and highlight the roles of transient receptor potential (TRP) channels in these processes during heart transplantation. Understanding the roles of TRP channels in contributing to the key procedures for the development of CAV during heart transplantation could provide basic scientific knowledge for the development of new preventive and therapeutic approaches to manage patients with CAV after heart transplantation.

Nanoscale porosity in polymer films: fabrication and therapeutic applications

PubMed Central

Bernards, Daniel A.; Desai, Tejal A.

2011-01-01

This review focuses on current developments in the field of nanostructured bulk polymers and their application in bioengineering and therapeutic sciences. In contrast to well-established nanoscale materials, such as nanoparticles and nanofibers, bulk nanostructured polymers combine nanoscale structure in a macroscopic construct, which enables unique application of these materials. Contemporary fabrication and processing techniques capable of producing nanoporous polymer films are reviewed. Focus is placed on techniques capable of sub-100 nm features since this range approaches the size scale of biological components, such as proteins and viruses. The attributes of these techniques are compared, with an emphasis on the characteristic advantages and limitations of each method. Finally, application of these materials to biofiltration, immunoisolation, and drug delivery are reviewed. PMID:22140398

MagnetofectionTM platform: from magnetic nanoparticles to novel nucleic acid therapeutics.

PubMed

Plank, Christian; Vlaskou, Dialechti; Schillinger, Ulrike; Mykhaylyk, Olga

2011-06-01

Nucleic acid delivery to cells to make them produce a desired protein or to shut down the expression of endogenous genes opens unique possibilities for research and therapy. During the last decade, to realize the potential of this approach, nanomagnetic methods for delivering and targeting nucleic acids have been developed, methods which are often referred to as Magnetofection. Our research group at the Institute of Experimental Oncology and Therapy Research, located at the University Hospital Klinikum rechts der Isar in the center of Munich, Germany, develops new magnetic nanomaterials and, their formulations with gene-delivery vectors and technologies to allow localized and efficient gene delivery in vitro and in vivo for a variety of research, diagnostic and therapeutic applications.

Long-Term Delivery of Protein Therapeutics

PubMed Central

Vaishya, Ravi; Khurana, Varun; Patel, Sulabh; Mitra, Ashim K

2015-01-01

Introduction Proteins are effective biotherapetics with applications in diverse ailments. Despite being specific and potent, their full clinical potential has not yet been realized. This can be attributed to short half-lives, complex structures, poor in vivo stability, low permeability frequent parenteral administrations and poor adherence to treatment in chronic diseases. A sustained release system, providing controlled release of proteins, may overcome many of these limitations. Areas covered This review focuses on recent development in approaches, especially polymer-based formulations, which can provide therapeutic levels of proteins over extended periods. Advances in particulate, gel based formulations and novel approaches for extended protein delivery are discussed. Emphasis is placed on dosage form, method of preparation, mechanism of release and stability of biotherapeutics. Expert opinion Substantial advancements have been made in the field of extended protein delivery via various polymer-based formulations over last decade despite the unique delivery-related challenges posed by protein biologics. A number of injectable sustained-release formulations have reached market. However, therapeutic application of proteins is still hampered by delivery related issues. A large number of protein molecules are under clinical trials and hence there is an urgent need to develop new methods to deliver these highly potent biologics. PMID:25251334

Long-term delivery of protein therapeutics.

PubMed

Vaishya, Ravi; Khurana, Varun; Patel, Sulabh; Mitra, Ashim K

2015-03-01

Proteins are effective biotherapeutics with applications in diverse ailments. Despite being specific and potent, their full clinical potential has not yet been realized. This can be attributed to short half-lives, complex structures, poor in vivo stability, low permeability, frequent parenteral administrations and poor adherence to treatment in chronic diseases. A sustained release system, providing controlled release of proteins, may overcome many of these limitations. This review focuses on recent development in approaches, especially polymer-based formulations, which can provide therapeutic levels of proteins over extended periods. Advances in particulate, gel-based formulations and novel approaches for extended protein delivery are discussed. Emphasis is placed on dosage form, method of preparation, mechanism of release and stability of biotherapeutics. Substantial advancements have been made in the field of extended protein delivery via various polymer-based formulations over last decade despite the unique delivery-related challenges posed by protein biologics. A number of injectable sustained-release formulations have reached market. However, therapeutic application of proteins is still hampered by delivery-related issues. A large number of protein molecules are under clinical trials, and hence, there is an urgent need to develop new methods to deliver these highly potent biologics.

Antibody-mediated delivery of therapeutics for cancer therapy.

PubMed

Parakh, Sagun; Parslow, Adam C; Gan, Hui K; Scott, Andrew M

2016-01-01

Antibody-conjugated therapies (ACTs) combine the specificity of monoclonal antibodies to target cancer cells directly with highly potent payloads, often resulting in superior efficacy and/or reduced toxicity. This represents a new approach to the treatment of cancer. There have been highly promising clinical trial results using this approach with improvements in linker and payload technology. The breadth of current trials examining ACTs in haematological malignancies and solid tumours indicate the potential for clinical impact. This review will provide an overview of ACTs currently in clinical development as well as the principles of antibody delivery and types of payloads used, including cytotoxic drugs, radiolabelled isotopes, nanoparticle-based siRNA particles and immunotoxins. The focus of much of the clinical activity in ACTs has, understandably, been on their use as a monotherapy or in combination with standard of care drugs. This will continue, as will the search for better targets, linkers and payloads. Increasingly, as these drugs enter routine clinical care, important questions will arise regarding how to optimise ACT treatment approaches, including investigation of resistance mechanisms, biomarker and patient selection strategies, understanding of the unique toxicities of these drugs, and combinatorial approaches with standard therapies as well as emerging therapeutic agents like immunotherapy.

New strategies in glioblastoma: exploiting the new biology.

PubMed

Fine, Howard A

2015-05-01

Glioblastoma is one of the deadliest human cancers. There have been few significant therapeutic advances in the field over the past two decades, with median survival of only about 15 months despite aggressive neurosurgery, radiotherapy, and chemotherapy. Nevertheless, the past 5 years has seen an explosion in our understanding of the genetic and molecular underpinnings of these tumors, leading to renewed optimism about potential new therapeutic approaches. Several of the most promising new approaches include oncogenic signal transduction inhibition, angiogenesis inhibition, targeting canonical stem cell pathways in glioblastoma stem cells, and immunotherapy. As promising as many of these approaches appear, they have not had an impact yet on the natural history of the disease or on patient long-term outcomes. Nevertheless, it is hoped that with time such approaches will lead to more effective treatments, but issues such as the unique biology and anatomy of the central nervous system, impaired drug delivery, poor preclinical models with resultant nonpredictive preclinical screening, and poor clinical trial design potentially impede the rapid development of such new therapies. In this article, we review the excitement and challenges that face the development of effective new treatments that exploit this new biology. ©2015 American Association for Cancer Research.

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

DOE PAGES

Burt, T.; Yoshida, K.; Lappin, G.; ...

2016-02-26

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications andmore » design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. Lastly, all phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.« less

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

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

Burt, T.; Yoshida, K.; Lappin, G.

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications andmore » design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. Lastly, all phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.« less

Optogenetic Light Crafting Tools for the Control of Cardiac Arrhythmias.

PubMed

Richter, Claudia; Christoph, Jan; Lehnart, Stephan E; Luther, Stefan

2016-01-01

The control of spatiotemporal dynamics in biological systems is a fundamental problem in nonlinear sciences and has important applications in engineering and medicine. Optogenetic tools combined with advanced optical technologies provide unique opportunities to develop and validate novel approaches to control spatiotemporal complexity in neuronal and cardiac systems. Understanding of the mechanisms and instabilities underlying the onset, perpetuation, and control of cardiac arrhythmias will enable the development and translation of novel therapeutic approaches. Here we describe in detail the preparation and optical mapping of transgenic channelrhodopsin-2 (ChR2) mouse hearts, cardiac cell cultures, and the optical setup for photostimulation using digital light processing.

Generation of “LYmph Node Derived Antibody Libraries” (LYNDAL) for selecting fully human antibody fragments with therapeutic potential

PubMed Central

Diebolder, Philipp; Keller, Armin; Haase, Stephanie; Schlegelmilch, Anne; Kiefer, Jonathan D; Karimi, Tamana; Weber, Tobias; Moldenhauer, Gerhard; Kehm, Roland; Eis-Hübinger, Anna M; Jäger, Dirk; Federspil, Philippe A; Herold-Mende, Christel; Dyckhoff, Gerhard; Kontermann, Roland E; Arndt, Michaela AE; Krauss, Jürgen

2014-01-01

The development of efficient strategies for generating fully human monoclonal antibodies with unique functional properties that are exploitable for tailored therapeutic interventions remains a major challenge in the antibody technology field. Here, we present a methodology for recovering such antibodies from antigen-encountered human B cell repertoires. As the source for variable antibody genes, we cloned immunoglobulin G (IgG)-derived B cell repertoires from lymph nodes of 20 individuals undergoing surgery for head and neck cancer. Sequence analysis of unselected “LYmph Node Derived Antibody Libraries” (LYNDAL) revealed a naturally occurring distribution pattern of rearranged antibody sequences, representing all known variable gene families and most functional germline sequences. To demonstrate the feasibility for selecting antibodies with therapeutic potential from these repertoires, seven LYNDAL from donors with high serum titers against herpes simplex virus (HSV) were panned on recombinant glycoprotein B of HSV-1. Screening for specific binders delivered 34 single-chain variable fragments (scFvs) with unique sequences. Sequence analysis revealed extensive somatic hypermutation of enriched clones as a result of affinity maturation. Binding of scFvs to common glycoprotein B variants from HSV-1 and HSV-2 strains was highly specific, and the majority of analyzed antibody fragments bound to the target antigen with nanomolar affinity. From eight scFvs with HSV-neutralizing capacity in vitro, the most potent antibody neutralized 50% HSV-2 at 4.5 nM as a dimeric (scFv)2. We anticipate our approach to be useful for recovering fully human antibodies with therapeutic potential. PMID:24256717

Generation of “LYmph Node Derived Antibody Libraries” (LYNDAL) for selecting fully human antibody fragments with therapeutic potential.

PubMed

Diebolder, Philipp; Keller, Armin; Haase, Stephanie; Schlegelmilch, Anne; Kiefer, Jonathan D; Karimi, Tamana; Weber, Tobias; Moldenhauer, Gerhard; Kehm, Roland; Eis-Hübinger, Anna M; Jäger, Dirk; Federspil, Philippe A; Herold-Mende, Christel; Dyckhoff, Gerhard; Kontermann, Roland E; Arndt, Michaela A E; Krauss, Jürgen

2014-01-01

The development of efficient strategies for generating fully human monoclonal antibodies with unique functional properties that are exploitable for tailored therapeutic interventions remains a major challenge in the antibody technology field. Here, we present a methodology for recovering such antibodies from antigen-encountered human B cell repertoires. As the source for variable antibody genes, we cloned immunoglobulin G (IgG)-derived B cell repertoires from lymph nodes of 20 individuals undergoing surgery for head and neck cancer. Sequence analysis of unselected “LYmph Node Derived Antibody Libraries” (LYNDAL) revealed a naturally occurring distribution pattern of rearranged antibody sequences, representing all known variable gene families and most functional germline sequences. To demonstrate the feasibility for selecting antibodies with therapeutic potential from these repertoires, seven LYNDAL from donors with high serum titers against herpes simplex virus (HSV) were panned on recombinant glycoprotein B of HSV-1. Screening for specific binders delivered 34 single-chain variable fragments (scFvs) with unique sequences. Sequence analysis revealed extensive somatic hypermutation of enriched clones as a result of affinity maturation. Binding of scFvs to common glycoprotein B variants from HSV-1 and HSV-2 strains was highly specific, and the majority of analyzed antibody fragments bound to the target antigen with nanomolar affinity. From eight scFvs with HSV-neutralizing capacity in vitro,the most potent antibody neutralized 50% HSV-2 at 4.5 nM as a dimeric (scFv)2. We anticipate our approach to be useful for recovering fully human antibodies with therapeutic potential.

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

PubMed Central

Moreno, Paola; Ramos-Álvarez, Irene; Moody, Terry W.; Jensen, Robert T.

2016-01-01

Introduction Despite remarkable advances in tumor treatment, many patients still die from common tumors (breast, prostate, lung, CNS, colon, and pancreas), and thus, new approaches are needed. Many of these tumors synthesize bombesin (Bn)-related peptides and over-express their receptors (BnRs), hence functioning as autocrine-growth-factors. Recent studies support the conclusion that Bn-peptides/BnRs are well-positioned for numerous novel antitumor treatments, including interrupting autocrine-growth via the use of over-expressed receptors for imaging and targeting cytotoxic-compounds, either by direct-coupling or combined with nanoparticle-technology. Areas covered The unique ability of common neoplasms to synthesize, secrete, and show a growth/proliferative/differentiating response due to BnR over-expression, is reviewed, both in general and with regard to the most frequently investigated neoplasms (breast, prostate, lung, and CNS). Particular attention is paid to advances in the recent years. Also considered are the possible therapeutic approaches to the growth/differentiation effect of Bn-peptides, as well as the therapeutic implication of the frequent BnR over-expression for tumor-imaging and/or targeted-delivery. Expert opinion Given that Bn-related-peptides/BnRs are so frequently ectopically-expressed by common tumors, which are often malignant and become refractory to conventional treatments, therapeutic interventions using novel approaches to Bn-peptides and receptors are being explored. Of particular interest is the potential of reproducing BnRs in common tumors, such as the recent success of utilizing overexpression of somatostatin-receptors by neuroendocrine-tumors to provide the most sensitive imaging methods and targeted delivery of cytotoxic-compounds. PMID:26981612

INSULIN RESISTANCE POST-BURN: UNDERLYING MECHANISMS AND CURRENT THERAPEUTIC STRATEGIES

PubMed Central

Gauglitz, Gerd G.; Herndon, David N.; Jeschke, Marc G.

2014-01-01

The profound hypermetabolic response to burn injury is associated with insulin resistance and hyperglycemia, significantly contributing to the incidence of morbidity and mortality in this patient population. These responses are present in all trauma, surgical, or critically ill patients, but the severity, length, and magnitude is unique for burn patients. Although advances in therapeutic strategies to attenuate the post-burn hypermetabolic response have significantly improved the clinical outcome of these patients over the past years, therapeutic approaches to overcome stress-induced hyperglycemia have remained challenging. Intensive insulin therapy has been shown to significantly reduce morbidity and mortality in critically ill patients. High incidence of hypoglycemic events and difficult blood glucose titrations have led to investigation of alternative strategies, including the use of metformin, a biguanide, or fenofibrate, a PPAR-γ agonist. Nevertheless, weaknesses and potential side affects of these drugs reinforces the need for better understanding of the molecular mechanisms underlying insulin resistance post-burn that may lead to novel therapeutic strategies further improving the prognosis of these patients. This review aims to discuss the mechanisms underlying insulin resistance induced hyperglycemia post-burn and outlines current therapeutic strategies that are being used to modulate hyperglycemia following thermal trauma. PMID:18695610

Hydrotherapy combined with Snoezelen multi-sensory therapy.

PubMed

Lavie, Efrat; Shapiro, Michele; Julius, Mona

2005-01-01

The aim of this article is to present a new and challenging model of treatment that combines two therapeutic interventions: hydrotherapy and Snoezelen or controlled multisensory stimulation. The combination of the two therapeutic approaches enhances the treatment effect by utilizing the unique characteristics of each approach. We believe that this combined model will further enhance each media to the benefit of the clients and create a new intervention approach. This article relates to a hydrotherapy swimming pool facility that has been established at the Williams Island Therapeutic Swimming and Recreation Center, Beit Issie Shapiro, Raanana in Israel, after acquiring many years of experience and gaining substantial knowledge both in the field of hydrotherapy and Snoezelen intervention. Beit Issie Shapiro is a non-profit community organization providing a range of services for children with developmental disabilities and their families. The organization provides direct services for nearly 6,000 children and adults each year. This article provides an overview of hydrotherapy and Snoezelen and presents a case study, which will demonstrate the new model of treatment and show how this new and innovative form of therapy can be used as a successful intervention. We believe it will open a path to enriching the repertoire of therapists helping people with special needs. This article is also addressed to researchers to provide ideas for further studies in this area.

Cytoreductive nephrectomy vs medical therapy as initial treatment: a rational approach to the sequence question in metastatic renal cell carcinoma.

PubMed

Spiess, Philippe E; Fishman, Mayer N

2010-10-01

Renal cell carcinoma (RCC) can be considered as two distinct entities: localized and metastatic disease. We conducted a review of the scientific literature published within the past decade pertaining to cytoreductive nephrectomy for metastatic RCC. Retrospective data and historical prospective series have demonstrated the survival benefit of debulking nephrectomy in well-selected RCC patients. New medical therapies, including vascular endothelial growth factor and mTOR pathway blocking drugs, are active biological agents, with survival improvement and potential regression of metastatic and primary tumors. Our current therapeutic challenge is the optimal integration of multimodal therapy consisting of systemic therapy and surgery including cytoreductive nephrectomy, debulking, and metastasectomy. Empiric data to guide this decision are limited. The decision concerning whether medical or surgical therapy should be the primary treatment approach selected must be made on an individual basis, taking into account patient performance status, clinical parameters, and physician expertise and recommendations, thus making each case a unique therapeutic challenge.

A unique case of magnet ingestion with respect to presentation and management.

PubMed

Yalçin, Sule; Karnak, Ibrahim; Ekinci, Saniye; Senocak, Mehmet Emin

2012-01-01

Magnet ingestion may lead to serious complications with delay in diagnosis and treatment. The forceful attraction between magnets, with gastric and/or intestinal wall entrapped between them, can cause injury through pressure necrosis. The radiological appearance of more than one magnet on X-ray can be easily misinterpreted as belonging to only one rod-like radiopaque foreign body, even if the magnets are located in different parts of the gastrointestinal tract, thus delaying the management up to the onset of emergent surgical complications. A 17-month-old female with ingestion of a pair of magnets is presented, together with introduction of the clinical picture and therapeutic approach, which differed from the other previously reported cases. The ovoid shape of the magnets, their localization in the gastrointestinal tract (leading to entrapped gastric and intestinal wall between them), absence of any complication, and the therapeutic approach of endoscopic retrieval are the main distinguishing features of this case from those previously reported.

Nanotechnology based approaches in cancer therapeutics

NASA Astrophysics Data System (ADS)

Kumer Biswas, Amit; Reazul Islam, Md; Sadek Choudhury, Zahid; Mostafa, Asif; Fahim Kadir, Mohammad

2014-12-01

The current decades are marked not by the development of new molecules for the cure of various diseases but rather the development of new delivery methods for optimum treatment outcome. Nanomedicine is perhaps playing the biggest role in this concern. Nanomedicine offers numerous advantages over conventional drug delivery approaches and is particularly the hot topic in anticancer research. Nanoparticles (NPs) have many unique criteria that enable them to be incorporated in anticancer therapy. This topical review aims to look at the properties and various forms of NPs and their use in anticancer treatment, recent development of the process of identifying new delivery approaches as well as progress in clinical trials with these newer approaches. Although the outcome of cancer therapy can be increased using nanomedicine there are still many disadvantages of using this approach. We aim to discuss all these issues in this review.

Telepsychotherapy and the Therapeutic Relationship: Principles, Advantages, and Case Examples.

PubMed

Kocsis, Barbara J; Yellowlees, Peter

2018-05-01

As the use of technology continues to expand within our mental healthcare system, there has been an increasing interest in conducting psychotherapy online using videoconferencing. Literature pertaining to telepsychotherapy has explored possible drawbacks of this modality on the therapeutic relationship, although several studies have shown that the efficacy of online psychotherapy is equivalent to in-person approaches. Little is written about the potential advantages to the psychotherapeutic relationship when psychotherapy is carried out over videoconferencing. The available literature was reviewed, as were the general principles of telepsychotherapy and the therapeutic relationship, followed by a more in-depth consideration of patient populations for whom telepsychotherapy may offer distinct advantages. The current literature, as well as our own clinical experience, suggests that telepsychotherapy may be effective for a broad range of patients, and it may offer distinct advantages in the building of a trusting psychotherapeutic relationship. Telepsychotherapy offers a novel way to reach and form strong psychotherapeutic relationships with many different types of patients, and it may foster therapeutic intimacy in ways that in-person psychotherapy cannot. More research is needed to further explore this unique modality.

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

Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease

PubMed Central

Simmons, Olivia; Maples, Phillip B.; Senzer, Neil; Nemunaitis, John

2012-01-01

Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. These unique target sequences provide opportunity for RNA interference(i)-based therapy. A summary of RNAi mechanism and therapeutically designed products including siRNA, shRNA and bi-shRNA are described. Comparison is made between each of these approaches. Systemic RNAi-based therapy, however, requires protected delivery to the Ewing's sarcoma tumor site for activity. Delivery systems which have been most effective in preclinical and clinical testing are reviewed, followed by preclinical assessment of various silencing strategies with demonstration of effectiveness to EWS/FLI-1 target sequences. It is concluded that RNAi-based therapeutics may have testable and achievable activity in management of Ewing's sarcoma. PMID:22523703

Novel Nanotechnologies for Brain Cancer Therapeutics and Imaging.

PubMed

Ferroni, Letizia; Gardin, Chiara; Della Puppa, Alessandro; Sivolella, Stefano; Brunello, Giulia; Scienza, Renato; Bressan, Eriberto; D'Avella, Domenico; Zavan, Barbara

2015-11-01

Despite progress in surgery, radiotherapy, and in chemotherapy, an effective curative treatment of brain cancer, specifically malignant gliomas, does not yet exist. The efficacy of current anti-cancer strategies in brain tumors is limited by the lack of specific therapies against malignant cells. Besides, the delivery of the drugs to brain tumors is limited by the presence of the blood-brain barrier. Nanotechnology today offers a unique opportunity to develop more effective brain cancer imaging and therapeutics. In particular, the development of nanocarriers that can be conjugated with several functional molecules including tumor-specific ligands, anticancer drugs, and imaging probes, can provide new devices which are able to overcome the difficulties of the classical strategies. Nanotechnology-based approaches hold great promise for revolutionizing brain cancer medical treatments, imaging, and diagnosis.

Building Basic Therapeutic Skills: A Practical Guide for Current Mental Health Practice.

ERIC Educational Resources Information Center

Heaton, Jeanne Albronda

Each therapeutic contact provides unique opportunities to ameliorate suffering and cultivate change. This volume addresses the inherent struggle in therapy to create a therapeutic relationship and make the work compassionate, efficient, and effective. It provides assistance to students, supervisors, and educators in doing therapeutic work while…

Computational approaches for identification of conserved/unique binding pockets in the A chain of ricin

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

Ecale Zhou, C L; Zemla, A T; Roe, D

2005-01-29

Specific and sensitive ligand-based protein detection assays that employ antibodies or small molecules such as peptides, aptamers, or other small molecules require that the corresponding surface region of the protein be accessible and that there be minimal cross-reactivity with non-target proteins. To reduce the time and cost of laboratory screening efforts for diagnostic reagents, we developed new methods for evaluating and selecting protein surface regions for ligand targeting. We devised combined structure- and sequence-based methods for identifying 3D epitopes and binding pockets on the surface of the A chain of ricin that are conserved with respect to a set ofmore » ricin A chains and unique with respect to other proteins. We (1) used structure alignment software to detect structural deviations and extracted from this analysis the residue-residue correspondence, (2) devised a method to compare corresponding residues across sets of ricin structures and structures of closely related proteins, (3) devised a sequence-based approach to determine residue infrequency in local sequence context, and (4) modified a pocket-finding algorithm to identify surface crevices in close proximity to residues determined to be conserved/unique based on our structure- and sequence-based methods. In applying this combined informatics approach to ricin A we identified a conserved/unique pocket in close proximity (but not overlapping) the active site that is suitable for bi-dentate ligand development. These methods are generally applicable to identification of surface epitopes and binding pockets for development of diagnostic reagents, therapeutics, and vaccines.« less

Therapeutic potential of gel-based injectables for vocal fold regeneration

PubMed Central

Bartlett, Rebecca S.; Thibeault, Susan L.; Prestwich, Glenn D.

2012-01-01

Vocal folds are anatomically and biomechanically unique, thus complicating the design and implementation of tissue engineering strategies for repair and regeneration. Integration of an enhanced understanding of tissue biomechanics, wound healing dynamics and innovative gel-based therapeutics has generated enthusiasm for the notion that an efficacious treatment for vocal fold scarring could be clinically attainable within several years. Fibroblast phenotype and gene expression are mediated by the three-dimensional mechanical and chemical microenvironment at an injury site. Thus, therapeutic approaches need to coordinate spatial and temporal aspects of the wound healing response in an injured vocal tissue to achieve an optimal clinical outcome. Successful gel-based injectables for vocal fold scarring will require a keen understanding of how the native inflammatory response sets into motion the later extracellular matrix remodeling, which in turn will determine the ultimate biomechanical properties of the tissue. We present an overview of the challenges associated with this translation as well as the proposed gel-based injectable solutions. PMID:22456756

Armed Therapeutic Viruses – A Disruptive Therapy on the Horizon of Cancer Immunotherapy

PubMed Central

Bauzon, Maxine; Hermiston, Terry

2014-01-01

For the past 150 years cancer immunotherapy has been largely a theoretical hope that recently has begun to show potential as a highly impactful treatment for various cancers. In particular, the identification and targeting of immune checkpoints have given rise to exciting data suggesting that this strategy has the potential to activate sustained antitumor immunity. It is likely that this approach, like other anti-cancer strategies before it, will benefit from co-administration with an additional therapeutic and that it is this combination therapy that may generate the greatest clinical outcome for the patient. In this regard, oncolytic viruses are a therapeutic moiety that is well suited to deliver and augment these immune-modulating therapies in a highly targeted and economically advantageous way over current treatment. In this review, we discuss the blockade of immune checkpoints, how oncolytic viruses complement and extend these therapies, and speculate on how this combination will uniquely impact the future of cancer immunotherapy. PMID:24605114

Yeast synthetic biology for the production of recombinant therapeutic proteins.

PubMed

Kim, Hyunah; Yoo, Su Jin; Kang, Hyun Ah

2015-02-01

The production of recombinant therapeutic proteins is one of the fast-growing areas of molecular medicine and currently plays an important role in treatment of several diseases. Yeasts are unicellular eukaryotic microbial host cells that offer unique advantages in producing biopharmaceutical proteins. Yeasts are capable of robust growth on simple media, readily accommodate genetic modifications, and incorporate typical eukaryotic post-translational modifications. Saccharomyces cerevisiae is a traditional baker's yeast that has been used as a major host for the production of biopharmaceuticals; however, several nonconventional yeast species including Hansenula polymorpha, Pichia pastoris, and Yarrowia lipolytica have gained increasing attention as alternative hosts for the industrial production of recombinant proteins. In this review, we address the established and emerging genetic tools and host strains suitable for recombinant protein production in various yeast expression systems, particularly focusing on current efforts toward synthetic biology approaches in developing yeast cell factories for the production of therapeutic recombinant proteins. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

Current therapies for Morquio A syndrome and their clinical outcomes

PubMed Central

Sawamoto, Kazuki; Suzuki, Yasuyuki; Mackenzie, William G.; Theroux, Mary C.; Pizarro, Christian; Yabe, Hiromasa; Orii, Kenji E.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2016-01-01

Introduction Morquio A syndrome is characterized by a unique skeletal dysplasia, leading to short neck and trunk, pectus carinatum, laxity of joints, kyphoscoliosis, and tracheal obstruction. Cervical spinal cord compression/inability, a restrictive and obstructive airway, and/or bone deformity and imbalance of growth, are life-threatening to Morquio A patients, leading to a high morbidity and mortality. It is critical to review the current therapeutic approaches with respect to their efficacy and limitations. Areas covered Patients with progressive skeletal dysplasia often need to undergo orthopedic surgical interventions in the first two decades of life. Recently, we have treated four patients with a new surgery to correct progressive tracheal obstruction. Enzyme replacement therapy (ERT) has been approved clinically. Cell-based therapies such as hematopoietic stem cell therapy (HSCT) and gene therapy are typically one-time, permanent treatments for enzyme deficiencies. We report here on four Morquio A patients treated with HSCT approved in Japan and followed for at least ten years after treatment. Gene therapy is under investigation on mouse models but not yet available as a therapeutic option. Expert opinion ERT and HSCT in combination with surgical intervention(s) are a therapeutic option for Morquio A; however, the approach for bone and cartilage lesion remains an unmet challenge. PMID:28217429

Pathophysiology of Tumor Neovascularization

PubMed Central

Furuya, Mitsuko; Nishiyama, Mariko; Kasuya, Yoshitoshi; Kimura, Sadao; Ishikura, Hiroshi

2005-01-01

Neovascularization is essential to the process of development and differentiation of tissues in the vertebrate embryo, and is also involved in a wide variety of physiological and pathological conditions in adults, including wound repair, metabolic diseases, inflammation, cardiovascular disorders, and tumor progression. Thanks to cumulative studies on vasculature, new therapeutic approaches have been opened for us to some life-threatening diseases by controlling angiogenesis in the affected organs. In cancer therapy, for example, modulation of factors responsible for tumor angiogenesis may be beneficial in inhibiting of tumor progression. Several antiangiogenic approaches are currently under preclinical trial. However, the mechanisms of neovascularization in tumors are complicated and each tumor shows unique features in its vasculature, depending on tissue specificity, angiogenic micromilieu, grades and stages, host immunity, and so on. For better understanding and effective therapeutic approaches, it is important to clarify both the general mechanism of angiogenic events and the disease-specific mechanism of neovascularization. This review discusses the general features of angiogenesis under physiological and pathological conditions, mainly in tumor progression. In addition, recent topics such as contribution of the endothelial progenitor cells, tumor vasculogenic mimicry, markers for tumor-derived endothelial cells and pericytes, and angiogenic/angiostatic chemokines are summarized. PMID:17315600

Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

PubMed Central

Boison, Detlev

2010-01-01

Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affect several signal transduction pathways simultaneously and therefore have the unique potential to modify complex neurochemical networks; (ii) by acting on the network level, inhibitors of nucleoside metabolism are highly suited to fine-tune, restore, or amplify physiological functions of nucleosides; (iii) therefore inhibitors of nucleoside metabolism have promise for the “soft and smart” therapy of neurological diseases with the added advantage of reduced systemic side effects. This review will first highlight the role of nucleoside function and dysfunction in physiological and pathophysiological situations with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. The second part of this review will cover pharmacological approaches to use inhibitors of nucleoside metabolism, with a special emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, novel gene-based therapeutic strategies to inhibit nucleoside metabolism and focal treatment approaches will be discussed. PMID:21401494

Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment

PubMed Central

Kim, Yong Sook; Jeong, Hye-yun; Kim, Ah Ra; Kim, Woong-Hee; Cho, Haaglim; Um, JungIn; Seo, Youngha; Kang, Wan Seok; Jin, Suk-Won; Kim, Min Chul; Kim, Yong-Chul; Jung, Da-Woon; Williams, Darren R.; Ahn, Youngkeun

2016-01-01

The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2′Z,3′E)-6-Bromoindirubin-3′-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti-fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3β inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI. PMID:27510556

Transcriptomic analysis of the venom glands from the scorpion Hadogenes troglodytes revealed unique and extremely high diversity of the venom peptides.

PubMed

Zhong, Jie; Zeng, Xian-Chun; Zeng, Xin; Nie, Yao; Zhang, Lei; Wu, Shifen; Bao, Aorigele

2017-01-06

Hadogenes is a genus of large African scorpions with 18 described species. However, little is known about the venom peptide composition of any species from Hadogenes so far. Here, we fully explored the composition of venom gland peptides from Hadogenes troglodytes using transcriptomic approach. We discovered 121 novel peptides from the scorpion, including 20 new-type peptides cross-linked with one, two, three, four or seven disulfide bridges, respectively, 11 novel K + -channel toxin-like peptides, 2 novel ryanodine receptors-specific toxin-like peptides, a unique peptide containing the cysteine knots of spider toxins, 15 novel La1-like toxins, 3 novel TIL domain-containing peptides, 5 novel peptides with atypical cysteine patterns, 19 novel antimicrobial peptides, 6 novel cysteine-free peptides and 39 new-type cysteine-free peptides. Among them, the new-type peptides are largely dominant; this highlights the unique diversity of the venom gland peptides from H. troglodytes. Some of the new peptides would serve as new molecular probes for the investigations of cellular ion channels and other receptors, or offer new templates for the development of therapeutic drugs for the treatment of ion channel-associated diseases, and infections caused by antibiotics-resistant pathogens. In this study, we fully explored the composition of venom gland peptides from the scorpion Hadogenes troglodytes using transcriptomic approach. We discovered a total of 121 novel peptides from the venom glands of the scorpion, of which new-type peptides are largely dominant. These data highlight the unique diversity of the venom gland peptides from the scorpion H. troglodytes, gain insights into new mechanisms for the scorpion to subdue its prey and predators, and enlarge the protein database of scorpion venom glands. The discovery of a lot of novel peptides provides new templates for the development of therapeutic drugs, and offers new molecular materials for the basic researches of various cellular receptors, and for the evolutionary investigations of scorpion toxins. Copyright © 2016 Elsevier B.V. All rights reserved.

Spherical Nucleic Acids as Intracellular Agents for Nucleic Acid Based Therapeutics

NASA Astrophysics Data System (ADS)

Hao, Liangliang

Recent functional discoveries on the noncoding sequences of human genome and transcriptome could lead to revolutionary treatment modalities because the noncoding RNAs (ncRNAs) can be applied as therapeutic agents to manipulate disease-causing genes. To date few nucleic acid-based therapeutics have been translated into the clinic due to challenges in the delivery of the oligonucleotide agents in an effective, cell specific, and non-toxic fashion. Unmodified oligonucleotide agents are destroyed rapidly in biological fluids by enzymatic degradation and have difficulty crossing the plasma membrane without the aid of transfection reagents, which often cause inflammatory, cytotoxic, or immunogenic side effects. Spherical nucleic acids (SNAs), nanoparticles consisting of densely organized and highly oriented oligonucleotides, pose one possible solution to circumventing these problems in both the antisense and RNA interference (RNAi) pathways. The unique three dimensional architecture of SNAs protects the bioactive oligonucleotides from unspecific degradation during delivery and supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. Owing to their unique structure, SNAs are able to cross cell membranes and regulate target genes expression as a single entity, without triggering the cellular innate immune response. Herein, my thesis has focused on understanding the interactions between SNAs and cellular components and developing SNA-based nanostructures to improve therapeutic capabilities. Specifically, I developed a novel SNA-based, nanoscale agent for delivery of therapeutic oligonucleotides to manipulate microRNAs (miRNAs), the endogenous post-transcriptional gene regulators. I investigated the role of SNAs involving miRNAs in anti-cancer or anti-inflammation responses in cells and in in vivo murine disease models via systemic injection. Furthermore, I explored using different strategies to construct novel SNA-based nanomaterials with desired properties and applying targeting moieties to the SNA platform to achieve cell type specific gene regulation effects. Due to the flexibility of the SNA approach, the SNA platform can potentially be applied to many genetic disorders through tailored target specificities.

Driving While Impaired (DWI) Intervention Service Provider Orientations: The Scales of the DWI Therapeutic Educator Inventory (DTEI)

ERIC Educational Resources Information Center

DeMuro, Scott; Wanberg, Kenneth; Anderson, Rachel

2011-01-01

The therapeutic educator who provides services to driving while impaired (DWI) offenders is a unique professional hybrid, combining education and therapeutic service delivery. In an effort to understand and address this service provider, a 69-item DWI Therapeutic Educator Inventory (DTEI) was constructed. Using principal components and common…

Structural insights into simocyclinone as an antibiotic, effector ligand and substrate

PubMed Central

Buttner, Mark J; Schäfer, Martin; Lawson, David M

2017-01-01

Abstract Simocyclinones are antibiotics produced by Streptomyces and Kitasatospora species that inhibit the validated drug target DNA gyrase in a unique way, and they are thus of therapeutic interest. Structural approaches have revealed their mode of action, the inducible-efflux mechanism in the producing organism, and given insight into one step in their biosynthesis. The crystal structures of simocyclinones bound to their target (gyrase), the transcriptional repressor SimR and the biosynthetic enzyme SimC7 reveal fascinating insight into how molecular recognition is achieved with these three unrelated proteins. PMID:29126195

Structural insights into simocyclinone as an antibiotic, effector ligand and substrate.

PubMed

Buttner, Mark J; Schäfer, Martin; Lawson, David M; Maxwell, Anthony

2018-01-01

Simocyclinones are antibiotics produced by Streptomyces and Kitasatospora species that inhibit the validated drug target DNA gyrase in a unique way, and they are thus of therapeutic interest. Structural approaches have revealed their mode of action, the inducible-efflux mechanism in the producing organism, and given insight into one step in their biosynthesis. The crystal structures of simocyclinones bound to their target (gyrase), the transcriptional repressor SimR and the biosynthetic enzyme SimC7 reveal fascinating insight into how molecular recognition is achieved with these three unrelated proteins. © FEMS 2017.

The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction

PubMed Central

Hoshyar, Nazanin; Gray, Samantha; Han, Hongbin; Bao, Gang

2016-01-01

Nanoparticle-based technologies offer exciting new approaches to disease diagnostics and therapeutics. To take advantage of unique properties of nanoscale materials and structures, the size, shape and/or surface chemistry of nanoparticles need to be optimized, allowing their functionalities to be tailored for different biomedical applications. Here we review the effects of nanoparticle size on cellular interaction and in vivo pharmacokinetics, including cellular uptake, biodistribution and circulation half-life of nanoparticles. Important features of nanoparticle probes for molecular imaging and modeling of nanoparticle size effects are also discussed. PMID:27003448

Emerging Therapeutics to Overcome Chemoresistance in Epithelial Ovarian Cancer: A Mini-Review.

PubMed

Cornelison, Robert; Llaneza, Danielle C; Landen, Charles N

2017-10-18

Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial-mesenchymal transition, DNA damage and repair capacity. We also discuss novel therapeutics that may address some of the challenges in bringing approaches that target chemoresistant processes from bench to bedside. Some of these new therapies include novel drug delivery systems, targets that may halt adaptive changes in the tumor, exploitation of tumor mutations that leave cancer cells vulnerable to irreversible damage, and novel drugs that target ribosomal biogenesis, a process that may be uniquely different in cancer versus non-cancerous cells. Each of these approaches, or a combination of them, may provide a greater number of positive outcomes for a broader population of HGSOC patients.

[Surgery for thoracic tuberculosis].

PubMed

Kilani, T; Boudaya, M S; Zribi, H; Ouerghi, S; Marghli, A; Mestiri, T; Mezni, F

2015-01-01

Tuberculosis is mainly a medical disease. Surgery has been the unique therapeutic tool for a long time before the advent of specific antituberculous drugs, and the role of surgery was then confined to the treatment of the sequelae of tuberculosis and their complications. The resurgence of tuberculosis and the emergence of multidrug-resistant TB combined to immunosuppressed patients represent a new challenge for tuberculosis surgery. Surgery may be indicated for a diagnostic purpose in patients with pulmonary, pleural, mediastinal or thoracic wall involvement, or with a therapeutic purpose (drainage, resection, residual cavity obliteration). Modern imaging techniques and the advent of video-assisted thoracic surgery allowed a new approach of this pathology; the majority of diagnostic interventions and selected cases requiring lung resection can be performed through a mini-invasive approach. Patients proposed for aggressive surgery may be treated with the best results thanks to a good evaluation of the thoracic lesions, of the patients' nutritional, infectious and general status combined with a good coordination between the specialized medical team for an optimal preparation to surgery. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Hematopoietic recovery of acute radiation syndrome by human superoxide dismutase-expressing umbilical cord mesenchymal stromal cells.

PubMed

Gan, Jingyi; Meng, Fanwei; Zhou, Xin; Li, Chan; He, Yixin; Zeng, Xiaoping; Jiang, Xingen; Liu, Jia; Zeng, Guifang; Tang, Yunxia; Liu, Muyun; Mrsny, Randall J; Hu, Xiang; Hu, Jifan; Li, Tao

2015-04-01

Acute radiation syndrome (ARS) leads to pancytopenia and multi-organ failure. Transplantation of hematopoietic stem cells provides a curative option for radiation-induced aplasia, but this therapy is limited by donor availability. We examined an alternative therapeutic approach to ARS with the use of human extracellular superoxide dismutase (ECSOD)-modified umbilical cord mesenchymal stromal cells (UCMSCs). This treatment combines the unique regenerative role of UCMSCs with the anti-oxidative activity of ECSOD. We demonstrated that systemically administered ECSOD-UCMSCs are able to protect mice from sub-lethal doses of radiation and improve survival by promoting multilineage hematopoietic recovery. The therapeutic effect of this treatment is related to the decrease in radiation-induced O(2)(-) and apoptosis. Our data highlight the clinical potential of this two-pronged approach to the treatment of ARS, thereby serving as a rapid and effective first-line strategy to combat the hematopoietic failure resulting from a radiation accident, nuclear terrorism and other radiologic emergencies. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Topical retinoids in the management of photodamaged skin: from theory to evidence-based practical approach.

PubMed

Darlenski, R; Surber, C; Fluhr, J W

2010-12-01

Skin, being exposed directly to the environment, represents a unique model for demonstrating the synergistic effects of intrinsic and extrinsic factors on the ageing process. Ultraviolet radiation (UVR) is the major factor among exogenous stressors responsible for premature skin ageing. The problem of skin ageing has captured public attention and has an important social impact. Different therapeutic approaches have been developed to treat cutaneous ageing and to diminish or prevent the negative effects of UVR. Topical retinoids represent an important and powerful class of molecules in the dermatologist's hands for the treatment of photodamaged skin. Since their introduction more than 20 years ago, topical retinoids have shown beneficial efficacy and good safety profiles in the management of photodamaged skin, and as therapeutic anti-ageing agents. This review provides a brief retrospective of the development of topical retinoids in the treatment of photodamaged skin, elucidates their mechanism of action, delineates their use and addresses clinical, pharmaceutical and regulatory issues in connection with their intended use. © 2010 The Authors. BJD © 2010 British Association of Dermatologists.

A Practice-Based Theory of Healing Through Therapeutic Touch: Advancing Holistic Nursing Practice.

PubMed

Hanley, Mary Anne; Coppa, Denise; Shields, Deborah

2017-08-01

For nearly 50 years, Therapeutic Touch (TT) has contributed to advancing holistic nursing practice and has been recognized as a uniquely human approach to healing. This narrative explores the development of a practice-based theory of healing through TT, which occurred between 2010 and 2016. Through the in-depth self-inquiry of participatory reflective dialogue in concert with constant narrative analysis, TT practitioners revealed the meaning of healing within the context of their TT practice. As the community of TT experts participated in an iterative process of small group and community dialogues with analysis and synthesis of emerging themes, the assumptions and concepts central to a theory of healing emerged, were clarified and verified. Exemplars of practice illustrate the concepts. A model of the theory of healing illuminates the movement and relationship among concepts and evolved over time. Feedback from nursing and inter-professional practitioners indicate that the theory of healing, while situated within the context of TT, may be useful in advancing holistic nursing practice, informing healing and caring approaches, stimulating research and education, and contributing to future transformations in health care.

Development of a large peptoid-DOTA combinatorial library.

PubMed

Singh, Jaspal; Lopes, Daniel; Gomika Udugamasooriya, D

2016-09-01

Conventional one-bead one-compound (OBOC) library synthesis is typically used to identify molecules with therapeutic value. The design and synthesis of OBOC libraries that contain molecules with imaging or even potentially therapeutic and diagnostic capacities (e.g. theranostic agents) has been overlooked. The development of a therapeutically active molecule with a built-in imaging component for a certain target is a daunting task, and structure-based rational design might not be the best approach. We hypothesize to develop a combinatorial library with potentially therapeutic and imaging components fused together in each molecule. Such molecules in the library can be used to screen, identify, and validate as direct theranostic candidates against targets of interest. As the first step in achieving that aim, we developed an on-bead library of 153,600 Peptoid-DOTA compounds in which the peptoids are the target-recognizing and potentially therapeutic components and the DOTA is the imaging component. We attached the DOTA scaffold to TentaGel beads using one of the four arms of DOTA, and we built a diversified 6-mer peptoid library on the remaining three arms. We evaluated both the synthesis and the mass spectrometric sequencing capacities of the test compounds and of the final library. The compounds displayed unique ionization patterns including direct breakages of the DOTA scaffold into two units, allowing clear decoding of the sequences. Our approach provides a facile synthesis method for the complete on-bead development of large peptidomimetic-DOTA libraries for screening against biological targets for the identification of potential theranostic agents in the future. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 673-684, 2016. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc.

Nanocarrier mediated Delivery of siRNA/miRNA in Combination with Chemotherapeutic Agents for Cancer Therapy: Current Progress and Advances

PubMed Central

Gandhi, Nishant S.; Tekade, Rakesh K.; Chougule, Mahavir B.

2014-01-01

Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibits drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), Multidrug resistant protein 1(MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. PMID:25204288

Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances.

PubMed

Gandhi, Nishant S; Tekade, Rakesh K; Chougule, Mahavir B

2014-11-28

Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibit drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms, etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), multidrug resistant protein 1 (MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. Copyright © 2014 Elsevier B.V. All rights reserved.

Scaleable processes for the manufacture of therapeutic quantities of plasmid DNA.

PubMed

Shamlou, Parviz Ayazi

2003-06-01

The need for scaleable processes to manufacture therapeutic plasmid DNA (pDNA) is easy to overlook when attention is focused primarily on vector design and establishment of early clinical results. pDNA is a large molecule and has properties that are similar to those of the contaminating chromosomal DNA. These, combined with the low initial concentration of plasmids in the host cell, provide unique process challenges that require significant upfront design to establish robust manufacturing processes that can also comply with current Good Manufacturing Practice ('cGMP') and produce milligram-to-kilogram quantities of pDNA product. This review describes promising scaleable processes that are currently being assessed for production of therapeutic supercoiled pDNA. Fermentation strategies for improving supercoiled plasmid yield and reducing contaminant concentrations are reviewed, and downstream processes are assessed for their ability to efficiently remove cellular contaminants, separate the supercoiled form of the pDNA from its open circular and linear forms, and prepare the purified drug substance for formulation. Current strategies are presented for developing stable delivery systems, and approaches to quality assurance and quality control are discussed.

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.

Folate-decorated anticancer drug and magnetic nanoparticles encapsulated polymeric carrier for liver cancer therapeutics.

PubMed

Li, Yu-Ji; Dong, Ming; Kong, Fan-Min; Zhou, Jian-Ping

2015-07-15

Nanoparticulate system with theranostic applications has attracted significant attention in cancer therapeutics. In the present study, we have developed a novel composite PLGA NP co-encapsulated with anticancer drug (sorafenib) and magnetic NP (SPION). We have successfully developed nanosized folate-conjugated PEGylated PLGA nanoparticles (SRF/FA-PEG-PLGA NP) with both anticancer and magnetic resonance property. We have showed that FA-conjugated NP exhibits sustained drug release and enhanced cellular uptake in BEL7402 cancer cells. The targeted NP effectively suppressed the tumor cell proliferation and has improved the anticancer efficacy than that of free drug or non-targeted one. Additionally, enhanced MRI properties demonstrate this formulation has good imaging agent characteristics. Finally, SRF/FA-PEG-PLGA NP effectively inhibited the colony forming ability indicating its superior anticancer effect. Together, these multifunctional nanoparticles would be most ideal to improve the therapeutic response in cancer and holds great potential to be a part of future nanomedicine. Our unique approach could be extended for multiple biomedical applications. Copyright © 2015. Published by Elsevier B.V.

Photonanomedicine: a convergence of photodynamic therapy and nanotechnology

NASA Astrophysics Data System (ADS)

Obaid, Girgis; Broekgaarden, Mans; Bulin, Anne-Laure; Huang, Huang-Chiao; Kuriakose, Jerrin; Liu, Joyce; Hasan, Tayyaba

2016-06-01

As clinical nanomedicine has emerged over the past two decades, phototherapeutic advancements using nanotechnology have also evolved and impacted disease management. Because of unique features attributable to the light activation process of molecules, photonanomedicine (PNM) holds significant promise as a personalized, image-guided therapeutic approach for cancer and non-cancer pathologies. The convergence of advanced photochemical therapies such as photodynamic therapy (PDT) and imaging modalities with sophisticated nanotechnologies is enabling the ongoing evolution of fundamental PNM formulations, such as Visudyne®, into progressive forward-looking platforms that integrate theranostics (therapeutics and diagnostics), molecular selectivity, the spatiotemporally controlled release of synergistic therapeutics, along with regulated, sustained drug dosing. Considering that the envisioned goal of these integrated platforms is proving to be realistic, this review will discuss how PNM has evolved over the years as a preclinical and clinical amalgamation of nanotechnology with PDT. The encouraging investigations that emphasize the potent synergy between photochemistry and nanotherapeutics, in addition to the growing realization of the value of these multi-faceted theranostic nanoplatforms, will assist in driving PNM formulations into mainstream oncological clinical practice as a necessary tool in the medical armamentarium.

Sundew-Inspired Adhesive Hydrogels Combined with Adipose-Derived Stem Cells for Wound Healing

PubMed Central

Sun, Leming; Huang, Yujian; Bian, Zehua; Petrosino, Jennifer; Fan, Zhen; Wang, Yongzhong; Park, Ki Ho; Yue, Tao; Schmidt, Michael; Galster, Scott; Ma, Jianjie; Zhu, Hua; Zhang, Mingjun

2016-01-01

The potential to harness the unique physical, chemical, and biological properties of the sundew (Drosera) plant’s adhesive hydrogels has long intrigued researchers searching for novel wound-healing applications. However, the ability to collect sufficient quantities of the sundew plant’s adhesive hydrogels is problematic and has eclipsed their therapeutic promise. Inspired by these natural hydrogels, we asked if sundew-inspired adhesive hydrogels could overcome the drawbacks associated with natural sundew hydrogels and be used in combination with stem-cell-based therapy to enhance wound-healing therapeutics. Using a bioinspired approach, we synthesized adhesive hydrogels comprised of sodium alginate, gum arabic, and calcium ions to mimic the properties of the natural sundew-derived adhesive hydrogels. We then characterized and showed that these sundew-inspired hydrogels promote wound healing through their superior adhesive strength, nanostructure, and resistance to shearing when compared to other hydrogels in vitro. In vivo, sundew-inspired hydrogels promoted a “suturing” effect to wound sites, which was demonstrated by enhanced wound closure following topical application of the hydrogels. In combination with mouse adipose-derived stem cells (ADSCs) and compared to other therapeutic biomaterials, the sundew-inspired hydrogels demonstrated superior wound-healing capabilities. Collectively, our studies show that sundew-inspired hydrogels contain ideal properties that promote wound healing and suggest that sundew-inspired-ADSCs combination therapy is an efficacious approach for treating wounds without eliciting noticeable toxicity or inflammation. PMID:26731614

Sundew-Inspired Adhesive Hydrogels Combined with Adipose-Derived Stem Cells for Wound Healing.

PubMed

Sun, Leming; Huang, Yujian; Bian, Zehua; Petrosino, Jennifer; Fan, Zhen; Wang, Yongzhong; Park, Ki Ho; Yue, Tao; Schmidt, Michael; Galster, Scott; Ma, Jianjie; Zhu, Hua; Zhang, Mingjun

2016-01-27

The potential to harness the unique physical, chemical, and biological properties of the sundew (Drosera) plant's adhesive hydrogels has long intrigued researchers searching for novel wound-healing applications. However, the ability to collect sufficient quantities of the sundew plant's adhesive hydrogels is problematic and has eclipsed their therapeutic promise. Inspired by these natural hydrogels, we asked if sundew-inspired adhesive hydrogels could overcome the drawbacks associated with natural sundew hydrogels and be used in combination with stem-cell-based therapy to enhance wound-healing therapeutics. Using a bioinspired approach, we synthesized adhesive hydrogels comprised of sodium alginate, gum arabic, and calcium ions to mimic the properties of the natural sundew-derived adhesive hydrogels. We then characterized and showed that these sundew-inspired hydrogels promote wound healing through their superior adhesive strength, nanostructure, and resistance to shearing when compared to other hydrogels in vitro. In vivo, sundew-inspired hydrogels promoted a "suturing" effect to wound sites, which was demonstrated by enhanced wound closure following topical application of the hydrogels. In combination with mouse adipose-derived stem cells (ADSCs) and compared to other therapeutic biomaterials, the sundew-inspired hydrogels demonstrated superior wound-healing capabilities. Collectively, our studies show that sundew-inspired hydrogels contain ideal properties that promote wound healing and suggest that sundew-inspired-ADSCs combination therapy is an efficacious approach for treating wounds without eliciting noticeable toxicity or inflammation.

Myoblast-mediated gene transfer for therapeutic angiogenesis and arteriogenesis.

PubMed

von Degenfeld, Georges; Banfi, Andrea; Springer, Matthew L; Blau, Helen M

2003-10-01

Therapeutic angiogenesis aims at generating new blood vessels by delivering growth factors such as VEGF and FGF. Clinical trials are underway in patients with peripheral vascular and coronary heart disease. However, increasing evidence indicates that the new vasculature needs to be stabilized to avoid deleterious effects such as edema and hemangioma formation. Moreover, a major challenge is to induce new vessels that persist following cessation of the angiogenic stimulus. Mature vessels may be generated by modulating timing and dosage of growth factor expression, or by combination of 'growth' factors with 'maturation' factors like PDGF-BB, angiopoietin-1 or TGF-beta. Myoblast-mediated gene transfer has unique characteristics that make it a useful tool for studying promising novel approaches to therapeutic angiogenesis. It affords robust and long-lasting expression, and can be considered as a relatively rapid form of 'adult transgenesis' in muscle. The combined insertion of different gene constructs into single myoblasts and their progeny allows the simultaneous expression of different 'growth' and 'maturation' factors within the same cell in vivo. The additional insertion of a reporter gene makes it possible to analyze the phenotype of the vessels surrounding the transgenic muscle fibers into which the myoblasts have fused. The effects of timing and duration of gene expression can be studied by using tetracycline-inducible constructs, and dosage effects by selecting subpopulations consistently expressing distinct levels of growth factors. Finally, the autologous cell-based approach using transduced myoblasts could be an alternative gene delivery system for therapeutic angiogenesis in patients, avoiding the toxicities seen with some viral vectors.

Functionalised carbon nanotubes: From intracellular uptake and cell-related toxicity to systemic brain delivery.

PubMed

Costa, Pedro M; Bourgognon, Maxime; Wang, Julie T-W; Al-Jamal, Khuloud T

2016-11-10

Carbon nanotubes (CNTs) have long been regarded as promising carriers in biomedicine. Due to their high surface area and unique needle-like structure, CNTs are uniquely equipped to carry therapeutic molecules across biological membranes and, therefore, have been widely researched for use in theranostic applications. The attractive properties of the CNTs entice also their use in the brain environment. Cutting edge brain-specific therapies, capable of circumventing the physical and biochemical blockage of the blood-brain barrier, could be a precious tool to tackle brain disorders. With an increasing number of applications and expanding production, the effects of direct and indirect exposure to CNTs on cellular and molecular levels and more globally the general health, must be carefully assessed and limited. In this chapter, we review the most recent trends on the development and application of CNT-based nanotechnologies, with a particular focus on the carrier properties, cell internalisation and processing, and mechanisms involved in cell toxicity. Novel approaches for CNT-based systemic therapeutic brain delivery following intravenous administration are also reviewed. Moreover, we highlight fundamental questions that should be addressed in future research involving CNTs, aiming at achieving its safe introduction into the clinics. Copyright © 2016 Elsevier B.V. All rights reserved.

Translational study of microRNAs and its application in kidney disease and hypertension research

PubMed Central

KRIEGEL, Alison J.; MLADINOV, Domagoj; LIANG, Mingyu

2015-01-01

MicroRNA research in humans and mammalian model organisms is in a crucial stage of development. Diagnostic and therapeutic values of microRNAs appear promising, but remain to be established. The physiological and pathophysiological significance of microRNAs is generally recognized, but much better understood in some organ systems and disease areas than others. In the present paper, we review several translational studies of microRNAs, including those showing the potential value of therapeutic agents targeting microRNAs and diagnostic or prognostic microRNA markers detectable in body fluids. We discuss the lessons learned and the experience gained from these studies. Several recent studies have begun to explore translational microRNA research in kidney disease and hypertension. Translational research of microRNAs in the kidney faces unique challenges, but provides many opportunities to develop and apply new methods, and to merge complementary basic and clinical approaches. PMID:22283365

Orphan diseases: state of the drug discovery art.

PubMed

Volmar, Claude-Henry; Wahlestedt, Claes; Brothers, Shaun P

2017-06-01

Since 1983 more than 300 drugs have been developed and approved for orphan diseases. However, considering the development of novel diagnosis tools, the number of rare diseases vastly outpaces therapeutic discovery. Academic centers and nonprofit institutes are now at the forefront of rare disease R&D, partnering with pharmaceutical companies when academic researchers discover novel drugs or targets for specific diseases, thus reducing the failure risk and cost for pharmaceutical companies. Considerable progress has occurred in the art of orphan drug discovery, and a symbiotic relationship now exists between pharmaceutical industry, academia, and philanthropists that provides a useful framework for orphan disease therapeutic discovery. Here, the current state-of-the-art of drug discovery for orphan diseases is reviewed. Current technological approaches and challenges for drug discovery are considered, some of which can present somewhat unique challenges and opportunities in orphan diseases, including the potential for personalized medicine, gene therapy, and phenotypic screening.

Cell-based therapeutic strategies for multiple sclerosis

PubMed Central

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A; Atkins, Harold; Banwell, Brenda; Bar-Or, Amit; Bebo, Bruce; Bowen, James; Burt, Richard; Calabresi, Peter; Cohen, Jeffrey; Comi, Giancarlo; Connick, Peter; Cross, Anne; Cutter, Gary; Derfuss, Tobias; Ffrench-Constant, Charles; Freedman, Mark; Galipeau, Jacques; Goldman, Myla; Goldman, Steven; Goodman, Andrew; Green, Ari; Griffith, Linda; Hartung, Hans-Peter; Hemmer, Bernhard; Hyun, Insoo; Iacobaeus, Ellen; Inglese, Matilde; Jubelt, Burk; Karussis, Dimitrios; Küry, Patrick; Landsman, Douglas; Laule, Cornelia; Liblau, Roland; Mancardi, Giovanni; Ann Marrie, Ruth; Miller, Aaron; Miller, Robert; Miller, David; Mowry, Ellen; Muraro, Paolo; Nash, Richard; Ontaneda, Daniel; Pasquini, Marcelo; Pelletier, Daniel; Peruzzotti-Jametti, Luca; Pluchino, Stefano; Racke, Michael; Reingold, Stephen; Rice, Claire; Ringdén, Olle; Rovira, Alex; Saccardi, Riccardo; Sadiq, Saud; Sarantopoulos, Stefanie; Savitz, Sean; Scolding, Neil; Soelberg Sorensen, Per; Pia Sormani, Maria; Stuve, Olaf; Tesar, Paul; Thompson, Alan; Trojano, Maria; Uccelli, Antonio; Uitdehaag, Bernard; Utz, Ursula; Vukusic, Sandra; Waubant, Emmanuelle; Wilkins, Alastair

2017-01-01

Abstract The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. PMID:29053779

Tantalus, Restraint Theory, and the Low-Sacrifice Diet: The Art of Reverse Abstraction

PubMed Central

Blair-West, George W.

2007-01-01

This paper argues that clinicians face the unique artistic challenge of taking concrete pieces of data – scientific findings – and abstracting them into effective therapeutic interventions. Moreover, this abstraction has to be modified for different personality types. The process of therapeutic change and how it can be impeded by the traditional medical model are briefly explored. The doctor-patient dyadic treatment relationship, while appropriate and necessary for many medical interventions, can disavow the source of change when it comes to lifestyle conditions such as obesity. Restraint theory and its origins in Greek mythology are briefly reviewed and integrated with Bowlby's attachment theory as precepts in developing a psychologically based dietary approach. By retaining in people's diets foods they have a deep emotional attachment to, the low-sacrifice diet attempts to encourage caloric restriction in a way that does not trigger rebound overeating. PMID:18311368

Treponema pallidum Putative Novel Drug Target Identification and Validation: Rethinking Syphilis Therapeutics with Plant-Derived Terpenoids

PubMed Central

Tiwari, Sameeksha; Singh, Priyanka; Singh, Swati; Awasthi, Manika; Pandey, Veda P.

2015-01-01

Abstract Syphilis, a slow progressive and the third most common sexually transmitted disease found worldwide, is caused by a spirochete gram negative bacteria Treponema pallidum. Emergence of antibiotic resistant T. pallidum has led to a search for novel drugs and their targets. Subtractive genomics analyses of pathogen T. pallidum and host Homo sapiens resulted in identification of 126 proteins essential for survival and viability of the pathogen. Metabolic pathway analyses of these essential proteins led to discovery of nineteen proteins distributed among six metabolic pathways unique to T. pallidum. One hundred plant-derived terpenoids, as potential therapeutic molecules against T. pallidum, were screened for their drug likeness and ADMET (absorption, distribution, metabolism, and toxicity) properties. Subsequently the resulting nine terpenoids were docked with five unique T. pallidum targets through molecular modeling approaches. Out of five targets analyzed, D-alanine:D-alanine ligase was found to be the most promising target, while terpenoid salvicine was the most potent inhibitor. A comparison of the inhibitory potential of the best docked readily available natural compound, namely pomiferin (flavonoid) with that of the best docked terpenoid salvicine, revealed that salvicine was a more potent inhibitor than that of pomiferin. To the best of our knowledge, this is the first report of a terpenoid as a potential therapeutic molecule against T. pallidum with D-alanine:D-alanine ligase as a novel target. Further studies are warranted to evaluate and explore the potential clinical ramifications of these findings in relation to syphilis that has public health importance worldwide. PMID:25683888

Aptamers and their Applications in Nanomedicine

PubMed Central

Sun, Hongguang; Zu, Youli

2015-01-01

Aptamers are composed of short RNA or single-stranded DNA sequences that, when folded into their unique three-dimensional conformation, can specifically bind to their cognate targets with high specificity and affinity. Although functionally similar to protein antibodies, oligonucleotide aptamers offer several advantages over protein antibodies in biomedical and clinical applications. Additionally, through the enhanced permeability and retention (EPR) effect, nanomedicines can improve the therapeutic index of a treatment and reduce side effects by enhancing accumulation at the disease site. However, this EPR effect is “passive targeting” to tumors and thus, may not be an ideal approach for targeted cancer therapy. To construct ligand-directed “active targeting” nano-based delivery systems, aptamer technology has been widely studied. The aptamer-equipped nanomedicines have been tested for in vitro diagnosis, in vivo imaging, targeted cancer therapy, theranostic approaches, sub-cellular molecule detection, food safety, and environment monitoring. This review will focus on the development of aptamer-conjugated nanomedicines and their application for in vivo imaging, targeted therapy, and theranostics. In some applications, aptamers can also be used as drug carriers or ON/OFF switches. Herein, some outstanding therapeutic approaches are also discussed on a case-by-case basis, such as an “on-command” release system and a combinational therapy strategy. PMID:25677591

The Collaborative Assessment and Management of Suicidality (CAMS): an evolving evidence-based clinical approach to suicidal risk.

PubMed

Jobes, David A

2012-12-01

The Collaborative Assessment and Management of Suicidality (CAMS) is an evidence-based clinical intervention that has significantly evolved over 25 years of clinical research. CAMS is best understood as a therapeutic framework that emphasizes a unique collaborative assessment and treatment planning process between the suicidal patient and clinician. This process is designed to enhance the therapeutic alliance and increase treatment motivation in the suicidal patient. Central to the CAMS approach is the use of the Suicide Status Form (SSF), which is a multipurpose clinical assessment, treatment planning, tracking, and outcome tool. The original development of CAMS was largely rooted in SSF-based quantitative and qualitative assessment of suicidal risk. As this line of research progressed, CAMS emerged as a problem-focused clinical intervention that is designed to target and treat suicidal "drivers" and ultimately eliminate suicidal coping. To date, CAMS (and the clinical use of the SSF) has been supported by six published correlational studies and one randomized clinical trial (RCT). Currently, two well-powered RCTs are under way, and various new CAMS-related projects are also being pursued. The clinical and empirical evolution of CAMS-how it was developed and what are the next steps for this clinical approach-are described here. © 2012 The American Association of Suicidology.

IFN-λ: A New Inducer of Local Immunity against Cancer and Infections.

PubMed

Lasfar, Ahmed; Zloza, Andrew; de la Torre, Andrew; Cohen-Solal, Karine A

2016-01-01

IFN-λ is the newly established type III IFN with unique immunomodulatory functions. In contrast to the IFN-α/β family and to some extent IFN-γ, IFN-λ is apparently acting in specific areas of the body to activate resident immune cells and induces a local immunity, instrumental in preventing particular infections and also keeping transformed cells under control. Mucosal areas of lung and gastrointestinal tracts are now under scrutiny to elucidate the immune mechanisms triggered by IFN-λ and leading to viral protection. New evidence also indicates the crucial role of IFN-λ in promoting innate immunity in solid cancer models. Based on its unique biological activities among the IFN system, new immunotherapeutic approaches are now emerging for the treatment of cancer, infection, and autoimmune diseases. In the present review, we highlight the recent advances of IFN-λ immunomodulatory functions. We also discuss the perspectives of IFN-λ as a therapeutic agent.

Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics

PubMed Central

Haake, Scott M.; Li, Jiannong; Bai, Yun; Kinose, Fumi; Fang, Bin; Welsh, Eric; Zent, Roy; Dhillon, Jasreman; Pow-Sang, Julio; Chen, Yian Ann; Koomen, John; Rathmell, W. Kimryn; Fishman, Mayer; Haura, Eric B.

2016-01-01

Purpose Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. Experimental Design Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. In order to describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed. Results Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, while DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets. Conclusions Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology amongst kidney cancer subtypes. PMID:27220961

Concise Review: Mesenchymal Stem Cell Therapy for Pediatric Disease: Perspectives on Success and Potential Improvements

PubMed Central

Nitkin, Christopher R.

2016-01-01

Abstract Mesenchymal stem cells (MSCs) represent a potentially revolutionary therapy for a wide variety of pediatric diseases, but the optimal cell‐based therapeutics for such diversity have not yet been specified. The published clinical trials for pediatric pulmonary, cardiac, orthopedic, endocrine, neurologic, and hematologic diseases provide evidence that MSCs are indeed efficacious, but the significant heterogeneity in therapeutic approaches between studies raises new questions. The purpose of this review is to stimulate new preclinical and clinical trials to investigate these factors. First, we discuss recent clinical trials for pediatric diseases studying MSCs obtained from bone marrow, umbilical cord and umbilical cord blood, placenta, amniotic fluid, and adipose tissue. We then identify factors, some unique to pediatrics, which must be examined to optimize therapeutic efficacy, including route of administration, dose, timing of administration, the role of ex vivo differentiation, cell culture techniques, donor factors, host factors, and the immunologic implications of allogeneic therapy. Finally, we discuss some of the practicalities of bringing cell‐based therapy into the clinic, including regulatory and manufacturing considerations. The aim of this review is to inform future studies seeking to maximize therapeutic efficacy for each disease and for each patient. Stem Cells Translational Medicine 2017;6:539–565 PMID:28191766

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

PubMed Central

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

2016-01-01

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

An Integrative Approach to Treatment-Resistant Obsessive-Compulsive Disorder.

PubMed

Woon, Luke Sy-Cherng; Kanapathy, Anita; Zakaria, Hazli; Alfonso, César A

2017-01-01

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder that often runs a chronic unremitting course. Treatment outcomes can be unsatisfactory despite the availability of various somatic and psychological therapies. Psychodynamic psychotherapy in combination with cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) could help patients with treatment-resistant OCD achieve better outcomes. An integrative approach can help patients gain insight, strengthen the therapeutic alliance, improve treatment adherence, and provide symptomatic relief when other treatments seem insufficient or have failed. We describe the treatment process of a person with treatment-resistant OCD who received pharmacotherapy, concurrent CBT/ERP, and a brief course of psychodynamic psychotherapy. Case formulations from cognitive behavioral and psychodynamic perspectives are presented. The authors discuss the advantages of doing a psychodynamic assessment and formulation in treatment refractory cases and the wisdom of integrating psychotherapy interventions for OCD, as well as the unique clinical features of cases that warrant a multimodal treatment approach.

Non-genetic engineering of cells for drug delivery and cell-based therapy.

PubMed

Wang, Qun; Cheng, Hao; Peng, Haisheng; Zhou, Hao; Li, Peter Y; Langer, Robert

2015-08-30

Cell-based therapy is a promising modality to address many unmet medical needs. In addition to genetic engineering, material-based, biochemical, and physical science-based approaches have emerged as novel approaches to modify cells. Non-genetic engineering of cells has been applied in delivering therapeutics to tissues, homing of cells to the bone marrow or inflammatory tissues, cancer imaging, immunotherapy, and remotely controlling cellular functions. This new strategy has unique advantages in disease therapy and is complementary to existing gene-based cell engineering approaches. A better understanding of cellular systems and different engineering methods will allow us to better exploit engineered cells in biomedicine. Here, we review non-genetic cell engineering techniques and applications of engineered cells, discuss the pros and cons of different methods, and provide our perspectives on future research directions. Copyright © 2014 Elsevier B.V. All rights reserved.

Holistic Medicine: Advances and Shortcomings

PubMed Central

Gordon, James S.

1982-01-01

Holistic medicine is an attitudinal approach to health care rather than a particular set of techniques. It addresses the psychological, familial, societal, ethical and spiritual as well as biological dimensions of health and illness. The holistic approach emphasizes the uniqueness of each patient, the mutuality of the doctor-patient relationship, each person's responsibility for his or her own health care and society's responsibility for the promotion of health. As holism has become an increasingly popular concept, it has been distorted by both proponents and critics. Tendencies to equate holism with particular therapeutic modalities, to neglect public health for a one-sided emphasis on individual responsibility and to reject rather than elaborate on the scientific method have hampered the movement's progress. In the future orthodox and alternative approaches and techniques must all be seen as complementary parts of a larger synthesis that will genuinely deserve the name of holism. PMID:7113200

Drug conjugated nanoparticles activated by cancer cell specific mRNA.

PubMed

Gossai, Nathan P; Naumann, Jordan A; Li, Nan-Sheng; Zamora, Edward A; Gordon, David J; Piccirilli, Joseph A; Gordon, Peter M

2016-06-21

We describe a customizable approach to cancer therapy in which a gold nanoparticle (Au-NP) delivers a drug that is selectively activated within the cancer cell by the presence of an mRNA unique to the cancer cell. Fundamental to this approach is the observation that the amount of drug released from the Au-NP is proportional to both the presence and abundance of the cancer cell specific mRNA in a cell. As proof-of-principle, we demonstrate both the efficient delivery and selective release of the multi-kinase inhibitor dasatinib from Au-NPs in leukemia cells with resulting efficacy in vitro and in vivo. Furthermore, these Au-NPs reduce toxicity against hematopoietic stem cells and T-cells. This approach has the potential to improve the therapeutic efficacy of a drug and minimize toxicity while being highly customizable with respect to both the cancer cell specific mRNAs targeted and drugs activated.

Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards.

PubMed

French, Anna; Bravery, Christopher; Smith, James; Chandra, Amit; Archibald, Peter; Gold, Joseph D; Artzi, Natalie; Kim, Hae-Won; Barker, Richard W; Meissner, Alexander; Wu, Joseph C; Knowles, Jonathan C; Williams, David; García-Cardeña, Guillermo; Sipp, Doug; Oh, Steve; Loring, Jeanne F; Rao, Mahendra S; Reeve, Brock; Wall, Ivan; Carr, Andrew J; Bure, Kim; Stacey, Glyn; Karp, Jeffrey M; Snyder, Evan Y; Brindley, David A

2015-03-01

There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes. ©AlphaMed Press.

Recent Advances of Light-Mediated Theranostics

PubMed Central

Ai, Xiangzhao; Mu, Jing; Xing, Bengang

2016-01-01

Currently, precision theranostics have been extensively demanded for the effective treatment of various human diseases. Currently, efficient therapy at the targeted disease areas still remains challenging since most available drug molecules lack of selectivity to the pathological sites. Among different approaches, light-mediated therapeutic strategy has recently emerged as a promising and powerful tool to precisely control the activation of therapeutic reagents and imaging probes in vitro and in vivo, mostly attributed to its unique properties including minimally invasive capability and highly spatiotemporal resolution. Although it has achieved initial success, the conventional strategies for light-mediated theranostics are mostly based on the light with short wavelength (e.g., UV or visible light), which may usually suffer from several undesired drawbacks, such as limited tissue penetration depth, unavoidable light absorption/scattering and potential phototoxicity to healthy tissues, etc. Therefore, a near-infrared (NIR) light-mediated approach on the basis of long-wavelength light (700-1000 nm) irradiation, which displays deep-tissue penetration, minimized photo-damage and low autofluoresence in living systems, has been proposed as an inspiring alternative for precisely phototherapeutic applications in the last decades. Despite numerous NIR light-responsive molecules have been currently proposed for clinical applications, several inherent drawbacks, such as troublesome synthetic procedures, low water solubility and limited accumulation abilities in targeted areas, heavily restrict their applications in deep-tissue therapeutic and imaging studies. Thanks to the amazing properties of several nanomaterials with large extinction coefficient in the NIR region, the construction of NIR light responsive nanoplatforms with multifunctions have become promising approaches for deep-seated diseases diagnosis and therapy. In this review, we summarized various light-triggered theranostic strategies and introduced their great advances in biomedical applications in recent years. Moreover, some other promising light-assisted techniques, such as photoacoustic and Cerenkov radiation, were also systemically discussed. Finally, the potential challenges and future perspectives for light-mediated deep-tissue diagnosis and therapeutics were proposed. PMID:27877246

Enabling Consistency in Pluripotent Stem Cell-Derived Products for Research and Development and Clinical Applications Through Material Standards

PubMed Central

Bravery, Christopher; Smith, James; Chandra, Amit; Archibald, Peter; Gold, Joseph D.; Artzi, Natalie; Kim, Hae-Won; Barker, Richard W.; Meissner, Alexander; Wu, Joseph C.; Knowles, Jonathan C.; Williams, David; García-Cardeña, Guillermo; Sipp, Doug; Oh, Steve; Loring, Jeanne F.; Rao, Mahendra S.; Reeve, Brock; Wall, Ivan; Carr, Andrew J.; Bure, Kim; Stacey, Glyn; Karp, Jeffrey M.

2015-01-01

Summary There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify “signatures” for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes. PMID:25650438

Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities

PubMed Central

Nadeau, Kristen J.; Anderson, Barbara J.; Berg, Erika G.; Chiang, Jane L.; Chou, Hubert; Copeland, Kenneth C.; Hannon, Tamara S.; Huang, Terry T.-K.; Lynch, Jane L.; Powell, Jeff; Sellers, Elizabeth; Tamborlane, William V.

2016-01-01

Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments. PMID:27486237

Microbial ecology of the skin in the era of metagenomics and molecular microbiology.

PubMed

Hannigan, Geoffrey D; Grice, Elizabeth A

2013-12-01

The skin is the primary physical barrier between the body and the external environment and is also a substrate for the colonization of numerous microbes. Previously, dermatological microbiology research was dominated by culture-based techniques, but significant advances in genomic technologies have enabled the development of less-biased, culture-independent approaches to characterize skin microbial communities. These molecular microbiology approaches illustrate the great diversity of microbiota colonizing the skin and highlight unique features such as site specificity, temporal dynamics, and interpersonal variation. Disruptions in skin commensal microbiota are associated with the progression of many dermatological diseases. A greater understanding of how skin microbes interact with each other and with their host, and how we can therapeutically manipulate those interactions, will provide powerful tools for treating and preventing dermatological disease.

Nanotechnology based approaches for detection and delivery of microRNA in healthcare and crop protection.

PubMed

Chaudhary, Vrantika; Jangra, Sumit; Yadav, Neelam R

2018-04-13

Nanobiotechnology has the potential to revolutionize diverse sectors including medicine, agriculture, food, textile and pharmaceuticals. Disease diagnostics, therapeutics and crop protection strategies are fast emerging using nanomaterials preferably nanobiomaterials. It has potential for development of novel nanobiomolecules which offer several advantages over conventional treatment methods. RNA nanoparticles with many unique features are promising candidates in disease treatment. The miRNAs are involved in many biochemical and developmental pathways and their regulation in plants and animals. These appear to be a powerful tool for controlling various pathological diseases in human, plants and animals, however there are challenges associated with miRNA based nanotechnology. Several advancements made in the field of miRNA therapeutics make it an attractive approach, but a lot more has to be explored in nanotechnology assisted miRNA therapy. The miRNA based technologies can be employed for detection and combating crop diseases as well. Despite these potential advantages, nanobiotechnology applications in the agricultural sector are still in its infancy and have not yet made its mark in comparison with healthcare sector. The review provides a platform to discuss nature, role and use of miRNAs in nanobiotechnology applications.

Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future

PubMed Central

Chen, Lieping; Han, Xue

2015-01-01

Major progress has been made toward our understanding of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway (referred to as the PD pathway). mAbs are already being used to block the PD pathway to treat human cancers (anti-PD therapy), especially advanced solid tumors. This therapy is based on principles that were discovered through basic research more than a decade ago, but the great potential of this pathway to treat a broad spectrum of advanced human cancers is just now becoming apparent. In this Review, we will briefly review the history and development of anti-PD therapy, from the original benchwork to the most up-to-date clinical results. We will then focus the discussion on three basic principles that define this unique therapeutic approach and highlight how anti-PD therapy is distinct from other immunotherapeutic approaches, namely tumor site immune modulation, targeting tumor-induced immune defects, and repairing ongoing (rather than generating de novo) tumor immunity. We believe that these fundamental principles set the standard for future immunotherapies and will guide our efforts to develop more efficacious and less toxic immune therapeutics to treat human cancers. PMID:26325035

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.

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.

Scavenger Receptor B1 is a Potential Biomarker of Human Nasopharyngeal Carcinoma and Its Growth is Inhibited by HDL-mimetic Nanoparticles

PubMed Central

Zheng, Ying; Liu, Yanyan; Jin, Honglin; Pan, Shaotao; Qian, Yuan; Huang, Chuan; Zeng, Yixin; Luo, Qingming; Zeng, Musheng; Zhang, Zhihong

2013-01-01

Nasopharyngeal carcinoma (NPC) is a very regional malignant head and neck cancer that has attracted widespread attention for its unique etiology, epidemiology and therapeutic options. To achieve high cure rates in NPC patients, theranostic approaches are actively being pursued and improved efforts remain desirable in identifying novel biomarkers and establishing effective therapeutic approaches with low long-term toxicities. Here, we discovered that the scavenger receptor class B type I (SR-B1) was overexpressed in all investigated NPC cell lines and 75% of NPC biopsies, demonstrating that SR-B1 is a potential biomarker of NPC. Additional functional analysis showed that SR-B1 has great effect on cell motility while showing no significant impact on cell proliferation. As high-density lipoproteins (HDL) exhibit strong binding affinities to SR-B1 and HDL mimetic peptides are reportedly capable of inhibiting tumor growth, we further examined the SR-B1 targeting ability of a highly biocompatible HDL-mimicking peptide-phospholipid scaffold (HPPS) nanocarrier and investigated its therapeutic effect on NPC. Results show that NPC cells with higher SR-B1 expression have superior ability in taking up the core constituents of HPPS. Moreover, HPPS inhibited the motility and colony formation of 5-8F cells, and significantly suppressed the NPC cell growth in nude mice without inducing tumor cell necrosis or apoptosis. These results indicate that HPPS is not only a NPC-targeting nanocarrier but also an effective anti-NPC drug. Together, the identification of SR-B1 as a potential biomarker and the use of HPPS as an effective anti-NPC agent may shed new light on the diagnosis and therapeutics of NPC. PMID:23843895

Functional mesoporous silica nanoparticles for bio-imaging applications.

PubMed

Cha, Bong Geun; Kim, Jaeyun

2018-03-22

Biomedical investigations using mesoporous silica nanoparticles (MSNs) have received significant attention because of their unique properties including controllable mesoporous structure, high specific surface area, large pore volume, and tunable particle size. These unique features make MSNs suitable for simultaneous diagnosis and therapy with unique advantages to encapsulate and load a variety of therapeutic agents, deliver these agents to the desired location, and release the drugs in a controlled manner. Among various clinical areas, nanomaterials-based bio-imaging techniques have advanced rapidly with the development of diverse functional nanoparticles. Due to the unique features of MSNs, an imaging agent supported by MSNs can be a promising system for developing targeted bio-imaging contrast agents with high structural stability and enhanced functionality that enable imaging of various modalities. Here, we review the recent achievements on the development of functional MSNs for bio-imaging applications, including optical imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), ultrasound imaging, and multimodal imaging for early diagnosis. With further improvement in noninvasive bio-imaging techniques, the MSN-supported imaging agent systems are expected to contribute to clinical applications in the future. This article is categorized under: Diagnostic Tools > In vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology. © 2018 Wiley Periodicals, Inc.

Complementary and alternative medicine whole systems research: beyond identification of inadequacies of the RCT.

PubMed

Verhoef, Marja J; Lewith, George; Ritenbaugh, Cheryl; Boon, Heather; Fleishman, Susan; Leis, Anne

2005-09-01

Complementary and alternative medicine (CAM) often consists of whole systems of care (such as naturopathic medicine or traditional Chinese medicine (TCM)) that combine a wide range of modalities to provide individualised treatment. The complexity of these interventions and their potential synergistic effect requires innovative evaluative approaches. Model validity, which encompasses the need for research to adequately address the unique healing theory and therapeutic context of the intervention, is central to whole systems research (WSR). Classical randomised controlled trials (RCTs) are limited in their ability to address this need. Therefore, we propose a mixed methods approach that includes a range of relevant and holistic outcome measures. As the individual components of most whole systems are inseparable, complementary and synergistic, WSR must not focus only on the "active" ingredients of a system. An emerging WSR framework must be non-hierarchical, cyclical, flexible and adaptive, as knowledge creation is continuous, evolutionary and necessitates a continuous interplay between research methods and "phases" of knowledge. Finally, WSR must hold qualitative and quantitative research methods in equal esteem to realize their unique research contribution. Whole systems are complex and therefore no one method can adequately capture the meaning, process and outcomes of these interventions.

Identification and characterization of potential druggable targets among hypothetical proteins of extensively drug resistant Mycobacterium tuberculosis (XDR KZN 605) through subtractive genomics approach.

PubMed

Uddin, Reaz; Siddiqui, Quratulain Nehal; Azam, Syed Sikander; Saima, Bibi; Wadood, Abdul

2018-03-01

Among the resistant isolates of tuberculosis (TB), the multidrug resistance tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) are the areas of growing concern for which the front-line antibiotics are no more effective. As a result, the search of new therapeutic targets against TB is an imperative need of time. On the other hand, the target identification is an a priori step in drug discovery based research. Furthermore, the availability of the complete proteomic data of extensively drug resistant Mycobacterium tuberculosis (XDR-MTB) made it possible to carry out in silico analysis for the discovery of new drug targets. In the current study, we aimed to prioritize the potential drug targets among the hypothetical proteins of XDR-TB via subtractive genomics approach. In the subtractive genomics, we stepwise reduced the complete proteome of XDR-MTB to only two hypothetical proteins and evidently proposed them as new therapeutic targets. The 3D structure of one of the two target proteins was predicted via homology modeling and later on, validated by various analysis tools. Our study suggested that the domains identified and the motif hits found in the sequences of the shortlisted drug targets are crucial for the survival of the XDR-MTB. To the best of our knowledge, the current study is the first attempt in which the complete proteomic data of XDR-MTB was subjected to the computational subtractive genomics approach and therefore, would provide an opportunity to identify the unique therapeutic targets against deadly XDR-MTB. Copyright © 2017 Elsevier B.V. All rights reserved.

A model for treating voice disorders in school-age children within a video gaming environment.

PubMed

King, Suzanne N; Davis, Larry; Lehman, Jeffrey J; Ruddy, Bari Hoffman

2012-09-01

Clinicians use a variety of approaches to motivate children with hyperfunctional voice disorders to comply with voice therapy in a therapeutic session and improve the motivation of children to practice home-based exercises. Utilization of current entertainment technology in such approaches may improve participation and motivation in voice therapy. The purpose of this study is to test the feasibility of using an entertainment video game as a therapy device. Prospective cohort and case-control study. Three levels of game testing were conducted to an existing entertainment video game for use as a voice therapy protocol. The game was tested by two computer programmers and five normal participants. The third level of testing was a case study with a child diagnosed with a hyperfunctional voice disorder. Modifications to the game were made after each feasibility test. Errors with the video game performance were modified, including the addition of a time stamp directory and game controller. Resonance voice exercises were modified to accommodate the gaming environment and unique competitive situation, including speech rate, acoustic parameters, game speed, and point allocations. The development of video games for voice therapeutic purposes attempt to replicate the high levels of engagement and motivation attained with entertainment video games, stimulating a more productive means of learning while doing. This case study found that a purely entertainment video game can be implemented as a voice therapeutic protocol based on information obtained from the case study. Copyright © 2012 The Voice Foundation. All rights reserved.

Image-Guided Drug Delivery with Single-Photon Emission Computed Tomography: A Review of Literature

PubMed Central

Chakravarty, Rubel; Hong, Hao; Cai, Weibo

2014-01-01

Tremendous resources are being invested all over the world for prevention, diagnosis, and treatment of various types of cancer. Successful cancer management depends on accurate diagnosis of the disease along with precise therapeutic protocol. The conventional systemic drug delivery approaches generally cannot completely remove the competent cancer cells without surpassing the toxicity limits to normal tissues. Therefore, development of efficient drug delivery systems holds prime importance in medicine and healthcare. Also, molecular imaging can play an increasingly important and revolutionizing role in disease management. Synergistic use of molecular imaging and targeted drug delivery approaches provides unique opportunities in a relatively new area called `image-guided drug delivery' (IGDD). Single-photon emission computed tomography (SPECT) is the most widely used nuclear imaging modality in clinical context and is increasingly being used to guide targeted therapeutics. The innovations in material science have fueled the development of efficient drug carriers based on, polymers, liposomes, micelles, dendrimers, microparticles, nanoparticles, etc. Efficient utilization of these drug carriers along with SPECT imaging technology have the potential to transform patient care by personalizing therapy to the individual patient, lessening the invasiveness of conventional treatment procedures and rapidly monitoring the therapeutic efficacy. SPECT-IGDD is not only effective for treatment of cancer but might also find utility in management of several other diseases. Herein, we provide a concise overview of the latest advances in SPECT-IGDD procedures and discuss the challenges and opportunities for advancement of the field. PMID:25182469

Blood–brain barrier dysfunction and epilepsy: Pathophysiologic role and therapeutic approaches

PubMed Central

Marchi, Nicola; Granata, Tiziana; Ghosh, Chaitali; Janigro, Damir

2016-01-01

The blood–brain barrier (BBB) is located within a unique anatomic interface and has functional ramifications to most of the brain and blood cells. In the past, the BBB was considered a pharmacokinetic impediment to antiepileptic drug penetration into the brain; nowadays it is becoming increasingly evident that targeting of the damaged or dysfunctional BBB may represent a therapeutic approach to reduce seizure burden. Several studies have investigated the mechanisms linking the onset and sustainment of seizures to BBB dysfunction. These studies have shown that the BBB is at the crossroad of a multifactorial pathophysiologic process that involves changes in brain milieu, altered neuroglial physiology, development of brain inflammation, leukocyte–endothelial interactions, faulty angiogenesis, and hemodynamic changes leading to energy mismatch. A number of knowledge gaps, conflicting points of view, and discordance between clinical and experimental data currently characterize this field of neuroscience. As more pieces are added to this puzzle, it is apparent that each mechanism needs to be validated in an appropriate clinical context. We now offer a BBB-centric view of seizure disorders, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction. We have reviewed the therapeutic, antiseizure effect of drugs that promote BBB repair. We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add-on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs. PMID:22905812

Breast Cancer: A Molecular and Redox Snapshot.

PubMed

Raman, Deepika; Foo, Chuan Han Jonathan; Clement, Marie-Veronique; Pervaiz, Shazib

2016-08-20

Breast cancer is a unique disease characterized by heterogeneous cell populations causing roadblocks in therapeutic medicine, owing to its complex etiology and primeval understanding of the biology behind its genesis, progression, and sustenance. Globocan statistics indicate over 1.7 million new breast cancer diagnoses in 2012, accounting for 25% of all cancer morbidities. Despite these dismal statistics, the introduction of molecular gene signature platforms, progressive therapeutic approaches in diagnosis, and management of breast cancer has led to more effective treatment strategies and control measures concurrent with an equally reassuring decline in the mortality rate. However, an enormous body of research in this area is requisite as high mortality associated with metastatic and/or drug refractory tumors continues to present a therapeutic challenge. Despite advances in systemic chemotherapy, the median survival of patients harboring metastatic breast cancers continues to be below 2 years. Hence, a massive effort to scrutinize and evaluate chemotherapeutics on the basis of the molecular classification of these cancers is undertaken with the objective to devise more attractive and feasible approaches to treat breast cancers and improve patients' quality of life. This review aims to summarize the current understanding of the biology of breast cancer as well as challenges faced in combating breast cancer, with special emphasis on the current battery of treatment strategies. We will also try and gain perspective from recent encounters on novel findings responsible for the progression and metastatic transformation of breast cancer cells in an endeavor to develop more targeted treatment options. Antioxid. Redox Signal. 25, 337-370.

How therapeutic communities work: Specific factors related to positive outcome

PubMed Central

Pearce, Steve; Pickard, Hanna

2012-01-01

Background Therapeutic communities (TCs) are becoming increasingly widespread as a form of treatment for entrenched mental health problems, particularly addictions and personality disorders, and are equally used in educational, prison and learning disability settings. Despite growing evidence for their effectiveness, little research has been conducted to establish how TCs work to produce positive outcomes. We hypothesize that there are two specific factors that in combination contribute to TC effectiveness: the promotion of a sense of belongingness and the capacity for responsible agency. Although both factors are found in other therapeutic approaches and are important to the psychosocial aspects of psychiatric care more generally, we argue that their combination, extent and emphasis are unique to TCs. Material Drawing on social and experimental psychology, we: (1) review research on a sense of belongingness and the capacity for responsible agency; (2) establish the mechanisms by which TCs appear to promote them; (3) draw lessons for TC practice; and (4) suggest why they may contribute to positive outcome. Discussion A sense of belongingness is correlated with improved self-esteem and overall well-being. The capacity for responsible agency is central to behavioural change. TCs are typically used in fields where positive outcome requires both personal growth and behavioural change. We suggest that TCs are uniquely placed to demand such growth and change of their members because the sense of belongingness engendered by TC methods protects against the risks engendered by this demand. Conclusion Empirically informed, evidence-driven research is necessary to understand how TCs work and how TC practice can be improved. This understanding may offer lessons for the improvement of psychosocial aspects of psychiatric care more generally. PMID:22820178

Both MC1 and MC3 Receptors Provide Protection from Cerebral Ischemia Reperfusion Induced Neutrophil Recruitment

PubMed Central

Holloway, Paul M.; Durrenberger, Pascal F.; Trutschl, Marjan; Cvek, Urska; Cooper, Dianne; Orr, A. Wayne; Perretti, Mauro; Getting, Stephen J.; Gavins, Felicity N. E.

2015-01-01

Objective Neutrophil recruitment is a key process in the pathogenesis of stroke, and may provide a valuable therapeutic target. Targeting the melanocortin receptors (MC) has previously shown to inhibit leukocyte recruitment in peripheral inflammation, however it is not known whether treatments are effective in the unique cerebral microvascular environment. Here, we provide novel research highlighting the effects of the melanocortin peptides on cerebral neutrophil recruitment, demonstrating important yet discrete roles for both MC1 and MC3. Approach and Results Using intravital microscopy, in two distinct murine models of cerebral ischemia-reperfusion (I/R) injury we have investigated melanocortin control over neutrophil recruitment. Following global I/R, pharmacological treatments suppressed pathological neutrophil recruitment. MC1 selective treatment rapidly inhibited neutrophil recruitment while a non-selective MC agonist provided protection even when co-administered with an MC3/4 antagonist, suggesting the importance of early MC1 signaling. However by 2h reperfusion, MC1 mediated effects were reduced, and MC3 anti-inflammatory circuits predominated. Mice bearing a non-functional MC1 displayed a transient exacerbation of neutrophil recruitment following global I/R, which diminished by 2h. However importantly, enhanced inflammatory responses in both MC1 mutant and MC3-/- mice resulted in increased infarct size and poor functional outcome following focal I/R. Furthermore we utilized an in vitro model of leukocyte recruitment to demonstrate these anti-inflammatory actions are also effective in human cells. Conclusions These studies reveal for the first time melanocortin control over neutrophil recruitment in the unique pathophysiological context of cerebral I/R, whilst also demonstrating the potential therapeutic value of targeting multiple MCs in developing effective therapeutics. PMID:26112010

Spontaneous regression of neuroblastoma.

PubMed

Brodeur, Garrett M

2018-05-01

Neuroblastomas are characterized by heterogeneous clinical behavior, from spontaneous regression or differentiation into a benign ganglioneuroma, to relentless progression despite aggressive, multimodality therapy. Indeed, neuroblastoma is unique among human cancers in terms of its propensity to undergo spontaneous regression. The strongest evidence for this comes from the mass screening studies conducted in Japan, North America and Europe and it is most evident in infants with stage 4S disease. This propensity is associated with a pattern of genomic change characterized by whole chromosome gains rather than segmental chromosome changes but the mechanism(s) underlying spontaneous regression are currently a matter of speculation. There is evidence to support several possible mechanisms of spontaneous regression in neuroblastomas: (1) neurotrophin deprivation, (2) loss of telomerase activity, (3) humoral or cellular immunity and (4) alterations in epigenetic regulation and possibly other mechanisms. It is likely that a better understanding of the mechanisms of spontaneous regression will help to identify targeted therapeutic approaches for these tumors. The most easily targeted mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A (TrkA) pathway. Pan-Trk inhibitors are currently in clinical trials and so Trk inhibition might be used as the first line of therapy in infants with biologically favorable tumors that require treatment. Alternative approaches consist of breaking immune tolerance to tumor antigens but approaches to telomere shortening or epigenetic regulation are not easily druggable. The different mechanisms of spontaneous neuroblastoma regression are reviewed here, along with possible therapeutic approaches.

Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics.

PubMed

Haake, Scott M; Li, Jiannong; Bai, Yun; Kinose, Fumi; Fang, Bin; Welsh, Eric A; Zent, Roy; Dhillon, Jasreman; Pow-Sang, Julio M; Chen, Y Ann; Koomen, John M; Rathmell, W Kimryn; Fishman, Mayer; Haura, Eric B

2016-11-15

Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed. Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets. Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. ©2016 AACR. ©2016 American Association for Cancer Research.

Hemodynamic and oxygen transport patterns for outcome prediction, therapeutic goals, and clinical algorithms to improve outcome. Feasibility of artificial intelligence to customize algorithms.

PubMed

Shoemaker, W C; Patil, R; Appel, P L; Kram, H B

1992-11-01

A generalized decision tree or clinical algorithm for treatment of high-risk elective surgical patients was developed from a physiologic model based on empirical data. First, a large data bank was used to do the following: (1) describe temporal hemodynamic and oxygen transport patterns that interrelate cardiac, pulmonary, and tissue perfusion functions in survivors and nonsurvivors; (2) define optimal therapeutic goals based on the supranormal oxygen transport values of high-risk postoperative survivors; (3) compare the relative effectiveness of alternative therapies in a wide variety of clinical and physiologic conditions; and (4) to develop criteria for titration of therapy to the endpoints of the supranormal optimal goals using cardiac index (CI), oxygen delivery (DO2), and oxygen consumption (VO2) as proxy outcome measures. Second, a general purpose algorithm was generated from these data and tested in preoperatively randomized clinical trials of high-risk surgical patients. Improved outcome was demonstrated with this generalized algorithm. The concept that the supranormal values represent compensations that have survival value has been corroborated by several other groups. We now propose a unique approach to refine the generalized algorithm to develop customized algorithms and individualized decision analysis for each patient's unique problems. The present article describes a preliminary evaluation of the feasibility of artificial intelligence techniques to accomplish individualized algorithms that may further improve patient care and outcome.

[Self-selection processes in the choice of the therapeutic training approach: differences in therapeutic attitudes, personality traits and attributional complexity].

PubMed

Taubner, Svenja; Munder, Thomas; Möller, Heidi; Hanke, Wiebke; Klasen, Jennifer

2014-06-01

Treatment approaches differ to a great extent in terms of basic psychological assumptions and practical procedures. This creates questions about the fitting of therapist and therapeutic approach. This paper examines the influence of therapeutic attitudes, mentalization interest and personality traits on the decision for an approach. 184 participants of training programs in one of the 3 licensed treatment approaches in Germany were examined with questionnaires at the beginning of their training. Participants significantly differed in terms of therapeutic attitudes and the metallization interest but not in personality traits except openness. Satisfaction with training was not related to the individual fit of participants to the therapeutic attitudes typical for their approach. Therapeutic attitudes, the extent of mentalization interest, and openness may play a role in self-selection processes in the choice of the approach. © Georg Thieme Verlag KG Stuttgart · New York.

Garp as a therapeutic target for modulation of T regulatory cell function.

PubMed

Shevach, Ethan M

2017-02-01

Foxp3 + T regulatory cells (Tregs) play critical roles in immune homeostasis primarily by suppressing many aspects of the immune response. Tregs uniquely express GARP on their cell surface and GARP functions as a delivery system for latent TGF-β. As Treg-derived TGF-β may mediate the suppressive functions of Tregs, GARP may represent a target to inhibit Treg suppression in cancer or augment suppression in autoimmunity. Areas covered: This article will focus on 1) the role of Treg-derived TGF-β in the suppressive activity of Treg, 2) the cellular and molecular regulation of expression of GARP on mouse and human Tregs, 3) the role of integrins in the activation of latent-TGF-β/GARP complex, 4) an overview of our present understanding of the function of the latent-TGF-β/GARP complex. Expert opinion: Two approaches are outlined for targeting the L-TGF-β1/GARP complex for therapeutic purposes. Tregs play a major role in suppressive effector T cell responses to tumors and TGF-β1 may be a major contributor to this process. One approach is to specifically block the production of active TGF-β1 from Tregs as an adjunct to tumor immunotherapy. The second approach in autoimmunity is to selectively enhance the production of TGF-β by Tregs at sites of chronic inflammation.

Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey-Holden Prostate Cancer Academy Meeting.

PubMed

Miyahira, Andrea K; Cheng, Heather H; Abida, Wassim; Ellis, Leigh; Harshman, Lauren C; Spratt, Daniel E; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2017-11-01

The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer," was held in Carlsbad, California from June 14-17, 2017. The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer. © 2017 Wiley Periodicals, Inc.

Role of genotype-based approach in the clinical management of adult acute myeloid leukemia with normal cytogenetics.

PubMed

Cagnetta, Antonia; Adamia, Sophia; Acharya, Chirag; Patrone, Franco; Miglino, Maurizio; Nencioni, Alessio; Gobbi, Marco; Cea, Michele

2014-06-01

Acute myeloid leukemia (AML) is the most common form of acute leukemia affecting adults. Although it is a complex disease driven by numerous genetic and epigenetic abnormalities, nearly 50% of patients exhibit a normal karyotype (CN-AML) with an intermediate cytogenetic risk. However, a widespread genomic analysis has recently shown the recurrence of genomic aberrations in this category (mutations of FLT3, CEBPA, NPM1, RUNX1, TET2, IDH1/2, DNMT3A, ASXL1, MLL and WT1) thus revealing its marked genomic heterogeneity. In this perspective, a global gene expression analysis of AML patients provides an independent prognostic marker to categorize each patient into clinic-pathologic subgroups based on its molecular genetic defects. Consistently such classification, taking into account the uniqueness of each AML patient, furnishes an individualized treatment approach leading a step closer to personalized medicine. Overall the genome-wide analysis of AML patients, by providing novel insights into biology of this tumor, furnishes accurate prognostic markers as well as useful tools for selecting the most appropriate treatment option. Moreover it provides novel therapeutic targets useful to enhance efficacy of the current anti-AML therapeutics. Here we describe the prognostic relevance of such new genetic data and discuss how this approach can be used to improve survival and treatment of AML patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

OLITA: an alternative in the treatment of therapy-resistant chronic alcoholics. First evaluation of a new approach.

PubMed

Ehrenreich, H; Mangholz, A; Schmitt, M; Lieder, P; Völkel, W; Rüther, E; Poser, W

1997-01-01

The Outpatient Long-term Intensive Therapy for Alcoholics (OLITA) is a four-step program of care for severely affected chronic alcoholics which, after inpatient detoxification, extends over a total of 2 years. High-frequency short-term individual therapeutic contacts, initially daily, are followed by a slow tapering of individual contact frequency and resolve in a group session once weekly towards the end of the second abstinent year. Further elements of OLITA are: (a) induction of alcohol intolerance by the application of aldehyde dehydrogenase inhibitors; (b) introduction of control factors, i.e. controlled intake of deterrent medication and regular urine analysis for alcohol; and (c) allocation of responsibility to the patient with respect to the overall success of the therapeutic concept including his own physical rehabilitation. Thus far, 30 male alcoholic patients from two recruitment periods have been treated for 6-26 months with a success rate of 60% abstinent patients. In conclusion, OLITA, based on the gradual tapering of high-frequency therapeutic contacts, thus far unique among outpatient programs for alcoholics, represents a promising advance in the treatment of therapy-resistant chronic alcoholics.

Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways

PubMed Central

Chowdhury, Fabliha Ahmed; Hossain, Md Kamal; Mostofa, A. G. M.; Akbor, Maruf Mohammad

2018-01-01

Glioblastoma multiforme (GBM) is one of the most devastating brain tumors with median survival of one year and presents unique challenges to therapy because of its aggressive behavior. Current treatment strategy involves surgery, radiotherapy, immunotherapy, and adjuvant chemotherapy even though optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment. Thymoquinone (TQ), the main bioactive component of Nigella sativa L., has exhibited anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteract carcinogenesis, malignant growth, invasion, migration, and angiogenesis. TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells. Its potential to enter brain via nasal pathway due to volatile nature of TQ adds another advantage in overcoming blood-brain barrier. In this review, we summarized the potential role of TQ in different signaling pathways in GBM that have undergone treatment with standard therapeutic modalities or with TQ. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical level to delineate its implied utility as novel therapeutics to combat the challenges for the treatment of GBM. PMID:29651429

Trespassing cancer cells: ‘fingerprinting’ invasive protrusions reveals metastatic culprits

PubMed Central

Klemke, Richard L.

2012-01-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial “omics” approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. PMID:22980730

Complex Care Options for Patients With Advanced Heart Failure Approaching End of Life.

PubMed

Wordingham, Sara E; McIlvennan, Colleen K; Dionne-Odom, J Nicholas; Swetz, Keith M

2016-02-01

Care for patients with advanced cardiac disease continues to evolve in a complex milieu of therapeutic options, advanced technological interventions, and efforts at improving patient-centered care and shared decision-making. Despite improvements in quality of life and survival with these interventions, optimal supportive care across the advanced illness trajectory remains diverse and heterogeneous. Herein, we outline challenges in prognostication, communication, and caregiving in advanced heart failure and review the unique needs of patients who experience frequent hospitalizations, require chronic home inotropic support, and who have implantable cardioverter-defibrillators and mechanical circulatory support in situ, to name a few.

Genetic Control of Wayward Pluripotent Stem Cells and Their Progeny after Transplantation

PubMed Central

Kiuru, Maija; Boyer, Julie L.; O’Connor, Timothy P.; Crystal, Ronald G.

2011-01-01

The proliferative capacity of pluripotent stem cells and their progeny brings a unique aspect to therapeutics, in that once a transplant is initiated the therapist no longer has control of the therapy. In the context of the recent FDA approval of a human ESC trial and report of a neuronal-stem-cell-derived tumor in a human trial, strategies need to be developed to control wayward pluripotent stem cells. Here, we focus on one approach: direct genetic modification of the cells prior to transplantation with genes that can prevent the adverse events and/or eliminate the transplanted cells and their progeny. PMID:19341619

Update and new approaches in the treatment of Castleman disease

PubMed Central

Chan, Kah-Lok; Lade, Stephen; Prince, H Miles; Harrison, Simon J

2016-01-01

First described 60 years ago, Castleman disease comprises a rare and heterogeneous cluster of disorders, characterized by lymphadenopathy with unique histological features and associated with cytokine-driven constitutional symptoms and biochemical disturbances. Although unicentric Castleman disease is curable with complete surgical excision, its multicentric counterpart is a considerable therapeutic challenge. The recent development of biological agents, particularly monoclonal antibodies to interleukin-6 and its receptor, allow for more targeted disease-specific intervention that promises improved response rates and more durable disease control; however, further work is required to fill knowledge gaps in terms of underlying pathophysiology and to facilitate alternative treatment options for refractory cases. PMID:27536166

Toward a Biology-Driven Treatment Strategy for Peripheral T-cell Lymphoma

PubMed Central

Hildyard, CAT; Shiekh, S; Browning, JAB; Collins, GP

2017-01-01

T-cell and natural killer–cell lymphomas are a relatively rare and heterogeneous group of diseases that are difficult to treat and usually have poor outcomes. To date, therapeutic interventions are of limited efficacy and there is a pressing need to find better treatments. In recent years, advances in molecular biology have helped to elucidate the underlying genetic complexity of this group of diseases and to identify mutations and signaling pathways involved in lymphomagenesis. In this review, we highlight the unique biological characteristics of some of the different subtypes and discuss how these may be targeted to provide more individualized and effective treatment approaches. PMID:28579857

Femtosecond laser beam propagation through corneal tissue: Evaluation of therapeutic laser-stimulated second and third- harmonic generation

NASA Astrophysics Data System (ADS)

Calhoun, William R., III

One of the most recent advancements in laser technology is the development of ultrashort pulsed femtosecond lasers (FSLs). FSLs are improving many fields due to their unique extreme precision, low energy and ablation characteristics. In the area of laser medicine, ophthalmic surgeries have seen very promising developments. Some of the most commonly performed surgical operations in the world, including laser-assisted in-situ keratomileusis (LASIK), lens replacement (cataract surgery), and keratoplasty (cornea transplant), now employ FSLs for their unique abilities that lead to improved clinical outcome and patient satisfaction. The application of FSLs in medical therapeutics is a recent development, and although they offer many benefits, FSLs also stimulate nonlinear optical effects (NOEs), many of which were insignificant with previously developed lasers. NOEs can change the laser characteristics during propagation through a medium, which can subsequently introduce unique safety concerns for the surrounding tissues. Traditional approaches for characterizing optical effects, laser performance, safety and efficacy do not properly account for NOEs, and there remains a lack of data that describe NOEs in clinically relevant procedures and tissues. As FSL technology continues to expand towards new applications, FSL induced NOEs need to be better understood in order to ensure safety as FSL medical devices and applications continue to evolve at a rapid pace. In order to improve the understanding of FSL-tissue interactions related to NOEs stimulated during laser beam propagation though corneal tissue, research investigations were conducted to evaluate corneal optical properties and determine how corneal tissue properties including corneal layer, collagen orientation and collagen crosslinking, and laser parameters including pulse energy, repetition rate and numerical aperture affect second and third-harmonic generation (HG) intensity, duration and efficiency. The results of these studies revealed that all laser parameters and tissue properties had a substantial influence on HG. The dynamic relationship between optical breakdown and HG was responsible for many observed changes in HG metrics. The results also demonstrated that the new generation of therapeutic FSLs has the potential to generate hazardous effects if not carefully controlled. Finally, recommendations are made to optimize current and guide future FSL applications.

A Network Pharmacology Approach to Understanding the Mechanisms of Action of Traditional Medicine: Bushenhuoxue Formula for Treatment of Chronic Kidney Disease

PubMed Central

Zheng, Xiao-yong; Cao, Dong-sheng; Ye, Fa-qing; Xiang, Zheng

2014-01-01

Traditional Chinese medicine (TCM) has unique therapeutic effects for complex chronic diseases. However, for the lack of an effective systematic approach, the research progress on the effective substances and pharmacological mechanism of action has been very slow. In this paper, by incorporating network biology, bioinformatics and chemoinformatics methods, an integrated approach was proposed to systematically investigate and explain the pharmacological mechanism of action and effective substances of TCM. This approach includes the following main steps: First, based on the known drug targets, network biology was used to screen out putative drug targets; Second, the molecular docking method was used to calculate whether the molecules from TCM and drug targets related to chronic kidney diseases (CKD) interact or not; Third, according to the result of molecular docking, natural product-target network, main component-target network and compound-target network were constructed; Finally, through analysis of network characteristics and literature mining, potential effective multi-components and their synergistic mechanism were putatively identified and uncovered. Bu-shen-Huo-xue formula (BSHX) which was frequently used for treating CKD, was used as the case to demonstrate reliability of our proposed approach. The results show that BSHX has the therapeutic effect by using multi-channel network regulation, such as regulating the coagulation and fibrinolytic balance, and the expression of inflammatory factors, inhibiting abnormal ECM accumulation. Tanshinone IIA, rhein, curcumin, calycosin and quercetin may be potential effective ingredients of BSHX. This research shows that the integration approach can be an effective means for discovering active substances and revealing their pharmacological mechanisms of TCM. PMID:24598793

Interoceptive Awareness Skills for Emotion Regulation: Theory and Approach of Mindful Awareness in Body-Oriented Therapy (MABT).

PubMed

Price, Cynthia J; Hooven, Carole

2018-01-01

Emotion regulation involves a coherent relationship with the self, specifically effective communication between body, mind, and feelings. Effective emotion regulation involves the ability to accurately detect and evaluate cues related to physiological reactions to stressful events, accompanied by appropriate regulation strategies that temper and influence the emotional response. There is compelling evidence demonstrating links between poor or disrupted awareness of sensory information, or interoceptive awareness, and difficulties with emotion regulation. This paper presents a framework, based on psychological and neurobiological research, for understanding how interoceptive awareness facilitates regulation and an integrated sense of self, and thus contributes to health and well-being. A mind-body therapeutic approach called mindful awareness in body-oriented therapy (MABT), uniquely designed to teach fundamental skills of interoceptive awareness, is described. MABT develops the distinct interoceptive awareness capacities of identifying, accessing, and appraising internal bodily signals that are identified in physiological models as the critical components of interoception for emotion regulation. The explanatory model is that the development of these key interoceptive capacities improves sensory (physical and emotional) awareness, reduces distress, and improves regulation. Strategies for teaching and learning interoceptive awareness are not well-developed in mindfulness or psychotherapeutic approaches, particularly important for people who may have difficulty attending to interoceptive awareness due to stress, chronic pain or trauma. To address this issue, MABT provides an individualized protocol for scaffolding interoceptive awareness through a combination of psychoeducation and somatic approaches explicitly addressing difficulties with interoceptive processing. Clinical vignettes are included to provide exemplars of this approach and to highlight key components of the therapeutic process. Results from research are also included to highlight the acceptability, safety, health outcomes, and possible mechanisms underlying the MABT approach.

Diagnosis, pathogenesis and treatment of myositis: recent advances

PubMed Central

Carstens, P-O; Schmidt, J

2014-01-01

Dermatomyositis (DM), polymyositis (PM), necrotizing myopathy (NM) and inclusion body myositis (IBM) are four distinct subtypes of idiopathic inflammatory myopathies – in short myositis. Recent studies have shed some light on the unique pathogenesis of each entity. Some of the clinical features are distinct, but muscle biopsy is indispensable for making a reliable diagnosis. The use of magnetic resonance imaging of skeletal muscles and detection of myositis-specific autoantibodies have become useful additions to our diagnostic repertoire. Only few controlled trials are available to substantiate current treatment approaches for myositis and hopes are high that novel modalities will become available within the next few years. In this review we provide an up-to-date overview of the pathogenesis and diagnostic approach of myositis. We aim to present a guide towards therapeutic and general management. PMID:23981102

Diagnosis, pathogenesis and treatment of myositis: recent advances.

PubMed

Carstens, P-O; Schmidt, J

2014-03-01

Dermatomyositis (DM), polymyositis (PM), necrotizing myopathy (NM) and inclusion body myositis (IBM) are four distinct subtypes of idiopathic inflammatory myopathies - in short myositis. Recent studies have shed some light on the unique pathogenesis of each entity. Some of the clinical features are distinct, but muscle biopsy is indispensable for making a reliable diagnosis. The use of magnetic resonance imaging of skeletal muscles and detection of myositis-specific autoantibodies have become useful additions to our diagnostic repertoire. Only few controlled trials are available to substantiate current treatment approaches for myositis and hopes are high that novel modalities will become available within the next few years. In this review we provide an up-to-date overview of the pathogenesis and diagnostic approach of myositis. We aim to present a guide towards therapeutic and general management. © 2013 British Society for Immunology.

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.

PubMed

Pérez-Pérez, María-Jesús; Priego, Eva-María; Bueno, Oskía; Martins, Maria Solange; Canela, María-Dolores; Liekens, Sandra

2016-10-13

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

A new neuroinformatics approach to personalized medicine in neurology: The Virtual Brain

PubMed Central

Falcon, Maria I.; Jirsa, Viktor; Solodkin, Ana

2017-01-01

Purpose of review An exciting advance in the field of neuroimaging is the acquisition and processing of very large data sets (so called ‘big data’), permitting large-scale inferences that foster a greater understanding of brain function in health and disease. Yet what we are clearly lacking are quantitative integrative tools to translate this understanding to the individual level to lay the basis for personalized medicine. Recent findings Here we address this challenge through a review on how the relatively new field of neuroinformatics modeling has the capacity to track brain network function at different levels of inquiry, from microscopic to macroscopic and from the localized to the distributed. In this context, we introduce a new and unique multiscale approach, The Virtual Brain (TVB), that effectively models individualized brain activity, linking large-scale (macroscopic) brain dynamics with biophysical parameters at the microscopic level. We also show how TVB modeling provides unique biological interpretable data in epilepsy and stroke. Summary These results establish the basis for a deliberate integration of computational biology and neuroscience into clinical approaches for elucidating cellular mechanisms of disease. In the future, this can provide the means to create a collection of disease-specific models that can be applied on the individual level to personalize therapeutic interventions. Video abstract http://links.lww.com/CONR/A41 PMID:27224088

Family Play Therapy.

ERIC Educational Resources Information Center

Ariel, Shlomo

This paper examines a case study of family play therapy in Israel. The unique contributions of play therapy are evaluated including the therapy's accessibility to young children, its richness and flexibility, its exposure of covert patterns, its wealth of therapeutic means, and its therapeutic economy. The systematization of the therapy attempts…

Therapeutic assessment for preadolescent boys with oppositional defiant disorder: a replicated single-case time-series design.

PubMed

Smith, Justin D; Handler, Leonard; Nash, Michael R

2010-09-01

The Therapeutic Assessment (TA) model is a relatively new treatment approach that fuses assessment and psychotherapy. The study examines the efficacy of this model with preadolescent boys with oppositional defiant disorder and their families. A replicated single-case time-series design with daily measures is used to assess the effects of TA and to track the process of change as it unfolds. All 3 families benefitted from participation in TA across multiple domains of functioning, but the way in which change unfolded was unique for each family. These findings are substantiated by the Behavior Assessment System for Children (Reynolds & Kamphaus, 2004). The TA model is shown to be an effective treatment for preadolescent boys with oppositional defiant disorder and their families. Further, the time-series design of this study illustrated how this empirically grounded case-based methodology reveals when and how change unfolds during treatment in a way that is usually not possible with other research designs.

Nano-vectors for efficient liver specific gene transfer

PubMed Central

Pathak, Atul; Vyas, Suresh P; Gupta, Kailash C

2008-01-01

Recent progress in nanotechnology has triggered the site specific drug/gene delivery research and gained wide acknowledgment in contemporary DNA therapeutics. Amongst various organs, liver plays a crucial role in various body functions and in addition, the site is a primary location of metastatic tumor growth. In past few years, a plethora of nano-vectors have been developed and investigated to target liver associated cells through receptor mediated endocytosis. This emerging paradigm in cellular drug/gene delivery provides promising approach to eradicate genetic as well as acquired diseases affecting the liver. The present review provides a comprehensive overview of potential of various delivery systems, viz., lipoplexes, liposomes, polyplexes, nanoparticles and so forth to selectively relocate foreign therapeutic DNA into liver specific cell type via the receptor mediated endocytosis. Various receptors like asialoglycoprotein receptors (ASGP-R) provide unique opportunity to target liver parenchymal cells. The results obtained so far reveal tremendous promise and offer enormous options to develop novel DNA-based pharmaceuticals for liver disorders in near future. PMID:18488414

Tantalus, restraint theory, and the low-sacrifice diet: the art of reverse abstraction: 10th International Congress on Obesity; September 4, 2006; Sydney,Australia - Symposium: obesity management: adding art to the science, invited presentation.

PubMed

Blair-West, George W

2007-10-24

This paper argues that clinicians face the unique artistic challenge of taking concrete pieces of data - scientific findings - and abstracting them into effective therapeutic interventions. Moreover, this abstraction has to be modified for different personality types. The process of therapeutic change and how it can be impeded by the traditional medical model are briefly explored. The doctor-patient dyadic treatment relationship, while appropriate and necessary for many medical interventions, can disavow the source of change when it comes to lifestyle conditions such as obesity. Restraint theory and its origins in Greek mythology are briefly reviewed and integrated with Bowlby's attachment theory as precepts in developing a psychologically based dietary approach. By retaining in people's diets foods they have a deep emotional attachment to, the low-sacrifice diet attempts to encourage caloric restriction in a way that does not trigger rebound overeating.

Intravital Microscopy Imaging Approaches for Image-Guided Drug Delivery Systems

PubMed Central

Kirui, Dickson K.; Ferrari, Mauro

2016-01-01

Rapid technical advances in the field of non-linear microscopy have made intravital microscopy a vital pre-clinical tool for research and development of imaging-guided drug delivery systems. The ability to dynamically monitor the fate of macromolecules in live animals provides invaluable information regarding properties of drug carriers (size, charge, and surface coating), physiological, and pathological processes that exist between point-of-injection and the projected of site of delivery, all of which influence delivery and effectiveness of drug delivery systems. In this Review, we highlight how integrating intravital microscopy imaging with experimental designs (in vitro analyses and mathematical modeling) can provide unique information critical in the design of novel disease-relevant drug delivery platforms with improved diagnostic and therapeutic indexes. The Review will provide the reader an overview of the various applications for which intravital microscopy has been used to monitor the delivery of diagnostic and therapeutic agents and discuss some of their potential clinical applications. PMID:25901526

Advanced Ultrasound Technologies for Diagnosis and Therapy.

PubMed

Rix, Anne; Lederle, Wiltrud; Theek, Benjamin; Lammers, Twan; Moonen, Chrit; Schmitz, Georg; Kiessling, Fabian

2018-05-01

Ultrasound is among the most rapidly advancing imaging techniques. Functional methods such as elastography have been clinically introduced, and tissue characterization is improved by contrast-enhanced scans. Here, novel superresolution techniques provide unique morphologic and functional insights into tissue vascularization. Functional analyses are complemented by molecular ultrasound imaging, to visualize markers of inflammation and angiogenesis. The full potential of diagnostic ultrasound may become apparent by integrating these multiple imaging features in radiomics approaches. Emerging interest in ultrasound also results from its therapeutic potential. Various applications of tumor ablation with high-intensity focused ultrasound are being clinically evaluated, and its performance strongly benefits from the integration into MRI. Additionally, oscillating microbubbles mediate sonoporation to open biologic barriers, thus improving the delivery of drugs or nucleic acids that are coadministered or coformulated with microbubbles. This article provides an overview of recent developments in diagnostic and therapeutic ultrasound, highlighting multiple innovation tracks and their translational potential. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective.

PubMed

Moghimi, S M; Hunter, A C; Andresen, T L

2012-01-01

Intravenously injected nanoparticulate drug carriers provide a wide range of unique opportunities for site-specific targeting of therapeutic agents to many areas within the vasculature and beyond. Pharmacokinetics and biodistribution of these carriers are controlled by a complex array of interrelated core and interfacial physicochemical and biological factors. Pertinent to realizing therapeutic goals, definitive maps that establish the interdependency of nanoparticle size, shape, and surface characteristics in relation to interfacial forces, biodistribution, controlled drug release, excretion, and adverse effects must be outlined. These concepts are critically evaluated and an integrated perspective is provided on the basis of the recent application of nanoscience approaches to nanocarrier design and engineering. The future of this exciting field is bright; some regulatory-approved products are already on the market and many are in late-phase clinical trials. With concomitant advances in extensive computational knowledge of the genomics and epigenomics of interindividual variations in drug responses, the boundaries toward development of personalized nanomedicines can be pushed further.

The Third Therapeutic System: Faith Healing Strategies in the Context of a Generalized AIDS Epidemic

PubMed Central

Manglos, Nicolette D.; Trinitapoli, Jenny

2014-01-01

Faith healing in sub-Saharan Africa has primarily been studied qualitatively among Pentecostal-Charismatic groups, and considered as its own phenomenon with little attention to its relationship to other modes of healing. Using data from Malawi, a religiously diverse African country with high HIV prevalence, we find that faith healing is pervasive across multiple religious traditions. For individuals, attending a faith healing congregation is associated with lower levels of generalized worry about AIDS, and this association is driven by those who switched churches before AIDS became widespread in rural areas. Use of condoms and traditional medicine are, on the other hand, positively associated with worry about AIDS. We argue that faith healing can be understood as a third therapeutic system that coexists with the well-documented biomedical and traditional systems. The success of faith healing approaches lies in their unique ability to combine individual-pragmatic and communal-ritualized aspects of healing to inform interpretations of the AIDS epidemic and its consequences. PMID:21362615

Canine prostate models in preclinical studies of minimally invasive interventions: part II, benign prostatic hyperplasia models

PubMed Central

Báez-Díaz, Claudia; Sánchez-Margallo, Francisco Miguel

2017-01-01

Canine prostate is widely used as animal model in the preclinical evaluation of emerging therapeutic interventions. Spontaneous benign prostatic hyperplasia (BPH) is common in adult intact male dogs with two distinct pathological types: glandular and complex form of prostatic hyperplasia. The complex form of prostatic hyperplasia, usually occurring in older dogs, represents an ideal model because of its unique pathologic feature, including not only glandular hyperplasia but also an increase in prostate stromal components. The limited commercial availability of adult dogs with spontaneous BPH motivates experimentally induced BPH in young dogs. Hormone-induced canine BPH model has been well established with various hormonal treatment regimens and administration approaches. The goal of this review is to provide the veterinary background in spontaneous BPH in dogs, summarize the techniques in hormonal induction of canine BPH, and highlight the pathological and clinical limitations of the canine models that may lead to distinct therapeutic responses compared to clinical trials in humans. PMID:28725598

Recent Advances in Flexible and Stretchable Bio-Electronic Devices Integrated with Nanomaterials.

PubMed

Choi, Suji; Lee, Hyunjae; Ghaffari, Roozbeh; Hyeon, Taeghwan; Kim, Dae-Hyeong

2016-06-01

Flexible and stretchable electronics and optoelectronics configured in soft, water resistant formats uniquely address seminal challenges in biomedicine. Over the past decade, there has been enormous progress in the materials, designs, and manufacturing processes for flexible/stretchable system subcomponents, including transistors, amplifiers, bio-sensors, actuators, light emitting diodes, photodetector arrays, photovoltaics, energy storage elements, and bare die integrated circuits. Nanomaterials prepared using top-down processing approaches and synthesis-based bottom-up methods have helped resolve the intrinsic mechanical mismatch between rigid/planar devices and soft/curvilinear biological structures, thereby enabling a broad range of non-invasive, minimally invasive, and implantable systems to address challenges in biomedicine. Integration of therapeutic functional nanomaterials with soft bioelectronics demonstrates therapeutics in combination with unconventional diagnostics capabilities. Recent advances in soft materials, devices, and integrated systems are reviewes, with representative examples that highlight the utility of soft bioelectronics for advanced medical diagnostics and therapies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cell-based therapeutic strategies for multiple sclerosis.

PubMed

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A

2017-11-01

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions.

PubMed

Lee, Chang-Han; Romain, Gabrielle; Yan, Wupeng; Watanabe, Makiko; Charab, Wissam; Todorova, Biliana; Lee, Jiwon; Triplett, Kendra; Donkor, Moses; Lungu, Oana I; Lux, Anja; Marshall, Nicholas; Lindorfer, Margaret A; Goff, Odile Richard-Le; Balbino, Bianca; Kang, Tae Hyun; Tanno, Hidetaka; Delidakis, George; Alford, Corrine; Taylor, Ronald P; Nimmerjahn, Falk; Varadarajan, Navin; Bruhns, Pierre; Zhang, Yan Jessie; Georgiou, George

2017-08-01

Engineered crystallizable fragment (Fc) regions of antibody domains, which assume a unique and unprecedented asymmetric structure within the homodimeric Fc polypeptide, enable completely selective binding to the complement component C1q and activation of complement via the classical pathway without any concomitant engagement of the Fcγ receptor (FcγR). We used the engineered Fc domains to demonstrate in vitro and in mouse models that for therapeutic antibodies, complement-dependent cell-mediated cytotoxicity (CDCC) and complement-dependent cell-mediated phagocytosis (CDCP) by immunological effector molecules mediated the clearance of target cells with kinetics and efficacy comparable to those of the FcγR-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with FcγR engagement. Collectively, our data highlight the importance of CDCC and CDCP in monoclonal-antibody function and provide an experimental approach for delineating the effect of complement-dependent effector-cell engagement in various therapeutic settings.

Using Acellular Bioactive Extracellular Matrix Scaffolds to Enhance Endogenous Cardiac Repair

PubMed Central

Svystonyuk, Daniyil A.; Mewhort, Holly E. M.; Fedak, Paul W. M.

2018-01-01

An inability to recover lost cardiac muscle following acute ischemic injury remains the biggest shortcoming of current therapies to prevent heart failure. As compared to standard medical and surgical treatments, tissue engineering strategies offer the promise of improved heart function by inducing regeneration of functional heart muscle. Tissue engineering approaches that use stem cells and genetic manipulation have shown promise in preclinical studies but have also been challenged by numerous critical barriers preventing effective clinical translational. We believe that surgical intervention using acellular bioactive ECM scaffolds may yield similar therapeutic benefits with minimal translational hurdles. In this review, we outline the limitations of cellular-based tissue engineering strategies and the advantages of using acellular biomaterials with bioinductive properties. We highlight key anatomic targets enriched with cellular niches that can be uniquely activated using bioactive scaffold therapy. Finally, we review the evolving cardiovascular tissue engineering landscape and provide critical insights into the potential therapeutic benefits of acellular scaffold therapy. PMID:29696148

An insight into the exploration of druggable genome of Streptococcus gordonii for the identification of novel therapeutic candidates.

PubMed

Azam, Syed Sikander; Shamim, Amen

2014-09-01

The discovery of novel drug targets of a genome that can bind with high affinity to drug-like compounds is a significant challenge in drug development. Streptococcus gordonii initiates dental plaque formation and endocarditis by entering into the blood stream, usually after oral trauma. The prolonged use of antibiotics is raising a problem of multi-drug resistance and lack of an optimal therapeutic regime that necessitates the drug discovery of vital importance in curing various infections. To overcome this dilemma, the in silico approach paves the way for identification and qualitative characterization of promising drug targets for S. gordonii that encompass three phases of analyses. The present study deciphers drug target genomes of S. gordonii in which 93 proteins were identified as potential drug targets and 16 proteins were found to be involved in unique metabolic pathways. Highlighted information will convincingly render to facilitate selection of S. gordonii proteins for successful entry into drug design pipelines. Copyright © 2014 Elsevier Inc. All rights reserved.

Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy.

PubMed

Qin, Si-Yong; Feng, Jun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Liu, Xiang-Ji; Luo, Guo-Feng; Zhuo, Ren-Xi; Zhang, Xian-Zheng

2014-02-12

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Notch Decoys that Selectively Block Dll/Notch or Jagged/Notch Disrupt Angiogenesis by Unique Mechanisms to Inhibit Tumor Growth

PubMed Central

Kangsamaksin, Thaned; Murtomaki, Aino; Kofler, Natalie M.; Cuervo, Henar; Chaudhri, Reyhaan A.; Tattersall, Ian W.; Rosenstiel, Paul E.; Shawber, Carrie J.; Kitajewski, Jan

2015-01-01

A pro-angiogenic role for Jagged-dependent activation of Notch signaling in the endothelium has yet to be described. Using proteins that encoded different NOTCH1 EGF-like repeats, we identified unique regions of DLL-class and JAG-class ligand/receptor interactions, and developed Notch decoys that function as ligand-specific Notch inhibitors. N110-24 decoy blocked JAG1/JAG2-mediated NOTCH1 signaling, angiogenic sprouting in vitro and retinal angiogenesis, demonstrating JAG-dependent Notch signal activation promotes angiogenesis. In tumors, N110-24 decoy reduced angiogenic sprouting, vessel perfusion, pericyte coverage, and tumor growth. JAG/NOTCH signaling uniquely inhibited expression of anti-angiogenic sVEFGFR-1/sFlt-1. N11-13 decoy interfered with DLL1/DLL4-mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis and in tumors. Thus, blockade of JAG- or DLL-mediated Notch signaling inhibits angiogenesis by distinct mechanisms. JAG/Notch signaling positively regulates angiogenesis by suppressing sVEGFR-1/sFlt-1 and promoting mural/endothelial cell interactions. Blockade of JAG-class ligands represents a novel, viable therapeutic approach to block tumor angiogenesis and growth. PMID:25387766

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…

Some Common and Unique Features of Special Education in the Nordic Countries.

ERIC Educational Resources Information Center

Juul, Kristen D.

1989-01-01

Similarities in special education services in the five Scandinavian countries include their normalization philosophy and cooperative policy development. Among unique Scandinavian innovations are camp schools, folk high schools, toy libraries (lekoteks), therapeutic communities or collectives for young substance abuses, and measures to combat…

IFN-λ: A New Inducer of Local Immunity against Cancer and Infections

PubMed Central

Lasfar, Ahmed; Zloza, Andrew; de la Torre, Andrew; Cohen-Solal, Karine A.

2016-01-01

IFN-λ is the newly established type III IFN with unique immunomodulatory functions. In contrast to the IFN-α/β family and to some extent IFN-γ, IFN-λ is apparently acting in specific areas of the body to activate resident immune cells and induces a local immunity, instrumental in preventing particular infections and also keeping transformed cells under control. Mucosal areas of lung and gastrointestinal tracts are now under scrutiny to elucidate the immune mechanisms triggered by IFN-λ and leading to viral protection. New evidence also indicates the crucial role of IFN-λ in promoting innate immunity in solid cancer models. Based on its unique biological activities among the IFN system, new immunotherapeutic approaches are now emerging for the treatment of cancer, infection, and autoimmune diseases. In the present review, we highlight the recent advances of IFN-λ immunomodulatory functions. We also discuss the perspectives of IFN-λ as a therapeutic agent. PMID:28018361

Adolescents and young adults with acute lymphoblastic leukemia.

PubMed

Stock, Wendy

2010-01-01

During the last decade, increasing attention has been paid to a unique group of patients with acute lymphoblastic leukemia (ALL) who lie at the crossroad of therapeutic care by pediatric and adult hematologists/oncologists. ALL is a disease that affects infants, children, adolescents, and adult patients. With current therapies, the vast majority of children with ALL are now long-term survivors; unfortunately, the same good results have not yet been obtained for adults with ALL. This review will describe current controversies surrounding the treatment of adolescents and young adults with ALL--a group who finds themselves in the transition from "pediatric" to "adult" treatment approaches. The review focuses on recent insights into disease biology, prognostic factors, and treatment outcomes that have led to a series of prospective clinical trials specifically designed for adolescents and younger adults (AYAs) with ALL. These trials have been designed to provide important new clinical, psychosocial, and biological insights, and to further improve the survival of this challenging and unique group of patients.

Imaging Sex Differences in Regional Brain Metabolism during Acute Opioid Withdrawal

PubMed Central

Santoro, Giovanni C; Carrion, Joseph; Dewey, Stephen L

2017-01-01

The rate of opioid overdose continues to rise, necessitating improved treatment options. Current therapeutic approaches rely on administration of either a blocking agent, such as naloxone, or chronic treatment with replacement drugs, including methadone and/or buprenorphine. Recent findings suggest that males and females respond to these treatments uniquely. In an effort to better understand this sex-specific variation in treatment efficacy, we investigated the effects of acute opioid withdrawal in male and female rats using 18FDG and microPET. These data demonstrate that acute opioid withdrawal produces metabolic alterations in brain regions associated with reward and drug dependence, namely corpus striatum, thalamic nuclei, septum, and frontal cortex. Furthermore, certain changes are unique to males. Specifically, males demonstrated increased metabolism in the anterior cingulate cortex and the ventral hippocampus (CA3) following acute opioid withdrawal. If males and females exhibit sex-specific changes in regional brain metabolism following acute opioid withdrawal, then perhaps it is not surprising that they respond to treatment differently. PMID:29046888

Epilepsy: habilitation and rehabilitation.

PubMed

Marks, Warren A; Hernandez, Angel; Gabriel, Marsha

2003-06-01

Rehabilitation represents not only a distinct field of medicine, but also a philosophical and practical treatment approach that can be applied to a variety of chronic disorders. Neurology encompasses many chronic disorders, making it ideal for the application of rehabilitation principles in daily practice. Epilepsy offers a unique opportunity to incorporate rehabilitation principles into the management of a complex medical disorder. Epilepsy is an evolving disease process that changes with the maturation of the central nervous system. The rehabilitative model provides the framework for a dynamic treatment plan to meet the changing needs of the child with epilepsy through the social and developmental changes of childhood, adolescence, and adulthood. The development of epilepsy may complicate the recovery from many acute and chronic conditions that affect the central nervous system. The rehabilitation process must address these many aspects of the disease process and its sequelae. This makes neurologists uniquely qualified to manage the rehabilitation team. The impact of the therapeutic milieu on the recovery process may be as important as any specific medical or surgical intervention.

Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery.

PubMed

Vaidya, Bhuvaneshwar; Gupta, Vivek

2015-08-10

Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder characterized by increased blood pressure in the small arterioles supplying blood to lungs for oxygenation. Advances in understanding of molecular and cellular biology techniques have led to the findings that PAH is indeed a cascade of diseases exploiting multi-faceted complex pathophysiology, with cellular proliferation and vascular remodeling being the key pathogenic events along with several cellular pathways involved. While current therapies for PAH do provide for amelioration of disease symptoms and acute survival benefits, their full therapeutic potential is hindered by patient incompliance and off-target side effects. To overcome the issues related with current therapy and to devise a more selective therapy, various novel pathways are being investigated for PAH treatment. In addition, inability to deliver anti-PAH drugs to the disease site i.e., distal pulmonary arterioles has been one of the major challenges in achieving improved patient outcomes and improved therapeutic efficacy. Several novel carriers have been explored to increase the selectivity of currently approved anti-PAH drugs and to act as suitable carriers for the delivery of investigational drugs. In the present review, we have discussed potential of various novel molecular pathways/targets including RhoA/Rho kinase, tyrosine kinase, endothelial progenitor cells, vasoactive intestinal peptide, and miRNA in PAH therapeutics. We have also discussed various techniques for site-specific drug delivery of anti-PAH therapeutics so as to improve the efficacy of approved and investigational drugs. This review will provide gainful insights into current advances in PAH therapeutics with an emphasis on site-specific drug payload delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Therapeutic Opportunities for Self-Control Repair in Addiction and Related Disorders: Change and the Limits of Change in Trans-Disease Processes

PubMed Central

Bickel, Warren K.; Quisenberry, Amanda J.; Moody, Lara; Wilson, A. George

2014-01-01

Contemporary neuro-economic approaches hypothesize that self-control failure results from drugs annexing normal learning mechanisms that produce pathological reward processing and distort decision-making as a result from the dysregulation of two valuation systems. An emphasis on processes shared across different diseases and disorders is at odds with the contemporary approach that assumes unique disease etiologies and treatments. Studying trans-disease processes can identify mechanisms that operate in multiple disease states and ascertain if factors that influence processes in one disease state may be applicable to all disease states. In this paper we review the dual model of self-control failure, the Competing Neurobehavioral Decision Systems approach, the relationship of delay discounting to the relative control of these two systems, and evidence that the executive system can be strengthened. Future research that could result in more potent interventions for executive system improvement and potential constraints on the repair of self-control failure are discussed. PMID:25664226

Expanding the chemical toolbox for the synthesis of large and uniquely modified proteins

NASA Astrophysics Data System (ADS)

Bondalapati, Somasekhar; Jbara, Muhammad; Brik, Ashraf

2016-05-01

Methods to prepare proteins that include a specific modification at a desired position are essential for understanding their cellular functions and physical properties in living systems. Chemical protein synthesis, which relies on the chemoselective ligation of unprotected peptides, enables the preparation of modified proteins that are not easily fabricated by other methods. In contrast to recombinant approaches, chemical synthesis can be used to prepare protein analogues such as D-proteins, which are useful in protein structure determination and the discovery of novel therapeutics. Post-translationally modifying proteins is another example where chemical protein synthesis proved itself as a powerful approach for preparing samples with high homogeneity and in workable quantities. In this Review, we discuss the basic principles of the field, focusing on novel chemoselective peptide ligation approaches such as native chemical ligation and the recent advances based on this method with a proven record of success in the synthesis of highly important protein targets.

Personal suffering and social criticism in T. S. Eliot's The Waste Land and A. Ginsberg's Howl: Implications for social psychiatry.

PubMed

Wigand, Moritz E; Wiegand, Hauke F; Rüsch, Nicolas; Becker, Thomas

2016-09-19

T. S. Eliot's The Waste Land and A. Ginsberg's Howl are two landmark poems of the 20th century which have a unique way of dealing with emotional suffering. (a) To explore the interplay between emotional suffering, conflicting relationships and societal perceptions; (b) to show the therapeutic effect of the writing process; (c) to analyse the portrayal of 'madness'; and (d) to discuss, in contemporary psychiatric terms, the 'solutions' offered by the poets. Qualitative research with a narrative, hermeneutic approach. Against the background of wartime/genocide and postwar disillusionment, close relationships are projected onto societal perceptions. Concepts of (self-)control, compassion, empowerment and self-efficacy are offered as solutions to overcome feelings of despair. In a time of perceived societal and environmental crises, both poems help us understand people's fears and how to counteract them. Besides biological approaches, the narrative approach to the suffering human being has not lost its significance. © The Author(s) 2016.

Bioinspired Composite Materials: Applications in Diagnostics and Therapeutics

NASA Astrophysics Data System (ADS)

Prasad, Alisha; Mahato, Kuldeep; Chandra, Pranjal; Srivastava, Ananya; Joshi, Shrikrishna N.; Maurya, Pawan Kumar

2016-08-01

Evolution-optimized specimens from nature with inimitable properties, and unique structure-function relationships have long served as a source of inspiration for researchers all over the world. For instance, the micro/nanostructured patterns of lotus-leaf and gecko feet helps in self-cleaning, and adhesion, respectively. Such unique properties shown by creatures are results of billions of years of adaptive transformation, that have been mimicked by applying both science and engineering concepts to design bioinspired materials. Various bioinspired composite materials have been developed based on biomimetic principles. This review presents the latest developments in bioinspired materials under various categories with emphasis on diagnostic and therapeutic applications.

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

PubMed

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

2017-10-01

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

Engineered Salmonella enterica serovar Typhimurium overcomes limitations of anti-bacterial immunity in bacteria-mediated tumor therapy

PubMed Central

Felgner, Sebastian; Kocijancic, Dino; Frahm, Michael; Heise, Ulrike; Rohde, Manfred; Zimmermann, Kurt; Falk, Christine; Weiss, Siegfried

2018-01-01

ABSTRACT Cancer is one of the leading causes of death in the industrialized world and represents a tremendous social and economic burden. As conventional therapies fail to provide a sustainable cure for most cancer patients, the emerging unique immune therapeutic approach of bacteria-mediated tumor therapy (BMTT) is marching towards a feasible solution. Although promising results have been obtained with BMTT using various preclinical tumor models, for advancement a major concern is immunity against the bacterial vector itself. Pre-exposure to the therapeutic agent under field conditions is a reasonable expectation and may limit the therapeutic efficacy of BMTT. In the present study, we investigated the therapeutic potential of Salmonella and E. coli vector strains in naïve and immunized tumor bearing mice. Pre-exposure to the therapeutic agent caused a significant aberrant phenotype of the microenvironment of colonized tumors and limited the in vivo efficacy of established BMTT vector strains Salmonella SL7207 and E. coli Symbioflor-2. Using targeted genetic engineering, we generated the optimized auxotrophic Salmonella vector strain SF200 (ΔlpxR9 ΔpagL7 ΔpagP8 ΔaroA ΔydiV ΔfliF) harboring modifications in Lipid A and flagella synthesis. This combination of mutations resulted in an increased immune-stimulatory capacity and as such the strain was able to overcome the efficacy-limiting effects of pre-exposure. Thus, we conclude that any limitations of BMTT concerning anti-bacterial immunity may be countered by strategies that optimize the immune-stimulatory capacity of the attenuated vector strains. PMID:29308303

Positive allosteric modulators as an approach to nicotinic acetylcholine receptor- targeted therapeutics: advantages and limitations

PubMed Central

Williams, Dustin K.; Wang, Jingyi; Papke, Roger L.

2011-01-01

Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues. PMID:21575610

Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.

PubMed

Williams, Dustin K; Wang, Jingyi; Papke, Roger L

2011-10-15

Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high-affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues. Copyright © 2011 Elsevier Inc. All rights reserved.

Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities.

PubMed

Roybal, Kole T; Lim, Wendell A

2017-04-26

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.

Power in the hypnotic relationship: therapeutic or abusive?

PubMed

Walling, D P; Levine, R E

1997-01-01

The unique relationship between hypnotist and subject has been theorized as one explanation for the effectiveness of hypnosis. This relationship carries a power differential, present in most therapeutic relationships, but accentuated by hypnosis. The power differential is sometimes perceived as the ability of the hypnotist to control the subject. Perceptions of hypnosis offered by stage hypnotists, the popular media, and some clinicians perpetuate the notion that the hypnotist has the ability to exert undue influence upon the client. The present article examines the relationship between hypnotist and subject focusing on issues of power and control. The authors examine the unique dynamics accompanying the use of hypnosis and their impact on the therapeutic dyad. Evidence is offered demonstrating the power differential, and how this differential can serve as either a positive or negative agent of change. Therapists should be aware of the dynamics created by using hypnosis. Implications for training therapists in the use of hypnosis are suggested.

Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities

PubMed Central

Roybal, Kole T.; Lim, Wendell A.

2017-01-01

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases. PMID:28446063

[Therapeutic education, a factor of compliance and autonomy].

PubMed

Paput, Aurore

2014-03-01

Improving the daily life of patients suffering from inflammatory bowel disease is one of the objectives of the gastroenterological team of Nice general hospital. Therapeutic patient education has been developed in the hospital, through the Edu MICI programme. The practice of this multi-disciplinary team gives nurses the opportunity to fully express their unique role.

Targeting IFN-λ: therapeutic implications.

PubMed

Eslam, Mohammed; George, Jacob

2016-12-01

Type-III interferons (IFN-λ), the most recently discovered family of IFNs, shares common features with other family members, but also has many distinctive activities. IFN-λ uniquely has a different receptor complex, and a more focused pattern of tissue expression and signaling effects, from other classes of IFNs. Multiple genome-wide association studies (GWAS) and subsequent validation reports suggest a pivotal role for polymorphisms near the IFNL3 gene in hepatitis C clearance and control, as also for several other epithelial cell tropic viruses. Apart from its antiviral activity, IFN-λ possesses anti-tumor, immune-inflammatory and homeostatic functions. The overlapping effects of IFN-λ with type I IFN, with a restricted tissue expression pattern renders IFN-λ an attractive therapeutic target for viral infection, cancer and autoimmune diseases, with limited side effects. Areas covered: This review will summarize the current and future therapeutic opportunities offered by this most recently discovered family of interferons. Expert opinion: Our knowledge on IFN-λ is rapidly expanding. Though there are many remaining questions and challenges that require elucidation, the unique characteristics of IFN-λ increases enthusiasm that multiple therapeutic options will emerge.

The Botulinum Toxin as a Therapeutic Agent: Molecular Structure and Mechanism of Action in Motor and Sensory Systems.

PubMed

Kumar, Raj; Dhaliwal, Harkiran Preet; Kukreja, Roshan Vijay; Singh, Bal Ram

2016-02-01

Botulinum neurotoxin (BoNT) produced by Clostridium botulinum is the most potent molecule known to mankind. Higher potency of BoNT is attributed to several factors, including structural and functional uniqueness, target specificity, and longevity. Although BoNT is an extremely toxic molecule, it is now increasingly used for the treatment of disorders related to muscle hyperactivity and glandular hyperactivity. Weakening of muscles due to peripheral action of BoNT produces a therapeutic effect. Depending on the target tissue, BoNT can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. In recent observations of the analgesic properties of BoNT, the toxin modifies the sensory feedback loop to the central nervous system. Differential effects of BoNT in excitatory and inhibitory neurons provide a unique therapeutic tool. In this review the authors briefly summarize the structure and mechanism of actions of BoNT on motor and sensory neurons to explain its therapeutic effects and future potential. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Catalytic activity of certain antibodies as a potential tool for drug synthesis and for directed prodrug therapies.

PubMed

Wójcik, T; Kieć-Kononowicz, K

2008-01-01

Catalytic activity of certain antibodies was proposed by Linus Pauling for the very first time more than six decades ago. Since then few examples of catalytic antibodies (abzymes) were found in human organism. From late 80's many synthetic abzymes were obtained after immunization by Transition State Analogs (TSA). Another approach is based on functional mimicry of antibody to an active site of an enzyme. Detection of an abzymatic activity requires special immunoassays. This unique strategy can be employed for new methods of drug synthesis, as well as for in vivo therapies. Catalytic antibodies seem to be a promising tool for therapeutic purposes, because of their specifity and stereoselectivity.

Trespassing cancer cells: 'fingerprinting' invasive protrusions reveals metastatic culprits.

PubMed

Klemke, Richard L

2012-10-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial 'omics' approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Numerical analysis for characterization of the gold nanorod mediated-plasmonic heating with temporary NIR laser radiation for superficial breast cancer therapy

NASA Astrophysics Data System (ADS)

Bae, Ji Yong; Nam, Ki-Hwan; Jeong, Chan Bae; Kim, Geon-hee; Chang, Ki Soo

2016-09-01

Over the last decade, plasmonic photothermal therapy (PPTT) has received significant attention as the new therapeutic strategy for the cancer therapy due to unique characteristics of the gold-nanoparticles. The characterization of the spatiotemporal heating potential for the gold nanorods (GNR) through mimicking PPTT process on the various conditions can help more quantitative approaches to treatment planning. The purpose of this study was to clearly understand the optical-thermal interactions between the laser, GNRs, and bio-tissues, and provide the information in clinical applications to implement the concept of heterogeneity, which can enable the optimization of treatment parameters for superficial breast cancer treatment.

Teaching legal competencies through an individualized elective in medicine and law.

PubMed

Kapp, Marshall B

2016-10-14

Medical education, including education intended to prepare future physicians to care to older individuals, should include development and implementation of competencies relating to a physician's ability to understand and interact with the legal environment and legal actors who will affect the practice of medicine. The wisdom of integrating legal knowledge into the medical curriculum has been documented, and literature discusses the content and methods of teaching medical students and residents about law and the legal system. This article describes one unique but replicable, pedagogical approach to preparing future physicians to thrive in their inevitably interprofessional careers as they fulfill the fiduciary responsibilities that lie at the heart of their therapeutic and advocacy relationships with older patients.

Dental caries - not just holes in teeth! A perspective.

PubMed

Bowen, W H

2016-06-01

Cavitation in teeth results from a pathogenic process termed dental caries that has occurred on the tooth surface for weeks or even years. Accumulation of dental plaque (biofilm) on the tooth is usually the first manifestation of the disease. Although acid production is the immediate and proximal cause of dissolution of teeth; it is the milieu within which the acid is formed that should be of primary concern. Focusing on the 'critical pH' has detracted attention from the more biological aspects (biofilm formation) of dental caries. Dental caries is unique; it is a biological process occurring on essentially an inert surface. Investigation of the multitude of interactions occurring in plaque ranging from enamel interfaces to surfaces of bacteria and matrices poses challenges worthy of the best scientific minds. The mouth clearly offers unique opportunities to investigate the multi facets of biofilm formation in vivo, generating data that have relevance way beyond the mouth. Prevention of this ubiquitous disease, dental caries, continues to present serious challenges. The public health benefits of fluoride delivered in its various formats are well recognized. Nevertheless, additional preventive approaches are required. Overcoming the rapid clearance of agents from the mouth is particularly challenging. Building on the polymerizing capacity of glucosyltransferases it may be possible to incorporate a therapeutic agent into the matrix plaque, thereby delivering therapeutic agents precisely to where they are needed. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Edible plants for oral delivery of biopharmaceuticals.

PubMed

Merlin, Matilde; Pezzotti, Mario; Avesani, Linda

2017-01-01

Molecular farming is the use of plants for the production of high value recombinant proteins. Over the last 25 years, molecular farming has achieved the inexpensive, scalable and safe production of pharmaceutical proteins using a range of strategies. One of the most promising approaches is the use of edible plant organs expressing biopharmaceuticals for direct oral delivery. This approach has proven to be efficacious in several clinical vaccination and tolerance induction trials as well as multiple preclinical studies for disease prevention. The production of oral biopharmaceuticals in edible plant tissues could revolutionize the pharmaceutical industry by reducing the cost of production systems based on fermentation, and also eliminating expensive downstream purification, cold storage and transportation costs. This review considers the unique features that make plants ideal as platforms for the oral delivery of protein-based therapeutics and describes recent developments in the production of plant derived biopharmaceuticals for oral administration. © 2016 The British Pharmacological Society.

Perfluorocarbon Nanoparticles for Physiological and Molecular Imaging and Therapy

PubMed Central

Chen, Junjie; Pan, Hua; Lanza, Gregory M.; Wickline, Samuel A.

2014-01-01

Herein we review the use of non-nephrotoxic perfluorocarbon nanoparticles (PFC NP) for noninvasive detection and therapy of kidney diseases, and provide a synopsis of other related literature pertinent to anticipated clinical application. Recent reports indicate that PFC NP allow quantitative mapping of kidney perfusion, and oxygenation after ischemia-reperfusion injury with the use of a novel multi-nuclear 1H/19F magnetic resonance imaging (MRI) approach,. Furthermore, when conjugated with targeting ligands, the functionalized PFC NP offer unique and quantitative capabilities for imaging inflammation in the kidney of atherosclerotic ApoE-null mice. Additionally, PFC NP can facilitate drug delivery for treatment of inflammation, thrombosis, and angiogenesis in selected conditions that are comorbidities for to kidney failure. The excellent safety profile of PFC NP with respect to kidney injury positions these nanomedicine approaches as promising diagnostic and therapeutic candidates for treating and following acute and chronic kidney diseases. PMID:24206599

Helicases as Prospective Targets for Anti-Cancer Therapy

PubMed Central

Gupta, Rigu; Brosh, Robert M.

2008-01-01

It has been proposed that selective inactivation of a DNA repair pathway may enhance anti-cancer therapies that eliminate cancerous cells through the cytotoxic effects of DNA damaging agents or radiation. Given the unique and critically important roles of DNA helicases in the DNA damage response, DNA repair, and maintenance of genomic stability, a number of strategies currently being explored or in use to combat cancer may be either mediated or enhanced through the modulation of helicase function. The focus of this review will be to examine the roles of helicases in DNA repair that might be suitably targeted by cancer therapeutic approaches. Treatment of cancers with anti-cancer drugs such as small molecule compounds that modulate helicase expression or function is a viable approach to selectively kill cancer cells through the inactivation of helicase-dependent DNA repair pathways, particularly those associated with DNA recombination, replication restart, and cell cycle checkpoint. PMID:18473724

Inhibition of Protein-Protein Interactions and Signaling by Small Molecules

NASA Astrophysics Data System (ADS)

Freire, Ernesto

2010-03-01

Protein-protein interactions are at the core of cell signaling pathways as well as many bacterial and viral infection processes. As such, they define critical targets for drug development against diseases such as cancer, arthritis, obesity, AIDS and many others. Until now, the clinical inhibition of protein-protein interactions and signaling has been accomplished with the use of antibodies or soluble versions of receptor molecules. Small molecule replacements of these therapeutic agents have been extremely difficult to develop; either the necessary potency has been hard to achieve or the expected biological effect has not been obtained. In this presentation, we show that a rigorous thermodynamic approach that combines differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC) provides a unique platform for the identification and optimization of small molecular weight inhibitors of protein-protein interactions. Recent advances in the development of cell entry inhibitors of HIV-1 using this approach will be discussed.

[Consensus document about the nutritional evaluation and management of eating disorders: bulimia nervosa, binge eating disorder, and others].

PubMed

Gómez Candela, Carmen; Palma Milla, Samara; Miján-de-la-Torre, Alberto; Rodríguez Ortega, Pilar; Matía Martín, Pilar; Loria Cohen, Viviana; Campos Del Portillo, Rocío; Virgili Casas, M ª Nuria; Martínez Olmos, Miguel Á; Mories Álvarez, M ª Teresa; Castro Alija, M ª José; Martín-Palmero, Ángela

2018-03-07

Bulimia nervosa and binge eating disorder are unique nosological entities. Both show a large variability related to its presentation and severity which involves different therapeutic approaches and the need to individualize the treatment, thus it is indispensable a multidisciplinary approach. Patients with bulimia nervosa may suffer from malnutrition and deficiency states or even excess weight, while in binge eating disorders, it is common overweight or obesity, which determine other comorbidities. Many of the symptoms and complications are associated with compensatory behaviors. There are many therapeutic tools available for the treatment of these patients. The nutritional approach contemplates the individualized dietary advice which guarantees an adequate nutritional state and nutritional education. Its objective is to facilitate the voluntary adoption of eating behaviors that promote health and allow the long-term modification of eating habits and the cessation of purgatory and bingeing behaviors. Psychological support is a first-line treatment and it must address the frequent disorder of eating behavior and psychiatric comorbidities. Psychotropic drugs are effective and widely used although these drugs are not essential. The management is carried out mainly at an outpatient level, being the day hospital useful in selected patients. Hospitalization should be reserved to correct serious somatic or psychiatric complications or as a measure to contain non-treatable conflict situations. Most of the guidelines' recommendations are based on expert consensus, with little evidence which evaluates clinical results and cost-effectiveness.

Designing Inhibitors of Anthrax Toxin

PubMed Central

Nestorovich, Ekaterina M.; Bezrukov, Sergey M.

2014-01-01

Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals with anti-PA therapeutics can be time-dependent, requiring coordinated use of membrane permeable small-molecule inhibitors, which block the LF and EF enzymatic activity intracellularly. The desperate search for an ideal anthrax antitoxin allowed researchers to gain important knowledge of the basic principles of small-molecule interactions with their protein targets that could be easily transferred to other systems. At the same time, better identification and validation of anthrax toxin therapeutic targets at the molecular level, which include understanding of the physical forces underlying the target/drug interaction, as well as elucidation of the parameters determining the corresponding therapeutic windows, require further examination. PMID:24447197

Potential roles of microRNAs and ROS in colorectal cancer: diagnostic biomarkers and therapeutic targets

PubMed Central

Lin, Jingmei; Chuang, Chia-Chen; Zuo, Li

2017-01-01

As one of the most commonly diagnosed cancers worldwide, colorectal adenocarcinoma often occurs sporadically in individuals aged 50 or above and there is an increase among younger patients under 50. Routine screenings are recommended for this age group to improve early detection. The multifactorial etiology of colorectal cancer consists of both genetic and epigenetic factors. Recently, studies have shown that the development and progression of colorectal cancer can be attributed to aberrant expression of microRNA. Reactive oxygen species (ROS) that play a key role in cancer cell survival, can also lead to carcinogenesis and cancer exacerbations. Given the rapid accumulating knowledge in the field, an updated review regarding microRNA and ROS in colorectal cancer is necessary. An extensive literature search has been conducted in PubMed/Medline databases to review the roles of microRNAs and ROS in colorectal cancer. Unique microRNA expression in tumor tissue, peripheral blood, and fecal samples from patients with colorectal cancer is outlined. Therapeutic approaches focusing on microRNA and ROS in colorectal cancer treatment is also delineated. This review aims to summarize the newest knowledge on the pathogenesis of colorectal cancer in the hopes of discovering novel diagnostic biomarkers and therapeutic techniques. PMID:28061475

Redirecting adenovirus tropism by genetic, chemical, and mechanical modification of the adenovirus surface for cancer gene therapy.

PubMed

Yoon, A-Rum; Hong, Jinwoo; Kim, Sung Wan; Yun, Chae-Ok

2016-06-01

Despite remarkable advancements, clinical evaluations of adenovirus (Ad)-mediated cancer gene therapies have highlighted the need for improved delivery and targeting. Genetic modification of Ad capsid proteins has been extensively attempted. Although genetic modification enhances the therapeutic potential of Ad, it is difficult to successfully incorporate extraneous moieties into the capsid and the engineering process is laborious. Recently, chemical modification of the Ad surface with nanomaterials and targeting moieties has been found to enhance Ad internalization into the target by both passive and active mechanisms. Alternatively, external stimulus-mediated targeting can result in selective accumulation of Ad in the tumor and prevent dissemination of Ad into surrounding nontarget tissues. In the present review, we discuss various genetic, chemical, and mechanical engineering strategies for overcoming the challenges that hinder the therapeutic efficacy of Ad-based approaches. Surface modification of Ad by genetic, chemical, or mechanical engineering strategies enables Ad to overcome the shortcomings of conventional Ad and enhances delivery efficiency through distinct and unique mechanisms that unmodified Ad cannot mimic. However, although the therapeutic potential of Ad-mediated gene therapy has been enhanced by various surface modification strategies, each strategy still possesses innate limitations that must be addressed, requiring innovative ideas and designs.

Combining bio-electrospraying with gene therapy: a novel biotechnique for the delivery of genetic material via living cells.

PubMed

Ward, Eliot; Chan, Emma; Gustafsson, Kenth; Jayasinghe, Suwan N

2010-05-01

The investigations reported in this article demonstrate the ability of bio-electrosprays and cell electrospinning to deliver a genetic construct in association with living cells. Previous studies on both bio-electrosprays and cell electrospinning demonstrated great promise for tissue engineering and regenerative biology/medicine. The investigations described herein widen the applicability of these biotechniques by combining gene therapy protocols, resulting in a novel drug delivery methodology previously unexplored. In these studies a human cell line was transduced with recombinant self-inactivating lentiviral particles. These particles incorporated a green fluorescent protein fused to an endosomal targeting construct. This construct encodes a peptide, which can subsequently be detected on the surface of cells by specific T-cells. The transduced cell line was subsequently manipulated in association with either bio-electrospraying or cell electrospinning. Hence this demonstrates (i) the ability to safely handle genetically modified living cells and (ii) the ability to directly form pre-determined architectures bearing living therapeutic cells. This merged technology demonstrates a unique approach for directly forming living therapeutic architectures for controlled and targeted release of experimental cells/genes, as well as medical cell/gene therapeutics for a plethora of biological and medical applications. Hence, such developments could be applied to personalised medicine.

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.

Carbon nanotubes (CNTs) based advanced dermal therapeutics: current trends and future potential.

PubMed

Kuche, Kaushik; Maheshwari, Rahul; Tambe, Vishakha; Mak, Kit-Kay; Jogi, Hardi; Raval, Nidhi; Pichika, Mallikarjuna Rao; Kumar Tekade, Rakesh

2018-05-17

The search for effective and non-invasive delivery modules to transport therapeutic molecules across skin has led to the discovery of a number of nanocarriers (viz.: liposomes, ethosomes, dendrimers, etc.) in the last few decades. However, available literature suggests that these delivery modules face several issues including poor stability, low encapsulation efficiency, and scale-up hurdles. Recently, carbon nanotubes (CNTs) emerged as a versatile tool to deliver therapeutics across skin. Superior stability, high loading capacity, well-developed synthesis protocol as well as ease of scale-up are some of the reason for growing interest in CNTs. CNTs have a unique physical architecture and a large surface area with unique surface chemistry that can be tailored for vivid biomedical applications. CNTs have been thus largely engaged in the development of transdermal systems such as tuneable hydrogels, programmable nonporous membranes, electroresponsive skin modalities, protein channel mimetic platforms, reverse iontophoresis, microneedles, and dermal buckypapers. In addition, CNTs were also employed in the development of RNA interference (RNAi) based therapeutics for correcting defective dermal genes. This review expounds the state-of-art synthesis methodologies, skin penetration mechanism, drug liberation profile, loading potential, characterization techniques, and transdermal applications along with a summary on patent/regulatory status and future scope of CNT based skin therapeutics.

Statistical Approaches to Assess Biosimilarity from Analytical Data.

PubMed

Burdick, Richard; Coffey, Todd; Gutka, Hiten; Gratzl, Gyöngyi; Conlon, Hugh D; Huang, Chi-Ting; Boyne, Michael; Kuehne, Henriette

2017-01-01

Protein therapeutics have unique critical quality attributes (CQAs) that define their purity, potency, and safety. The analytical methods used to assess CQAs must be able to distinguish clinically meaningful differences in comparator products, and the most important CQAs should be evaluated with the most statistical rigor. High-risk CQA measurements assess the most important attributes that directly impact the clinical mechanism of action or have known implications for safety, while the moderate- to low-risk characteristics may have a lower direct impact and thereby may have a broader range to establish similarity. Statistical equivalence testing is applied for high-risk CQA measurements to establish the degree of similarity (e.g., highly similar fingerprint, highly similar, or similar) of selected attributes. Notably, some high-risk CQAs (e.g., primary sequence or disulfide bonding) are qualitative (e.g., the same as the originator or not the same) and therefore not amenable to equivalence testing. For biosimilars, an important step is the acquisition of a sufficient number of unique originator drug product lots to measure the variability in the originator drug manufacturing process and provide sufficient statistical power for the analytical data comparisons. Together, these analytical evaluations, along with PK/PD and safety data (immunogenicity), provide the data necessary to determine if the totality of the evidence warrants a designation of biosimilarity and subsequent licensure for marketing in the USA. In this paper, a case study approach is used to provide examples of analytical similarity exercises and the appropriateness of statistical approaches for the example data.

Protein based therapeutic delivery agents: Contemporary developments and challenges.

PubMed

Yin, Liming; Yuvienco, Carlo; Montclare, Jin Kim

2017-07-01

As unique biopolymers, proteins can be employed for therapeutic delivery. They bear important features such as bioavailability, biocompatibility, and biodegradability with low toxicity serving as a platform for delivery of various small molecule therapeutics, gene therapies, protein biologics and cells. Depending on size and characteristic of the therapeutic, a variety of natural and engineered proteins or peptides have been developed. This, coupled to recent advances in synthetic and chemical biology, has led to the creation of tailor-made protein materials for delivery. This review highlights strategies employing proteins to facilitate the delivery of therapeutic matter, addressing the challenges for small molecule, gene, protein and cell transport. Copyright © 2017 Elsevier Ltd. All rights reserved.

Vaidyavallabha: An Authoritative Work on Ayurveda Therapeutics.

PubMed

Jain, Arhanth Kumar; Manjunath, Shreevathsa

2016-01-01

The text " Vaidyavallabha " is an authoritative work on Ayurvedic therapeutics written by Hastiruci , a Jain scholar. It belongs to the time period of 1673-1726 CE. Different physical and mental ailments with their treatments are addressed in the 274 verses spanned over eight chapters in this work. In this text many unique, special and simple medicinal preparations for different diseases are given. Many drugs which were easily available in the local area are given much more importance in the treatment. Added to this, method and uniqueness of naming the diseases in the text stand differently when compared to other texts. Even though the text seems to be small, the contribution to the field of Ayurveda practice is priceless.

Application criteria of enteral nutrition in patients with anorexia nervosa: correlation between clinical and psychological data in a "lifesaving" treatment.

PubMed

Paccagnella, Agostino; Mauri, Alessandra; Baruffi, Carla; Berto, Rita; Zago, Raffaella; Marcon, Maria Lisa; Pizzolato, Daniela; Fontana, Francesca; Rizzo, Lenio; Bisetto, Mario; Agostini, Silvana; Foscolo, Giancarlo

2006-01-01

Data and research increasingly point to multiple factors in the genesis of eating-behavior disorders, but the lack of a clear etiological definition prevents a unique therapeutic or prognostic approach from being defined. Therapeutic approaches, as well as scientific research, have separately analyzed the psychological aspects and the clinical-nutrition aspects without integrating the variables or correlating clinical and psychological data. This work has several goals because it aims at considering the problem from the 2 different perspectives. Psychological and clinical variables are analyzed both separately and together in order to assess (a) the minimal criteria to define a cure as "lifesaving" and submit a patient to artificial nutrition; (b) the kind of implementation artificial nutrition should follow; (c) which indicators of the efficacy of artificial nutrition must be taken into account; (d) the results in nutrition terms that may be obtained during the follow-up; (e) if artificial nutrition may be used as a therapeutic tool; (f) if there are any psychological effects after artificial nutrition; (g) if there are any effects due to the patients' age; and (h) the correlation between the psychological profile of a patient and the acceptance of the nutrition treatment. Several psychological and pharmacologic variables, together with clinical and anthropometric data and blood chemical values, were all considered. Besides defining minimal criteria for a "lifesaving" cure and proposing 2 ad hoc scales for the assessment of patients' subjective willingness toward feeding and for the objective measurement of feeding itself, clinical data and correlations with psychological data evidenced the importance of artificial nutrition and specifically of enteral nutrition as a therapeutic tool, allowing us to define the modalities of implementation of enteral nutrition. Results show that, because enteral nutrition did not deteriorate the psychological state of the patients, and was found to be accepted more positively than feeding orally in the most critical initial phase, it should be included in the therapy.

Generation and characterization of a unique reagent that recognizes a panel of recombinant human monoclonal antibody therapeutics in the presence of endogenous human IgG.

PubMed

Wang, Xiangdan; Quarmby, Valerie; Ng, Carl; Chuntharapai, Anan; Shek, Theresa; Eigenbrot, Charles; Kelley, Robert F; Shia, Steven; McCutcheon, Krista; Lowe, John; Leddy, Cecilia; Coachman, Kyle; Cain, Gary; Chu, Felix; Hotzel, Isidro; Maia, Mauricio; Wakshull, Eric; Yang, Jihong

2013-01-01

Pharmacokinetic (PK) and immunohistochemistry (IHC) assays are essential to the evaluation of the safety and efficacy of therapeutic monoclonal antibodies (mAb) during drug development. These methods require reagents with a high degree of specificity because low concentrations of therapeutic antibody need to be detected in samples containing high concentrations of endogenous human immunoglobulins. Current assay reagent generation practices are labor-intensive and time-consuming. Moreover, these practices are molecule-specific and so only support one assay for one program at a time. Here, we describe a strategy to generate a unique assay reagent, 10C4, that preferentially recognizes a panel of recombinant human mAbs over endogenous human immunoglobulins. This "panel-specific" feature enables the reagent to be used in PK and IHC assays for multiple structurally-related therapeutic mAbs. Characterization revealed that the 10C4 epitope is conformational, extensive and mainly composed of non-CDR residues. Most key contact residues were conserved among structurally-related therapeutic mAbs, but the combination of these residues exists at low prevalence in endogenous human immunoglobulins. Interestingly, an indirect contact residue on the heavy chain of the therapeutic appears to play a critical role in determining whether or not it can bind to 10C4, but has no affect on target binding. This may allow us to improve the binding of therapeutic mAbs to 10C4 for assay development in the future. Here, for the first time, we present a strategy to develop a panel-specific reagent that can expedite the development of multiple clinical assays for structurally-related therapeutic mAbs.

Understanding and preventing type 1 diabetes through the unique working model of TrialNet.

PubMed

Battaglia, Manuela; Anderson, Mark S; Buckner, Jane H; Geyer, Susan M; Gottlieb, Peter A; Kay, Thomas W H; Lernmark, Åke; Muller, Sarah; Pugliese, Alberto; Roep, Bart O; Greenbaum, Carla J; Peakman, Mark

2017-11-01

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.

Understanding and preventing type 1 diabetes through the unique working model of TrialNet

PubMed Central

Anderson, Mark S.; Buckner, Jane H.; Geyer, Susan M.; Gottlieb, Peter A.; Kay, Thomas W. H.; Lernmark, Åke; Muller, Sarah; Pugliese, Alberto; Roep, Bart O.; Greenbaum, Carla J.

2018-01-01

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches. PMID:28770323

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy

PubMed Central

Monga, Isha; Qureshi, Abid; Thakur, Nishant; Gupta, Amit Kumar; Kumar, Manoj

2017-01-01

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single-nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://crdd.osdd.net/servers/aspsirna/) covering three components viz (i) ASPsiDb, (ii) ASPsiPred, and (iii) analysis tools like ASP-siOffTar. ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Effmut) and wild-type allele (Effwild) with one mismatch by ASPsiPredSVM and ASPsiPredmatrix, respectively. In ASPsiPredSVM, 922 unique ASP-siRNAs with experimentally validated quantitative Effmut were used. During 10-fold cross-validation (10nCV) employing various sequence features on the training/testing dataset (T737), the best predictive model achieved a maximum Pearson’s correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Effmut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPredmatrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19 different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm, and off-target analysis tool that is expected to accelerate research in the field of RNAi-based therapeutics for human genetic diseases. PMID:28696921

Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

PubMed Central

2012-01-01

Background Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets. Results As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels. Conclusions These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type. PMID:22280838

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

PubMed

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

2016-10-15

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

The Dead Sea Mud and Salt: A Review of Its Characterization, Contaminants, and Beneficial Effects

NASA Astrophysics Data System (ADS)

Bawab, Abeer Al; Bozeya, Ayat; Abu-Mallouh, Saida; Abu Irmaileh, Basha'er; Daqour, Ismail; Abu-Zurayk, Rund A.

2018-02-01

The Dead Sea has been known for its therapeutic and cosmetic properties. The unique climatic conditions in the Dead Sea area make it a renowned site worldwide for the field of climatotherapy, which is a natural approach for the provision of medications for many human diseases including unusual exclusive salt composition of the water, a special natural mud, thermal mineral springs, solar irradiation, oxygen-rich and bromine-rich haze. This review focuses on the physical, chemical, and biological characteristics of the Dead Sea mud and salts, in addition to their contaminants, allowing this review to serve as a guide to interested researchers to their risks and the importance of treatment. Beneficial effects of Dead Sea mud and salts are discussed in terms of therapy and cosmetics. Additional benefits of both Dead Sea mud and salts are also discussed, such as antimicrobial action of the mud in relation to its therapeutic properties, and the potency of mud and salts to be a good medium for the growth of a halophilic unicellular algae, used for the commercial production of β-carotene Dunaliella.

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

PubMed Central

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

2016-01-01

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

Children's Oncology Group's 2013 blueprint for research: acute myeloid leukemia.

PubMed

Gamis, Alan S; Alonzo, Todd A; Perentesis, John P; Meshinchi, Soheil

2013-06-01

For the 365 children diagnosed with acute myeloid leukemia in the US annually, 5-year survival for patients on COG trials with low, intermediate, and high risk disease is 83%, 62%, and 23%, respectively. Recent advances include improved therapeutic stratification, improved survival with dose intensification, and further elucidation of the heterogeneity specific to childhood AML. These discoveries now guide current strategy incorporating targeted agents to pathways specific to childhood AML as well as evaluating methods to increase the sensitivity of the leukemic stem cell, first in Phase II feasibility trials followed by Phase III efficacy trials of the most promising agents. Acute myeloid leukemia in children, though with similar subgroups to adults, remains uniquely different based upon quite different prevalence of subtypes as well as overall response to therapy. The Children's Oncology Group's research agenda builds upon earlier efforts to better elucidate the leukemogenic steps distinct to childhood AML in order to more scientifically develop and test novel therapeutic approaches to the treatment and ultimate cure for children with this disorder. Pediatr Blood Cancer 2013; 60: 964-971. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders

PubMed Central

Pokrass, Michael J; Klauer, Neal R; De Credico, Nicole E

2017-01-01

Introduction Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases. Areas covered This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders. Expert opinion Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders. PMID:25331742

Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.

PubMed

Guiastrennec, Benjamin; Ramachandran, Geetha; Karlsson, Mats O; Kumar, A K Hemanth; Bhavani, Perumal Kannabiran; Gangadevi, N Poorana; Swaminathan, Soumya; Gupta, Amita; Dooley, Kelly E; Savic, Radojka M

2017-12-16

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P unfavorable ). Model-based simulation of optimized (P unfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines. © 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Ceramic nanocarriers: versatile nanosystem for protein and peptide delivery.

PubMed

Singh, Deependra; Dubey, Pooja; Pradhan, Madhulika; Singh, Manju Rawat

2013-02-01

Proteins and peptides have been established to be the potential drug candidate for various human diseases. But, delivery of these therapeutic protein and peptides is still a challenge due to their several unfavorable properties. Nanotechnology is expanding as a promising tool for the efficient delivery of proteins and peptides. Among numerous nano-based carriers, ceramic nanoparticles have proven themselves as a unique carrier for protein and peptide delivery as they provide a more stable, bioavailable, readily manufacturable, and acceptable proteins and polypeptide formulation. This article provides an overview of the various aspects of ceramic nanoparticles including their classification, methods of preparation, latest advances, and applications as protein and peptide delivery carriers. Ceramic nanocarriers seem to have potential for preserving structural integrity of proteins and peptides, thereby promoting a better therapeutic effect. This approach thus provides pharmaceutical scientists with a new hope for the delivery of proteins and peptides. Still, considerable study on ceramic nanocarrier is necessary with respect to pharmacokinetics, toxicology, and animal studies to confirm their efficiency as well as safety and to establish their clinical usefulness and scale-up to industrial level.

The cancer paradigms of mammalian regeneration: can mammals regenerate as amphibians?

PubMed

Sarig, Rachel; Tzahor, Eldad

2017-04-01

Regeneration in mammals is restricted to distinct tissues and occurs mainly by expansion and maturation of resident stem cells. During regeneration, even subtle mutations in the proliferating cells may cause a detrimental effect by eliciting abnormal differentiation or malignant transformation. Indeed, cancer in mammals has been shown to arise through deregulation of stem cells maturation, which often leads to a differentiation block and cell transformation. In contrast, lower organisms such as amphibians retain a remarkable regenerative capacity in various organs, which occurs via de- and re-differentiation of mature cells. Interestingly, regenerating amphibian cells are highly resistant to oncogenic transformation. Therapeutic approaches to improve mammalian regeneration mainly include stem-cell transplantations; but, these have proved unsuccessful in non-regenerating organs such as the heart. A recently developed approach is to induce de-differentiation of mature cardiomyocytes using factors that trigger their re-entry into the cell cycle. This novel approach raises numerous questions regarding the balance between transformation and regeneration induced by de-differentiation of mature mammalian somatic cells. Can this balance be controlled artificially? Do de-differentiated cells acquire the protection mechanisms seen in regenerating cells of lower organisms? Is this model unique to the cardiac tissue, which rarely develops tumors? This review describes regeneration processes in both mammals and lower organisms and, particularly, the ability of regenerating cells to avoid transformation. By comparing the characteristics of mammalian embryonic and somatic cells, we discuss therapeutic strategies of using various cell populations for regeneration. Finally, we describe a novel cardiac regeneration approach and its implications for regenerative medicine. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Molecular Innovations Toward Theranostics of Aggressive Prostate Cancer

DTIC Science & Technology

2015-09-01

therapeutic agents assisted with new imaging probe is expect to bring a new frontier for prostate cancer management. Our objective is to develop dendrimer ...selective dendrimer nanoparticle platform with both targeted imaging and drug delivery capabilities to target metastatic PCa. Using this unique...constructing dendrimer conjugated with therapeutic peptide, determining the mechanism of action and preparing chelator for conjugating PET tracer and

Biology and medicine of turtles and tortoises.

PubMed

Mautino, M; Page, C D

1993-11-01

Turtles and tortoises are unique reptiles that are gaining popularity as pets. Their anatomy and defense posture hinder, but do not preclude, clinical assessment and performance of routine diagnostic and therapeutic procedures by the clinician. A basic working knowledge of chelonian taxonomy, anatomy, physiology, husbandry, common diseases, and therapeutics will enable the veterinarian to provide health care to this order of reptiles.

Structurally flexible triethanolamine-core poly(amidoamine) dendrimers as effective nanovectors to deliver RNAi-based therapeutics.

PubMed

Liu, Xiaoxuan; Liu, Cheng; Catapano, Carlo V; Peng, Ling; Zhou, Jiehua; Rocchi, Palma

2014-01-01

RNAi-based nucleic acid molecules have attracted considerable attention as compelling therapeutics providing safe and competent delivery systems are available. Dendrimers are emerging as appealing nanocarriers for nucleic acid delivery thanks to their unique well-defined architecture and the resulting cooperativity and multivalency confined within a nanostructure. The present review offers a brief overview of the structurally flexible triethanolamine-core poly(amidoamine) (PAMAM) dendrimers developed in our group as nanovectors for the delivery of RNAi therapeutics. Their excellent activity for delivering different RNAi therapeutics in various disease models in vitro and in vivo will be highlighted here. © 2013.

Psychotherapy of Arab patients in the West: uniqueness, empathy, and "otherness".

PubMed

Sayed, Mohamed A

2003-01-01

The study of Arab patients seeking treatment for their psychological problems in the West has previously been underrepresented in mainstream American journals. Notwithstanding various attempts that deal with Arab Americans as a minority group, there has been a paucity of scholarship dealing with Arab patients' unique characteristics related to sociopolitical, cultural, and other factors that impact the therapeutic process for those individuals who are not acculturated to the American way of life. These patients present challenges to their therapists owing to the contrasting cultural understanding and conceptualization of mental illness and therapeutic process. Therapists need to fully appreciate the relationship between culture and psychotherapy. Patients' and clinicians' awareness of differences may contribute to the ability of both sides of the therapeutic dyad to overcome some of the differences encountered when Arab patients are treated outside their cultural domain. A case vignette serves to illuminate how issues of cultural transference and countertransference can be managed for the benefit of the patient and the enlightenment of the therapist.

Network Modeling of MDM2 Inhibitor-Oxaliplatin Combination Reveals Biological Synergy in wt-p53 solid tumors

PubMed Central

Azmi, Asfar S.; Banerjee, Sanjeev; Ali, Shadan; Wang, Zhiwei; Bao, Bin; Beck, Frances W.J.; Maitah, Main; Choi, Minsig; Shields, Tony F.; Philip, Philip A.; Sarkar, Fazlul H.; Mohammad, Ramzi M.

2011-01-01

Earlier we had shown that the MDM2 inhibitor (MI-219) belonging to the spiro-oxindole family can synergistically enhance the efficacy of platinum chemotherapeutics leading to 50% tumor free survival in a genetically complex pancreatic ductal adenocarcinoma (PDAC) xenograft model. In this report, we have taken a systems and network modeling approach in order to understand central mechanisms behind MI219-oxaliplatin synergy with validation in PDAC, colon and breast cancer cell lines. Microarray profiling of drug treatments (MI-219, oxaliplatin or their combination) in capan-2 cells reveal a similar unique set of gene alterations that is duplicated in other solid tumor cells. As single agent, MI-219 or oxaliplatin induced alterations in 48 and 761 genes respectively. The combination treatment resulted in 767 gene alterations with emergence of 286 synergy unique genes. Ingenuity network modeling of combination and synergy unique genes showed the crucial role of five key local networks CREB, CARF, EGR1, NF-kB and E Cadherin. The network signatures were validated at the protein level in all three cell lines. Individually silencing central nodes in these five hubs resulted in abrogation of MI-219-oxaliplatin activity confirming their critical role in aiding p53 mediated apoptotic response. We anticipate that our MI219-oxaliplatin network blueprints can be clinically translated in the rationale design and application of this unique therapeutic combination in a genetically pre-defined subset of patients. PMID:21623005

United We Stand: Emphasizing Commonalities Across Cognitive-Behavioral Therapies

PubMed Central

Mennin, Douglas S.; Ellard, Kristen K.; Fresco, David M.; Gross, James J.

2016-01-01

Cognitive behavioral therapy (CBT) has a rich history of alleviating the suffering associated with mental disorders. Recently, there have been exciting new developments, including multi-component approaches, incorporated alternative therapies (e.g., meditation), targeted and cost-effective technologies, and integrated biological and behavioral frameworks. These field-wide changes have led some to emphasize the differences among variants of CBT. Here, we draw attention to commonalities across cognitive-behavioral therapies, including shared goals, change principles, and therapeutic processes. Specifically, we offer a framework for examining common CBT characteristics that emphasizes behavioral adaptation as a unifying goal and three core change principles, namely (1) context engagement to promote adaptive imagining and enacting of new experiences; (2) attention change to promote adaptive sustaining, shifting, and broadening of attention; and (3) cognitive change to promote adaptive perspective taking on events so as to alter verbal meanings. Further, we argue that specific intervention components including behavioral exposure/activation, attention training, acceptance/tolerance, decentering/defusion, and cognitive reframing may be emphasized to a greater or lesser degree by different treatment packages but are still fundamentally common therapeutic processes that are present across approaches and are best understood by their relationships to these core CBT change principles. We conclude by arguing for shared methodological and design frameworks for investigating unique and common characteristics to advance a unified and strong voice for CBT in a widening, increasingly multimodal and interdisciplinary, intervention science. PMID:23611074

Facilitation of Drug Transport across the Blood-Brain Barrier with Ultrasound and Microbubbles.

PubMed

Meairs, Stephen

2015-08-31

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood-brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer's disease is presented.

Complete TCRα gene locus control region activity in T cells derived in vitro from embryonic stem cells

PubMed Central

Lahiji, Armin; Kučerová-Levisohn, Martina; Lovett, Jordana; Holmes, Roxanne; Zúñiga-Pflücker, Juan Carlos; Ortiz, Benjamin D.

2013-01-01

Locus Control Regions (LCR) are cis-acting gene regulatory elements with the unique, integration site-independent ability to transfer the characteristics of their locus-of-origin’s gene expression pattern to a linked transgene in mice. LCR activities have been discovered in numerous T cell lineage expressed gene loci. These elements can be adapted to the design of stem cell gene therapy vectors that direct robust therapeutic gene expression to the T cell progeny of engineered stem cells. Currently, transgenic mice provide the only experimental approach that wholly supports all the critical aspects of LCR activity. Herein we report manifestation of all key features of mouse T cell receptor (TCR)-α gene LCR function in T cells derived in vitro from mouse embryonic stem cells (ESC). High level, copy number-related TCRα LCR-linked reporter gene expression levels are cell type-restricted in this system, and upregulated during the expected stage transition of T cell development. We further report that de novo introduction of TCRα LCR linked transgenes into existing T cell lines yields incomplete LCR activity. Together, these data indicate that establishing full TCRα LCR activity requires critical molecular events occurring prior to final T-lineage determination. This study additionally validates a novel, tractable and more rapid approach for the study of LCR activity in T cells, and its translation to therapeutic genetic engineering. PMID:23720809

Magnetic nanoparticles for precision oncology: theranostic magnetic iron oxide nanoparticles for image-guided and targeted cancer therapy

PubMed Central

Zhu, Lei; Zhou, Zhiyang; Mao, Hui; Yang, Lily

2017-01-01

Recent advances in the development of magnetic nanoparticles (MNPs) have shown promise in the development of new personalized therapeutic approaches for clinical management of cancer patients. The unique physicochemical properties of MNPs endow them with novel multifunctional capabilities for imaging, drug delivery and therapy, which are referred to as theranostics. To facilitate the translation of those theranostic MNPs into clinical applications, extensive efforts have been made on designing and improving biocompatibility, stability, safety, drug-loading ability, targeted delivery, imaging signal and thermal- or photodynamic response. In this review, we provide an overview of the physicochemical properties, toxicity and theranostic applications of MNPs with a focus on magnetic iron oxide nanoparticles. PMID:27876448

Science to Practice: Killing Dormant Cells-Is Targeting Autophagy the Key to Complete Tumor Response in Transarterial Chemoembolization?

PubMed

Savic, Lynn Jeanette; Chapiro, Julius; Geschwind, Jean-François

2017-06-01

In this issue of Radiology, Gade et al ( 1 ) describe a unique mechanism of hepatocellular carcinoma (HCC) cells for surviving ischemia induced by transarterial embolization (TAE)/transarterial chemoembolization (TACE) in a state of cell cycle arrest-a function that may serve as a defensive shield against conventional chemotherapeutic agents. This finding adds to our knowledge and establishes a previously poorly understood mechanism of chemoresistance in HCC. As the Achilles heel in terms of this process, a concurrent upregulation of autophagic flux as an adaptive response to TAE-like ischemia was found by the authors. This is a targetable mechanism that can potentially be exploited for combined therapeutic approaches of embolotherapy and autophagy inhibition in HCC.

Tocotrienols: The lesser known form of natural vitamin E

PubMed Central

Patel, Viren; Rink, Cameron; Khanna, Savita; Sen, Chandan K

2014-01-01

A recent and growing body of research has shown that members of this vitamin E family posses unique biologic functions. Tocotrienols have garnered much of this recent attention, and in particular α-tocotrienol has been shown to be the most potent neuroprotective form of vitamin E. Protection exclusively mediated through tocotrienols has been arbitrated to many mechanisms including inhibition of 12-LOX, c-Src, PLA2 and through up-regulation of MRP1. Further, tocotrienols have recently been shown to induce arteriogenesis through induction of TIMP1 and decreased activation of MMP2. However, the unique therapeutic potential of tocotrienols is not limited to neuroprotection. Tocotrienols have been shown to have molecular targets including: apoptotic regulators, cytokines, adhesion molecules, enzymes, kinases, receptors, transcription factors, and growth factors. In spite of this large and unique therapeutic potential, scientific literature on tocotrienols only accounts for approximately 1% of vitamin E research. Given the potential of tocotrienols and relatively scant literature, further investigation is warranted. PMID:22013739

Innovative pharmaceutical development based on unique properties of nanoscale delivery formulation

PubMed Central

Mozhi, Anbu; Zhang, Xu; Zhao, Yuanyuan; Xue, Xiangdong; Hao, Yanli; Zhang, Xiaoning; Wang, Paul C.; Liang, Xing-Jie

2014-01-01

The advent of nanotechnology has reignited interest in the field of pharmaceutical science for the development of nanomedicine. Nanomedicinal formulations are nanometer-sized carrier materials designed for increasing the drug tissue bioavailability, thereby improving the treatment of systemically applied chemotherapeutic drugs. Nanomedicine is a new approach to deliver the pharmaceuticals through different routes of administration with safer and more effective therapies compared to conventional methods. To date, various kinds of nanomaterials have been developed over the years to make delivery systems more effective for the treatment of various diseases. Even though nanomaterials have significant advantages due to their unique nanoscale properties, there are still significant challenges in the improvement and development of nanoformulations with composites and other materials. Here in this review, we highlight the nanomedicinal formulations aiming to improve the balance between the efficacy and the toxicity of therapeutic interventions through different routes of administration and how to design nanomedicine for safer and more effective ways to improve the treatment quality. We also emphasize the environmental and health prospects of nanomaterials for human health care. PMID:23860639

Innovative pharmaceutical development based on unique properties of nanoscale delivery formulation

NASA Astrophysics Data System (ADS)

Kumar, Anil; Chen, Fei; Mozhi, Anbu; Zhang, Xu; Zhao, Yuanyuan; Xue, Xiangdong; Hao, Yanli; Zhang, Xiaoning; Wang, Paul C.; Liang, Xing-Jie

2013-08-01

The advent of nanotechnology has reignited interest in the field of pharmaceutical science for the development of nanomedicine. Nanomedicinal formulations are nanometer-sized carrier materials designed for increasing the drug tissue bioavailability, thereby improving the treatment of systemically applied chemotherapeutic drugs. Nanomedicine is a new approach to deliver the pharmaceuticals through different routes of administration with safer and more effective therapies compared to conventional methods. To date, various kinds of nanomaterials have been developed over the years to make delivery systems more effective for the treatment of various diseases. Even though nanomaterials have significant advantages due to their unique nanoscale properties, there are still significant challenges in the improvement and development of nanoformulations with composites and other materials. Here in this review, we highlight the nanomedicinal formulations aiming to improve the balance between the efficacy and the toxicity of therapeutic interventions through different routes of administration and how to design nanomedicine for safer and more effective ways to improve the treatment quality. We also emphasize the environmental and health prospects of nanomaterials for human health care.

YogaHome: teaching and research challenges in a yoga program with homeless adults.

PubMed

Davis-Berman, Jennifer; Farkas, Jean

2012-01-01

YogaHome is a therapeutic yoga program for homeless women. Developing and refining YogaHome provided a unique opportunity to explore the process of teaching yoga to women faced with the physical and emotional stress of living in a homeless shelter. Unique teaching and research challenges are presented and recommendations for future programs are discussed.

BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia.

PubMed

Cuellar, Sandra; Vozniak, Michael; Rhodes, Jill; Forcello, Nicholas; Olszta, Daniel

2017-01-01

The management of chronic myeloid leukemia with BCR-ABL1 tyrosine kinase inhibitors has evolved chronic myeloid leukemia into a chronic, manageable disease. A patient-centered approach is important for the appropriate management of chronic myeloid leukemia and optimization of long-term treatment outcomes. The pharmacist plays a key role in treatment selection, monitoring drug-drug interactions, identification and management of adverse events, and educating patients on adherence. The combination of tyrosine kinase inhibitors with unique safety profiles and individual patients with unique medical histories can make managing treatment difficult. This review will provide up-to-date information regarding tyrosine kinase inhibitor-based treatment of patients with chronic myeloid leukemia. Management strategies for adverse events and considerations for drug-drug interactions will not only vary among patients but also across tyrosine kinase inhibitors. Drug-drug interactions can be mild to severe. In instances where co-administration of concomitant medications cannot be avoided, it is critical to understand how drug levels are impacted and how subsequent dose modifications ensure therapeutic drug levels are maintained. An important component of patient-centered management of chronic myeloid leukemia also includes educating patients on the significance of early and regular monitoring of therapeutic milestones, emphasizing the importance of adhering to treatment in achieving these targets, and appropriately modifying treatment if these clinical goals are not being met. Overall, staying apprised of current research, utilizing the close pharmacist-patient relationship, and having regular interactions with patients, will help achieve successful long-term treatment of chronic myeloid leukemia in the age of BCR-ABL1 tyrosine kinase inhibitors.

A Comprehensive Infrastructure for Big Data in Cancer Research: Accelerating Cancer Research and Precision Medicine

PubMed Central

Hinkson, Izumi V.; Davidsen, Tanja M.; Klemm, Juli D.; Chandramouliswaran, Ishwar; Kerlavage, Anthony R.; Kibbe, Warren A.

2017-01-01

Advancements in next-generation sequencing and other -omics technologies are accelerating the detailed molecular characterization of individual patient tumors, and driving the evolution of precision medicine. Cancer is no longer considered a single disease, but rather, a diverse array of diseases wherein each patient has a unique collection of germline variants and somatic mutations. Molecular profiling of patient-derived samples has led to a data explosion that could help us understand the contributions of environment and germline to risk, therapeutic response, and outcome. To maximize the value of these data, an interdisciplinary approach is paramount. The National Cancer Institute (NCI) has initiated multiple projects to characterize tumor samples using multi-omic approaches. These projects harness the expertise of clinicians, biologists, computer scientists, and software engineers to investigate cancer biology and therapeutic response in multidisciplinary teams. Petabytes of cancer genomic, transcriptomic, epigenomic, proteomic, and imaging data have been generated by these projects. To address the data analysis challenges associated with these large datasets, the NCI has sponsored the development of the Genomic Data Commons (GDC) and three Cloud Resources. The GDC ensures data and metadata quality, ingests and harmonizes genomic data, and securely redistributes the data. During its pilot phase, the Cloud Resources tested multiple cloud-based approaches for enhancing data access, collaboration, computational scalability, resource democratization, and reproducibility. These NCI-led efforts are continuously being refined to better support open data practices and precision oncology, and to serve as building blocks of the NCI Cancer Research Data Commons. PMID:28983483

Nanoparticle-based Therapies for Wound Biofilm Infection: Opportunities and Challenges

PubMed Central

Kim, Min-Ho

2016-01-01

Clinical data from human chronic wounds implicates biofilm formation with the onset of wound chronicity. Despite the development of novel antimicrobial agents, the cost and complexity of treating chronic wound infections associated with biofilms remain a serious challenge, which necessitates the development of new and alternative approaches for effective anti-biofilm treatment. Recent advancement in nanotechnology for developing a new class of nanoparticles that exhibit unique chemical and physical properties holds promise for the treatment of biofilm infections. Over the last decade, nanoparticle-based approaches against wound biofilm infection have been directed toward developing nanoparticles with intrinsic antimicrobial properties, utilizing nanoparticles for controlled antimicrobials delivery, and applying nanoparticles for antibacterial hyperthermia therapy. In addition, a strategy to functionalize nanoparticles towards enhanced penetration through the biofilm matrix has been receiving considerable interest recently by means of achieving an efficient targeting to the bacterial cells within biofilm matrix. This review summarizes and highlights the recent development of these nanoparticle-based approaches as potential therapeutics for controlling wound biofilm infection, along with current challenges that need to be overcome for their successful clinical translation. PMID:26955044

A Reverse-Translational Approach to Bipolar Disorder: Rodent and human studies in the Behavioral Pattern Monitor

PubMed Central

Young, Jared W.; Minassian, Arpi; Paulus, Martin P.; Geyer, Mark A.; Perry, William

2007-01-01

Mania is the defining feature of Bipolar Disorder (BD). There has been limited progress in understanding the neurobiological underpinnings of BD mania and developing novel therapeutics, in part due to a paucity of relevant animal models with translational potential. Hyperactivity is a cardinal symptom of mania, traditionally measured in humans using observer-rated scales. Multivariate assessment of unconditioned locomotor behavior using the rat Behavioral Pattern Monitor (BPM) developed in our laboratory has shown that hyperactivity includes complex multifaceted behaviors. The BPM has been used to demonstrate differential effects of drugs on locomotor activity and exploratory behavior in rats. Studies of genetically engineered mice in a mouse BPM have confirmed its utility as a cross-species tool. In a “reverse-translational” approach to this work, we developed the human BPM to characterize motor activity in BD patients. Increased activity, object interactions, and altered locomotor patterns provide multidimensional phenotypes to model in the rodent BPM. This unique approach to modeling BD provides an opportunity to identify the neurobiology underlying BD mania and test novel antimanic agents. PMID:17706782

Animal models of speech and vocal communication deficits associated with psychiatric disorders

PubMed Central

Konopka, Genevieve; Roberts, Todd F.

2015-01-01

Disruptions in speech, language and vocal communication are hallmarks of several neuropsychiatric disorders, most notably autism spectrum disorders. Historically, the use of animal models to dissect molecular pathways and connect them to behavioral endophenotypes in cognitive disorders has proven to be an effective approach for developing and testing disease-relevant therapeutics. The unique aspects of human language when compared to vocal behaviors in other animals make such an approach potentially more challenging. However, the study of vocal learning in species with analogous brain circuits to humans may provide entry points for understanding this human-specific phenotype and diseases. Here, we review animal models of vocal learning and vocal communication, and specifically link phenotypes of psychiatric disorders to relevant model systems. Evolutionary constraints in the organization of neural circuits and synaptic plasticity result in similarities in the brain mechanisms for vocal learning and vocal communication. Comparative approaches and careful consideration of the behavioral limitations among different animal models can provide critical avenues for dissecting the molecular pathways underlying cognitive disorders that disrupt speech, language and vocal communication. PMID:26232298

Receptor tyrosine kinase-like orphan receptor 1 (ROR-1): An emerging target for diagnosis and therapy of chronic lymphocytic leukemia.

PubMed

Aghebati-Maleki, Leili; Shabani, Mahdi; Baradaran, Behzad; Motallebnezhad, Morteza; Majidi, Jafar; Yousefi, Mehdi

2017-04-01

Chronic lymphocytic leukemia (CLL) is characterized by reposition of malignant B cells in the blood, bone marrow, spleen and lymph nodes. It remains the most common leukemia in the Western world. Within the recent years, major breakthroughs have been made to prolong the survival and improve the health of patients. Despite these advances, CLL is still recognized as a disease without definitive cure. New treatment approaches, based on unique targets and novel drugs, are highly desired for CLL therapy. The Identification and subsequent targeting of molecules that are overexpressed uniquely in malignant cells not normal ones play critical roles in the success of anticancer therapeutic strategies. In this regard, ROR family proteins are known as a subgroup of protein kinases which have gained huge popularity in the scientific community for the diagnosis and treatment of different cancer types. ROR1 as an antigen exclusively expressed on the surface of tumor cells can be a target for immunotherapy. ROR-1 targeting using different approaches such as siRNA, tyrosine kinase inhibitors, cell therapy and antibody induces tumor growth suppression in cancer cells. In the current review, we aim to present an overview of the efforts and scientific achievements in targeting ROR family, particularly ROR-1, for the diagnosis and treatment of chronic lymphocytic leukemia (CLL). Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[Anorexia nervosa in children and adolescent: new therapeutic approaches].

PubMed

Doyen, C; Le Heuzey, M F; Cook, S; Flého, F; Mouren-Siméoni, M C

1999-11-01

Classical therapeutic recommendations requires that girls with anorexia nervosa be separated from their parents. Refeeding, and later individual psychodynamic approaches were also emphasized. These guidelines are now broadened towards psychotherapeutic approaches (psychodynamic, familial, cognitive-behavioral) associated with psychoeducational and dietetic strategies. In the Child and Adolescent Psychopathology Unit of Robert-Debre Hospital in Paris, individual therapeutic programs are applied to young anorectic girls and their families. These programs are implemented within an inpatient (full-time, part-time) or outpatient (consultations, weekly day-therapeutic program) framework. In order to forge a therapeutic alliance with parents and restore "parental competences" feelings, we do not separate any longer anorectic girls from their parents during hospitalization, and we have developed an alternative therapeutic model to full-time hospitalization.

Biominetic High Density Lipoproteins for the Delivery of Therapeutic Oligonucleotides

NASA Astrophysics Data System (ADS)

Tripathy, Sushant

Advances in nanotechnology have brought about novel inorganic and hybrid nanoparticles with unique physico-chemical properties that make them suitable for a broad range of applications---from nano-circuitry to drug delivery. A significant part of those advancements have led to ground-breaking discoveries that have changed the approaches to formulation of therapeutics against diseases, such as cancer. Now-a-days the focus does not lie solely on finding a candidate small-molecule therapeutic with minimal adverse effects, but researchers are looking up to nanoparticles to improve biodistribution and biocompatibility profile of clinically proven therapeutics. The plethora of conjugation chemistries offered by currently extant inorganic nanoparticles have, in recent years, led to great leaps in the field of biomimicry---a modality that promises high biocompatibility. Further, in the pursuit of highly specific therapeutic molecules, researchers have turned to silencing oligonucleotides and some have already brought together the strengths of nanoparticles and silencing oligonucleotides in search of an efficacious therapy for cancer with minimal adverse effects. This dissertation work focuses on such a biomimetic platform---a gold nanoparticle based high density lipoprotein biomimetic (HDL NP), for the delivery of therapeutic oligonucleotides. The first chapter of this body of work introduces the molecular target of the silencing oligonucleotides---VEGFR2, and its role in the progression of solid tumor cancers. The background information also covers important aspects of natural high density lipoproteins (HDL), especially their innate capacity to bind and deliver exogenous and endogenous silencing oligonucleotides to tissues that express their high affinity receptor SRB1. We subsequently describe the synthesis of the biomimetic HDL NP and its oligonucleotide conjugates, and establish their biocompatibility. Further on, experimental data demonstrate the efficacy of silencing oligonucleotides conjugated HDL NPs in regulating the expression and function of VEGFR2 in cultured endothelial cells. Finally, the efficacy of the conjugates in two animal models of angiogenesis is presented.

Endovascular approach to treat ascending aortic pseudoaneurysm in a patient with previous CABG and very high surgical risk.

PubMed

Zago, Alexandre C; Saadi, Eduardo K; Zago, Alcides J

2011-10-01

Pseudoaneurysm of the ascending aorta is an uncommon pathology and a challenge in high-risk patients who undergo conventional surgery because of high operative morbidity and mortality. Endovascular exclusion of an aortic pseudoaneurysm using an endoprosthesis is a less invasive approach, but few such cases have been reported. Moreover, the use of this approach poses unique therapeutic challenges because there is no specific endoprosthesis for ascending aortic repair, particularly to treat patients with previous coronary artery bypass graft (CABG). We describe the case of a 74-year-old patient who had undergone CABG and later presented with an iatrogenic ascending aortic pseudoaneurysm that occurred during an angiography. This patient was at very high risk for surgical treatment and, therefore, an endovascular approach was adopted: percutaneous coronary intervention for the left main coronary artery, left anterior descending and left circumflex native coronary arteries followed by endovascular endoprosthesis deployment in the ascending aorta to exclude the pseudoaneurysm. Both procedures were successfully performed, and the patient was discharged without complications 4 days later. At 5 months' clinical follow-up, his clinical condition was good and he had no complications. Copyright © 2011 Wiley-Liss, Inc.

Active and passive immunization for cancer.

PubMed

Baxter, David

2014-01-01

Vaccination started around the 10th century AD as a means of preventing smallpox. By the end of the 19th century such therapeutic vaccines were well established with both active and passive preparations being used in clinical practice. Active immunization involved administering an immunogen that might be live/ attenuated, killed/ inactivated, toxoid or subunit in origin. Passive immunization involved giving pre-formed antibodies, usually to very recently exposed individuals. At about the same time such approaches were also tried to treat a variety of cancers - proof of principle for the protective role of the immune response against malignancy was established by the observation that tumors transplanted into syngeneic hosts were rejected by the host innate and adaptive responses. The impact of these therapeutic vaccination has taken a considerable time to become established - in part because target antigens against which an adaptive response can be directed do not appear to be uniquely expressed on malignant transformed cells; and also because tumor cells are able to manipulate their environment to downregulate the host immune response. Therapeutic cancer vaccines are also divided into active and passive types - the latter being subdivided into specific and non-specific vaccines. Active immunization utilizes an immunogen to generate a host response designed to eliminate the malignant cells, whereas in passive immunization preformed antibodies or cells are administered to directly eliminate the transformed cells - examples of each are considered in this review.

Active and passive immunization for cancer

PubMed Central

Baxter, David

2014-01-01

Vaccination started around the 10th century AD as a means of preventing smallpox. By the end of the 19th century such therapeutic vaccines were well established with both active and passive preparations being used in clinical practice. Active immunization involved administering an immunogen that might be live/ attenuated, killed/ inactivated, toxoid or subunit in origin. Passive immunization involved giving pre-formed antibodies, usually to very recently exposed individuals. At about the same time such approaches were also tried to treat a variety of cancers – proof of principle for the protective role of the immune response against malignancy was established by the observation that tumors transplanted into syngeneic hosts were rejected by the host innate and adaptive responses. The impact of these therapeutic vaccination has taken a considerable time to become established - in part because target antigens against which an adaptive response can be directed do not appear to be uniquely expressed on malignant transformed cells; and also because tumor cells are able to manipulate their environment to downregulate the host immune response. Therapeutic cancer vaccines are also divided into active and passive types – the latter being subdivided into specific and non-specific vaccines. Active immunization utilizes an immunogen to generate a host response designed to eliminate the malignant cells, whereas in passive immunization preformed antibodies or cells are administered to directly eliminate the transformed cells - examples of each are considered in this review. PMID:25424829

Consumer satisfaction with psychiatric services: The role of shared decision making and the therapeutic relationship.

PubMed

Klingaman, Elizabeth A; Medoff, Deborah R; Park, Stephanie G; Brown, Clayton H; Fang, Lijuan; Dixon, Lisa B; Hack, Samantha M; Tapscott, Stephanie L; Walsh, Mary Brighid; Kreyenbuhl, Julie A

2015-09-01

Although dissatisfaction is a primary reason for disengagement from outpatient psychiatric care among consumers with serious mental illnesses, little is known about predictors of their satisfaction with medication management visits. The primary purpose of this study was to explore how dimensions of consumer preferences for shared decision making (i.e., preferences for obtaining knowledge about one's mental illness, being offered and asked one's opinion about treatment options, and involvement in treatment decisions) and the therapeutic relationship (i.e., positive collaboration and type of clinician input) were related to visit satisfaction. Participants were 228 Veterans with serious mental illnesses who completed a 19-item self-report questionnaire assessing satisfaction with visits to prescribers (524 assessments) immediately after visits. In this correlational design, a 3-level mixed model with the restricted maximum likelihood estimation procedure was used to examine shared decision-making preferences and therapeutic alliance as predictors of visit satisfaction. Preferences for involvement in treatment decisions was the unique component of shared decision making associated with satisfaction, such that the more consumers desired involvement, the less satisfied they were. Positive collaboration and prescriber input were associated with greater visit satisfaction. When consumers with serious mental illnesses express preferences to be involved in shared decision making, it may not be sufficient to only provide information and treatment options; prescribers should attend to consumers' interest in involvement in actual treatment decisions. Assessment and tailoring of treatment approaches to consumer preferences for shared decision making should occur within the context of a strong therapeutic relationship. (c) 2015 APA, all rights reserved).

Mass Spectrometry Approaches for Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory.

PubMed

Ladwig, Paula M; Barnidge, David R; Willrich, Maria A V

2017-05-01

Therapeutic monoclonal antibodies (MAbs) are an important class of drugs used to treat diseases ranging from autoimmune disorders to B cell lymphomas to other rare conditions thought to be untreatable in the past. Many advances have been made in the characterization of immunoglobulins as a result of pharmaceutical companies investing in technologies that allow them to better understand MAbs during the development phase. Mass spectrometry is one of the new advancements utilized extensively by pharma to analyze MAbs and is now beginning to be applied in the clinical laboratory setting. The rise in the use of therapeutic MAbs has opened up new challenges for the development of assays for monitoring this class of drugs. MAbs are larger and more complex than typical small-molecule therapeutic drugs routinely analyzed by mass spectrometry. In addition, they must be quantified in samples that contain endogenous immunoglobulins with nearly identical structures. In contrast to an enzyme-linked immunosorbent assay (ELISA) for quantifying MAbs, mass spectrometry-based assays do not rely on MAb-specific reagents such as recombinant antigens and/or anti-idiotypic antibodies, and time for development is usually shorter. Furthermore, using molecular mass as a measurement tool provides increased specificity since it is a first-order principle unique to each MAb. This enables rapid quantification of MAbs and multiplexing. This review describes how mass spectrometry can become an important tool for clinical chemists and especially immunologists, who are starting to develop assays for MAbs in the clinical laboratory and are considering mass spectrometry as a versatile platform for the task. Copyright © 2017 Ladwig et al.

Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

PubMed Central

Pandey, Udai Bhan

2011-01-01

The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process. PMID:21415126

Recent Advances on Inorganic Nanoparticle-Based Cancer Therapeutic Agents

PubMed Central

Wang, Fenglin; Li, Chengyao; Cheng, Jing; Yuan, Zhiqin

2016-01-01

Inorganic nanoparticles have been widely investigated as therapeutic agents for cancer treatments in biomedical fields due to their unique physical/chemical properties, versatile synthetic strategies, easy surface functionalization and excellent biocompatibility. This review focuses on the discussion of several types of inorganic nanoparticle-based cancer therapeutic agents, including gold nanoparticles, magnetic nanoparticles, upconversion nanoparticles and mesoporous silica nanoparticles. Several cancer therapy techniques are briefly introduced at the beginning. Emphasis is placed on how these inorganic nanoparticles can provide enhanced therapeutic efficacy in cancer treatment through site-specific accumulation, targeted drug delivery and stimulated drug release, with elaborations on several examples to highlight the respective strategies adopted. Finally, a brief summary and future challenges are included. PMID:27898016

Recent Advances on Inorganic Nanoparticle-Based Cancer Therapeutic Agents.

PubMed

Wang, Fenglin; Li, Chengyao; Cheng, Jing; Yuan, Zhiqin

2016-11-25

Inorganic nanoparticles have been widely investigated as therapeutic agents for cancer treatments in biomedical fields due to their unique physical/chemical properties, versatile synthetic strategies, easy surface functionalization and excellent biocompatibility. This review focuses on the discussion of several types of inorganic nanoparticle-based cancer therapeutic agents, including gold nanoparticles, magnetic nanoparticles, upconversion nanoparticles and mesoporous silica nanoparticles. Several cancer therapy techniques are briefly introduced at the beginning. Emphasis is placed on how these inorganic nanoparticles can provide enhanced therapeutic efficacy in cancer treatment through site-specific accumulation, targeted drug delivery and stimulated drug release, with elaborations on several examples to highlight the respective strategies adopted. Finally, a brief summary and future challenges are included.

The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment

PubMed Central

Mitwally, Mohamed FM; Casper, Robert F; Diamond, Michael P

2005-01-01

Clinical utilization of ovulation stimulation to facilitate the ability of a couple to conceive has not only provided a valuable therapeutic approach, but has also yielded extensive information on the physiology of ovarian follicular recruitment, endometrial receptivity and early embryo competency. One of the consequences of the use of fertility enhancing agents for ovarian stimulation has been the creation of a hyperestrogenic state, which may influence each of these parameters. Use of aromatase inhibitors reduces hyperestrogenism inevitably attained during ovarian stimulation. In addition, the adjunct use of aromatase inhibitors during ovarian stimulation reduces amount of gonadotropins required for optimum stimulation. The unique approach of reducing hyperestrogenism, as well as lowering amount of gonadotropins without affecting the number of mature ovarian follicles is an exciting strategy that could result in improvement in the treatment outcome by ameliorating the deleterious effects of the ovarian stimulation on follicular development, endometrial receptivity, as well as oocyte and embryo quality. PMID:16202169

Controlling tissue microenvironments: biomimetics, transport phenomena, and reacting systems.

PubMed

Fisher, Robert J; Peattie, Robert A

2007-01-01

The reconstruction of tissues ex vivo and production of cells capable of maintaining a stable performance for extended time periods in sufficient quantity for synthetic or therapeutic purposes are primary objectives of tissue engineering. The ability to characterize and manipulate the cellular microenvironment is critical for successful implementation of such cell-based bioengineered systems. As a result, knowledge of fundamental biomimetics, transport phenomena, and reaction engineering concepts is essential to system design and development. Once the requirements of a specific tissue microenvironment are understood, the biomimetic system specifications can be identified and a design implemented. Utilization of novel membrane systems that are engineered to possess unique transport and reactive features is one successful approach presented here. The limited availability of tissue or cells for these systems dictates the need for microscale reactors. A capstone illustration based on cellular therapy for type 1 diabetes mellitus via encapsulation techniques is presented as a representative example of this approach, to stress the importance of integrated systems.

Extracellular matrix in lung development, homeostasis and disease

DOE PAGES

Zhou, Yong; Horowitz, Jeffrey C.; Naba, Alexandra; ...

2018-03-08

Here, the lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECMmore » in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases.« less

Extracellular matrix in lung development, homeostasis and disease

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

Zhou, Yong; Horowitz, Jeffrey C.; Naba, Alexandra

Here, the lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECMmore » in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases.« less

Idiopathic Inflammatory Myopathies: Clinical Approach and Management

PubMed Central

Malik, Asma; Hayat, Ghazala; Kalia, Junaid S.; Guzman, Miguel A.

2016-01-01

Idiopathic inflammatory myopathies (IIM) are a group of chronic, autoimmune conditions affecting primarily the proximal muscles. The most common types are dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myopathy (NAM), and sporadic inclusion body myositis (sIBM). Patients typically present with sub-acute to chronic onset of proximal weakness manifested by difficulty with rising from a chair, climbing stairs, lifting objects, and combing hair. They are uniquely identified by their clinical presentation consisting of muscular and extramuscular manifestations. Laboratory investigations, including increased serum creatine kinase (CK) and myositis specific antibodies (MSA) may help in differentiating clinical phenotype and to confirm the diagnosis. However, muscle biopsy remains the gold standard for diagnosis. These disorders are potentially treatable with proper diagnosis and initiation of therapy. Goals of treatment are to eliminate inflammation, restore muscle performance, reduce morbidity, and improve quality of life. This review aims to provide a basic diagnostic approach to patients with suspected IIM, summarize current therapeutic strategies, and provide an insight into future prospective therapies. PMID:27242652

Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues

PubMed Central

Aartsma-Rus, Annemieke; Straub, Volker; Hemmings, Robert; Haas, Manuel; Schlosser-Weber, Gabriele; Stoyanova-Beninska, Violeta; Mercuri, Eugenio; Muntoni, Francesco; Sepodes, Bruno; Vroom, Elizabeth

2017-01-01

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience. PMID:28796573

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

PubMed Central

Gorini, Giorgio; Adron Harris, R; Dayne Mayfield, R

2014-01-01

Recent studies have shown that gene regulation is far more complex than previously believed and does not completely explain changes at the protein level. Therefore, the direct study of the proteome, considerably different in both complexity and dynamicity to the genome/transcriptome, has provided unique insights to an increasing number of researchers. During the past decade, extraordinary advances in proteomic techniques have changed the way we can analyze the composition, regulation, and function of protein complexes and pathways underlying altered neurobiological conditions. When combined with complementary approaches, these advances provide the contextual information for decoding large data sets into meaningful biologically adaptive processes. Neuroproteomics offers potential breakthroughs in the field of alcohol research by leading to a deeper understanding of how alcohol globally affects protein structure, function, interactions, and networks. The wealth of information gained from these advances can help pinpoint relevant biomarkers for early diagnosis and improved prognosis of alcoholism and identify future pharmacological targets for the treatment of this addiction. PMID:23900301

Improving CRISPR-Cas specificity with chemical modifications in single-guide RNAs.

PubMed

Ryan, Daniel E; Taussig, David; Steinfeld, Israel; Phadnis, Smruti M; Lunstad, Benjamin D; Singh, Madhurima; Vuong, Xuan; Okochi, Kenji D; McCaffrey, Ryan; Olesiak, Magdalena; Roy, Subhadeep; Yung, Chong Wing; Curry, Bo; Sampson, Jeffrey R; Bruhn, Laurakay; Dellinger, Douglas J

2018-01-25

CRISPR systems have emerged as transformative tools for altering genomes in living cells with unprecedented ease, inspiring keen interest in increasing their specificity for perfectly matched targets. We have developed a novel approach for improving specificity by incorporating chemical modifications in guide RNAs (gRNAs) at specific sites in their DNA recognition sequence ('guide sequence') and systematically evaluating their on-target and off-target activities in biochemical DNA cleavage assays and cell-based assays. Our results show that a chemical modification (2'-O-methyl-3'-phosphonoacetate, or 'MP') incorporated at select sites in the ribose-phosphate backbone of gRNAs can dramatically reduce off-target cleavage activities while maintaining high on-target performance, as demonstrated in clinically relevant genes. These findings reveal a unique method for enhancing specificity by chemically modifying the guide sequence in gRNAs. Our approach introduces a versatile tool for augmenting the performance of CRISPR systems for research, industrial and therapeutic applications. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Improving CRISPR–Cas specificity with chemical modifications in single-guide RNAs

PubMed Central

Ryan, Daniel E; Taussig, David; Steinfeld, Israel; Phadnis, Smruti M; Lunstad, Benjamin D; Singh, Madhurima; Vuong, Xuan; Okochi, Kenji D; McCaffrey, Ryan; Olesiak, Magdalena; Roy, Subhadeep; Yung, Chong Wing; Curry, Bo; Sampson, Jeffrey R; Dellinger, Douglas J

2018-01-01

Abstract CRISPR systems have emerged as transformative tools for altering genomes in living cells with unprecedented ease, inspiring keen interest in increasing their specificity for perfectly matched targets. We have developed a novel approach for improving specificity by incorporating chemical modifications in guide RNAs (gRNAs) at specific sites in their DNA recognition sequence (‘guide sequence’) and systematically evaluating their on-target and off-target activities in biochemical DNA cleavage assays and cell-based assays. Our results show that a chemical modification (2′-O-methyl-3′-phosphonoacetate, or ‘MP’) incorporated at select sites in the ribose-phosphate backbone of gRNAs can dramatically reduce off-target cleavage activities while maintaining high on-target performance, as demonstrated in clinically relevant genes. These findings reveal a unique method for enhancing specificity by chemically modifying the guide sequence in gRNAs. Our approach introduces a versatile tool for augmenting the performance of CRISPR systems for research, industrial and therapeutic applications. PMID:29216382

Extracellular matrix in lung development, homeostasis and disease

DOE PAGES

Zhou, Yong; Horowitz, Jeffrey C.; Naba, Alexandra; ...

2018-03-08

The lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this paper, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECM inmore » normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. Finally, we identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases.« less

Aggregates, Crystals, Gels, and Amyloids: Intracellular and Extracellular Phenotypes at the Crossroads of Immunoglobulin Physicochemical Property and Cell Physiology

PubMed Central

2013-01-01

Recombinant immunoglobulins comprise an important class of human therapeutics. Although specific immunoglobulins can be purposefully raised against desired antigen targets by various methods, identifying an immunoglobulin clone that simultaneously possesses potent therapeutic activities and desirable manufacturing-related attributes often turns out to be challenging. The variable domains of individual immunoglobulins primarily define the unique antigen specificities and binding affinities inherent to each clone. The primary sequence of the variable domains also specifies the unique physicochemical properties that modulate various aspects of individual immunoglobulin life cycle, starting from the biosynthetic steps in the endoplasmic reticulum, secretory pathway trafficking, secretion, and the fate in the extracellular space and in the endosome-lysosome system. Because of the diverse repertoire of immunoglobulin physicochemical properties, some immunoglobulin clones' intrinsic properties may manifest as intriguing cellular phenotypes, unusual solution behaviors, and serious pathologic outcomes that are of scientific and clinical importance. To gain renewed insights into identifying manufacturable therapeutic antibodies, this paper catalogs important intracellular and extracellular phenotypes induced by various subsets of immunoglobulin clones occupying different niches of diverse physicochemical repertoire space. Both intrinsic and extrinsic factors that make certain immunoglobulin clones desirable or undesirable for large-scale manufacturing and therapeutic use are summarized. PMID:23533417

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.

PubMed

Singer, Daniel E; Hellkamp, Anne S; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R; Piccini, Jonathan P; Hankey, Graeme J; Breithardt, Günter; Halperin, Jonathan L; Becker, Richard C; Hacke, Werner; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2015-03-03

In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted. TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported. URL: ClinicalTrials.gov. Unique identifier: NCT00403767. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial

PubMed Central

Singer, Daniel E.; Hellkamp, Anne S.; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R.; Piccini, Jonathan P.; Hankey, Graeme J.; Breithardt, Günter; Halperin, Jonathan L.; Becker, Richard C.; Hacke, Werner; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

2015-01-01

Background In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. Methods and Results We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted. Conclusions TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00403767. PMID:25736441

Preparation, Surface Properties, and Therapeutic Applications of Gold Nanoparticles in Biomedicine.

PubMed

Panahi, Yunes; Mohammadhosseini, Majid; Nejati-Koshki, Kazem; Abadi, Azam Jafari Najaf; Moafi, Hadi Fallah; Akbarzadeh, Abolfazl; Farshbaf, Masoud

2017-02-01

Gold nanoparticles (AuNPs) due to their unique properties and manifold surface functionalities have been applied in bio-nanotechnology. The application of GNPs in recent medical and biological research is very extensive. Especially it involves applications such as detection and photothermalysis of microorganisms and cancer stem cells, biosensors; optical bio-imaging and observing of cells and these nanostructures also serve as practical platforms for therapeutic agents. In this review we studied all therapeutic applications of gold nanoparticles in biomedicine, synthesis methods, and surface properties. © Georg Thieme Verlag KG Stuttgart · New York.

Zebrafish Models of Human Leukemia: Technological Advances and Mechanistic Insights.

PubMed

Harrison, Nicholas R; Laroche, Fabrice J F; Gutierrez, Alejandro; Feng, Hui

2016-01-01

Insights concerning leukemic pathophysiology have been acquired in various animal models and further efforts to understand the mechanisms underlying leukemic treatment resistance and disease relapse promise to improve therapeutic strategies. The zebrafish (Danio rerio) is a vertebrate organism with a conserved hematopoietic program and unique experimental strengths suiting it for the investigation of human leukemia. Recent technological advances in zebrafish research including efficient transgenesis, precise genome editing, and straightforward transplantation techniques have led to the generation of a number of leukemia models. The transparency of the zebrafish when coupled with improved lineage-tracing and imaging techniques has revealed exquisite details of leukemic initiation, progression, and regression. With these advantages, the zebrafish represents a unique experimental system for leukemic research and additionally, advances in zebrafish-based high-throughput drug screening promise to hasten the discovery of novel leukemia therapeutics. To date, investigators have accumulated knowledge of the genetic underpinnings critical to leukemic transformation and treatment resistance and without doubt, zebrafish are rapidly expanding our understanding of disease mechanisms and helping to shape therapeutic strategies for improved outcomes in leukemic patients.

Zebrafish Models of Human Leukemia: Technological Advances and Mechanistic Insights

PubMed Central

Harrison, Nicholas R.; Laroche, Fabrice J.F.; Gutierrez, Alejandro

2016-01-01

Insights concerning leukemic pathophysiology have been acquired in various animal models and further efforts to understand the mechanisms underlying leukemic treatment resistance and disease relapse promise to improve therapeutic strategies. The zebrafish (Danio rerio) is a vertebrate organism with a conserved hematopoietic program and unique experimental strengths suiting it for the investigation of human leukemia. Recent technological advances in zebrafish research including efficient transgenesis, precise genome editing, and straightforward transplantation techniques have led to the generation of a number of leukemia models. The transparency of the zebrafish when coupled with improved lineage-tracing and imaging techniques has revealed exquisite details of leukemic initiation, progression, and regression. With these advantages, the zebrafish represents a unique experimental system for leukemic research and additionally, advances in zebrafish-based high-throughput drug screening promise to hasten the discovery of novel leukemia therapeutics. To date, investigators have accumulated knowledge of the genetic underpinnings critical to leukemic transformation and treatment resistance and without doubt, zebrafish are rapidly expanding our understanding of disease mechanisms and helping to shape therapeutic strategies for improved outcomes in leukemic patients. PMID:27165361

Diffusion-weighted Breast MRI: Clinical Applications and Emerging Techniques

PubMed Central

Partridge, Savannah C.; Nissan, Noam; Rahbar, Habib; Kitsch, Averi E.; Sigmund, Eric E.

2016-01-01

Diffusion weighted MRI (DWI) holds potential to improve the detection and biological characterization of breast cancer. DWI is increasingly being incorporated into breast MRI protocols to address some of the shortcomings of routine clinical breast MRI. Potential benefits include improved differentiation of benign and malignant breast lesions, assessment and prediction of therapeutic efficacy, and non-contrast detection of breast cancer. The breast presents a unique imaging environment with significant physiologic and inter-subject variations, as well as specific challenges to achieving reliable high quality diffusion weighted MR images. Technical innovations are helping to overcome many of the image quality issues that have limited widespread use of DWI for breast imaging. Advanced modeling approaches to further characterize tissue perfusion, complexity, and glandular organization may expand knowledge and yield improved diagnostic tools. PMID:27690173

Treating Drug Abuse and Addiction in the Criminal Justice System: Improving Public Health and Safety

PubMed Central

Chandler, Redonna K.; Fletcher, Bennett W.; Volkow, Nora D.

2009-01-01

Despite increasing evidence that addiction is a treatable disease of the brain, most individuals do not receive treatment. Involvement in the criminal justice system often results from illegal drug-seeking behavior and participation in illegal activities that reflect, in part, disrupted behavior ensuing from brain changes triggered by repeated drug use. Treating drug-involved offenders provides a unique opportunity to decrease substance abuse and reduce associated criminal behavior. Emerging neuroscience has the potential to transform traditional sanction-oriented public safety approaches by providing new therapeutic strategies against addiction that could be used in the criminal justice system. We summarize relevant neuroscientific findings and evidence-based principles of addiction treatment that, if implemented in the criminal justice system, could help improve public heath and reduce criminal behavior. PMID:19141766

Negotiating "The Social" and Managing Tuberculosis in Georgia.

PubMed

Koch, Erin

2016-03-01

In this paper I utilize anthropological insights to illuminate how health professionals and patients navigate and negotiate what for them is social about tuberculosis in order to improve treatment outcomes and support patients as human beings. I draw on ethnographic research about the implementation of the DOTS (Directly Observed Therapy, Short Course) approach in Georgia's National Tuberculosis Program in the wake of the Soviet healthcare system. Georgia is a particularly unique context for exploring these issues given the country's rich history of medical professionalism and the insistence that the practice of medicine is a moral commitment to society. I argue for critical attention to the ways in which treatment recipients and providers navigate what, for them, is "social" about therapeutic practices and their significance for avoiding biological and social reductionism.

Genetics of eosinophilic esophagitis

PubMed Central

Kottyan, LC; Rothenberg, ME

2017-01-01

Eosinophilic esophagitis (EoE) is a chronic, allergic disease associated with marked mucosal eosinophil accumulation. EoE disease risk is multifactorial and includes environmental and genetic factors. This review will focus on the contribution of genetic variation to EoE risk, as well as the experimental tools and statistical methodology used to identify EoE risk loci. Specific disease-risk loci that are shared between EoE and other allergic diseases (TSLP, LRRC32) or unique to EoE (CAPN14), as well as Mendellian Disorders associated with EoE, will be reviewed in the context of the insight that they provide into the molecular pathoetiology of EoE. We will also discuss the clinical opportunities that genetic analyses provide in the form of decision support tools, molecular diagnostics, and novel therapeutic approaches. PMID:28224995

Genetics of eosinophilic esophagitis.

PubMed

Kottyan, L C; Rothenberg, M E

2017-05-01

Eosinophilic esophagitis (EoE) is a chronic, allergic disease associated with marked mucosal eosinophil accumulation. EoE disease risk is multifactorial and includes environmental and genetic factors. This review will focus on the contribution of genetic variation to EoE risk, as well as the experimental tools and statistical methodology used to identify EoE risk loci. Specific disease-risk loci that are shared between EoE and other allergic diseases (TSLP, LRRC32) or unique to EoE (CAPN14), as well as Mendellian Disorders associated with EoE, will be reviewed in the context of the insight that they provide into the molecular pathoetiology of EoE. We will also discuss the clinical opportunities that genetic analyses provide in the form of decision support tools, molecular diagnostics, and novel therapeutic approaches.

Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives.

PubMed

Lazarević, Tatjana; Rilak, Ana; Bugarčić, Živadin D

2017-12-15

Metallodrugs offer potential for unique mechanism of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. Examples of metal compounds and chelating agents currently in clinical use, clinical trials or preclinical development are highlighted. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Multifunctional Quantum Dots for Personalized Medicine

PubMed Central

Zrazhevskiy, Pavel; Gao, Xiaohu

2009-01-01

Successes in biomedical research and state-of-the-art medicine have undoubtedly improved the quality of life. However, a number of diseases, such as cancer, immunodeficiencies, and neurological disorders, still evade conventional diagnostic and therapeutic approaches. A transformation towards personalized medicine may help to combat these diseases. For this, identification of disease molecular fingerprints and their association with prognosis and targeted therapy must become available. Quantum dots (QDs), semiconductor nanocrystals with unique photo-physical properties, represent a novel class of fluorescence probes to address many of the needs of personalized medicine. This review outlines the properties of QDs that make them a suitable platform for advancing personalized medicine, examines several proof-of-concept studies showing utility of QDs for clinically relevant applications, and discusses current challenges in introducing QDs into clinical practice. PMID:20161004

A unique tripartite collision tumor of the esophagus

PubMed Central

Schizas, Dimitrios; Michalinos, Adamantios; Alexandrou, Paraskevi; Moris, Demetrios; Baliou, Evangelia; Tsilimigras, Diamantis; Throupis, Theodore; Liakakos, Theodore

2017-01-01

Abstract Rationale: We report a unique case of a tripartite esophageal collision tumor consisting of three separate histologic types. Patients concerns: Therapeutic dilemmas on the proper treatment of those rare neoplasms remain unanswered considering both proper surgical therapy and adjuvant therapy. Diagnose: In this paper, we report a unique case of a patient with a tripartite esophageal collision tumor consisting of a small cell carcinoma, an adenocarcinoma of medium differentiation and a signet ring cell carcinoma. Diagnosis is difficult as clinical presentation of the patient was undistinguishable from other, commoner tumor types. Interventions: The patient's diagnostic and therapeutic course along with available data on the collisions tumor's biological behavior and treatment are briefly discussed. Outcomes: Esophagectomy is the best treatment options for these patients. Unique nature of this tumor demands aggresive oncologic treatment. Lessons: Collision tumors are rare neoplasms consisting of distinct cell populations developing in juxtaposition to one another without any areas of intermingling. Various cell types can be found. However, collision neoplasms of the esophagus combining adenomatous and neuroendocrine components are exceedingly rare, with only 5 cases described to date in the literature. Given their rarity, limited information is available on their tumorigenesis, biological behavior and clinical course. In general, these tumors are aggressive neoplasms and significantly affect patient treatment and prognosis. PMID:29245236

Goethe's anxieties, depressive episodes and (self-)therapeutic strategies: a contribution to method integration in psychotherapy.

PubMed

Holm-Hadulla, Rainer M

2013-01-01

In psychiatry and psychotherapy, abstract scientific principles need to be exemplified by narrative case reports to gain practical precision. Goethe was one of the most creative writers, productive scientists, and effective statesmen that ever lived. His descriptions of feelings, emotions, and mental states related to anxieties, depressive episodes, dysthymia, and creativity are unique in their phenomenological precision and richness. His life and work can thus serve as an excellent example enhancing our understanding of the relationship between anxiety, depression and creativity. Furthermore, he described (self-)therapeutic strategies that reinforce and refine modern views. Goethe's self-assessments in his works and letters, and the descriptions by others are analyzed under the perspective of current psychiatric classification. His therapeutic techniques and recommendations are compared with cognitive-behavioral, psychodynamic, and existential psychotherapy to amplify modern concepts of psychotherapy. From a scientific perspective, several distinctive depressive episodes can be diagnosed in Goethe's life. They were characterized by extended depressive moods, lack of drive, and loss of interest and self-esteem combined with social retreat. Goethe displayed diffuse and phobic anxieties as well as dysthymia. His (self-)therapeutic strategies were: (a) the systematic use of helping alliances, (b) behavioral techniques, (c) cognitive reflection on meanings and beliefs, (d) psychodynamic and psychoanalytic remembering, repeating, and working through, and (e) existential striving for self-actualization, social commitment, meaning, and creativity. In Goethe's life, creative incubation, illumination, and elaboration appear to have been associated with psychic instability and dysthymia, sometimes with depressive episodes in a clinical sense. On the one hand, his creative work was triggered by anxieties, dysthymia, and depressive moods. On the other hand, his creativity helped him to cope with psychic disorders and suicidal tendencies. Furthermore, Goethe described psychotherapeutic strategies that resemble modern techniques. He integrated relational, behavioral, cognitive, psychodynamic, and existential techniques and attitudes. These modern psychotherapeutic approaches can be exemplified and enhanced by reflecting upon the (self-)therapeutic efforts of one of the most creative persons that have ever lived. Hermeneutics as the art of communication and understanding derived from Goethe's (self-)therapy and creative works can serve as a meta-theoretical framework for the integration of different psychotherapeutic approaches. Copyright © 2012 S. Karger AG, Basel.

The management of a sexually charged clinical problem: social structural and psychoanalytic functionalist approaches in a therapeutic community.

PubMed

James, O W

1986-03-01

An event in a therapeutic community is examined from the perspectives of the structuralism of Durkheim and the functionalism of psychoanalysis. Although these two approaches might appear theoretically contradictory, analysis of the evidence shows them to be clinically complementary. The role of social structure in therapeutic communities requires deliberate conceptualization if such communities are to be demonstrably therapeutic.

United we stand: emphasizing commonalities across cognitive-behavioral therapies.

PubMed

Mennin, Douglas S; Ellard, Kristen K; Fresco, David M; Gross, James J

2013-06-01

Cognitive behavioral therapy (CBT) has a rich history of alleviating the suffering associated with mental disorders. Recently, there have been exciting new developments, including multicomponent approaches, incorporated alternative therapies (e.g., meditation), targeted and cost-effective technologies, and integrated biological and behavioral frameworks. These field-wide changes have led some to emphasize the differences among variants of CBT. Here, we draw attention to commonalities across cognitive-behavioral therapies, including shared goals, change principles, and therapeutic processes. Specifically, we offer a framework for examining common CBT characteristics that emphasizes behavioral adaptation as a unifying goal and three core change principles, namely (a) context engagement to promote adaptive imagining and enacting of new experiences; (b) attention change to promote adaptive sustaining, shifting, and broadening of attention; and (c) cognitive change to promote adaptive perspective taking on events so as to alter verbal meanings. Further, we argue that specific intervention components, including behavioral exposure/activation, attention training, acceptance/tolerance, decentering/defusion, and cognitive reframing, may be emphasized to a greater or lesser degree by different treatment packages but are still fundamentally common therapeutic processes that are present across approaches and are best understood by their relationships to these core CBT change principles. We conclude by arguing for shared methodological and design frameworks for investigating unique and common characteristics to advance a unified and strong voice for CBT in a widening, increasingly multimodal and interdisciplinary, intervention science. Copyright © 2013 Elsevier Ltd. All rights reserved.

Novel paths towards neural cellular products for neurological disorders.

PubMed

Daadi, Marcel M

2011-11-01

The prospect of using neural cells derived from stem cells or from reprogrammed adult somatic cells provides a unique opportunity in cell therapy and drug discovery for developing novel strategies for brain repair. Cell-based therapeutic approaches for treating CNS afflictions caused by disease or injury aim to promote structural repair of the injured or diseased neural tissue, an outcome currently not achieved by drug therapy. Preclinical research in animal models of various diseases or injuries report that grafts of neural cells enhance endogenous repair, provide neurotrophic support to neurons undergoing degeneration and replace lost neural cells. In recent years, the sources of neural cells for treating neurological disorders have been rapidly expanding and in addition to offering therapeutic potential, neural cell products hold promise for disease modeling and drug discovery use. Specific neural cell types have been derived from adult or fetal brain, from human embryonic stem cells, from induced pluripotent stem cells and directly transdifferentiated from adult somatic cells, such as skin cells. It is yet to be determined if the latter approach will evolve into a paradigm shift in the fields of stem cell research and regenerative medicine. These multiple sources of neural cells cover a wide spectrum of safety that needs to be balanced with efficacy to determine the viability of the cellular product. In this article, we will review novel sources of neural cells and discuss current obstacles to developing them into viable cellular products for treating neurological disorders.

Laser microporation of the skin: prospects for painless application of protective and therapeutic vaccines

PubMed Central

Scheiblhofer, Sandra; Thalhamer, Josef; Weiss, Richard

2013-01-01

Introduction: In contrast to muscle and subcutaneous tissue, the skin is easily accessible and provides unique immunological properties. Increasing knowledge about the complex interplay of skin-associated cell types in the development of cutaneous immune responses has fueled efforts to target the skin for vaccination as well as for immunotherapy. Areas covered: This review provides an overview on skin layers and their resident immunocompetent cell types. Advantages and shortcomings of standard methods and innovative technologies to circumvent the outermost skin barrier are addressed. Studies employing fractional skin ablation by infrared lasers for cutaneous delivery of drugs, as well as high molecular weight molecules such as protein antigens or antibodies, are reviewed, and laserporation is introduced as a versatile transcutaneous vaccination platform. Specific targeting of the epidermis or the dermis by different laser settings, the resulting kinetics of uptake and transport and the immune response types elicited are discussed, and the potential of this transcutaneous delivery platform for allergen-specific immunotherapy is demonstrated. Expert opinion: Needle-free and painless vaccination approaches have the potential to replace standard methods due to their improved safety and optimal patient compliance. The use of fractional laser devices for stepwise ablation of skin layers might be advantageous for both vaccination against microbial pathogens, as well as immunotherapeutic approaches, such as allergen-specific immunotherapy. Thorough investigation of the underlying immunological mechanisms will help to provide the knowledge for a rational design of transcutaneous protective/therapeutic vaccines. PMID:23425032

A novel modeling and simulation technique of photo--thermal interactions between lasers and living biological tissues undergoing multiple changes in phase.

PubMed

Dua, Rajan; Chakraborty, Suman

2005-06-01

Knowledge of heat transfer in biological bodies has many therapeutic applications involving either raising or lowering of temperature, and often requires precise monitoring of the spatial distribution of thermal histories that are produced during a treatment protocol. Extremes of temperature into the freezing and burning ranges are useful in surgical procedures for selective killing and/or removal of target tissues. For example, the primary objective of hyperthermia is to raise the temperature of the diseased tissue to a therapeutic value, typically 41- 44 degrees C, and then thermally destroy it. The present paper therefore aims to develop a mathematical model for effective simulation of photo--thermal interactions between laser rays and biological tissues. In particular, damage of biological tissues when subjected to single point laser diathermy is numerically investigated using a unique enthalpy-based approach for modeling multiple phase change, (namely, melting of fat and vaporization of water content of the tissues) and the associated release/absorption of latent heat in conjunction with unsteady state heat conduction mechanisms. The governing equations of bio-heat transfer coupled with initial and boundary conditions are solved using a finite volume approach in conjunction with line by a line tri-diagonal matrix algorithm (TDMA) solver. Temperature responses of tissues subject to laser heating are quantitatively investigated in detail using the present model, and the resultant solutions are expected to be immensely useful in a variety of Bio-thermal practices in medicine and surgery.

Glycation sites of human plasma proteins are affected to different extents by hyperglycemic conditions in type 2 diabetes mellitus.

PubMed

Frolov, Andrej; Blüher, Matthias; Hoffmann, Ralf

2014-09-01

Glucose can modify proteins in human blood, forming early glycation products (e.g., Amadori compounds), which can slowly degrade to advanced glycation endproducts (AGEs). AGEs contribute significantly to complications of diabetes mellitus and, thus, represent markers of advanced disease stages. They are, however, currently unsuitable for early diagnosis and therapeutic monitoring. Here, we report sensitive strategies to identify and relatively quantify protein glycation sites in human plasma samples obtained from type 2 diabetes mellitus (T2DM) patients and age-matched nondiabetic individuals using a bottom-up approach. Specifically, Amadori peptides were enriched from tryptic digests by boronic acid affinity chromatography, separated by reversed-phase chromatography, and analyzed on-line by high-resolution mass spectrometry. Among the 52 Amadori peptides studied here were 20 peptides resembling 19 glycation sites in six human proteins detected at statistically significantly higher levels in T2DM than in the normoglycemic controls. Four positions appeared to be unique for T2DM within the detection limit. All 19 glycation sites represent promising new biomarker candidates for early diagnosis of T2DM and adequate therapeutic control, as they may indicate early metabolic changes preceding T2DM.

Brain Enhancing Ingredients from Āyurvedic Medicine: Quintessential Example of Bacopa monniera, a Narrative Review

PubMed Central

Singh, Hemant K.

2013-01-01

Āyurveda, the science (ved) of life (ayu), owing its origin to Veda, the oldest recorded wisdom of human civilization written in 3500 BCE, contains extensive knowledge of various diseases and their therapeutic approaches. It essentially relied on nature and the immune system of an individual, and therapeutic interventions were introduced only to augment the immune system. Āyurveda had eight specialties, including psycho-neuroscience (a combination of psychology, clinical psychology and psychiatry) and a unique promotive therapy encompassing nutrition, rejuvenation and geriatrics. The symptoms of various brain disorders, including memory disorder, were well defined. The goal of Āyurveda was to help an individual to achieve his cherished goal of leading a healthy life of 100 years. To achieve this, great emphasis was laid on nutrition, diet and a good conduct by the two great exponents of Āyurveda viz. Carak and Suśruta. By following these regimens, an individual could lead a less stressful life free from emotional disturbances. Both Carak and Suśruta had believed that these in combination with rasayana (rejuvenating) plants could enable an individual to lead a healthy life of 100 years. PMID:23389306

Biomaterial-mesenchymal stem cell constructs for immunomodulation in composite tissue engineering.

PubMed

Hanson, Summer; D'Souza, Rena N; Hematti, Peiman

2014-08-01

Cell-based treatments are being developed as a novel approach for the treatment of many diseases in an effort to repair injured tissues and regenerate lost tissues. Interest in the potential use of multipotent progenitor or stem cells has grown significantly in recent years, specifically the use of mesenchymal stem cells (MSCs), for tissue engineering in combination with extracellular matrix-based scaffolds. An area that warrants further attention is the local or systemic host responses toward the implanted cell-biomaterial constructs. Such immunological responses could play a major role in determining the clinical efficacy of the therapeutic device or biomaterials used. MSCs, due to their unique immunomodulatory properties, hold great promise in tissue engineering as they not only directly participate in tissue repair and regeneration but also modulate the host foreign body response toward the engineered constructs. The purpose of this review was to summarize the current state of knowledge and applications of MSC-biomaterial constructs as a potential immunoregulatory tool in tissue engineering. Better understanding of the interactions between biomaterials and cells could translate to the development of clinically relevant and novel cell-based therapeutics for tissue reconstruction and regenerative medicine.

Design and Application of Multifunctional DNA Nanocarriers for Therapeutic Delivery

PubMed Central

Charoenphol, Phapanin; Bermudez, Harry

2013-01-01

The unique programmability of nucleic acids offers versatility and flexibility in the creation of self-assembled DNA nanostructures. To date, many three-dimensional DNA architectures have been precisely formed of varying sizes and shapes. Their biocompatibility, biodegradability, and high intrinsic stability in physiological environments emphasize their emerging use as carriers for drug and gene delivery. Furthermore, DNA nanocarriers have been shown to enter cells efficiently and without the aid of transfection reagents. A key strength of DNA nanocarriers over other delivery systems is their modularity and their ability to control the spatial distribution of cargoes and ligands. Optimizing DNA nanocarrier properties to dictate their localization, uptake, and intracellular trafficking is also possible. In this review, we present design considerations for DNA nanocarriers and examples of their use in the context of therapeutic delivery applications. The assembly of DNA nanocarriers and approaches for loading and releasing cargo are described. The stability and safety of DNA nanocarriers is also discussed, with particular attention to the in vivo physiological environment. Mechanisms of cellular uptake and intracellular trafficking are examined, and we conclude with strategies to enhance the delivery efficiency of DNA nanocarriers. PMID:23896566

Brain enhancing ingredients from Āyurvedic medicine: quintessential example of Bacopa monniera, a narrative review.

PubMed

Singh, Hemant K

2013-02-06

Āyurveda, the science (ved) of life (ayu), owing its origin to Veda, the oldest recorded wisdom of human civilization written in 3500 BCE, contains extensive knowledge of various diseases and their therapeutic approaches. It essentially relied on nature and the immune system of an individual, and therapeutic interventions were introduced only to augment the immune system. Āyurveda had eight specialties, including psycho-neuroscience (a combination of psychology, clinical psychology and psychiatry) and a unique promotive therapy encompassing nutrition, rejuvenation and geriatrics. The symptoms of various brain disorders, including memory disorder, were well defined. The goal of Āyurveda was to help an individual to achieve his cherished goal of leading a healthy life of 100 years. To achieve this, great emphasis was laid on nutrition, diet and a good conduct by the two great exponents of Āyurveda viz. Carak and Suśruta. By following these regimens, an individual could lead a less stressful life free from emotional disturbances. Both Carak and Suśruta had believed that these in combination with rasayana (rejuvenating) plants could enable an individual to lead a healthy life of 100 years.

Targeting the Notch signaling pathway in autoimmune diseases.

PubMed

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

2010-05-01

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

Tasty THC: Promises and Challenges of Cannabis Edibles.

PubMed

Barrus, Daniel G; Capogrossi, Kristen L; Cates, Sheryl C; Gourdet, Camille K; Peiper, Nicholas C; Novak, Scott P; Lefever, Timothy W; Wiley, Jenny L

2016-11-01

Food products containing cannabis extract (edibles) have emerged as a popular and lucrative facet of the legalized market for both recreational and medicinal cannabis. The many formulations of cannabis extracts used in edibles present a unique regulatory challenge for policy makers. Though edibles are often considered a safe, discreet, and effective means of attaining the therapeutic and/or intoxicating effects of cannabis without exposure to the potentially harmful risks of cannabis smoking, little research has evaluated how ingestion differs from other methods of cannabis administration in terms of therapeutic efficacy, subjective effects, and safety. The most prominent difference between ingestion and inhalation of cannabis extracts is the delayed onset of drug effect with ingestion. Consumers often do not understand this aspect of edible use and may consume a greater than intended amount of drug before the drug has taken effect, often resulting in profoundly adverse effects. Written for the educated layperson and for policy makers, this paper explores the current state of research regarding edibles, highlighting the promises and challenges that edibles present to both users and policy makers, and describes the approaches that four states in which recreational cannabis use is legal have taken regarding regulating edibles.

Biomaterials-based 3D cell printing for next-generation therapeutics and diagnostics.

PubMed

Jang, Jinah; Park, Ju Young; Gao, Ge; Cho, Dong-Woo

2018-02-01

Building human tissues via 3D cell printing technology has received particular attention due to its process flexibility and versatility. This technology enables the recapitulation of unique features of human tissues and the all-in-one manufacturing process through the design of smart and advanced biomaterials and proper polymerization techniques. For the optimal engineering of tissues, a higher-order assembly of physiological components, including cells, biomaterials, and biomolecules, should meet the critical requirements for tissue morphogenesis and vascularization. The convergence of 3D cell printing with a microfluidic approach has led to a significant leap in the vascularization of engineering tissues. In addition, recent cutting-edge technology in stem cells and genetic engineering can potentially be adapted to the 3D tissue fabrication technique, and it has great potential to shift the paradigm of disease modeling and the study of unknown disease mechanisms required for precision medicine. This review gives an overview of recent developments in 3D cell printing and bioinks and provides technical requirements for engineering human tissues. Finally, we propose suggestions on the development of next-generation therapeutics and diagnostics. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cancer Vaccines: Moving Beyond Current Paradigms

PubMed Central

Schlom, Jeffrey; Arlen, Philip M.; Gulley, James L.

2008-01-01

The field of cancer vaccines is currently in an active state of preclinical and clinical investigations. While no therapeutic cancer vaccine has to date been approved by the FDA, several new paradigms are emerging from recent clinical findings in both the use of combination therapy approaches and, perhaps more importantly, in clinical trial design and endpoint analyses. This paper will review recent clinical trials involving several different cancer vaccines from which data are emerging contrasting classical “tumor response” (RECIST) criteria with “patient response” in the manifestation of increased patient survival post-vaccine therapy. Also described are several strategies in which cancer vaccines can be exploited in combination with other agents and therapeutic modalities that are quite unique when compared with “conventional” combination therapies. This is most likely due to the phenomena that (a) cancer vaccines initiate a dynamic immune process that can be exploited in subsequent therapies, and (b) both radiation and certain chemotherapeutic agents have been shown to alter the phenotype of tumor cells as to render them more susceptible to T-cell–mediated killing. Consequently, evidence is emerging from several studies in which patient cohorts who first receive a cancer vaccine (as contrasted with control cohorts) benefit clinically from subsequent therapies. PMID:17606707

Tasty THC: Promises and Challenges of Cannabis Edibles

PubMed Central

Barrus, Daniel G.; Capogrossi, Kristen L.; Cates, Sheryl C.; Gourdet, Camille K.; Peiper, Nicholas C.; Novak, Scott P.; Lefever, Timothy W.; Wiley, Jenny L.

2016-01-01

Food products containing cannabis extract (edibles) have emerged as a popular and lucrative facet of the legalized market for both recreational and medicinal cannabis. The many formulations of cannabis extracts used in edibles present a unique regulatory challenge for policy makers. Though edibles are often considered a safe, discreet, and effective means of attaining the therapeutic and/or intoxicating effects of cannabis without exposure to the potentially harmful risks of cannabis smoking, little research has evaluated how ingestion differs from other methods of cannabis administration in terms of therapeutic efficacy, subjective effects, and safety. The most prominent difference between ingestion and inhalation of cannabis extracts is the delayed onset of drug effect with ingestion. Consumers often do not understand this aspect of edible use and may consume a greater than intended amount of drug before the drug has taken effect, often resulting in profoundly adverse effects. Written for the educated layperson and for policy makers, this paper explores the current state of research regarding edibles, highlighting the promises and challenges that edibles present to both users and policy makers, and describes the approaches that four states in which recreational cannabis use is legal have taken regarding regulating edibles. PMID:28127591

Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

DTIC Science & Technology

2014-10-01

AD_________________ Award Number: W81XWH-13-1-0325 TITLE: Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using ...Genetically Engineered Mouse Models and Human Circulating Tumor Cells PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD CONTRACTING ORGANIZATION ...Novel Therapeutic Approaches in Small Cell Lung 5a. CONTRACT NUMBER W81XWH-13-1-0325 Carcinoma Using Genetically Engineered Mouse Models and 5b

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

PubMed Central

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

2015-01-01

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

Rational design of an enzyme mutant for anti-cocaine therapeutics

NASA Astrophysics Data System (ADS)

Zheng, Fang; Zhan, Chang-Guo

2008-09-01

(-)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (-)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the state-of-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (-)-cocaine. The computational design of BChE mutants have been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design high-activity mutants of human BChE for hydrolysis of (-)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (-)-cocaine. One of the discovered BChE mutants (i.e., A199S/S287G/A328W/Y332G) has a ˜456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.

Nanoparticle-Hydrogel: A Hybrid Biomaterial System for Localized Drug Delivery

PubMed Central

Gao, Weiwei; Zhang, Yue; Zhang, Qiangzhe; Zhang, Liangfang

2016-01-01

Nanoparticles have offered a unique set of properties for drug delivery including high drug loading capacity, combinatorial delivery, controlled and sustained drug release, prolonged stability and lifetime, and targeted delivery. To further enhance therapeutic index, especially for localized application, nanoparticles have been increasingly combined with hydrogels to form a hybrid biomaterial system for controlled drug delivery. Herein, we review recent progresses in engineering such nanoparticle-hydrogel hybrid system (namely ‘NP-gel’) with a particular focus on its application for localized drug delivery. Specifically, we highlight four research areas where NP-gel has shown great promises, including (1) passively controlled drug release, (2) stimuli-responsive drug delivery, (3) site-specific drug delivery, and (4) detoxification. Overall, integrating therapeutic nanoparticles with hydrogel technologies creates a unique and robust hybrid biomaterial system that enables effective localized drug delivery. PMID:26951462

Bax345/BLyS: a novel, completely human fusion protein targeting malignant B cells and delivering a unique mitochondrial toxin.

PubMed

Lyu, Mi-Ae; Cheung, Lawrence H; Hittelman, Walter N; Liu, Yuying; Marks, John W; Cho, Min-Jeong; Rosenblum, Michael G

2012-09-28

We generated a fusion protein Bax(345)/BLyS containing the truncated form of Bax (Bax(345)) at the N-terminus followed by a 218 linker to the B lymphocyte stimulator (BLyS). Bax(345)/BLyS was cytotoxic to a panel of diffuse large B cell lymphoma and mantle cell lymphoma lines expressing the BLyS receptors. Specific delivery of Bax(345)/BLyS to malignant B cells drove cells into apoptosis by mitochondrial dysfunction and treatment of cells with Bax(345)/BLyS induced down-regulation of Mcl-1, X-IAP, and survivin. Bax(345)/BLyS represents a new class of targeted therapeutic agents with a unique mechanism of action and may have therapeutic potential for malignant B cells. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Analyte-Responsive Hydrogels: Intelligent Materials for Biosensing and Drug Delivery.

PubMed

Culver, Heidi R; Clegg, John R; Peppas, Nicholas A

2017-02-21

Nature has mastered the art of molecular recognition. For example, using synergistic non-covalent interactions, proteins can distinguish between molecules and bind a partner with incredible affinity and specificity. Scientists have developed, and continue to develop, techniques to investigate and better understand molecular recognition. As a consequence, analyte-responsive hydrogels that mimic these recognitive processes have emerged as a class of intelligent materials. These materials are unique not only in the type of analyte to which they respond but also in how molecular recognition is achieved and how the hydrogel responds to the analyte. Traditional intelligent hydrogels can respond to environmental cues such as pH, temperature, and ionic strength. The functional monomers used to make these hydrogels can be varied to achieve responsive behavior. For analyte-responsive hydrogels, molecular recognition can also be achieved by incorporating biomolecules with inherent molecular recognition properties (e.g., nucleic acids, peptides, enzymes, etc.) into the polymer network. Furthermore, in addition to typical swelling/syneresis responses, these materials exhibit unique responsive behaviors, such as gel assembly or disassembly, upon interaction with the target analyte. With the diverse tools available for molecular recognition and the ability to generate unique responsive behaviors, analyte-responsive hydrogels have found great utility in a wide range of applications. In this Account, we discuss strategies for making four different classes of analyte-responsive hydrogels, specifically, non-imprinted, molecularly imprinted, biomolecule-containing, and enzymatically responsive hydrogels. Then we explore how these materials have been incorporated into sensors and drug delivery systems, highlighting examples that demonstrate the versatility of these materials. For example, in addition to the molecular recognition properties of analyte-responsive hydrogels, the physicochemical changes that are induced upon analyte binding can be exploited to generate a detectable signal for sensing applications. As research in this area has grown, a number of creative approaches for improving the selectivity and sensitivity (i.e., detection limit) of these sensors have emerged. For applications in drug delivery systems, therapeutic release can be triggered by competitive molecular interactions or physicochemical changes in the network. Additionally, including degradable units within the network can enable sustained and responsive therapeutic release. Several exciting examples exploiting the analyte-responsive behavior of hydrogels for the treatment of cancer, diabetes, and irritable bowel syndrome are discussed in detail. We expect that creative and combinatorial approaches used in the design of analyte-responsive hydrogels will continue to yield materials with great potential in the fields of sensing and drug delivery.

Xenogeneic therapeutic cancer vaccines as breakers of immune tolerance for clinical application: to use or not to use?

PubMed

Strioga, Marius M; Darinskas, Adas; Pasukoniene, Vita; Mlynska, Agata; Ostapenko, Valerijus; Schijns, Virgil

2014-07-07

Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens. Copyright © 2014. Published by Elsevier Ltd.

Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells

PubMed Central

Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi

2015-01-01

Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. PMID:25910782

Consumer Satisfaction with Psychiatric Services: The Role of Shared Decision-Making and the Therapeutic Relationship

PubMed Central

Klingaman, Elizabeth A.; Medoff, Deborah R.; Park, Stephanie G.; Brown, Clayton H.; Fang, Lijuan; Dixon, Lisa B.; Hack, Samantha M.; Tapscott, Stephanie L.; Walsh, Mary Brighid; Kreyenbuhl, Julie A.

2017-01-01

Objective Although dissatisfaction is a primary reason for disengagement from outpatient psychiatric care among consumers with serious mental illnesses, little is known about predictors of their satisfaction with medication management visits. The primary purpose of the present study was to explore how dimensions of consumer preferences for shared decision-making (i.e., preferences for obtaining knowledge about one’s mental illness, being offered and asked one’s opinion about treatment options, and involvement in treatment decisions) and the therapeutic relationship (i.e., positive collaboration and type of clinician input) were related to visit satisfaction. Methods Participants were 228 Veterans with serious mental illnesses who completed a 19-item self-report questionnaire assessing satisfaction with visits to prescribers (n=524 assessments) immediately after visits. In this correlational design, a 3-level mixed model with the restricted maximum likelihood estimation procedure was used to examine shared decision-making preferences and therapeutic alliance as predictors of visit satisfaction. Results Preferences for involvement in treatment decisions was the unique component of shared decision-making associated with satisfaction, such that the more consumers desired involvement, the less satisfied they were. Positive collaboration and prescriber input were associated with greater visit satisfaction. Conclusions and Implications for Practice When consumers with serious mental illnesses express preferences to be involved in shared decision-making, it may not be sufficient to only provide information and treatment options; prescribers should attend to consumers’ interest in involvement in actual treatment decisions. Assessment and tailoring of treatment approaches to consumer preferences for shared decision-making should occur within the context of a strong therapeutic relationship. PMID:25664755

p21-activated kinase inhibitors.

PubMed

Rudolph, Joachim; Crawford, James J; Hoeflich, Klaus P; Chernoff, Jonathan

2013-01-01

The p21-activated kinases (PAKs) are Ser/Thr kinases in the STE20 kinase family with important roles in regulating cytoskeletal organization, cell migration, and signaling. The PAK enzyme family comprises six members subdivided into two groups: Group I, represented by PAK1, 2, and 3, and Group II, represented by PAK 4, 5, and 6, based on sequence and structural homology. Individual PAK isoforms were found to be overexpressed and amplified in a variety of human cancers, and in vitro and in vivo studies using genetically engineered systems as well as small-molecule tool compounds have suggested therapeutic utility of PAKs as oncology targets. The identification of potent and kinome-selective ATP-competitive PAK inhibitors has proven challenging, likely caused by the openness and unique plasticity of the ATP-binding site of PAK enzymes. Progress in achieving increased kinase selectivity has been achieved with certain inhibitors but at the expense of increased molecular weight. Allosteric inhibitors, such as IPA-3, leverage the unique Group I PAK autoregulatory domain for selective inhibition, and this approach might provide an outlet to evade the kinase selectivity challenges observed with ATP-competitive PAK inhibitors. © 2013 Elsevier Inc. All rights reserved.

Temporomandibular Joint Regenerative Medicine

PubMed Central

Van Bellinghen, Xavier; Idoux-Gillet, Ysia; Pugliano, Marion; Strub, Marion; Bornert, Fabien; Clauss, Francois; Schwinté, Pascale; Keller, Laetitia; Benkirane-Jessel, Nadia; Lutz, Jean Christophe; Fioretti, Florence

2018-01-01

The temporomandibular joint (TMJ) is an articulation formed between the temporal bone and the mandibular condyle which is commonly affected. These affections are often so painful during fundamental oral activities that patients have lower quality of life. Limitations of therapeutics for severe TMJ diseases have led to increased interest in regenerative strategies combining stem cells, implantable scaffolds and well-targeting bioactive molecules. To succeed in functional and structural regeneration of TMJ is very challenging. Innovative strategies and biomaterials are absolutely crucial because TMJ can be considered as one of the most difficult tissues to regenerate due to its limited healing capacity, its unique histological and structural properties and the necessity for long-term prevention of its ossified or fibrous adhesions. The ideal approach for TMJ regeneration is a unique scaffold functionalized with an osteochondral molecular gradient containing a single stem cell population able to undergo osteogenic and chondrogenic differentiation such as BMSCs, ADSCs or DPSCs. The key for this complex regeneration is the functionalization with active molecules such as IGF-1, TGF-β1 or bFGF. This regeneration can be optimized by nano/micro-assisted functionalization and by spatiotemporal drug delivery systems orchestrating the 3D formation of TMJ tissues. PMID:29393880

Therapeutic Modalities in Diabetic Nephropathy: Future Approaches*

PubMed Central

Reeves, William Brian; Rawal, Bishal B.; Abdel-Rahman, Emaad M.; Awad, Alaa S.

2012-01-01

Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Several therapeutic interventions for the treatment of diabetic nephropathy have been developed and implemented over the past few decades with some degree of success. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are therefore urgently needed. Recently, several novel therapeutic strategies have been explored in treating DN patients including Islet cell transplant, Aldose reductase inhibitors, Sulodexide (GAC), Protein Kinase C (PKC) inhibitors, Connective tissue growth factor (CTGF) inhibitors, Transforming growth factor-beta (TGF-β) inhibitors and bardoxolone. The benefits and risks of these agents are still under investigation. This review aims to summarize the utility of these novel therapeutic approaches. PMID:23293752

[Uniqueness seeking behavior as a self-verification: an alternative approach to the study of uniqueness].

PubMed

Yamaoka, S

1995-06-01

Uniqueness theory explains that extremely high perceived similarity between self and others evokes negative emotional reactions and causes uniqueness seeking behavior. However, the theory conceptualizes similarity so ambiguously that it appears to suffer from low predictive validity. The purpose of the current article is to propose an alternative explanation of uniqueness seeking behavior. It posits that perceived uniqueness deprivation is a threat to self-concepts, and therefore causes self-verification behavior. Two levels of self verification are conceived: one based on personal categorization and the other on social categorization. The present approach regards uniqueness seeking behavior as the personal-level self verification. To test these propositions, a 2 (very high or moderate similarity information) x 2 (with or without outgroup information) x 2 (high or low need for uniqueness) between-subject factorial-design experiment was conducted with 95 university students. Results supported the self-verification approach, and were discussed in terms of effects of uniqueness deprivation, levels of self-categorization, and individual differences in need for uniqueness.

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy.

PubMed

Monga, Isha; Qureshi, Abid; Thakur, Nishant; Gupta, Amit Kumar; Kumar, Manoj

2017-09-07

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single-nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://crdd.osdd.net/servers/aspsirna/) covering three components viz (i) ASPsiDb , (ii) ASPsiPred , and (iii) analysis tools like ASP-siOffTar ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Eff mut ) and wild-type allele (Eff wild ) with one mismatch by ASPsiPred SVM and ASPsiPred matrix , respectively. In ASPsiPred SVM , 922 unique ASP-siRNAs with experimentally validated quantitative Eff mut were used. During 10-fold cross-validation (10nCV) employing various sequence features on the training/testing dataset (T737), the best predictive model achieved a maximum Pearson's correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Eff mut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPred matrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19 different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm, and off-target analysis tool that is expected to accelerate research in the field of RNAi-based therapeutics for human genetic diseases. Copyright © 2017 Monga et al.

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

The influence of supervision on manual adherence and therapeutic processes.

PubMed

Anderson, Timothy; Crowley, Mary Ellen J; Patterson, Candace L; Heckman, Bernadette D

2012-09-01

To identify the effectiveness of psychotherapy supervision on therapists' immediate (next session) and long-term (1 year) adherence to time-limited dynamic psychotherapy (TLDP). Sixteen therapists from the Vanderbilt II psychotherapy project were assigned new cases in pretraining, training, and booster/posttraining year-long cohorts. Technical adherence to the manual, as well as general therapeutic relational processes, were rated for clinical supervisory sessions in which the third therapy session was discussed. The therapy sessions immediately before and after the supervisory sessions were also rated for technical adherence and relational processes. Postsupervision adherence increased from the presupervision session during the training cohort. In supervision, therapists' discussion of techniques and strategies from the manual in supervision was significantly related to technical adherence in the session prior to (but not after) supervision. However, supervisors' discussion of specific techniques predicted therapists' total technical adherence in the therapy session after (but not before) supervision. In terms of the type of techniques, supervisors' influenced postsupervision therapy adherence on TLDP's unique approach to formulation, the cyclical maladaptive pattern, but did not influence technical adherence on the therapeutic relationship. In supervision, therapists tend to focus on how they adhered to techniques from the previous session, whereas supervisors' comments about specific techniques predicted how the therapist would adhere to techniques in the next therapy session. The findings provide support for the immediate effects of supervision in shaping therapist techniques as well as highlighting the challenges of altering common relational processes through technical training. © 2012 Wiley Periodicals, Inc.

Corrective Neuromuscular Approach to the Treatment of Iliotibial Band Friction Syndrome: A Case Report

PubMed Central

Pettitt, Robert; Dolski, Angela

2000-01-01

Objective: To describe the evaluation and treatment process for inappropriate functional patterns of neuromuscular activity within the scope of an iliotibial band friction syndrome protocol. Background: Runners with iliotibial band friction syndrome are frequently fitted with orthotic devices to restrict excessive midfoot or rearfoot, or both, motions during the stance phase. These devices may fail to yield favorable results when underlying neuromuscular factors are associated with functional iliotibial band tightening. Differential Diagnosis: Distal biceps femoris tendinitis, popliteal tendinitis, lateral meniscus lesion. Treatment: The athlete's physical examination revealed several patterns of inappropriate neuromuscular activity attributed partly to the prolonged daily wear of beach-type sandals. Modifications of casual footwear and a temporary reduction in training volume were recommended initially to prevent exacerbation of the athlete's condition. Stretching, massage, and soft tissue mobilization were administered in accordance with the athlete's specific needs. The protocol included progressions of nonweightbearing and weightbearing therapeutic exercises. Neuromuscular electric stimulation was incorporated into the protocol to re-educate the role of the first ray within the stance phase of the athlete's walking gait. Uniqueness: Upon stationary examination, this athlete presented with normal lumbar and lower extremity postures. Gait analysis, however, revealed inappropriate dorsiflexion of the great toe during ambulation. Further, the athlete's performances on a series of tests to assess neuromuscular function were substandard. This athlete's response to previous treatment and unique physical findings required a corrective neuromuscular approach that deviates from iliotibial band friction syndrome protocols advocating the use of orthotics. Conclusions: While the role of any single treatment in the athlete's recovery remains unknown, it seems that a corrective neuromuscular approach in the management of iliotibial band friction syndrome represents a viable alternative to orthotic intervention. ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 5. PMID:16558617

InFlo: a novel systems biology framework identifies cAMP-CREB1 axis as a key modulator of platinum resistance in ovarian cancer.

PubMed

Dimitrova, N; Nagaraj, A B; Razi, A; Singh, S; Kamalakaran, S; Banerjee, N; Joseph, P; Mankovich, A; Mittal, P; DiFeo, A; Varadan, V

2017-04-27

Characterizing the complex interplay of cellular processes in cancer would enable the discovery of key mechanisms underlying its development and progression. Published approaches to decipher driver mechanisms do not explicitly model tissue-specific changes in pathway networks and the regulatory disruptions related to genomic aberrations in cancers. We therefore developed InFlo, a novel systems biology approach for characterizing complex biological processes using a unique multidimensional framework integrating transcriptomic, genomic and/or epigenomic profiles for any given cancer sample. We show that InFlo robustly characterizes tissue-specific differences in activities of signalling networks on a genome scale using unique probabilistic models of molecular interactions on a per-sample basis. Using large-scale multi-omics cancer datasets, we show that InFlo exhibits higher sensitivity and specificity in detecting pathway networks associated with specific disease states when compared to published pathway network modelling approaches. Furthermore, InFlo's ability to infer the activity of unmeasured signalling network components was also validated using orthogonal gene expression signatures. We then evaluated multi-omics profiles of primary high-grade serous ovarian cancer tumours (N=357) to delineate mechanisms underlying resistance to frontline platinum-based chemotherapy. InFlo was the only algorithm to identify hyperactivation of the cAMP-CREB1 axis as a key mechanism associated with resistance to platinum-based therapy, a finding that we subsequently experimentally validated. We confirmed that inhibition of CREB1 phosphorylation potently sensitized resistant cells to platinum therapy and was effective in killing ovarian cancer stem cells that contribute to both platinum-resistance and tumour recurrence. Thus, we propose InFlo to be a scalable and widely applicable and robust integrative network modelling framework for the discovery of evidence-based biomarkers and therapeutic targets.

Ligand-targeted theranostic nanomedicines against cancer

DOE PAGES

Yao, Virginia J.; D'Angelo, Sara; Butler, Kimberly S.; ...

2016-01-06

Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20 years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentiallymore » overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. As a result, the modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.« less

Ligand-targeted theranostic nanomedicines against cancer

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

Yao, Virginia J.; D'Angelo, Sara; Butler, Kimberly S.

Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20 years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentiallymore » overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. As a result, the modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.« less

3D Bioprinting and In Vitro Cardiovascular Tissue Modeling.

PubMed

Jang, Jinah

2017-08-18

Numerous microfabrication approaches have been developed to recapitulate morphologically and functionally organized tissue microarchitectures in vitro; however, the technical and operational limitations remain to be overcome. 3D printing technology facilitates the building of a construct containing biomaterials and cells in desired organizations and shapes that have physiologically relevant geometry, complexity, and micro-environmental cues. The selection of biomaterials for 3D printing is considered one of the most critical factors to achieve tissue function. It has been reported that some printable biomaterials, having extracellular matrix-like intrinsic microenvironment factors, were capable of regulating stem cell fate and phenotype. In particular, this technology can control the spatial positions of cells, and provide topological, chemical, and complex cues, allowing neovascularization and maturation in the engineered cardiovascular tissues. This review will delineate the state-of-the-art 3D bioprinting techniques in the field of cardiovascular tissue engineering and their applications in translational medicine. In addition, this review will describe 3D printing-based pre-vascularization technologies correlated with implementing blood perfusion throughout the engineered tissue equivalent. The described engineering method may offer a unique approach that results in the physiological mimicry of human cardiovascular tissues to aid in drug development and therapeutic approaches.

3D Bioprinting and In Vitro Cardiovascular Tissue Modeling

PubMed Central

Jang, Jinah

2017-01-01

Numerous microfabrication approaches have been developed to recapitulate morphologically and functionally organized tissue microarchitectures in vitro; however, the technical and operational limitations remain to be overcome. 3D printing technology facilitates the building of a construct containing biomaterials and cells in desired organizations and shapes that have physiologically relevant geometry, complexity, and micro-environmental cues. The selection of biomaterials for 3D printing is considered one of the most critical factors to achieve tissue function. It has been reported that some printable biomaterials, having extracellular matrix-like intrinsic microenvironment factors, were capable of regulating stem cell fate and phenotype. In particular, this technology can control the spatial positions of cells, and provide topological, chemical, and complex cues, allowing neovascularization and maturation in the engineered cardiovascular tissues. This review will delineate the state-of-the-art 3D bioprinting techniques in the field of cardiovascular tissue engineering and their applications in translational medicine. In addition, this review will describe 3D printing-based pre-vascularization technologies correlated with implementing blood perfusion throughout the engineered tissue equivalent. The described engineering method may offer a unique approach that results in the physiological mimicry of human cardiovascular tissues to aid in drug development and therapeutic approaches. PMID:28952550

Promising new developments in cancer chemotherapy.

PubMed

Ferrante, K; Winograd, B; Canetta, R

1999-01-01

The positive impact on survival of traditional chemotherapeutic agents has renewed interest in developing newer cytotoxic agents and orally active compounds with improved therapeutic indices. In addition, new insights into the pathways of human tumorigenesis have led to novel approaches aimed at specific mechanism-based targets. The taxane class, of which paclitaxel was the first member, has the unique ability to promote and stabilize microtubule function directly, thereby inhibiting mitotic progression and inducing apoptotic cell death. Paclitaxel provides treatment benefit in a broad range of solid tumors including breast, ovarian, and lung cancer. The success with paclitaxel stimulated interest in the microtubule as a new therapeutic target. Taxane analogues with improved preclinical efficacy have been identified and are entering clinical trials. The enthusiasm for oral anticancer agents and the therapeutic importance of platinum compounds has led to the development of JM216 (satraplatin), a novel platinum IV coordination complex with oral activity in cisplatin-resistant cell lines, which is now in phase III trials in prostate cancer. Another compound in late development is DPPE, a chemopotentiator that enhances the in vivo antitumor effects of cytotoxic agents such as doxorubicin, cyclophosphamide, and cisplatin. Agents that inhibit topoisomerase I and II have also been of interest. TAS-103 is a dual topoisomerase I and II inhibitor with preclinical efficacy in a broad spectrum of tumors and in multidrug-resistant tumor cell lines. Vaccination strategies represent a rational therapeutic approach in the minimal residual disease or high-risk adjuvant therapy setting. The GMK and MGV vaccines utilizing ganglioside antigens overexpressed on human tumors such as melanoma and small cell lung cancer appear to induce antibody production reliably at tolerable doses and are under further clinical investigation. Inhibition of matrix metalloproteinases (MMPs) is another attractive target for intervention in several aspects of tumor progression. Local production of MMPs with subsequent degradation of the extracellular matrix is implicated in supporting tumor growth, invasion, and angiogenesis. The development of orally active, nontoxic MMP inhibitors is critical since these compounds will likely require chronic administration in conjunction with other therapies. Oncogenes and tumor suppressor genes are appealing targets for therapy since they are thought to be responsible for a significant number of cancers. Mutations in the Ras oncogene occur with great frequency in a number of human cancers including lung, pancreas, and colon cancer. Clinical development of potent and selective inhibitors of farnesyltransferase, the Ras-processing enzyme, is ongoing. These compounds uncouple Ras activity, affect tumor growth, and have demonstrated significant antitumor activity against experimental models of human cancer. The exciting compounds and novel therapeutic approaches currently under investigation by Bristol-Myers Squibb Pharmaceutical Research Institute offer great potential as effective cancer chemotherapy agents for the near future.

Therapeutic hypothermia: applications in pediatric cardiac arrest.

PubMed

Kochanek, Patrick M; Fink, Ericka L; Bell, Michael J; Bayir, Hülya; Clark, Robert S B

2009-03-01

There is a rich history for the use of therapeutic hypothermia after cardiac arrest in neonatology and pediatrics. Laboratory reports date back to 1824 in experimental perinatal asphyxia. Similarly, clinical reports in pediatric cold water drowning victims represented key initiating work in the field. The application of therapeutic hypothermia in pediatric drowning victims represented some of the seminal clinical use of this modality in modern neurointensive care. Uncontrolled application (too deep and too long) and unique facets of asphyxial cardiac arrest in children (a very difficult insult to affect any benefit) likely combined to result in abandonment of therapeutic hypothermia in the mid to late 1980s. Important studies in perinatal medicine have built upon the landmark clinical trials in adults, and are once again bringing therapeutic hypothermia into standard care for pediatrics. Although more work is needed, particularly in the use of mild therapeutic hypothermia in children, there is a strong possibility that this important therapy will ultimately have broad applications after cardiac arrest and central nervous system (CNS) insults in the pediatric arena.

Realizing the therapeutic potential of rare earth elements in designing nanoparticles to target and treat glioblastoma.

PubMed

Lu, Victor M; McDonald, Kerrie L; Townley, Helen E

2017-10-01

The prognosis of brain cancer glioblastoma (GBM) is poor, and despite intense research, there have been no significant improvements within the last decade. This stasis implicates the need for more novel therapeutic investigation. One such option is the use of nanoparticles (NPs), which can be beneficial due to their ability to penetrate the brain, overcome the blood-brain barrier and take advantage of the enhanced permeation and retention effect of GBM to improve specificity. Rare earth elements possess a number of interesting natural properties due to their unique electronic configuration, which may prove therapeutically advantageous in an NP formulation. The underexplored exciting potential for rare earth elements to augment the therapeutic potential of NPs in GBM treatment is discussed in this review.

Transdermal skin patch based on reduced graphene oxide: A new approach for photothermal triggered permeation of ondansetron across porcine skin.

PubMed

Teodorescu, Florina; Quéniat, Gurvan; Foulon, Catherine; Lecoeur, Marie; Barras, Alexandre; Boulahneche, Samia; Medjram, Mohmaed Salah; Hubert, Thomas; Abderrahmani, Amar; Boukherroub, Rabah; Szunerits, Sabine

2017-01-10

The development of a skin-mounted patch capable of controlled transcutaneous delivery of therapeutics through thermal activation provides a unique solution for the controlled release of active principles over long-term periods. Here, we report on a flexible transdermal patch for photothermal triggered release of ondansetron (ODS), a commonly used drug for the treatment of chemotherapy-induced nausea and vomiting and used as model compound here. To achieve this, a dispersion of ODS-loaded reduced graphene oxide (rGO-ODS) nanosheets were deposited onto Kapton to produce a flexible polyimide-based patch. It is demonstrated that ODS loaded Kapton/rGO patches have a high drug delivery performance upon irradiation with a continuous laser beam at 980nm for 10min due to an induced photothermal heating effect. The ability of ODS impregnated Kapton/rGO patches as transdermal delivery scaffolds for ODS across the skin is in addition investigated using porcine ear skin as a model. We show that the cumulative quantity and flux of ODS passing the skin are highly depending on the laser power density used. At 5Wcm -2 irradiation, the ODS flux across pig skin was determined to be 1.6μgcm -2 h -1 comparable to other approaches. The use of tween 20 as skin enhancer could significantly increase the ODS flux to 13.2μgcm -2 h -1 . While the skin penetration enhancement is comparable to that obtained using other well-known permeation enhancers, the actual superiority and interest of the proposed approach is that the Kapton/rGO photoactivatable skin patch can be loaded with any drugs and therapeutics of interest, making the approach extremely versatile. The on demand delivery of drugs upon local laser irradiation and the possibility to reload the interface with the drug makes this new drug administration route very appealing. Copyright © 2016 Elsevier B.V. All rights reserved.

Differentiating Performance Approach Goals and Their Unique Effects

ERIC Educational Resources Information Center

Edwards, Ordene V.

2014-01-01

The study differentiates between two types of performance approach goals (competence demonstration performance approach goal and normative performance approach goal) by examining their unique effects on self-efficacy, interest, and fear of failure. Seventy-nine students completed questionnaires that measure performance approach goals,…

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

[Inpatient psychotherapy].

PubMed

Spitzer, C; Rullkötter, N; Dally, A

2016-01-01

In German-speaking countries inpatient psychotherapy plays a major role in the mental healthcare system. Due to its characteristic features, i. e. multiprofessionalism, multimodality and method integration, the inpatient approach represents a unique and independent type of psychotherapy. In order to be helpful, the manifold verbal and non-verbal methods need to be embedded into an overall treatment plan. Additionally, the therapeutic milieu of the hospital represents an important effective factor and its organization requires a more active construction. The indications for inpatient psychotherapy are not only based on the mental disorder but also on illness, setting and healthcare system-related criteria. In integrative concepts, the multiprofessional team is a key component with many functions. The effectiveness of psychotherapeutic hospital treatment has been proven by meta-analysis studies; however, 20-30% of patients do not benefit from inpatient psychotherapy and almost 13% drop-out prematurely.

DNA-based immunotherapy for HPV-associated head and neck cancer.

PubMed

Aggarwal, Charu

2016-10-01

Squamous cell carcinoma of the head and neck (SCCHN) accounts for 3% of all cancers. Most patients present with locally advanced disease, where multimodality therapies are used with curative intent. Despite favorable early local treatment results, about one third of the patients will eventually develop metastatic disease. Immunotherapy offers a novel therapeutic strategy beyond cytotoxic chemotherapy, with initial approvals in melanoma and non-small-cell lung cancer. HPV-associated SCCHN is a distinct subset, with unique epidemiology and treatment outcomes. Both subsets of SCCHN (HPV-related or not) are particularly favorable for immunotherapy, as immune evasion and dysregulation have been shown to play a key role in the initiation and progression of disease. This review focuses on the latest developments in immunotherapy in SCCHN, with a particular focus on DNA-based approaches including vaccine and adoptive cellular therapies.

Cell-based delivery of oncolytic viruses: a new strategic alliance for a biological strike against cancer.

PubMed

Power, Anthony T; Bell, John C

2007-04-01

Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique approach has been hindered by vulnerability to host defenses and inefficient systemic delivery. However, it now appears that delivery of oncolytic viruses within carrier cells may offer one solution to this critical problem. In this review, we compare the advantages and limitations of the numerous cell lineages that have been investigated as delivery platforms for viral therapeutics, and discuss examples showing how combined cell-virus biotherapeutics can be used to achieve synergistic gains in antitumor activity. Finally, we highlight avenues for future preclinical research that might be taken in order to refine cell-virus biotherapeutics in preparation for human trials.

Pepducins as a potential treatment strategy for asthma and COPD.

PubMed

Panettieri, Reynold A; Pera, Tonio; Liggett, Stephen B; Benovic, Jeffrey L; Penn, Raymond B

2018-05-02

Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators. Recent evidence suggests that small molecule inhibitors of Gα q as well as pepducins targeting G q -coupled receptors can broadly inhibit contractile agonist-induced ASM function. Given these advances, new therapeutic approaches can be leveraged to diminish the global rise in morbidity and mortality associated with asthma and chronic obstructive pulmonary disease. Copyright © 2018. Published by Elsevier Ltd.

Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells.

PubMed

Mullally, Ann; Lane, Steven W; Ball, Brian; Megerdichian, Christine; Okabe, Rachel; Al-Shahrour, Fatima; Paktinat, Mahnaz; Haydu, J Erika; Housman, Elizabeth; Lord, Allegra M; Wernig, Gerlinde; Kharas, Michael G; Mercher, Thomas; Kutok, Jeffery L; Gilliland, D Gary; Ebert, Benjamin L

2010-06-15

We report a Jak2V617F knockin mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild-type HSCs. In contrast, myeloid progenitor populations are expanded and skewed toward the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F-positive MPN. Copyright 2010 Elsevier Inc. All rights reserved.

Uncovering the Biology of Cancers in Adolescents and Young Adults

Cancer.gov

Evidence suggests that some adolescent and young adult cancers may have unique genetic and biological features. Researchers are trying to better understand the biology of these cancers in order to identify potential therapeutic targets.

Use of Animal Models in Understanding Cancer-induced Bone Pain

PubMed Central

Slosky, Lauren M; Largent-Milnes, Tally M; Vanderah, Todd W

2015-01-01

Many common cancers have a propensity to metastasize to bone. Although malignancies often go undetected in their native tissues, bone metastases produce excruciating pain that severely compromises patient quality of life. Cancer-induced bone pain (CIBP) is poorly managed with existing medications, and its multifaceted etiology remains to be fully elucidated. Novel analgesic targets arise as more is learned about this complex and distinct pain state. Over the past two decades, multiple animal models have been developed to study CIBP’s unique pathology and identify therapeutic targets. Here, we review animal models of CIBP and the mechanistic insights gained as these models evolve. Findings from immunocompromised and immunocompetent host systems are discussed separately to highlight the effect of model choice on outcome. Gaining an understanding of the unique neuromolecular profile of cancer pain through the use of appropriate animal models will aid in the development of more effective therapeutics for CIBP. PMID:26339191

Nano Polymeric Carrier Fabrication Technologies for Advanced Antitumor Therapy

PubMed Central

Li, Wei; Zhao, Mengxin; Ke, Changhong; Zhang, Ge; Zhang, Li; Li, Huafei; Zhang, Fulei; Sun, Yun; Dai, Jianxin; Wang, Hao; Guo, Yajun

2013-01-01

Comparing with the traditional therapeutic methods, newly developed cancer therapy based on the nanoparticulates attracted extensively interest due to its unique advantages. However, there are still some drawbacks such as the unfavorable in vivo performance for nanomedicine and undesirable tumor escape from the immunotherapy. While as we know that the in vivo performance strongly depended on the nanocarrier structural properties, thus, the big gap between in vitro and in vivo can be overcome by nanocarrier's structural tailoring by fine chemical design and microstructural tuning. In addition, this fine nanocarrier's engineering can also provide practical solution to solve the problems in traditional cancer immunotherapy. In this paper, we review the latest development in nanomedicine, cancer therapy, and nanoimmunotherapy. We then give an explanation why fine nanocanrrie's engineering with special focus on the unique pathology of tumor microenvironments and properties of immunocells can obviously promote the in vivo performance and improve the therapeutic index of nanoimmunotherapy. PMID:24369011

Novel concept of the smart NIR-light-controlled drug release of black phosphorus nanostructure for cancer therapy.

PubMed

Qiu, Meng; Wang, Dou; Liang, Weiyuan; Liu, Liping; Zhang, Yin; Chen, Xing; Sang, David Kipkemoi; Xing, Chenyang; Li, Zhongjun; Dong, Biqin; Xing, Feng; Fan, Dianyuan; Bao, Shiyun; Zhang, Han; Cao, Yihai

2018-01-16

A biodegradable drug delivery system (DDS) is one the most promising therapeutic strategies for cancer therapy. Here, we propose a unique concept of light activation of black phosphorus (BP) at hydrogel nanostructures for cancer therapy. A photosensitizer converts light into heat that softens and melts drug-loaded hydrogel-based nanostructures. Drug release rates can be accurately controlled by light intensity, exposure duration, BP concentration, and hydrogel composition. Owing to sufficiently deep penetration of near-infrared (NIR) light through tissues, our BP-based system shows high therapeutic efficacy for treatment of s.c. cancers. Importantly, our drug delivery system is completely harmless and degradable in vivo. Together, our work proposes a unique concept for precision cancer therapy by external light excitation to release cancer drugs. If these findings are successfully translated into the clinic, millions of patients with cancer will benefit from our work.

Combining unique properties of dendrimers and magnetic nanoparticles towards cancer theranostics.

PubMed

Chandra, Sudeshna; Nigam, Saumya; Bahadur, Dhirendra

2014-01-01

Magnetic nanoparticles (MNPs) are a well explored class of nanomaterials, known for their high magnetization and biocompatibility thus finding their way in several biomedical applications viz., drug delivery, magnetic resonance imaging contrast agent, immunoassay, detoxification of biological fluids and cell separation, biosensing and hyperthermia. On other hand, dendrimers are a class of hyperbranched, mostly symmetrical polymers that originate from a central core with repetitive branching units, called monomers, thus forming a globular structure. Due to their structural properties and controlled size, dendrimers have emerged as an attractive material for biomedical applications particularly as carriers for therapeutic cargo. Of late, researchers have started attempting to combine the unique features of dendrimer chemistry with the versatile magnetic nanoparticles to provide a facile platform for enhanced therapeutics and biomedical applications. This review intends to present the advances made towards fabrication of dendrimer based magnetic nanoparticles with varied surface architecture and their contribution towards theranostics, particularly for cancer.

Lorcaserin: drug profile and illustrative model of the regulatory challenges of weight-loss drug development.

PubMed

Bays, Harold E

2011-03-01

Lorcaserin is a selective 5-hydroxytryptamine receptor 2c agonist developed as a weight-loss drug. Phase II and III clinical trials support lorcaserin as not only reducing adiposity (i.e., fat mass), but also as improving the metabolic diseases commonly associated with adiposopathy (i.e., fat dysfunction). At the time of this writing, regulatory processes continue towards evaluating lorcaserin as a potentially marketed weight-loss and weight-maintenance agent. Some of the challenges facing lorcaserin are similar to the difficulties encountered by all investigational weight-loss therapeutic agents, which include evolving paths towards approval. While important for clinicians to understand approval hurdles for all therapeutics, it is especially critical for researchers and developers to grasp the unique regulatory complexities of anti-obesity agents. This article profiles lorcaserin as an illustrative example of general drug development regulatory processes, and specifically details the unique challenge of weight-loss drug development.

Monitoring and guidance of HIFU beams with dual-mode ultrasound arrays.

PubMed

Ballard, John R; Casper, Andrew J; Ebbini, Emad S

2009-01-01

We present experimental results illustrating the unique advantages of dual-mode array (DMUA) systems in monitoring and guidance of high intensity focused ultrasound (HIFU) lesion formation. DMUAs offer a unique paradigm in image-guided surgery; one in which images obtained using the same therapeutic transducer provide feedback for: 1) refocusing the array in the presence of strongly scattering objects, e.g. the ribs, 2) temperature change at the intended location of the HIFU focus, and 3) changes in the echogenicity of the tissue in response to therapeutic HIFU. These forms of feedback have been demonstrated in vitro in preparation for the design and implementation of a real-time system for imaging and therapy with DMUAs. The results clearly demonstrate that DMUA image feedback is spatially accurate and provide sufficient spatial and contrast resolution for identification of high contrast objects like the ribs and significant blood vessels in the path of the HIFU beam.

Nano polymeric carrier fabrication technologies for advanced antitumor therapy.

PubMed

Li, Wei; Zhao, Mengxin; Ke, Changhong; Zhang, Ge; Zhang, Li; Li, Huafei; Zhang, Fulei; Sun, Yun; Dai, Jianxin; Wang, Hao; Guo, Yajun

2013-01-01

Comparing with the traditional therapeutic methods, newly developed cancer therapy based on the nanoparticulates attracted extensively interest due to its unique advantages. However, there are still some drawbacks such as the unfavorable in vivo performance for nanomedicine and undesirable tumor escape from the immunotherapy. While as we know that the in vivo performance strongly depended on the nanocarrier structural properties, thus, the big gap between in vitro and in vivo can be overcome by nanocarrier's structural tailoring by fine chemical design and microstructural tuning. In addition, this fine nanocarrier's engineering can also provide practical solution to solve the problems in traditional cancer immunotherapy. In this paper, we review the latest development in nanomedicine, cancer therapy, and nanoimmunotherapy. We then give an explanation why fine nanocanrrie's engineering with special focus on the unique pathology of tumor microenvironments and properties of immunocells can obviously promote the in vivo performance and improve the therapeutic index of nanoimmunotherapy.

Systems biology approach to developing S(2)RM-based "systems therapeutics" and naturally induced pluripotent stem cells.

PubMed

Maguire, Greg; Friedman, Peter

2015-05-26

The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell's power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely "systems therapeutic", can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called "systems therapeutics". A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S(2)RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S(2)RM technology, to develop a new class of therapeutics called "systems therapeutics." Given the ubiquitous and powerful nature of innate S(2)RM-based healing in the human body, this "systems therapeutic" approach using S(2)RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications.

A Therapeutic Approach to Teaching Poetry: Individual Development, Psychology, and Social Reparation. Psychoanalysis, Education and Social Transformation

ERIC Educational Resources Information Center

Williams, Todd O.

2012-01-01

A Therapeutic Approach to Teaching Poetry develops a poetry pedagogy that offers significant benefits to students by helping them to achieve a sense of renewal (a deeper awareness of self and potentials) and reparation (a realistic, but positive and proactive worldview). Todd O. Williams offers a thorough examination of the therapeutic potential…

Inorganic Nanoparticles in Cancer Therapy

PubMed Central

Bhattacharyya, Sanjib; Kudgus, Rachel A.; Bhattacharya, Resham; Mukherjee, Priyabrata

2011-01-01

Nanotechnology is an evolving field with enormous potential for biomedical applications. The growing interest to use inorganic nanoparticles in medicine is due to the unique size and shape-dependent optoelectronic properties. Herein, we will focus on gold, silver and platinum nanoparticles, discussing recent developments for therapeutic applications with regard to cancer in terms of nanoparticles being used as a delivery vehicle as well as therapeutic agents. We will also discuss some of the key challenges to be addressed in future studies. PMID:21104301

Methods and Compositions Based on Culturing Microorganisms in Low Sedimental Fluid Shear Conditions

NASA Technical Reports Server (NTRS)

Ott, C. Mark; Nickerson, Cheryl A.; Wilson, James W.; Sarker, Shameema; Nauman, Eric A.; Schurr, Michael J.; Nelman-Gonzalez, Mayra A.

2012-01-01

The benefits of applying a low sedimental fluid shear environment to manipulate microorganisms were examined. Microorganisms obtained from a low sedimental fluid shear culture, which exhibit modified phenotypic and molecular genetic characteristics, are useful for the development of novel and improved diagnostics, therapeutics, vaccines, and bio-industrial products. Furthermore, application of low sedimental fluid conditions to microorganisms permits identification of molecules uniquely expressed under these conditions, providing a basis for the design of new therapeutic targets.

Electrotherapy for melancholia: the pioneering contributions of Benjamin Franklin and Giovanni Aldini.

PubMed

Bolwig, Tom G; Fink, Max

2009-03-01

The electrical induction of seizures with a therapeutic aim began in 1938, but the history of electric currents to relieve mental illness began 2 centuries earlier with the pioneering work of the Italian Giovanni Aldini and the American Benjamin Franklin.These early experiments are described demonstrating that the electrical force encouraged hopeful applications. This history emphasizes the unique contribution in the induction of grand mal seizures as the therapeutic basis rather than the role of electricity alone.

D-amino acid-containing supramolecular nanofibers for potential cancer therapeutics.

PubMed

Wang, Huaimin; Feng, Zhaoqianqi; Xu, Bing

2017-02-01

Nanostructures formed by peptides that self-assemble in water through non-covalent interactions have attracted considerable attention because peptides possess several unique advantages, such as modular design and easiness of synthesis, convenient modification with known functional motifs, good biocompatibility, low immunogenicity and toxicity, inherent biodegradability, and fast responses to a wide range of external stimuli. After about two decades of development, peptide-based supramolecular nanostructures have already shown great potentials in the fields of biomedicine. Among a range of biomedical applications, using such nanostructures for cancer therapy has attracted increased interests since cancer remains the major threat for human health. Comparing with L-peptides, nanostructures containing peptides made of D-amino acid (i.e., D-peptides) bear a unique advantage, biostability (i.e., resistance towards most of endogenous enzymes). The exploration of nanostructures containing D-amino acids, especially their biomedical applications, is still in its infancy. Herein we review the recent progress of D-amino acid-containing supramolecular nanofibers as an emerging class of biomaterials that exhibit unique features for the development of cancer therapeutics. In addition, we give a brief perspective about the challenges and promises in this research direction. Copyright © 2016 Elsevier B.V. All rights reserved.

Recent developments in protein and peptide parenteral delivery approaches

PubMed Central

Patel, Ashaben; Cholkar, Kishore; Mitra, Ashim K

2014-01-01

Discovery of insulin in the early 1900s initiated the research and development to improve the means of therapeutic protein delivery in patients. In the past decade, great emphasis has been placed on bringing protein and peptide therapeutics to market. Despite tremendous efforts, parenteral delivery still remains the major mode of administration for protein and peptide therapeutics. Other routes such as oral, nasal, pulmonary and buccal are considered more opportunistic rather than routine application. Improving biological half-life, stability and therapeutic efficacy is central to protein and peptide delivery. Several approaches have been tried in the past to improve protein and peptide in vitro/in vivo stability and performance. Approaches may be broadly categorized as chemical modification and colloidal delivery systems. In this review we have discussed various chemical approaches such as PEGylation, hyperglycosylation, mannosylation, and colloidal carriers including microparticles, nanoparticles, liposomes, carbon nanotubes and micelles for improving protein and peptide delivery. Recent developments on in situ thermosensitive gel-based protein and peptide delivery have also been described. This review summarizes recent developments on some currently existing approaches to improve stability, bioavailability and bioactivity of peptide and protein therapeutics following parenteral administration. PMID:24592957

An innovative and highly drug-tolerant approach for detecting neutralizing antibodies directed to therapeutic antibodies.

PubMed

Sloan, John H; Conway, Richard G; Pottanat, Thomas G; Troutt, Jason S; Higgs, Richard E; Konrad, Robert J; Qian, Yue-Wei

2016-10-01

Immunogenicity testing of biotherapeutic drugs is a regulatory requirement. Herein, we describe a drug-tolerant assay for detecting neutralizing antibodies against a therapeutic antibody. Excess target of the therapeutic antibody was incorporated into the detection step of an affinity capture elution assay. Signal generated from binding of antidrug antibody (ADA) to the therapeutic antibody was compared with signal from binding of ADA to the therapeutic antibody preincubated with its target. The results demonstrated that the target blocked binding of the therapeutic antibody to neutralizing monkey ADA and to two anti-idiotypic antibodies. This highly drug-tolerant novel approach enables the detection of neutralizing antibodies and allows for one basic assay format to achieve complete characterization of ADA responses.

Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases.

PubMed

Gabathuler, Reinhard

2010-01-01

The central nervous system is protected by barriers which control the entry of compounds into the brain, thereby regulating brain homeostasis. The blood-brain barrier, formed by the endothelial cells of the brain capillaries, restricts access to brain cells of blood-borne compounds and facilitates nutrients essential for normal metabolism to reach brain cells. This very tight regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the blood-brain barrier (BBB). Therefore, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. In this review, we will address the different approaches used to increase the transport of therapeutics from blood into the brain parenchyma. We will mainly concentrate on the physiologic approach which takes advantage of specific receptors already expressed on the capillary endothelial cells forming the BBB and necessary for the survival of brain cells. Among all the approaches used for increasing brain delivery of therapeutics, the most accepted method is the use of the physiological approach which takes advantage of the transcytosis capacity of specific receptors expressed at the BBB. The low density lipoprotein receptor related protein (LRP) is the most adapted for such use with the engineered peptide compound (EPiC) platform incorporating the Angiopep peptide in new therapeutics the most advanced with promising data in the clinic.

Within-culture variations of uniqueness: towards an integrative approach based on social status, gender, life contexts, and interpersonal comparison.

PubMed

Causse, Elsa; Félonneau, Marie-Line

2014-01-01

Research on uniqueness is widely focused on cross-cultural comparisons and tends to postulate a certain form of within-culture homogeneity. Taking the opposite course of this classic posture, we aimed at testing an integrative approach enabling the study of within-culture variations of uniqueness. This approach considered different sources of variation: social status, gender, life contexts, and interpersonal comparison. Four hundred seventy-nine participants completed a measure based on descriptions of "self" and "other." Results showed important variations of uniqueness. An interaction between social status and life contexts revealed the expression of uniqueness in the low-status group. This study highlights the complexity of uniqueness that appears to be related to both cultural ideology and social hierarchy.

A Dual-Specific Targeting Approach Based on the Simultaneous Recognition of Duplex and Quadruplex Motifs.

PubMed

Nguyen, Thi Quynh Ngoc; Lim, Kah Wai; Phan, Anh Tuân

2017-09-20

Small-molecule ligands targeting nucleic acids have been explored as potential therapeutic agents. Duplex groove-binding ligands have been shown to recognize DNA in a sequence-specific manner. On the other hand, quadruplex-binding ligands exhibit high selectivity between quadruplex and duplex, but show limited discrimination between different quadruplex structures. Here we propose a dual-specific approach through the simultaneous application of duplex- and quadruplex-binders. We demonstrated that a quadruplex-specific ligand and a duplex-specific ligand can simultaneously interact at two separate binding sites of a quadruplex-duplex hybrid harbouring both quadruplex and duplex structural elements. Such a dual-specific targeting strategy would combine the sequence specificity of duplex-binders and the strong binding affinity of quadruplex-binders, potentially allowing the specific targeting of unique quadruplex structures. Future research can be directed towards the development of conjugated compounds targeting specific genomic quadruplex-duplex sites, for which the linker would be highly context-dependent in terms of length and flexibility, as well as the attachment points onto both ligands.

Therapeutic strategies to combat neointimal hyperplasia in vascular grafts

PubMed Central

Collins, Michael J; Li, Xin; Lv, Wei; Yang, Chenzi; Protack, Clinton D; Muto, Akihito; Jadlowiec, Caroline C; Shu, Chang; Dardik, Alan

2012-01-01

Neointimal hyperplasia (NIH) in bypass conduits such as veins and prosthetic grafts is an important clinical entity that limits the long-term success of vascular interventions. Although the development of NIH in the conduits shares many of the same features of NIH that develops in native arteries after injury, vascular grafts are exposed to unique circumstances that predispose them to NIH, including surgical trauma related to vein handling, hemodynamic changes creating areas of low flow, and differences in biocompatibility between the conduit and the host environment. Multiple different approaches, including novel surgical techniques and targeted gene therapies, have been developed to target and prevent the causes of NIH. Recently, the PREVENT trials, the first molecular biology trials in vascular surgery aimed at preventing NIH, have failed to produce improved clinical outcomes, highlighting the incomplete knowledge of the pathways leading to NIH in vascular grafts. In this review, we aim to summarize the pathophysiologic pathways that underlie the formation of NIH in both vein and synthetic grafts and discuss current and potential mechanical and molecular approaches under investigation that may limit NIH in vascular grafts. PMID:22651839

Case study for a vaccine against leishmaniasis.

PubMed

Alvar, Jorge; Croft, Simon L; Kaye, Paul; Khamesipour, Ali; Sundar, Shyam; Reed, Steven G

2013-04-18

Leishmaniasis in many ways offers a unique vaccine case study. Two reasons for this are that leishmaniasis is a disease complex caused by several different species of parasite that are highly related, thus raising the possibility of developing a single vaccine to protect against multiple diseases. Another reason is the demonstration that a leishmaniasis vaccine may be used therapeutically as well as prophylactically. Although there is no registered human leishmaniasis vaccine today, immunization approaches using live or killed organisms, as well as defined vaccine candidates, have demonstrated at least some degree of efficacy in humans to prevent and to treat some forms of leishmaniasis, and there is a vigorous pipeline of candidates in development. Current approaches include using individual or combined antigens of the parasite or of salivary gland extract of the parasites' insect vector, administered with or without formulation in adjuvant. Animal data obtained with several vaccine candidates are promising and some have been or will be entered into clinical testing in the near future. There is sufficient scientific and epidemiological justification to continue to invest in the development of vaccines against leishmaniasis. Copyright © 2012 Elsevier Ltd. All rights reserved.

Unraveling the complexities of invasive multimodality neuromonitoring.

PubMed

Sinha, Saurabh; Hudgins, Eric; Schuster, James; Balu, Ramani

2017-11-01

Acute brain injuries are a major cause of death and disability worldwide. Survivors of life-threatening brain injury often face a lifetime of dependent care, and novel approaches that improve outcome are sorely needed. A delayed cascade of brain damage, termed secondary injury, occurs hours to days and even weeks after the initial insult. This delayed phase of injury provides a crucial window for therapeutic interventions that could limit brain damage and improve outcome. A major barrier in the ability to prevent and treat secondary injury is that physicians are often unable to target therapies to patients' unique cerebral physiological disruptions. Invasive neuromonitoring with multiple complementary physiological monitors can provide useful information to enable this tailored, precision approach to care. However, integrating the multiple streams of time-varying data is challenging and often not possible during routine bedside assessment. The authors review and discuss the principles and evidence underlying several widely used invasive neuromonitors. They also provide a framework for integrating data for clinical decision making and discuss future developments in informatics that may allow new treatment paradigms to be developed.

Solitary extra-skeletal sinonasal metastasis from a primary skeletal Ewing's sarcoma.

PubMed

Hayes, S M; Jani, T N; Rahman, S M; Jogai, S; Harries, P G; Salib, R J

2011-08-01

Ewing's sarcoma is a rare, malignant tumour predominantly affecting young adolescent males. We describe a unique case of an isolated extra-skeletal metastasis from a skeletal Ewing's sarcoma primary, arising in the right sinonasal cavity of a young man who presented with severe epistaxis and periorbital cellulitis. Histologically, the lesion comprised closely packed, slightly diffuse, atypical cells with round, hyperchromatic nuclei, scant cytoplasm and occasional mitotic figures, arranged in a sheet-like pattern. Immunohistochemical analysis showed positive staining only for cluster of differentiation 99 glycoprotein. Fluorescent in situ hybridisation identified the Ewing's sarcoma gene, confirming the diagnosis. Complete surgical resection was achieved via a minimally invasive endoscopic transnasal approach; post-operative radiotherapy. Ten months post-operatively, there were no endoscopic or radiological signs of disease. Metastatic Ewing's sarcoma within the head and neck is incredibly rare and can pose significant diagnostic and therapeutic challenges. An awareness of different clinical presentations and distinct histopathological features is important to enable early diagnosis. This case illustrates one potential management strategy, and reinforces the evolving role of endoscopic transnasal approaches in managing sinonasal cavity and anterior skull base tumours.

Nanoparticles-Emerging Potential for Managing Leukemia and Lymphoma.

PubMed

Vinhas, Raquel; Mendes, Rita; Fernandes, Alexandra R; Baptista, Pedro V

2017-01-01

Nanotechnology has become a powerful approach to improve the way we diagnose and treat cancer. In particular, nanoparticles (NPs) possess unique features for enhanced sensitivity and selectivity for earlier detection of circulating cancer biomarkers. In vivo , NPs enhance the therapeutic efficacy of anticancer agents when compared with conventional chemotherapy, improving vectorization and delivery, and helping to overcome drug resistance. Nanomedicine has been mostly focused on solid cancers due to take advantage from the enhanced permeability and retention (EPR) effect experienced by tissues in the close vicinity of tumors, which enhance nanomedicine's accumulation and, consequently, improve efficacy. Nanomedicines for leukemia and lymphoma, where EPR effect is not a factor, are addressed differently from solid tumors. Nevertheless, NPs have provided innovative approaches to simple and non-invasive methodologies for diagnosis and treatment in liquid tumors. In this review, we consider the state of the art on different types of nanoconstructs for the management of liquid tumors, from preclinical studies to clinical trials. We also discuss the advantages of nanoplatforms for theranostics and the central role played by NPs in this combined strategy.

Targeting Super-Enhancers for Disease Treatment and Diagnosis.

PubMed

Shin, Ha Youn

2018-05-10

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

Subjective tinnitus assessment and treatment in clinical practice: the necessity of personalized medicine.

PubMed

Van de Heyning, Paul; Gilles, Annick; Rabau, Sarah; Van Rompaey, Vincent

2015-10-01

Subjective tinnitus can be triggered by a variety of causes, and therefore tinnitus patients constitute a very heterogeneous population difficult to manage. In this article, we reviewed the current literature to present our conceptual model of the conscious auditory percept and tinnitus - based on experimental research - in order to explain the clinical approach to the individual tinnitus patient. Fundamental research has provided evidence to support the neurophysiological model of tinnitus developed by Jastreboff. By manipulating the limbic, autonomic and auditory systems, tinnitus retraining therapy (TRT) aims to reduce the response to the abnormal stimulus. Evidence has confirmed the effectiveness of TRT and cognitive behavioral therapy in reducing the negative impact of subjective tinnitus on the patients' quality of life. Every patient with subjective tinnitus has its unique 'tinnitus profile' which provides a guide to the necessary combination of therapeutic actions. Evidence suggests the multidisciplinary approach combining etiological therapy as well as TRT, and cognitive behavioral therapy in specialized clinics is not only effective in reducing the patient's quality of life but also cost-effective from a healthcare and societal point of view.

Essential pitfalls in "essential” tremor

PubMed Central

Espay, AJ; Lang, AE; Erro, R; Merola, A; Fasano, A; Berardelli, A; Bhatia, KP

2016-01-01

While essential tremor has been considered the most common movement disorder, it has largely remained a diagnosis of exclusion: many tremor and non-tremor features must be absent for the clinical diagnosis to stand. The clinical features of “essential tremor” overlap with or may be part of other tremor disorders and, not surprisingly, this prevalent familial disorder has remained without a gene identified, without a consistent natural history, and without an acceptable pathology or pathophysiologic underpinning. The collective evidence suggests that under the rubric of essential tremor there exists multiple unique diseases, some of which represent cerebellar dysfunction, but for which there is no intrinsic “essence” other than a common oscillatory behavior on posture and action. One approach may be to use the term “essential tremor” only as a transitional node in the deep phenotyping of tremor disorders based on historical, phenomenological, and neurophysiological features, to facilitate its etiologic diagnosis or serve for future gene- and biomarker-discovery efforts. This approach deemphasizes essential tremor as a diagnostic entity and facilitates the understanding of the underlying disorders in order to develop biologically tailored diagnostic and therapeutic strategies. PMID:28116753

Protein Interactome of Muscle Invasive Bladder Cancer

PubMed Central

Bhat, Akshay; Heinzel, Andreas; Mayer, Bernd; Perco, Paul; Mühlberger, Irmgard; Husi, Holger; Merseburger, Axel S.; Zoidakis, Jerome; Vlahou, Antonia; Schanstra, Joost P.; Mischak, Harald; Jankowski, Vera

2015-01-01

Muscle invasive bladder carcinoma is a complex, multifactorial disease caused by disruptions and alterations of several molecular pathways that result in heterogeneous phenotypes and variable disease outcome. Combining this disparate knowledge may offer insights for deciphering relevant molecular processes regarding targeted therapeutic approaches guided by molecular signatures allowing improved phenotype profiling. The aim of the study is to characterize muscle invasive bladder carcinoma on a molecular level by incorporating scientific literature screening and signatures from omics profiling. Public domain omics signatures together with molecular features associated with muscle invasive bladder cancer were derived from literature mining to provide 286 unique protein-coding genes. These were integrated in a protein-interaction network to obtain a molecular functional map of the phenotype. This feature map educated on three novel disease-associated pathways with plausible involvement in bladder cancer, namely Regulation of actin cytoskeleton, Neurotrophin signalling pathway and Endocytosis. Systematic integration approaches allow to study the molecular context of individual features reported as associated with a clinical phenotype and could potentially help to improve the molecular mechanistic description of the disorder. PMID:25569276

Antiepileptic drug therapy: clinical laboratory significance.

PubMed

Naradzay, J F; Olshaker, J S

1996-01-01

When evaluating a patient who is taking an antiepileptic medication, it is important for the emergency physician to correlate the clinical presentation with the antiepileptic drug level. Therapeutic ranges have been suggested for most antiepileptic medications, but these must be interpreted in light of clinical efficacy and patient tolerance. When considering the efficacy of anti-epileptic medications, it is necessary to consider the patient's unique metabolism, side-effect tolerance, and overall response to therapy. Suggested therapeutic ranges should be the first reference for the emergency physician. The purpose of this report is to discuss the laboratory values of commonly prescribed antiepileptic medications. Therapeutic ranges, side-effects, and common medication interactions are discussed concerning phenytoin, phenobarbital, carbamezapine, and valproic acid.

Conservation of a unique mechanism of immune evasion across the Lyssavirus genus.

PubMed

Wiltzer, L; Larrous, F; Oksayan, S; Ito, N; Marsh, G A; Wang, L F; Blondel, D; Bourhy, H; Jans, D A; Moseley, G W

2012-09-01

The evasion of host innate immunity by Rabies virus, the prototype of the genus Lyssavirus, depends on a unique mechanism of selective targeting of interferon-activated STAT proteins by the viral phosphoprotein (P-protein). However, the immune evasion strategies of other lyssaviruses, including several lethal human pathogens, are unresolved. Here, we show that this mechanism is conserved between the most distantly related members of the genus, providing important insights into the pathogenesis and potential therapeutic targeting of lyssaviruses.

Conservation of a Unique Mechanism of Immune Evasion across the Lyssavirus Genus

PubMed Central

Wiltzer, L.; Larrous, F.; Oksayan, S.; Ito, N.; Marsh, G. A.; Wang, L. F.; Blondel, D.; Bourhy, H.; Jans, D. A.

2012-01-01

The evasion of host innate immunity by Rabies virus, the prototype of the genus Lyssavirus, depends on a unique mechanism of selective targeting of interferon-activated STAT proteins by the viral phosphoprotein (P-protein). However, the immune evasion strategies of other lyssaviruses, including several lethal human pathogens, are unresolved. Here, we show that this mechanism is conserved between the most distantly related members of the genus, providing important insights into the pathogenesis and potential therapeutic targeting of lyssaviruses. PMID:22740405

From crystal to compound: structure-based antimalarial drug discovery.

PubMed

Drinkwater, Nyssa; McGowan, Sheena

2014-08-01

Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

An integrated chemical biology approach identifies specific vulnerability of Ewing's sarcoma to combined inhibition of Aurora kinases A and B.

PubMed

Winter, Georg E; Rix, Uwe; Lissat, Andrej; Stukalov, Alexey; Müllner, Markus K; Bennett, Keiryn L; Colinge, Jacques; Nijman, Sebastian M; Kubicek, Stefan; Kovar, Heinrich; Kontny, Udo; Superti-Furga, Giulio

2011-10-01

Ewing's sarcoma is a pediatric cancer of the bone that is characterized by the expression of the chimeric transcription factor EWS-FLI1 that confers a highly malignant phenotype and results from the chromosomal translocation t(11;22)(q24;q12). Poor overall survival and pronounced long-term side effects associated with traditional chemotherapy necessitate the development of novel, targeted, therapeutic strategies. We therefore conducted a focused viability screen with 200 small molecule kinase inhibitors in 2 different Ewing's sarcoma cell lines. This resulted in the identification of several potential molecular intervention points. Most notably, tozasertib (VX-680, MK-0457) displayed unique nanomolar efficacy, which extended to other cell lines, but was specific for Ewing's sarcoma. Furthermore, tozasertib showed strong synergies with the chemotherapeutic drugs etoposide and doxorubicin, the current standard agents for Ewing's sarcoma. To identify the relevant targets underlying the specific vulnerability toward tozasertib, we determined its cellular target profile by chemical proteomics. We identified 20 known and unknown serine/threonine and tyrosine protein kinase targets. Additional target deconvolution and functional validation by RNAi showed simultaneous inhibition of Aurora kinases A and B to be responsible for the observed tozasertib sensitivity, thereby revealing a new mechanism for targeting Ewing's sarcoma. We further corroborated our cellular observations with xenograft mouse models. In summary, the multilayered chemical biology approach presented here identified a specific vulnerability of Ewing's sarcoma to concomitant inhibition of Aurora kinases A and B by tozasertib and danusertib, which has the potential to become a new therapeutic option.

Building a pipeline to discover and validate novel therapeutic targets and lead compounds for Alzheimer's disease

PubMed Central

Bennett, David A.; Yu, Lei; De Jager, Philip L.

2014-01-01

Cognitive decline, Alzheimer's disease (AD) and other causes are major public health problems worldwide. With changing demographics, the number of persons with dementia will increase rapidly. The treatment and prevention of AD and other dementias, therefore, is an urgent unmet need. There have been considerable advances in understanding the biology of many age-related disorders that cause dementia. Gains in understanding AD have led to the development of ante-mortem biomarkers of traditional neuropathology and the conduct of several phase III interventions in the amyloid-β cascade early in the disease process. Many other intervention strategies are in various stages of development. However, efforts to date have met with limited success. A recent National Institute on Aging Research Summit led to a number of requests for applications. One was to establish multi-disciplinary teams of investigators who use systems biology approaches and stem cell technology to identify a new generation of AD targets. We were recently awarded one of three such grants to build a pipeline that integrates epidemiology, systems biology, and stem cell technology to discover and validate novel therapeutic targets and lead compounds for AD treatment and prevention. Here we describe the two cohorts that provide the data and biospecimens being exploited for our pipeline and describe the available unique datasets. Second, we present evidence in support of a chronic disease model of AD that informs our choice of phenotypes as the target outcome. Third, we provide an overview of our approach. Finally, we present the details of our planned drug discovery pipeline. PMID:24508835

The importance of relationships in mental health care: A qualitative study of service users' experiences of psychiatric hospital admission in the UK

PubMed Central

Gilburt, Helen; Rose, Diana; Slade, Mike

2008-01-01

Background While a number of studies have looked at life on service users' experiences of life on psychiatric wards, no research exists that have approached these experiences from the user perspective since the introduction of community care. Methods This user-led study uses a participatory approach to develop an understanding of the processes and themes which define the user experience of hospitalisation. Nineteen service users who had all had inpatient stays in psychiatric hospitals in London were interviewed in the community. Results Relationships formed the core of service users' experiences. Three further codes, treatment, freedom and environment defined the role of hospital and its physical aspects. Themes of communication, safety, trust, coercion, and cultural competency contributed to the concept of relationships. Conclusion Relationships with an individual which comprised effective communication, cultural sensitivity, and the absence of coercion resulted in that person being attributed with a sense of trust. This resulted in the patient experiencing the hospital as a place of safety in terms of risk from other patients and staff. Barriers to positive relationships included ineffective and negative communication, a lack of trust, a lack of safety in terms of staff as ineffective in preventing violence, and as perpetrators themselves, and the use of coercion by staff. This unique perspective both acts as a source of triangulation with previous studies and highlights the importance of the therapeutic relationship in providing a safe and therapeutic milieu for the treatment of people with acute mental health problems. PMID:18439254

Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology".

PubMed

Insel, Paul A; Amara, Susan G; Blaschke, Terrence F; Meyer, Urs A

2017-01-06

Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e.g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e.g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care.

The Relations of Family Members’ Unique and Shared Perspectives of Family Dysfunction to Dyad Adjustment

PubMed Central

Jager, Justin; Yuen, Cynthia X.; Bornstein, Marc H.; Putnick, Diane L.; Hendricks, Charlene

2017-01-01

Among a community sample of families (N = 128), this study examined how family members’ shared and unique perspectives of family dysfunction relate to dyad members’ shared views of dyad adjustment within adolescent-mother, adolescent-father, and mother-father dyads. Independent of a family’s family perspective (shared perspective of family dysfunction), the adolescent’s unique perspective was associated with lower security and higher conflict with both mother and father, the father’s unique perspective was associated with lower security and higher conflict with the adolescent as well as lower marital quality with mother, and the mother unique perspective was associated with lower marital quality with the father. Moreover, for adolescent-parent dyads, compared to the parent unique perspective, the adolescent unique perspective was more strongly associated with dyad adjustment. These findings indicate that both shared and unique views of the family system – the adolescent’s unique view in particular - independently relate to the health of family subsystems. They also suggest that research as well as therapeutic interventions that focus on just the shared view of the family may miss important elements of family dysfunction. PMID:24884682

The relations of family members' unique and shared perspectives of family dysfunction to dyad adjustment.

PubMed

Jager, Justin; Yuen, Cynthia X; Bornstein, Marc H; Putnick, Diane L; Hendricks, Charlene

2014-06-01

Among a community sample of families (N = 128), this study examined how family members' shared and unique perspectives of family dysfunction relate to dyad members' shared views of dyad adjustment within adolescent-mother, adolescent-father, and mother-father dyads. Independent of a family's family perspective (shared perspective of family dysfunction), the adolescent's unique perspective was associated with lower security and higher conflict with both mother and father; the father's unique perspective was associated with lower security and higher conflict with the adolescent, as well as lower marital quality with mother; and the mother unique perspective was associated with lower marital quality with the father. Moreover, for adolescent-parent dyads, compared with the parent unique perspective, the adolescent unique perspective was more strongly associated with dyad adjustment. These findings indicate that both shared and unique views of the family system-the adolescent's unique view in particular-independently relate to the health of family subsystems. They also suggest that research, as well as therapeutic interventions, that focus on just the shared view of the family may miss important elements of family dysfunction. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Top-down approach to biological therapy of Crohn's disease.

PubMed

Hirschmann, Simon; Neurath, Markus F

2017-03-01

Crohn's disease (CD) is a chronic, immune-mediated condition with a potentially disabling and destructive course. Despite growing data on when to use a therapeutic 'top-down' strategy, clinical management of this complex disorder is still challenging. Currently, the discussion of 'top-down' strategy in CD mostly includes biological therapy alone or in combination. Areas covered: This article is based on a review of existing literature regarding the use of biological therapy in a 'top-down' approach for the treatment of Crohn's disease. The authors reviewed all the major databases including MEDLINE as well as DDW and ECCO abstracts, respectively. Expert opinion: A 'top-down' therapeutic approach in Crohn's disease is strongly supported by existing data in patients with several risk factors for a severe course of disease. Moreover, there is an increasing amount of published data recommending a more individualised therapeutic strategy to identify candidates for 'top-down' treatment, based on enhanced diagnostics using biomarkers. Emerging therapeutic approaches besides existing therapy concepts using biologicals may possibly redefine the 'top-down' therapeutic strategy for Crohn's disease in the future.

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 Elsevier Ltd. All rights reserved.

Could EU herbal monographs contribute to Malta's treatment armamentarium?

PubMed

Micallef, B; Attard, E; Serracino-Inglott, A; Borg, J J

2015-03-15

Ten years have passed since Directive 2004/24/EC regulating herbal medicinal products across the EU were published. The directive created the Committee on Herbal Medicinal Products within the European Medicines Agency whose remit includes the creation and publishing of official EU monographs on herbal medicinal products. These monographs include the official uses of the products and their evidence for efficacy and safety. To this effect, we are interested in analysing the potential impact herbal product EU monographs could have on the therapeutic treatment options available for prescribers in Malta. Therefore our aim was two-fold. First, to rationalise the spread of indications of the herbal substances listed in the community herbal monograph inventory and subsequently determine if these herbal substances could potentially contribute to the treatment options available in our local scenario (Malta). 128 EU monographs were analysed resulting in a total of 230 indications which subsequently codified into 42 unique ATC codes. The Malta Medicines List contains 1456 unique ATC codes. Comparative analysis of the Malta Medicines List revealed that the 21 therapeutic areas had 4 or less pharmaceutically used substances (5th level ATC codes) registered and therefore in our opinion are areas with limited therapeutic choice. The following 4 therapeutic areas, A05 bile and liver therapy, A13 tonics, A15 appetite stimulants and D03 preparations for treatment of wounds and ulcers, could potentially benefit from the registration of herbal medicinal products according to the EU herbal monographs. If such registration is effected the aforementioned areas would no longer be considered limited because more than 4 therapeutic choices would be available to prescribers. This study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and confirms the notion that herbal products could potentially increase the treatment options available in areas where few medical products have been registered due to Malta's small market size. Copyright © 2015 Elsevier GmbH. All rights reserved.

Micelle-like Nanoparticles as Carriers for DNA and siRNA

PubMed Central

Navarro, Gemma; Pan, Jiayi; Torchilin, Vladimir P.

2015-01-01

Gene therapy represents a potential efficient approach of disease prevention and therapy. However, due to their poor in vivo stability, gene molecules need to be associated with delivery systems to overcome extracellular and intracellular barriers and allow access to the site of action. Cationic polymeric nanoparticles are popular carriers for small interfering RNA (siRNA) and DNA-based therapeutics for which efficient and safe delivery are important factors that need to be optimized. Micelle-like nanoparticles (MNP) (half micelles, half polymeric nanoparticles) can overcome some of the disadvantages of such cationic carriers by unifying in one single carrier the best of both delivery systems. In this review, we will discuss how the unique properties of MNP including self-assembly, condensation and protection of nucleic acids, improved cell association and gene transfection, and low toxicity may contribute to the successful application of siRNA- and DNA-based therapeutics into the clinic. Recent developments of MNP involving the addition of stimulus-sensitive functions to respond specifically to pathological or externally applied “triggers” (e.g., temperature, pH or enzymatic catalysis, light, or magnetic fields) will be discussed. Finally, we will overview the use of MNP as two-in-one carriers for the simultaneous delivery of different agents (small molecules, imaging agents) and nucleic acid combinations. PMID:25557580

Retracted article: In vitro derivation of mammalian germ cells from stem cells and their potential therapeutic application.

PubMed

Saito, Shigeo; Lin, Ying-Chu; Murayama, Yoshinobu; Nakamura, Yukio; Eckner, Richard; Niemann, Heiner; Yokoyama, Kazunari K

2015-12-01

Pluripotent stem cells (PSCs) are a unique type of cells because they exhibit the characteristics of self-renewal and pluripotency. PSCs may be induced to differentiate into any cell type, even male and female germ cells, suggesting their potential as novel cell-based therapeutic treatment for infertility problems. Spermatogenesis is an intricate biological process that starts from self-renewal of spermatogonial stem cells (SSCs) and leads to differentiated haploid spermatozoa. Errors at any stage in spermatogenesis may result in male infertility. During the past decade, much progress has been made in the derivation of male germ cells from various types of progenitor stem cells. Currently, there are two main approaches for the derivation of functional germ cells from PSCs, either the induction of in vitro differentiation to produce haploid cell products, or combination of in vitro differentiation and in vivo transplantation. The production of mature and fertile spermatozoa from stem cells might provide an unlimited source of autologous gametes for treatment of male infertility. Here, we discuss the current state of the art regarding the differentiation potential of SSCs, embryonic stem cells, and induced pluripotent stem cells to produce functional male germ cells. We also discuss the possible use of livestock-derived PSCs as a novel option for animal reproduction and infertility treatment.

Use of bacteriophage to target bacterial surface structures required for virulence: a systematic search for antibiotic alternatives.

PubMed

Orndorff, Paul E

2016-11-01

Bacteriophages (phage) that infect pathogenic bacteria often attach to surface receptors that are coincidentally required for virulence. Receptor loss or modification through mutation renders mutants both attenuated and phage resistant. Such attenuated mutants frequently have no apparent laboratory growth defects, but in the host, they fail to exhibit properties needed to produce disease such as mucosal colonization or survival within professional phagocytic cells. The connection between attenuation and phage resistance has been exploited in experimental demonstrations of phage therapy. In such experiments, phage resistant mutants that arise naturally during therapy are inconsequential because of their attenuated status. A more contemporary approach to exploiting this connection involves identifying small effector molecules, identified in high-throughput screens, that inhibit one or more of the steps needed to produce a functioning phage receptor. Since such biosynthetic steps are unique to bacteria, inhibitors can be utilized therapeutically, in lieu of antibiotics. Also, since the inhibitor is specific to a particular bacterium or group of bacteria, no off-target resistance is generated in the host's commensal bacterial population. This brief review covers examples of how mutations that confer phage resistance produce attenuation, and how this coincidental relationship can be exploited in the search for the next generation of therapeutic agents for bacterial diseases.

A simple approach to design chitosan functionalized Fe3O4 nanoparticles for pH responsive delivery of doxorubicin for cancer therapy

NASA Astrophysics Data System (ADS)

Adimoolam, Mahesh G.; Amreddy, Narsireddy; Nalam, Madhusudana Rao; Sunkara, Manorama V.

2018-02-01

The use of magnetic nanoparticles (MNPs) in cancer therapy offer many advantages due to their unique size, physical and biocompatible properties. In this study we have developed a formulation, comprising of anti-cancer drug doxorubicin (Dox) conjugated to iron oxide nanoparticles via a pH sensitive imine linker. Different amounts of chitosan functionalized superparamagnetic iron oxide nanoparticles (Fe3O4-CHI) were synthesized in-situ by a simple hydrolysis method at room temperature. The synthesized nanoparticles were well characterized by TEM, Zeta Potential, TOC, XPS, TGA and VSM for their physicochemical properties. Dox was conjugated to the Fe3O4-CHI nanoparticles via a glutaraldehyde cross linker with the imine (sbnd Cdbnd Nsbnd) bond, which is sensitive to cleavage in the pH range of 4.4-6.4. The synthesized Fe3O4-Dox nanoparticles exhibited enhanced drug release in lower pH conditions which mimics the tumor microenvironment or intracellular organelles such as endosomes/lysosomes. The cell uptake and therapeutic efficacy of Fe3O4-Dox nanoparticles carried out in ovarian cancer cell (SK-OV-3) and breast cancer cell line (MCF7) showed improved therapeutic efficacy of Dox by nearly four-fold with Fe3O4-Dox nanoparticles.

Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction.

PubMed

Evans, Brian C; Hocking, Kyle M; Kilchrist, Kameron V; Wise, Eric S; Brophy, Colleen M; Duvall, Craig L

2015-06-23

A platform technology has been developed and tested for delivery of intracellular-acting peptides through electrostatically complexed nanoparticles, or nano-polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano-polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides.

Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound

PubMed Central

Miller, G. Wilson; Song, Ji; Louttit, Cameron; Klibanov, Alexander L; Shih, Ting-Yu; Swaminathan, Ganesh; Tamargo, Rafael J.; Woodworth, Graeme F.; Hanes, Justin; Price, Richard J.

2014-01-01

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer’s, Parkinson’s and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a noninvasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPN in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60 nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain. PMID:24979210

Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 - 2015).

PubMed

Lior, Yotam; Geyra, Assaf; Lewis, Eli C

2016-05-01

Identified as a circulating serine-protease inhibitor, the genetic deficiency of which predisposes to the development of lung emphysema, alpha1-antitrypsin (AAT) has recently been found to possess various anti-inflammatory and immunomodulatory activities outside the biochemical inhibition of serine-proteases. AAT is presently extracted from human plasma to supply life-long infusions to patients with genetic AAT deficiency. However, its newly appreciated functions point to extended therapeutic uses; these, alongside modified production attempts, represent a novel and dynamic niche of drug repurposing, set apart from addressing lung emphysema in AAT-deficient individuals. The review provides a comprehensive summary of patent-protected inventions in the field of novel clinical indications for AAT and innovations in AAT production. A molecule no longer patentable per se, presents with novel clinical applications; its mechanism still unfolding. While modified protein sequences are patentable and potentially superior, they are burdened by regulatory setbacks. Thus, recent approaches in the context of AAT appear in patents that describe combinations with other drugs, redefined clinical subclasses, and unique recombinant entities, carefully skirting saturated areas of AAT patentology. It will be fascinating to follow technologies and creative patenting as AAT navigates the trying trades of pharmaceutical industry towards an increasing lineup of unmet clinical needs.

Mesenchymal stem cells support hepatocyte function in engineered liver grafts.

PubMed

Kadota, Yoshie; Yagi, Hiroshi; Inomata, Kenta; Matsubara, Kentaro; Hibi, Taizo; Abe, Yuta; Kitago, Minoru; Shinoda, Masahiro; Obara, Hideaki; Itano, Osamu; Kitagawa, Yuko

2014-01-01

Recent studies suggest that organ decellularization is a promising approach to facilitate the clinical application of regenerative therapy by providing a platform for organ engineering. This unique strategy uses native matrices to act as a reservoir for the functional cells which may show therapeutic potential when implanted into the body. Appropriate cell sources for artificial livers have been debated for some time. The desired cell type in artificial livers is primary hepatocytes, but in addition, other supportive cells may facilitate this stem cell technology. In this context, the use of mesenchymal stem cells (MSC) is an option meeting the criteria for therapeutic organ engineering. Ideally, supportive cells are required to (1) reduce the hepatic cell mass needed in an engineered liver by enhancing hepatocyte function, (2) modulate hepatic regeneration in a paracrine fashion or by direct contact, and (3) enhance the preservability of parenchymal cells during storage. Here, we describe enhanced hepatic function achieved using a strategy of sequential infusion of cells and illustrate the advantages of co-cultivating bone marrow-derived MSCs with primary hepatocytes in the engineered whole-liver scaffold. These co-recellularized liver scaffolds colonized by MSCs and hepatocytes were transplanted into live animals. After blood flow was established, we show that expression of adhesion molecules and proangiogenic factors was upregulated in the graft.

Balanced regulation of the CCN family of matricellular proteins: a novel approach to the prevention and treatment of fibrosis and cancer.

PubMed

Riser, Bruce L; Barnes, Jeffrey L; Varani, James

2015-12-01

The CCN family of matricellular signaling proteins is emerging as a unique common link across multiple diseases and organs related to injury and repair. They are now being shown to play a central role in regulating the pathways to the initiation and resolution of normal wound healing and fibrosis in response to multiple forms of injury. Similarly, it is also emerging that they play a key role in regulating the establishment, growth, metastases and tissue regeneration in many forms of cancer via the interaction of cancer cells with the tumor stroma. Evidence has been recently provided that these proteins do not act independently but are co-regulated working in a yin/yang manner to alter the outcome of both normal physiological processes as well as pathology. The purpose of this review is to twofold. First, it will summarize work to date supporting CCN2 as a therapeutic target in the formation and progression of renal, skin, and other organ fibrosis, as well as cancer stroma formation. Second, it will highlight recent evidence for CCN3 as a counter-regulator and a potential therapeutic agent in these diseases with an exciting, novel potential to both treat and then restore tissue homeostasis in those afflicted by these devastating disorders.

Sigma receptors: biology and therapeutic potential.

PubMed

Guitart, Xavier; Codony, Xavier; Monroy, Xavier

2004-07-01

More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.

Potential Roles of Dental Pulp Stem Cells in Neural Regeneration and Repair

PubMed Central

Luo, Lihua; Wang, Xiaoyan; Key, Brian; Lee, Bae Hoon

2018-01-01

This review summarizes current advances in dental pulp stem cells (DPSCs) and their potential applications in the nervous diseases. Injured adult mammalian nervous system has a limited regenerative capacity due to an insufficient pool of precursor cells in both central and peripheral nervous systems. Nerve growth is also constrained by inhibitory factors (associated with central myelin) and barrier tissues (glial scarring). Stem cells, possessing the capacity of self-renewal and multicellular differentiation, promise new therapeutic strategies for overcoming these impediments to neural regeneration. Dental pulp stem cells (DPSCs) derive from a cranial neural crest lineage, retain a remarkable potential for neuronal differentiation, and additionally express multiple factors that are suitable for neuronal and axonal regeneration. DPSCs can also express immunomodulatory factors that stimulate formation of blood vessels and enhance regeneration and repair of injured nerve. These unique properties together with their ready accessibility make DPSCs an attractive cell source for tissue engineering in injured and diseased nervous systems. In this review, we interrogate the neuronal differentiation potential as well as the neuroprotective, neurotrophic, angiogenic, and immunomodulatory properties of DPSCs and its application in the injured nervous system. Taken together, DPSCs are an ideal stem cell resource for therapeutic approaches to neural repair and regeneration in nerve diseases. PMID:29853908

Combating atherosclerosis with targeted nanomedicines: recent advances and future prospective

PubMed Central

Nakhlband, Ailar; Eskandani, Morteza; Saeedi, Nazli; Ghaffari, Samad; Garjani, Alireza

2018-01-01

Introduction: Cardiovascular diseases (CVDs) is recognized as the leading cause of mortality worldwide. The increasing prevalence of such disease demands novel therapeutic and diagnostic approaches to overcome associated clinical/social issues. Recent advances in nanotechnology and biological sciences have provided intriguing insights to employ targeted Nanomachines to the desired location as imaging, diagnosis, and therapeutic modalities. Nanomedicines as novel tools for enhanced drug delivery, imaging, and diagnosis strategies have shown great promise to combat cardiovascular diseases. Methods: In the current study, we intend to review the most recent studies on the nano-based strategies for improved management of CVDs. Results: A cascade of events results in the formation of atheromatous plaque and arterial stenosis. Furthermore, recent studies have shown that nanomedicines have displayed unique functionalities and provided de novo applications in the diagnosis and treatment of atherosclerosis. Conclusion: Despite some limitations, nanomedicines hold considerable potential in the prevention, diagnosis, and treatment of various ailments including atherosclerosis. Fewer side effects, amenable physicochemical properties and multi-potential application of such nano-systems are recognized through various investigations. Therefore, it is strongly believed that with targeted drug delivery to atherosclerotic lesions and plaque, management of onset and progression of disease would be more efficient than classical treatment modalities. PMID:29713603

Adult soft tissue sarcomas: conventional therapies and molecularly targeted approaches.

PubMed

Mocellin, Simone; Rossi, Carlo R; Brandes, Alba; Nitti, Donato

2006-02-01

The therapeutic approach to soft tissue sarcomas (STS) has evolved over the past two decades based on the results from randomized controlled trials, which are guiding physicians in the treatment decision-making process. Despite significant improvements in the control of local disease, a significant number of patients ultimately die of recurrent/metastatic disease following radical surgery due to a lack of effective adjuvant treatments. In addition, the characteristic chemoresistance of STS has compromised the therapeutic value of conventional antineoplastic agents in cases of unresectable advanced/metastatic disease. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with STS. Recent advances in STS biology are paving the way to the development of molecularly targeted therapeutic strategies, the efficacy of which relies not only on the knowledge of the molecular mechanisms underlying cancer development/progression but also on the personalization of the therapeutic regimen according to the molecular features of individual tumours. In this work, we review the state-of-the-art of conventional treatments for STS and summarize the most promising findings in the development of molecularly targeted therapeutic approaches.

Integration of Molecular Pathology, Epidemiology, and Social Science for Global Precision Medicine

PubMed Central

Nishi, Akihiro; Milner, Danny A; Giovannucci, Edward L.; Nishihara, Reiko; Tan, Andy S.; Kawachi, Ichiro; Ogino, Shuji

2015-01-01

Summary The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations, and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial, and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors, and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference, and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology, and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors, and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging, and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science. PMID:26636627

Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future.

PubMed

Reichart, B; Niemann, H; Chavakis, T; Denner, J; Jaeckel, E; Ludwig, B; Marckmann, G; Schnieke, A; Schwinzer, R; Seissler, J; Tönjes, R R; Klymiuk, N; Wolf, E; Bornstein, S R

2015-01-01

Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation. A major strength of this consortium is the inclusion of members of the regulatory bodies, including the Paul-Ehrlich Institute (PEI), infection specialists from the Robert Koch Institute and PEI, veterinarians from the German Primate Center, and representatives of influential ethical and religious institutions. A major goal of this consortium is to promote islet xenotransplantation, based on the extensive expertise and experience of the existing clinical islet transplantation program. Besides comprehensive approaches to understand and prevent inflammation-mediated islet xenotransplant dysfunction [immediate blood-mediated inflammatory reaction (IBMIR)], we also take advantage of the availability of and experience with islet macroencapsulation, with the goal to improve graft survival and function. This consortium harbors a unique group of scientists with complementary expertise under a cohesive program aiming at developing new therapeutic approaches for islet replacement and solid organ xenotransplantation. © Georg Thieme Verlag KG Stuttgart · New York.

Integration of molecular pathology, epidemiology and social science for global precision medicine.

PubMed

Nishi, Akihiro; Milner, Danny A; Giovannucci, Edward L; Nishihara, Reiko; Tan, Andy S; Kawachi, Ichiro; Ogino, Shuji

2016-01-01

The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science.

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents

PubMed Central

Cragg, Gordon M.; Pezzuto, John M.

2016-01-01

Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

Multifaceted remodeling by vitamin C boosts sensitivity of Mycobacterium tuberculosis subpopulations to combination treatment by anti-tubercular drugs.

PubMed

Sikri, Kriti; Duggal, Priyanka; Kumar, Chanchal; Batra, Sakshi Dhingra; Vashist, Atul; Bhaskar, Ashima; Tripathi, Kritika; Sethi, Tavpritesh; Singh, Amit; Tyagi, Jaya Sivaswami

2018-05-01

Bacterial dormancy is a major impediment to the eradication of tuberculosis (TB), because currently used drugs primarily target actively replicating bacteria. Therefore, decoding of the critical survival pathways in dormant tubercle bacilli is a research priority to formulate new approaches for killing these bacteria. Employing a network-based gene expression analysis approach, we demonstrate that redox active vitamin C (vit C) triggers a multifaceted and robust adaptation response in Mycobacterium tuberculosis (Mtb) involving ~ 67% of the genome. Vit C-adapted bacteria display well-described features of dormancy, including growth stasis and progression to a viable but non-culturable (VBNC) state, loss of acid-fastness and reduction in length, dissipation of reductive stress through triglyceride (TAG) accumulation, protective response to oxidative stress, and tolerance to first line TB drugs. VBNC bacteria are reactivatable upon removal of vit C and they recover drug susceptibility properties. Vit C synergizes with pyrazinamide, a unique TB drug with sterilizing activity, to kill dormant and replicating bacteria, negating any tolerance to rifampicin and isoniazid in combination treatment in both in-vitro and intracellular infection models. Finally, the vit C multi-stress redox models described here also offer a unique opportunity for concurrent screening of compounds/combinations active against heterogeneous subpopulations of Mtb. These findings suggest a novel strategy of vit C adjunctive therapy by modulating bacterial physiology for enhanced efficacy of combination chemotherapy with existing drugs, and also possible synergies to guide new therapeutic combinations towards accelerating TB treatment. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Plateau Iris - Therapeutic options and functional results after treatment.

PubMed

Feraru, Crenguța; Bâlha, Andrei; Aursulesei, Victor; Filip, Andrei; Pantalon, Anca

2017-01-01

We present the therapeutic options and functional results in patients with plateau iris (syndrome or configuration) in consecutive case series. Material and method: Our study included newly diagnosed patients with acute angle closure by "plateau iris" (configuration or syndrome), between June 2016 and April 2017. Series of 8 consecutive patients met the inclusion criteria, all being females. All the patients underwent an individualized treatment according to the underlying mechanism and evolution. Functional results (visual acuity, IOP, topical medication) were reported in the current paper. Results: For 10 months, we diagnosed 14 eyes, from 9 patients with acute angle closure by Plateau Iris, distributed as it follows: 6 eyes with closed angle glaucoma (optic disk and visual field changes), 8 eyes with plateau iris syndrome and 2 eyes with plateau iris configuration. 7/ 8 patients were misdiagnosed with primary open angle glaucoma, whereas only one patient had the correct diagnosis of closed angle glaucoma and underwent peripheral laser iridotomy. As treatment options in our study, we recommended and performed argon laser peripheral iridoplasty + iridotomy in 10/ 14 eyes, cataract lens was extracted in 4 eyes and then replaced with PC-IOL, whereas 2 eyes required a filtering anti-glaucoma surgery (trabeculectomy + PI). 2 eyes from the same patient could not be treated as intended as the patient refused the treatment. In this unique case, Pilocarpine (4%) was temporarily indicated. Conclusion: Plateau iris represents a diagnostic trap, but based on a thorough gonioscopic examination and a good patient history, the right diagnosis can be made, all along with a correct therapeutic approach.

Assessment of FUS-Tissue Interactions In Vivo

NASA Astrophysics Data System (ADS)

Haritonova, Alyona V.

Focused ultrasound (FUS) has been proposed for a variety of minimally invasive therapeutic applications, including tumor ablation, neuromodulation, targeted drug delivery and blood brain barrier opening. To date, FUS beams have been primarily monitored through MR and ultrasound diagnostic imaging modalities. The recent introduction of real-time dual-mode ultrasound array (DMUA) systems offers a new paradigm for the guidance of therapeutic focused ultrasound. The DMUA approach allows for inherent registration between the therapeutic and imaging coordinate systems. In this thesis we investigated the use of ultrasound-based thermography to assess FUS-tissue interactions. Specifically, we focused on two aspects of image-guided therapy: 1) monitoring and localization of FUS-tissue interactions, and 2) tissue damage assessment. Towards this end, we presented first experimental results of ultrasound-guided transcranial FUS in a rat brain, both ex vivo and in vivo. DMUA imaging was used to monitor and localize FUS-tissue thermal interactions in real-time. The transcranial echo data allowed for a reliable estimation of temperature change in brain tissue, which had never been done before using ultrasound image guidance. Despite some measurable distortion and loss in focusing gain, transcranial FUS beams at 3.2 MHz were localized axially and laterally. This confirms the results obtained using DMUA-based transcranial ultrasound thermography. A high degree of focusing with the DMUA was then successfully leveraged to perform localized tissue damage assessment in both ex vivo and in vivo. The experimental results presented in this thesis demonstrate some of the unique aspects of image guidance using DMUAs, especially when FUS is subject to significant distortions as in transcranial applications.

Hepatocellular Cancer: New Kids on the Block.

PubMed

Hoffmann, Andreas-Claudiu; Gerken, Guido G H

2014-05-01

With over 600,000 newly diagnosed hepatocellular cancer (HCC) patients worldwide every year and ongoing clinical research, it is surprising that many of the new molecular entities have not yet resulted in significant prolongation of progression-free or overall survival. Nevertheless, there are a number of promising agents currently under investigation. Given the unique tumor biology and heterogeneous clinical manifestations of HCC, the application of molecular and cellular markers could also benefit patient selection, disease prognosis and trial design. This paper provides an overview of the current therapeutic strategies for HCC in the curative and palliative settings. Furthermore, we introduce some of the promising small molecules and antibodies that may find their way into clinical practice, with a focus on substances that are currently in phase III testing. Finally, we summarize the role of promising biomarkers, such as circulating tumor or cancer stem cells. Despite the rising prevalence of HCC and active clinical research, few therapeutic options besides sorafenib have been established. This review discusses the new therapeutic agents in the pipeline. Although many promising preclinical studies have resulted in phase I-II trials on HCC, so far only the tyrosine and Raf kinase inhibitor sorafenib has made its way into the hands of physicians. This multikinase inhibitor is the only approved option for systemic treatment of advanced HCC. Currently, the development of promising approaches for disease management is guided by biomarkers such as molecular markers or cellular characteristics. The use of biomarkers may facilitate early diagnosis in high-risk groups and therefore enhance outcomes by detecting patients whose disease is still curable.

Intensive Evening Outpatient Treatment for Patients With Personality Dysfunction: Early Group Process, Change in Interpersonal Distress, and Longer-Term Social Functioning.

PubMed

Joyce, Anthony S; Ogrodniczuk, John S; Kealy, David

2017-01-01

Entrenched interpersonal difficulties are a defining feature of those with personality dysfunction. Evening treatment-a comprehensive and intensive group-oriented outpatient therapy program-offers a unique approach to delivering mental health services to patients with chronic personality dysfunction. This study assessed change in interpersonal problems as a key outcome, the relevance of such change to future social functioning, and the influence of early group processes on this change. Consecutively admitted patients (N = 75) to a group-oriented evening treatment program were recruited; the majority were diagnosed with personality disorder. Therapy outcome was represented by scores on the Inventory of Interpersonal Problems. Follow-up outcome was represented by the global score of the Social Adjustment Scale. Group climate, group cohesion, and the therapeutic alliance were examined as process variables. Patients experienced substantial reduction in distress associated with interpersonal problems; early process factors that reflected a cohesive and engaged group climate and stronger therapeutic alliance were predictive of this outcome. Improvement in interpersonal distress was predictive of global social functioning six months later. The therapeutic alliance most strongly accounted for change in interpersonal problems at posttreatment and social functioning at follow-up. A comprehensive and integrated outpatient group therapy program, offered in the evening to accommodate patients' real-life demands, can facilitate considerable improvement in interpersonal problems, which in turn influences later social functioning. The intensity and intimacy of peer interactions in the therapy groups, and a strong alliance with the program therapists, are likely interacting factors that are particularly important to facilitate such change.

Therapeutic Approaches in the Stimulation of the Coronary Collateral Circulation

PubMed Central

Degen, Achim; Millenaar, Dominic; Schirmer, Stephan H.

2014-01-01

Arteriogenesis as a way to restore blood flow after arterial occlusion has been under investigation for the treatment of coronary artery disease (CAD) for decades. Therapeutic approaches so far have included delivery of cytokines and growth factors as well as mechanical stimulation such as external counterpulsation. As knowledge on the mechanisms of arteriogenesis expanded, new therapeutic approaches have emerged. This review summarizes recent attempts to stimulate the growth of the coronary vasculature and discusses their potential in clinical application. This article also delivers an overview of current studies and trials on coronary arteriogenesis. PMID:23721076

Clostridium difficile Infection in Children: Current State and Unanswered Questions

PubMed Central

Tamma, Pranita D.; Sandora, Thomas J.

2012-01-01

The incidence of Clostridium difficile infection (CDI) in children has increased over the past decade. In recent years, new and intriguing data on pediatric CDI have emerged. Community-onset infections are increasingly recognized, even in children who have not previously received antibiotics. A hypervirulent strain is responsible for up to 20% of pediatric CDI cases. Unique risk factors for CDI in children have been identified. Advances in diagnostic testing strategies, including the use of nucleic acid amplification tests, have raised new questions about the optimal approach to diagnosing CDI in children. Novel therapeutic options are available for adult patients with CDI, raising questions about the use of these agents in children. Updated recommendations about infection prevention and control measures are now available. We summarize these recent developments in pediatric CDI in this review and also highlight remaining knowledge gaps that should be addressed in future research efforts. PMID:23687578

Melanoma-Targeted Chemothermotherapy and In Situ Peptide Immunotherapy through HSP Production by Using Melanogenesis Substrate, NPrCAP, and Magnetite Nanoparticles

PubMed Central

Jimbow, Kowichi; Ishii-Osai, Yasue; Ito, Shosuke; Tamura, Yasuaki; Ito, Akira; Yoneta, Akihiro; Kamiya, Takafumi; Yamashita, Toshiharu; Honda, Hiroyuki; Wakamatsu, Kazumasa; Murase, Katsutoshi; Nohara, Satoshi; Nakayama, Eiichi; Hasegawa, Takeo; Yamamoto, Itsuo; Kobayashi, Takeshi

2013-01-01

Exploitation of biological properties unique to cancer cells may provide a novel approach to overcome difficult challenges to the treatment of advanced melanoma. In order to develop melanoma-targeted chemothermoimmunotherapy, a melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPrCAP), sulfur-amine analogue of tyrosine, was conjugated with magnetite nanoparticles. NPrCAP was exploited from melanogenesis substrates, which are expected to be selectively incorporated into melanoma cells and produce highly reactive free radicals through reacting with tyrosinase, resulting in chemotherapeutic and immunotherapeutic effects by oxidative stress and apoptotic cell death. Magnetite nanoparticles were conjugated with NPrCAP to introduce thermotherapeutic and immunotherapeutic effects through nonapoptotic cell death and generation of heat shock protein (HSP) upon exposure to alternating magnetic field (AMF). During these therapeutic processes, NPrCAP was also expected to provide melanoma-targeted drug delivery system. PMID:23533767

Injectable 3-D Fabrication of Medical Electronics at the Target Biological Tissues

NASA Astrophysics Data System (ADS)

Jin, Chao; Zhang, Jie; Li, Xiaokang; Yang, Xueyao; Li, Jingjing; Liu, Jing

2013-12-01

Conventional transplantable biomedical devices generally request sophisticated surgery which however often causes big trauma and serious pain to the patients. Here, we show an alternative way of directly making three-dimensional (3-D) medical electronics inside the biological body through sequential injections of biocompatible packaging material and liquid metal ink. As the most typical electronics, a variety of medical electrodes with different embedded structures were demonstrated to be easily formed at the target tissues. Conceptual in vitro experiments provide strong evidences for the excellent performances of the injectable electrodes. Further in vivo animal experiments disclosed that the formed electrode could serve as both highly efficient ECG (Electrocardiograph) electrode and stimulator electrode. These findings clarified the unique features and practicability of the liquid metal based injectable 3-D fabrication of medical electronics. The present strategy opens the way for directly manufacturing electrophysiological sensors or therapeutic devices in situ via a truly minimally invasive approach.

Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists Antibody-Drug Conjugate Working Group position paper.

PubMed

Gorovits, Boris; Alley, Stephen C; Bilic, Sanela; Booth, Brian; Kaur, Surinder; Oldfield, Phillip; Purushothama, Shobha; Rao, Chetana; Shord, Stacy; Siguenza, Patricia

2013-05-01

Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges. The growing number of ADCs being developed across the industry suggests the need for alignment of the bioanalytical methods or approaches used to assess the multiple species and facilitate consistent interpretation of the bioanalytical data. With limited clinical data, the current strategies that can be used to provide insight into the relationship between the multiple species and the observed clinical safety and efficacy are still evolving. Considerations of the bioanalytical strategies for ADCs based on the current industry practices that take into account the complexity and heterogeneity of ADCs are discussed.

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

PubMed Central

Parkinson, James R; Parkes, Harry G; So, Po Wah; Hajji, Nabil; Thomas, E Louise; Frost, Gary S

2017-01-01

Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53−/−. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo. PMID:28932113

Using exosomes, naturally-equipped nanocarriers, for drug delivery.

PubMed

Batrakova, Elena V; Kim, Myung Soo

2015-12-10

Exosomes offer distinct advantages that uniquely position them as highly effective drug carriers. Comprised of cellular membranes with multiple adhesive proteins on their surface, exosomes are known to specialize in cell-cell communications and provide an exclusive approach for the delivery of various therapeutic agents to target cells. In addition, exosomes can be amended through their parental cells to express a targeting moiety on their surface, or supplemented with desired biological activity. Development and validation of exosome-based drug delivery systems are the focus of this review. Different techniques of exosome isolation, characterization, drug loading, and applications in experimental disease models and clinic are discussed. Exosome-based drug formulations may be applied to a wide variety of disorders such as cancer, various infectious, cardiovascular, and neurodegenerative disorders. Overall, exosomes combine benefits of both synthetic nanocarriers and cell-mediated drug delivery systems while avoiding their limitations. Published by Elsevier B.V.

Immunostimulatory monoclonal antibodies for hepatocellular carcinoma therapy. Trends and perspectives.

PubMed

Mazzolini, Guillermo D; Malvicini, Mariana

2018-01-01

Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.

Therapeutic Application of Pluripotent Stem Cells: Challenges and Risks.

PubMed

Martin, Ulrich

2017-01-01

Stem-cell-based therapies are considered to be promising and innovative but complex approaches. Induced pluripotent stem cells (iPSCs) combine the advantages of adult stem cells with the hitherto unique characteristics of embryonic stem cells (ESCs). Major progress has already been achieved with regard to reprogramming technology, but also regarding targeted genome editing and scalable expansion and differentiation of iPSCs and ESCs, in some cases yielding highly enriched preparations of well-defined cell lineages at clinically required dimensions. It is noteworthy, however, that for many applications critical requirements such as the targeted specification into distinct cellular subpopulations and a proper cell maturation remain to be achieved. Moreover, current hurdles such as low survival rates and insufficient functional integration of cellular transplants remain to be overcome. Nevertheless, PSC technologies obviously have come of age and matured to a stage where various clinical applications of PSC-based cellular therapies have been initiated and are conducted.

Recombinant Mycobacterium bovis BCG for immunotherapy in nonmuscle invasive bladder cancer.

PubMed

Begnini, K R; Buss, J H; Collares, T; Seixas, F K

2015-05-01

In the past three decades, intravesical instillation of Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for treating bladder cancer and it still remains at the forefront of immunotherapy for cancer patients. Although BCG-based therapy is the most effective intravesical therapy for this kind of tumor and represents the only agent known to reduce progression into muscle invasive bladder cancer, BCG is ineffective in approximately 30-40 % of cases and disease recurs in up to 50 % of patients. Since that BCG is considered an effective vehicle for delivery of antigens due to its unique characteristics, the genetic manipulation of these mycobacteria has been appealing in the search for less toxic and more potent therapeutic agents for bladder cancer immunotherapy. Herein, we discuss current advances in recombinant BCG construction, research, concerns, and future directions to promote the development of this promising immunotherapeutic approach for bladder cancer.

Iron and Atherosclerosis: Nailing Down a Novel Target with Magnetic Resonance

PubMed Central

Sharkey-Toppen, Travis P.; Tewari, Arun K.; Raman, Subha V.

2014-01-01

Iron is an essential mineral in many proteins and enzymes in human physiology, with limited means of iron elimination to maintain iron balance. Iron accrual incurs various pathological mechanisms linked to cardiovascular disease. In atherosclerosis, iron catalyzes the creation of reactive oxygen free radicals that contribute to lipid modification, which is essential to atheroma formation. Inflammation further fuels iron-related pathologic processes associated with plaque progression. Given iron’s role in atherosclerosis development, in vivo detection techniques sensitive iron are needed for translational studies targeting iron for earlier diagnosis and treatment. Magnetic resonance imaging (MRI) is uniquely able to quantify iron in human tissues noninvasively and without ionizing radiation, offering appealing for longitudinal and interventional studies. Particularly intriguing is iron’s complementary biology vs. calcium, which is readily detectable by computed tomography (CT). This review summarizes the role of iron in atherosclerosis with considerable implications for novel diagnostic and therapeutic approaches. PMID:24590608

Expanded complexity of unstable repeat diseases

PubMed Central

Polak, Urszula; McIvor, Elizabeth; Dent, Sharon Y.R.; Wells, Robert D.; Napierala, Marek

2015-01-01

Unstable Repeat Diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human neurological diseases are caused by instability, predominantly expansion, of microsatellite sequences. Changes in the repeat size initiate a cascade of pathological processes, frequently characteristic of a unique disease or a small subgroup of the URDs. Understanding of both the mechanism of repeat instability and molecular consequences of the repeat expansions is critical to developing successful therapies for these diseases. Recent technological breakthroughs in whole genome, transcriptome and proteome analyses will almost certainly lead to new discoveries regarding the mechanisms of repeat instability, the pathogenesis of URDs, and will facilitate development of novel therapeutic approaches. The aim of this review is to give a general overview of unstable repeats diseases, highlight the complexities of these diseases, and feature the emerging discoveries in the field. PMID:23233240

Viral Activation of Cellular Metabolism

PubMed Central

Sanchez, Erica L.; Lagunoff, Michael

2015-01-01

To ensure optimal environments for their replication and spread, viruses have evolved to alter many host cell pathways. In the last decade, metabolomic studies have shown that eukaryotic viruses induce large-scale alterations in host cellular metabolism. Most viruses examined to date induce aerobic glycolysis also known as the Warburg effect. Many viruses tested also induce fatty acid synthesis as well as glutaminolysis. These modifications of carbon source utilization by infected cells can increase available energy for virus replication and virion production, provide specific cellular substrates for virus particles and create viral replication niches while increasing infected cell survival. Each virus species also likely requires unique metabolic changes for successful spread and recent research has identified additional virus-specific metabolic changes induced by many virus species. A better understanding of the metabolic alterations required for each virus may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways. PMID:25812764

Functional imaging of cerebral blood flow and glucose metabolism in Parkinson's disease and Huntington's disease.

PubMed

Ma, Yilong; Eidelberg, David

2007-01-01

Brain imaging of cerebral blood flow and glucose metabolism has been playing key roles in describing pathophysiology of Parkinson's disease (PD) and Huntington's disease (HD), respectively. Many biomarkers have been developed in recent years to investigate the abnormality in molecular substrate, track the time course of disease progression, and evaluate the efficacy of novel experimental therapeutics. A growing body of literature has emerged on neurobiology of these two movement disorders in resting states and in response to brain activation tasks. In this paper, we review the latest applications of these approaches in patients and normal volunteers at rest conditions. The discussions focus on brain mapping studies with univariate and multivariate statistical analyses on a voxel basis. In particular, we present data to validate the reproducibility and reliability of unique spatial covariance patterns related with PD and HD.

Computational prediction of protein hot spot residues.

PubMed

Morrow, John Kenneth; Zhang, Shuxing

2012-01-01

Most biological processes involve multiple proteins interacting with each other. It has been recently discovered that certain residues in these protein-protein interactions, which are called hot spots, contribute more significantly to binding affinity than others. Hot spot residues have unique and diverse energetic properties that make them challenging yet important targets in the modulation of protein-protein complexes. Design of therapeutic agents that interact with hot spot residues has proven to be a valid methodology in disrupting unwanted protein-protein interactions. Using biological methods to determine which residues are hot spots can be costly and time consuming. Recent advances in computational approaches to predict hot spots have incorporated a myriad of features, and have shown increasing predictive successes. Here we review the state of knowledge around protein-protein interactions, hot spots, and give an overview of multiple in silico prediction techniques of hot spot residues.

A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease.

PubMed

Mostafavi, Sara; Gaiteri, Chris; Sullivan, Sarah E; White, Charles C; Tasaki, Shinya; Xu, Jishu; Taga, Mariko; Klein, Hans-Ulrich; Patrick, Ellis; Komashko, Vitalina; McCabe, Cristin; Smith, Robert; Bradshaw, Elizabeth M; Root, David E; Regev, Aviv; Yu, Lei; Chibnik, Lori B; Schneider, Julie A; Young-Pearse, Tracy L; Bennett, David A; De Jager, Philip L

2018-06-01

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.

Cognitive-behavioral play therapy.

PubMed

Knell, S M

1998-03-01

Discusses cognitive-behavioral play therapy (CBPT), a developmentally sensitive treatment for young children that relies on flexibility, decreased expectation for verbalizations by the child, and increased reliance on experiential approaches. The development of CBPT for preschool-age children provides a relatively unique adaptation of cognitive therapy as it was originally developed for adults. CBPT typically contains a modeling component through which adaptive coping skills are demonstrated. Through the use of play, cognitive change is communicated indirectly, and more adaptive behaviors can be introduced to the child. Modeling is tailored for use with many specific cognitive and behavioral interventions. Generalization and response prevention are important features of CBPT. With minor modifications, many of the principles of cognitive therapy, as delineated for use with adults, are applicable to young children. Case examples are presented to highlight the application of CBPT. Although CBPT has a sound therapeutic base and utilizes proven techniques, more rigorous empirical scrutiny is needed.

Computational Prediction of Hot Spot Residues

PubMed Central

Morrow, John Kenneth; Zhang, Shuxing

2013-01-01

Most biological processes involve multiple proteins interacting with each other. It has been recently discovered that certain residues in these protein-protein interactions, which are called hot spots, contribute more significantly to binding affinity than others. Hot spot residues have unique and diverse energetic properties that make them challenging yet important targets in the modulation of protein-protein complexes. Design of therapeutic agents that interact with hot spot residues has proven to be a valid methodology in disrupting unwanted protein-protein interactions. Using biological methods to determine which residues are hot spots can be costly and time consuming. Recent advances in computational approaches to predict hot spots have incorporated a myriad of features, and have shown increasing predictive successes. Here we review the state of knowledge around protein-protein interactions, hot spots, and give an overview of multiple in silico prediction techniques of hot spot residues. PMID:22316154

Quantitative multimodality imaging in cancer research and therapy.

PubMed

Yankeelov, Thomas E; Abramson, Richard G; Quarles, C Chad

2014-11-01

Advances in hardware and software have enabled the realization of clinically feasible, quantitative multimodality imaging of tissue pathophysiology. Earlier efforts relating to multimodality imaging of cancer have focused on the integration of anatomical and functional characteristics, such as PET-CT and single-photon emission CT (SPECT-CT), whereas more-recent advances and applications have involved the integration of multiple quantitative, functional measurements (for example, multiple PET tracers, varied MRI contrast mechanisms, and PET-MRI), thereby providing a more-comprehensive characterization of the tumour phenotype. The enormous amount of complementary quantitative data generated by such studies is beginning to offer unique insights into opportunities to optimize care for individual patients. Although important technical optimization and improved biological interpretation of multimodality imaging findings are needed, this approach can already be applied informatively in clinical trials of cancer therapeutics using existing tools. These concepts are discussed herein.

Electrospun polymeric dressings functionalized with antimicrobial peptides and collagen type I for enhanced wound healing

NASA Astrophysics Data System (ADS)

Felgueiras, H. P.; Amorim, M. T. P.

2017-10-01

Modern wound dressings combine medical textiles with active compounds that stimulate wound healing while protecting against infection. Electrospun wound dressings have been extensively studied and the electrospinning technique recognized as an efficient approach for the production of nanoscale fibrous mats. The unique diverse function and architecture of antimicrobial peptides (AMPs) has attracted considerable attention as a tool for the design of new anti-infective drugs. Functionalizing electrospun wound dressings with these AMPs is nowadays being researched. In the present work, we explore these new systems by highlighting the most important characteristics of electropsun wound dressings, revealing the importance of AMPs to wound healing, and the methods available to functionalize the electrospun mats with these molecules. The combined therapeutic potential of collagen type I and these AMP functionalized dressings will be highlighted as well; the significance of these new strategies for the future of wound healing will be clarified.

Pre-clinical evidence of PIM kinase inhibitor activity in BCR-ABL1 unmutated and mutated Philadelphia chromosome-positive (Ph+) leukemias

PubMed Central

Curi, Dany A.; Beauchamp, Elspeth M.; Blyth, Gavin T.; Arslan, Ahmet Dirim; Donato, Nicholas J.; Giles, Francis J.; Altman, Jessica K.; Platanias, Leonidas C.

2015-01-01

We investigated the efficacy of targeting the PIM kinase pathway in Philadelphia chromosome-positive (Ph+) leukemias. We provide evidence that inhibition of PIM, with the pan-PIM inhibitor SGI-1776, results in suppression of classic PIM effectors and also elements of the mTOR pathway, suggesting interplay between PIM and mTOR signals. Our data demonstrate that PIM inhibition enhances the effects of imatinib mesylate on Ph+ leukemia cells. We also found that PIM inhibition results in suppression of leukemic cell proliferation and induction of apoptosis of Ph+ leukemia cells, including those resistant to imatinib mesylate. Importantly, inhibition of PIM results in enhanced suppression of primary leukemic progenitors from patients with CML. Altogether these findings suggest that pharmacological PIM targeting may provide a unique therapeutic approach for the treatment of Ph+ leukemias. PMID:26375673

Integrative Tumor Board: a Case Report and Discussion from Dana-Farber Cancer Institute

PubMed Central

Lu, Weidong; Ott, Mary Jane; Kennedy, Stacy; Mathay, Maria B.; Doherty-Gilman, Anne M.; Dean-Clower, Elizabeth; Hayes, Carolyn M.; Rosenthal, David S.

2010-01-01

A 34-year-old female carrying a BRCA1 gene and a significant family history was diagnosed with T1c, N1 breast cancer. The tumor was estrogen receptor, progesterone receptor and HER-2/Neu negative. The patient received dose-dense chemotherapy with Adriamycin and Cytoxan followed by Taxol, and left breast irradiation. Later, a bilateral S-GAP flap reconstruction with right prophylactic mastectomy and left mastectomy were performed. During her treatment, the patient had an integrative medicine consultation and was seen by a team of healthcare providers specializing in integrative therapies including integrative nutrition, therapeutic massage, acupuncture, and yoga. Each modality contributed unique benefit in her care that led to a satisfactory outcome of the patient. A detailed discussion regarding her care from each modality is presented. The case elucidates the need of integrative approaches for cancer patients in a conventional medical setting. PMID:19815593

Activation of Antitumorigenic Stat3beta in Breast Cancer by Splicing Redirection

DTIC Science & Technology

2013-07-01

4175) model system REPORTABLE OUTCOMES 1. Lee Spraggon and Luca Cartegni; Antisense Modulation of RNA Processing as a Therapeutic Approach in...modulation. Proc Natl Acad Sci U S A 108: 17779-17784. 26. Spraggon L, Cartegni L (2013) Antisense modulation of RNA processing as a therapeutic...pre-print copy 1 Antisense Modulation of RNA Processing as a Therapeutic Approach in Cancer Therapy Lee Spraggon and Luca Cartegni Molecular

Diagnosis and treatment of severely malnourished children with diarrhea

USDA-ARS?s Scientific Manuscript database

Children with severe acute malnutrition complicated by diarrhoea require special care due to their unique physiological vulnerability and increased mortality risks. A systematic literature review (1950-2013) was conducted to identify the most effective diagnostic and therapeutic measures for the com...

Ligand-targeted theranostic nanomedicines against cancer.

PubMed

Yao, Virginia J; D'Angelo, Sara; Butler, Kimberly S; Theron, Christophe; Smith, Tracey L; Marchiò, Serena; Gelovani, Juri G; Sidman, Richard L; Dobroff, Andrey S; Brinker, C Jeffrey; Bradbury, Andrew R M; Arap, Wadih; Pasqualini, Renata

2016-10-28

Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Carbon nanotubes as anti-bacterial agents.

PubMed

Mocan, Teodora; Matea, Cristian T; Pop, Teodora; Mosteanu, Ofelia; Buzoianu, Anca Dana; Suciu, Soimita; Puia, Cosmin; Zdrehus, Claudiu; Iancu, Cornel; Mocan, Lucian

2017-10-01

Multidrug-resistant bacterial infections that have evolved via natural selection have increased alarmingly at a global level. Thus, there is a strong need for the development of novel antibiotics for the treatment of these infections. Functionalized carbon nanotubes through their unique properties hold great promise in the fight against multidrug-resistant bacterial infections. This new family of nanovectors for therapeutic delivery proved to be innovative and efficient for the transport and cellular translocation of therapeutic molecules. The current review examines the latest progress in the antibacterial activity of carbon nanotubes and their composites.

Developing therapeutic microRNAs for cancer

PubMed Central

Bader, AG; Brown, D; Stoudemire, J; Lammers, P

2014-01-01

Despite substantial progress in understanding the cancer-signaling network, effective therapies remain scarce due to insufficient disruption of oncogenic pathways, drug resistance and drug-induced toxicity. This complexity of cancer defines an urgent goal for researchers and clinicians to develop novel therapeutic strategies. The discovery of microRNAs (miRNAs) provides new hope for accomplishing this task. Supported by solid evidence for a critical role in cancer and bolstered by a unique mechanism of action, miRNAs are likely to yield a new class of targeted therapeutics. In contrast to current cancer medicines, miRNA-based therapies function by subtle repression of gene expression on a yet large number of oncogenic factors and are, therefore, anticipated to be highly efficacious. After the completion of target validation for several candidates, the development of therapeutic miRNAs is now moving to a new stage that involves pharmacological drug delivery, preclinical toxicology and regulatory guidelines. PMID:21633392

ANMCO/ELAS/SIBioC Consensus Document: biomarkers in heart failure

PubMed Central

Gulizia, Michele Massimo; Clerico, Aldo; Di Tano, Giuseppe; Emdin, Michele; Feola, Mauro; Iacoviello, Massimo; Latini, Roberto; Mortara, Andrea; Valle, Roberto; Misuraca, Gianfranco; Passino, Claudio; Masson, Serge; Aimo, Alberto; Ciaccio, Marcello; Migliardi, Marco

2017-01-01

Abstract Biomarkers have dramatically impacted the way heart failure (HF) patients are evaluated and managed. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or pharmacological responses to a therapeutic intervention. Natriuretic peptides [B-type natriuretic peptide (BNP) and N-terminal proBNP] are the gold standard biomarkers in determining the diagnosis and prognosis of HF, and a natriuretic peptide-guided HF management looks promising. In the last few years, an array of additional biomarkers has emerged, each reflecting different pathophysiological processes in the development and progression of HF: myocardial insult, inflammation, fibrosis, and remodelling, but their role in the clinical care of the patient is still partially defined and more studies are needed before to be well validated. Moreover, several new biomarkers have the potential to identify patients with early renal dysfunction and appear to have promise to help the management cardio-renal syndrome. With different biomarkers reflecting HF presence, the various pathways involved in its progression, as well as identifying unique treatment options for HF management, a closer cardiologist-laboratory link, with a multi-biomarker approach to the HF patient, is not far ahead, allowing the unique opportunity for specifically tailoring care to the individual pathological phenotype. PMID:28751838

Training in time-limited dynamic psychotherapy: A systematic comparison of pre- and post-training cases treated by one therapist.

PubMed

Anderson, Timothy; Strupp, Hans H

2015-01-01

This qualitative study systematically compared cases treated by the same therapist in order to understand the group comparison findings of a larger study on training of experienced therapists (the "Vanderbilt II" psychotherapy project). The therapist, Dr C., was selected based on the therapist's overall treatment successes. His two patients were selected based on their outcomes and the relative training cohort from which they were drawn: a case with successful outcome from the pre-training cohort and a case of negligible improvement from the post-training cohort. Dr C. demonstrated a variety of interpersonal skills throughout his pre-training case, though there was also poor interpersonal process throughout. However, in the second case he had considerable difficulty in adapting his typical therapeutic approach to the requirements of the time-limited dynamic psychotherapy (TLDP) manual, even while appearing to work hard to find ways to use the manual. Dr C.'s spontaneity, and his unique set of interpersonal skills may enhanced his initial rapport and alliance building with clients and yet may not have interfaced well with TLDP. His unique interpersonal skills also may have contributed to problems of interpersonal process. Future research may benefit from examining the interaction of between therapist interpersonal skills and the implementation of the treatment manual.

Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin

PubMed Central

Wong, Ada Hang-Heng; Vazquez-Ortiz, Guelaguetza; Chen, Weiping; Xu, Xiaoling; Deng, Chu-Xia

2016-01-01

Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations. PMID:27806319

[Mechanism of action of intravesical BCG. Biological bases and clinical applicability.

PubMed

Carballido, Joaquín A; Rodríguez Monsalve, María

2018-05-01

The therapeutic approaches developed around immune system modulation find the therapeutic contribution of intravesical Bacillus Calmette Guerin (BCG) for transitional cell bladder cancer an unquestionable example as a proof of concept of antitumor immunotherapy since more than 30 years ago. Intravesical immunotherapy for urothelial carcinomas is considered with periodic intravesical instillations schedules, and the one with longer historic development and wider diffusion is BCG in the form of suspension. BCG is a unique strain obtained from Mycobacterium bovis at the end of the first third of the XX century and represents the historically most successful immunotherapeutic modality of all tumors with a high level body of evidence. Currently, we even see an unpredictable development potential of this therapeutic modality based on immunomodulation related with activation or suppression of T lymphocytes by blocking the immune system checkpoints. This option is at this time a decisive step in the treatment of chemotherapy refractory metastatic urothelial carcinoma. Over the last years, there have been advances in the intimate mechanism of action of intravesical BCG, but there are many open questions that will only be answered from complex basic and translational research platforms. The objective of this review article is to try to translate the basic mechanisms currently implicated in the different phases of antitumor response of BCG in its routine use in clinical practice. Also, to analyze the future lines already active under clinical research with and without implications of the mechanisms of action of BCG. We describe the role of interactions basally established between urothelial tumor cells and cellular and molecular elements of the immune system of the patients with ulterior antitumor effector capacity. After intravesical BCG therapy and its interaction, we describe the various phases of its mechanism of action, namely fixation, internalization and triggering of the lytic cytotoxic antitumor response, and its integration in the current intravesical treatment regimens The implication of all these mechanisms in the varied capacity of clinical response observed in patients, reviewing the current status of knowledge of BCG mechanisms of action, leads unavoidably to the search of better clinical efficacy through eventual immune response markers and to set the approach to the knowledge of the individual reactivity of the immune system of each patient as a determinant factor to be able to adopt adjusted therapeutic patterns.

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

Identification of a novel selective PPARγ ligand with a unique binding mode and improved therapeutic profile in vitro

PubMed Central

Yi, Wei; Shi, Jingjing; Zhao, Guanguan; Zhou, X. Edward; Suino-Powell, Kelly; Melcher, Karsten; Xu, H. Eric

2017-01-01

Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent “hit” compound, VSP-51, which is a novel selective PPARγ-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPARγ with improved insulin sensitivity due to its ability to bind PPARγ with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPARγ ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for anti-diabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPARγ with advantages over current TZD drugs. PMID:28128331

Delivery of multiple siRNAs using lipid-coated PLGA nanoparticles for treatment of prostate cancer.

PubMed

Hasan, Warefta; Chu, Kevin; Gullapalli, Anuradha; Dunn, Stuart S; Enlow, Elizabeth M; Luft, J Christopher; Tian, Shaomin; Napier, Mary E; Pohlhaus, Patrick D; Rolland, Jason P; DeSimone, Joseph M

2012-01-11

Nanotechnology can provide a critical advantage in developing strategies for cancer management and treatment by helping to improve the safety and efficacy of novel therapeutic delivery vehicles. This paper reports the fabrication of poly(lactic acid-co-glycolic acid)/siRNA nanoparticles coated with lipids for use as prostate cancer therapeutics made via a unique soft lithography particle molding process called Particle Replication In Nonwetting Templates (PRINT). The PRINT process enables high encapsulation efficiency of siRNA into neutral and monodisperse PLGA particles (32-46% encapsulation efficiency). Lipid-coated PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA in vitro to knockdown genes relevant to prostate cancer. © 2011 American Chemical Society

Nucleic acid aptamers: research tools in disease diagnostics and therapeutics.

PubMed

Santosh, Baby; Yadava, Pramod K

2014-01-01

Aptamers are short sequences of nucleic acid (DNA or RNA) or peptide molecules which adopt a conformation and bind cognate ligands with high affinity and specificity in a manner akin to antibody-antigen interactions. It has been globally acknowledged that aptamers promise a plethora of diagnostic and therapeutic applications. Although use of nucleic acid aptamers as targeted therapeutics or mediators of targeted drug delivery is a relatively new avenue of research, one aptamer-based drug "Macugen" is FDA approved and a series of aptamer-based drugs are in clinical pipelines. The present review discusses the aspects of design, unique properties, applications, and development of different aptamers to aid in cancer diagnosis, prevention, and/or treatment under defined conditions.

The regulatory framework for preventing cross-contamination of pharmaceutical products: History and considerations for the future.

PubMed

Sargent, Edward V; Flueckiger, Andreas; Barle, Ester Lovsin; Luo, Wendy; Molnar, Lance R; Sandhu, Reena; Weideman, Patricia A

2016-08-01

Cross-contamination in multi-product pharmaceutical manufacturing facilities can impact both product safety and quality. This issue has been recognized by regulators and industry for some time, leading to publication of a number of continually evolving guidelines. This manuscript provides a historical overview of the regulatory framework for managing cross-contamination in multi-product facilities to provide context for current approaches. Early guidelines focused on the types of pharmaceuticals for which dedicated facilities and control systems were needed, and stated the requirements for cleaning validation. More recent guidelines have promoted the idea of using Acceptable Daily Exposures (ADEs) to establish cleaning limits for actives and other potentially hazardous substances. The ADE approach is considered superior to previous methods for setting cleaning limits such as using a predetermined general limit (e.g., 10 ppm or a fraction of the median lethal dose (LD50) or therapeutic dose). The ADEs can be used to drive the cleaning process and as part of the overall assessment of whether dedicated production facilities are required. While great strides have been made in using the ADE approach, work remains to update good manufacturing practices (GMPs) to ensure that the approaches are clear, consistent with the state-of-the-science, and broadly applicable yet flexible enough for adaptation to unique products and situations. Copyright © 2016 Elsevier Inc. All rights reserved.

A Person-Centered Counseling Approach as a Primary Therapeutic Support for Women with a History of Childhood Sexual Abuse

ERIC Educational Resources Information Center

Edwards, Nivischi N.; Lambie, Glenn W.

2009-01-01

Childhood sexual abuse (CSA) is prevalent among women. Person-centered counseling (PCC) is an effective core therapeutic approach to use when treating women with this issue. This article provides (a) an overview of CSA, (b) an orientation to PCC, and (c) a case example illustrating the primary application of this approach.

The parent-child-therapist alliance: A case study using a strategic approach.

PubMed

Naidu, Thirusha; Behari, Sheethal

2010-06-01

In this paper we present a single case study of a clinical approach that addresses the needs of parents and their children in psychotherapy. The approach begins by addressing the child's and parent's concerns separately at first by establishing strong therapeutic alliances with each, and then proceeds to address the concerns of the parent-child dyad. The basic premise is that the therapeutic alliance is the central element to successful outcomes in psychotherapy. The nature of alliance-building and its associated methods and techniques have been extensively considered for adult therapy. However, there is considerably less written on the therapeutic alliance with children and adolescents in the context of family interventions. We briefly examine some theoretical dimensions and applications of the therapeutic alliance in psychotherapy with children/adolescents and their parents. A three-phase alliance-building psychotherapy strategy, founded on the idea that each therapeutic relationship warrants an effective working alliance, is proposed. The case of a single mother and her adolescent daughter is employed to illustrate the strategy.

Therapeutic targeting of the p53 pathway in cancer stem cells

PubMed Central

Prabhu, Varun V.; Allen, Joshua E.; Hong, Bo; Zhang, Shengliang; Cheng, Hairong; El-Deiry, Wafik S.

2013-01-01

Introduction Cancer stem cells are a high profile drug target for cancer therapeutics due to their indispensable role in cancer progression, maintenance, and therapeutic resistance. Restoring wild-type p53 function is an attractive new therapeutic approach for the treatment of cancer due to the well-described powerful tumor suppressor function of p53. As emerging evidence intimately links p53 and stem cell biology, this approach also provides an opportunity to target cancer stem cells. Areas covered Therapeutic approaches to restore the function of wild-type p53, cancer and normal stem cell biology in relation to p53, and the downstream effects of p53 on cancer stem cells. Expert opinion The restoration of wild-type p53 function by targeting p53 directly, its interacting proteins, or its family members holds promise as a new class of cancer therapies. This review examines the impact that such therapies may have on normal and cancer stem cells based on the current evidence linking p53 signaling with these populations. PMID:22998602

Enhancing Youth Participation Using the PREP Intervention: Parents’ Perspectives

PubMed Central

Anaby, Dana; Mercerat, Coralie; Tremblay, Stephanie

2017-01-01

Pathways and Resources for Engagement and Participation (PREP), an innovative intervention aimed at modifying the environment and coaching youth/parents, was found to be effective in improving youth participation in chosen community activities. In order to complement existing quantitative evidence, this study examined parents’ perspectives on the PREP approach. Twelve parents of youth with physical disabilities (12 to 18 years old) who received the PREP approach participated in individual semi-structured interviews following the 12-week intervention delivered by an occupational therapist. Thematic analysis revealed three inter-linked themes, the first of which was informative, describing the “nature of intervention”, and led to two reflective themes: “multi-faceted effects of care” and “process of care”. Parents highlighted the effect of the PREP intervention in a broad sense, extending beyond the accomplishment of the selected activities. This involved improvements on the physical, emotional, and social levels as well as in autonomy. Parents also discussed how their own needs were acknowledged through the intervention and recognized the unique role of the occupational therapist in supporting this process. The findings provide additional information about the usefulness of the PREP approach and describe the various benefits generated by a single intervention. Such knowledge can expand the therapeutic options for positive, health-promoting participation. PMID:28869491

Enhancing Youth Participation Using the PREP Intervention: Parents' Perspectives.

PubMed

Anaby, Dana; Mercerat, Coralie; Tremblay, Stephanie

2017-09-02

Pathways and Resources for Engagement and Participation (PREP), an innovative intervention aimed at modifying the environment and coaching youth/parents, was found to be effective in improving youth participation in chosen community activities. In order to complement existing quantitative evidence, this study examined parents' perspectives on the PREP approach. Twelve parents of youth with physical disabilities (12 to 18 years old) who received the PREP approach participated in individual semi-structured interviews following the 12-week intervention delivered by an occupational therapist. Thematic analysis revealed three inter-linked themes, the first of which was informative, describing the "nature of intervention", and led to two reflective themes: "multi-faceted effects of care" and "process of care". Parents highlighted the effect of the PREP intervention in a broad sense, extending beyond the accomplishment of the selected activities. This involved improvements on the physical, emotional, and social levels as well as in autonomy. Parents also discussed how their own needs were acknowledged through the intervention and recognized the unique role of the occupational therapist in supporting this process. The findings provide additional information about the usefulness of the PREP approach and describe the various benefits generated by a single intervention. Such knowledge can expand the therapeutic options for positive, health-promoting participation.

Intracellular co-delivery of Sr ion and phenamil drug through mesoporous bioglass nanocarriers synergizes BMP signaling and tissue mineralization.

PubMed

Lee, Jung-Hwan; Mandakhbayar, Nandin; El-Fiqi, Ahmed; Kim, Hae-Won

2017-09-15

Inducing differentiation and maturation of resident multipotent stem cells (MSCs) is an important strategy to regenerate hard tissues in mal-calcification conditions. Here we explore a co-delivery approach of therapeutic molecules comprised of ion and drug through a mesoporous bioglass nanoparticle (MBN) for this purpose. Recently, MBN has offered unique potential as a nanocarrier for hard tissues, in terms of high mesoporosity, bone bioactivity (and possibly degradability), tunable delivery of biomolecules, and ionic modification. Herein Sr ion is structurally doped to MBN while drug Phenamil is externally loaded as a small molecule activator of BMP signaling, for the stimulation of osteo/odontogenesis and mineralization of human MSCs derived from dental pulp. The Sr-doped MBN (85Si:10Ca:5Sr) sol-gel processed presents a high mesoporosity with a pore size of ∼6nm. In particular, Sr ion is released slowly at a daily rate of ∼3ppm per mg nanoparticles for up to 7days, a level therapeutically effective for cellular stimulation. The Sr-MBN is internalized to most MSCs via an ATP dependent macropinocytosis within hours, increasing the intracellular levels of Sr, Ca and Si ions. Phenamil is loaded maximally ∼30% into Sr-MBN and then released slowly for up to 7days. The co-delivered molecules (Sr ion and Phenamil drug) have profound effects on the differentiation and maturation of cells, i.e., significantly enhancing expression of osteo/odontogenic genes, alkaline phosphatase activity, and mineralization of cells. Of note, the stimulation is a result of a synergism of Sr and Phenamil, through a Trb3-dependent BMP signaling pathway. This biological synergism is further evidenced in vivo in a mal-calcification condition involving an extracted tooth implantation in dorsal subcutaneous tissues of rats. Six weeks post operation evidences the osseous-dentinal hard tissue formation, which is significantly stimulated by the Sr/Phenamil delivery, based on histomorphometric and micro-computed tomographic analyses. The bioactive nanoparticles releasing both Sr ion and Phenamil drug are considered to be a promising therapeutic nanocarrier platform for hard tissue regeneration. Furthermore, this novel ion/drug co-delivery concept through nanoparticles can be extensively used for other tissues that require different therapeutic treatment. This study reports a novel design concept in inorganic nanoparticle delivery system for hard tissues - the co-delivery of therapeutic molecules comprised of ion (Sr) and drug (Phenamil) through a unique nanoparticle of mesoporous bioactive glass (MBN). The physico-chemical and biological properties of MBN enabled an effective loading of both therapeutic molecules and a subsequently sustained/controlled release. The co-delivered Sr and Phenamil demonstrated significant stimulation of adult stem cell differentiation in vitro and osseous/dentinal regeneration in vivo, through BMP signaling pathways. We consider the current combination of Sr ion with Phenamil is suited for the osteo/odontogenesis of stem cells for hard tissue regeneration, and further, this ion/drug co-delivery concept can extend the applications to other areas that require specific cellular and tissue functions. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

50 years of computer simulation of the human thermoregulatory system.

PubMed

Hensley, Daniel W; Mark, Andrew E; Abella, Jayvee R; Netscher, George M; Wissler, Eugene H; Diller, Kenneth R

2013-02-01

This paper presents an updated and augmented version of the Wissler human thermoregulation model that has been developed continuously over the past 50 years. The existing Fortran code is translated into C with extensive embedded commentary. A graphical user interface (GUI) has been developed in Python to facilitate convenient user designation of input and output variables and formatting of data presentation. Use of the code with the GUI is described and demonstrated. New physiological elements were added to the model to represent the hands and feet, including the unique vascular structures adapted for heat transfer associated with glabrous skin. The heat transfer function and efficacy of glabrous skin is unique within the entire body based on the capacity for a very high rate of blood perfusion and the novel capability for dynamic regulation of blood flow. The model was applied to quantify the absolute and relative contributions of glabrous skin flow to thermoregulation for varying levels of blood perfusion. The model also was used to demonstrate how the unique features of glabrous skin blood flow may be recruited to implement thermal therapeutic procedures. We have developed proprietary methods to manipulate the control of glabrous skin blood flow in conjunction with therapeutic devices and simulated the effect of these methods with the model.

Screening native botanicals for bioactivity: an interdisciplinary approach

USGS Publications Warehouse

Boudreau, Anik; Cheng, Diana M.; Ruiz, Carmen; Ribnicky, David; Allain, Larry K.; Brassieur, C. Ray; Turnipseed, D. Phil; Cefalu, William T.; Floyd, Z. Elizabeth

2014-01-01

Conclusion: An interdisciplinary approach to screening botanical sources of therapeutic agents can be successfully applied to identify native plants used in folk medicine as potential sources of therapeutic agents in treating insulin resistance in skeletal muscle or inflammatory processes associated with obesity-related insulin resistance.

Family Therapy with Reconstituted Families: A Crisis-Induction Approach.

ERIC Educational Resources Information Center

Baptiste, David A.

1983-01-01

Describes a crisis-based therapeutic approach for overcoming resistance in reconstituted families. Presents therapeutically induced crisis as a means through which therapists might purposefully disequilibrate families in which resistance is high and subsequently redirect them to meaningful change. Reviews implications and contraindications for the…

[Towards new therapeutic paradigms beyond symptom control in the management of inflammatory bowel diseases.

PubMed

Festa, Stefano; Zerboni, Giulia; Aratari, Annalisa; Ballanti, Riccardo; Papi, Claudio

2018-01-01

Inflammatory bowel diseases, Crohn's disease and ulcerative colitis are chronic relapsing conditions that may result in progressive bowel damage, high risk of complications, surgery and permanent disability. The conventional therapeutic approach for inflammatory bowel diseases is based mainly on symptom control. Unfortunately, a symptom-based therapeutic approach has little impact on major long-term disease outcomes. In other chronic disabling conditions such as diabetes, hypertension and rheumatoid arthritis, the development of new therapeutic approaches has led to better outcomes. In this context a "treat to target" strategy has been developed. This strategy is based on identification of high-risk patients, regular assessment of disease activity by means of objective measures, adjustment of treatment to reach the pre-defined target. A treat to target approach has recently been proposed for inflammatory bowel disease with the aim at modifying the natural history of the disease. In this review, the evidence and the limitations of the treat to target paradigm in inflammatory bowel disease are analyzed and discussed.

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 APPROACH AND ITS RELATIONSHIP WITH SOCIAL AND ECONOMIC CHARACTERISTICS OF USERS OF CENTERS FOR PSYCHOSOCIAL CARE FOR CHILDREN AND ADOLESCENTS

PubMed Central

Gondim, Ana Paula Soares; Maciel, Ana Paula Pessoa; Monteiro, Mirian Parente

2017-01-01

ABSTRACT Objective: To analyze the therapeutic approach and its relationship with the economic and social characteristics and the care of children in Centers for Psychosocial Attention. Methods: Descriptive study with a sample of 294 children monitored in two Centers for Psychosocial Attention to Children and Adolescents in Fortaleza, Ceará, Northeast Brazil. The study was conducted from February to December, 2012. Participants were accompanied by their parents or caregivers. Data were collected in a structured questionnaire containing social, economic and care variables. The bivariate analysis used the χ2 test to test the association between variables. Results: In this study, 292 children aged 3-12 were selected, following the order of attendance at the service, most of them male (74.3%) and belonging to social classes D and E (89.3%). The most frequent diagnosis referred to by the caregivers was mental disorders. Three different therapeutic approaches were identified: pharmacological approach (44.5%); non-pharmacological approach (11.6%); association of both techniques (43.8%). For all therapeutic approaches, there was association with the variable living situation (p=0.021), as well as with the variables, “improving” with the treatment (p=0.002) and “problems” with the treatment (p=0,004). Conclusions: It was possible to highlight that the associated therapeutic approach (pharmacological and non-pharmacological treatment) provides more benefits to children. Therefore, associating the medicines to the psychotherapeutic practices may be recommended as a strategy in the mental health policy directed to children and adolescents. PMID:29185621

Nanoceria as Antioxidant: Synthesis and Biomedical Applications

USDA-ARS?s Scientific Manuscript database

The therapeutic application of nanomaterials has been a focus of numerous studies in the past decade. Due to its unique redox properties, cerium oxide (ceria) is finding widespread use in the treatment of medical disorders caused by the reactive oxygen intermediates (ROI). The radical-scavenging rol...

A receptor-grounded approach to teaching nonsteroidal antiinflammatory drug chemistry and structure-activity relationships.

PubMed

Roche, Victoria F

2009-12-17

To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Student performance on NSAID-focused quizzes and examinations documented the success of this approach.

Review of Diagnostic and Therapeutic Approach to Canine Myxomatous Mitral Valve Disease

PubMed Central

Borgarelli, Michele

2017-01-01

The most common heart disease that affects dogs is myxomatous mitral valve disease. In this article, we review the current diagnostic and therapeutic approaches to this disease, and we also present some of the latest technological advancements in this field. PMID:29056705

An in-depth snake venom proteopeptidome characterization: Benchmarking Bothrops jararaca.

PubMed

Nicolau, Carolina A; Carvalho, Paulo C; Junqueira-de-Azevedo, Inácio L M; Teixeira-Ferreira, André; Junqueira, Magno; Perales, Jonas; Neves-Ferreira, Ana Gisele C; Valente, Richard H

2017-01-16

A large-scale proteomic approach was devised to advance the understanding of venom composition. Bothrops jararaca venom was fractionated by OFFGEL followed by chromatography, generating peptidic and proteic fractions. The latter was submitted to trypsin digestion. Both fractions were separately analyzed by reversed-phase nanochromatography coupled to high resolution mass spectrometry. This strategy allowed deeper and joint characterizations of the peptidome and proteome (proteopeptidome) of this venom. Our results lead to the identification of 46 protein classes (with several uniquely assigned proteins per class) comprising eight high-abundance bona fide venom components, and 38 additional classes in smaller quantities. This last category included previously described B. jararaca venom proteins, common Elapidae venom constituents (cobra venom factor and three-finger toxin), and proteins typically encountered in lysosomes, cellular membranes and blood plasma. Furthermore, this report is the most complete snake venom peptidome described so far, both in number of peptides and in variety of unique proteins that could have originated them. It is hypothesized that such diversity could enclose cryptides, whose bioactivities would contribute to envenomation in yet undetermined ways. Finally, we propose that the broad range screening of B. jararaca peptidome will facilitate the discovery of bioactive molecules, eventually leading to valuable therapeutical agents. Our proteopeptidomic strategy yielded unprecedented insights into the remarkable diversity of B. jararaca venom composition, both at the peptide and protein levels. These results bring a substantial contribution to the actual pursuit of large-scale protein-level assignment in snake venomics. The detection of typical elapidic venom components, in a Viperidae venom, reinforces our view that the use of this approach (hand-in-hand with transcriptomic and genomic data) for venom proteomic analysis, at the specimen-level, can greatly contribute for venom toxin evolution studies. Furthermore, data were generated in support of a previous hypothesis that venom gland secretory vesicles are specialized forms of lysosomes. Two testable hypotheses also emerge from the results of this work. The first is that a nucleobindin-2-derived protein could lead to prey disorientation during envenomation, aiding in its capture by the snake. The other being that the venom's peptidome might contain a population of cryptides, whose biological activities could lead to the development of new therapeutical agents. Copyright © 2016 Elsevier B.V. All rights reserved.

The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach.

PubMed

Korf, Bruce; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Bakker, Annette; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D; Gripp, Karen W; Kerr, Bronwyn; Kontaridis, Maria; Lazaro, Conxi; Linardic, Corinne; Lozano, Reymundo; MacRae, Calum A; Messiaen, Ludwine; Mulero-Navarro, Sonia; Neel, Benjamin; Plotkin, Scott; Rauen, Katherine A; Roberts, Amy; Silva, Alcino J; Sittampalam, Sitta G; Zhang, Chao; Schoyer, Lisa

2015-08-01

"The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion. © 2015 Wiley Periodicals, Inc.

Teaching clinical pharmacology and therapeutics with an emphasis on the therapeutic reasoning of undergraduate medical students

PubMed Central

Richir, Milan C.; Tichelaar, Jelle; Geijteman, Eric C. T.

2008-01-01

Background The rational prescribing of drugs is an essential skill of medical doctors. Clinical pharmacologists play an important role in the development of these skills by teaching clinical pharmacology and therapeutics (CP&T) to undergraduate medical students. Although the approaches to teaching CP&T have undergone many changes over the last decennia, it is essential that the actual teaching of CP&T continues to be a major part of the undergraduate medical curriculum. Objectives The learning objectives of CP&T teaching in terms of developing the therapeutic competencies of undergraduate medical students are described, with an emphasis on therapeutic decision-making. On the basis of current theories of cognitive psychology and medical education, context-learning is presented as an effective approach by which to achieve therapeutic competencies. An example of a CP&T curriculum is presented. PMID:18228012

Family systems approach to attachment relations, war trauma, and mental health among Palestinian children and parents.

PubMed

Punamäki, Raija-Leena; Qouta, Samir R; Peltonen, Kirsi

2017-01-01

Background : Trauma affects the family unit as a whole; however, most existing research uses individual or, at most, dyadic approaches to analyse families with histories of trauma. Objective : This study aims to identify potentially distinct family types according to attachment, parenting, and sibling relations, to analyse how these family types differ with respect to war trauma, and to explore how children's mental health and cognitive processing differ across these family types. Method: Participants included Palestinian mothers and fathers ( N  = 325) and their children (one per family; 49.4% girls; 10-13 years old; mean ±  SD age = 11.35 ± 0.57 years) after the Gaza War of 2008-2009. Both parents reported their exposure to war trauma, secure attachment availability, and parenting practices, as well as the target child's internalizing and externalizing symptoms [Strengths and Difficulties Questionnaire (SDQ)]. Children reported their symptoms of post-traumatic stress disorder (on the Children's Revised Impact Event Scale), depression (Birleson), and SDQ, as well as their post-traumatic cognitions (Children's Post Traumatic Cognitions Inventory). Results: A cluster analysis identified four family types. The largest type reflected secure attachment and optimal relationships (security and positive family relationships, 36.2%, n  = 102), and the smallest exhibited insecurity and problematic relationships (insecurity and negative family relationships, 15.6%; n  = 44). Further, families with discrepant experiences (23.0%; n  = 65) and moderate security and neutral relationships (25.2%; n  = 71) emerged. The insecurity and negative relationships family type showed higher levels of war trauma; internalizing, externalizing, and depressive symptoms among children; and dysfunctional post-traumatic cognitions than other family types. Conclusion: The family systems approach to mental health is warranted in war conditions, and therapeutic interventions for children should, thus, also involve parents and siblings. Knowledge of unique family attachment patterns is fruitful for tailoring therapeutic treatments and preventive interventions for war-affected children and families.

Biodegradable Porous Silicon Nanomaterials for Imaging and Treatment of Cancer

NASA Astrophysics Data System (ADS)

Gu, Luo

Cancer is the second leading cause of death, claiming ˜0.56 million lives in the U.S. every year following heart diseases (˜0.62 million). From 1991 to 2007, mortality associated with heart diseases decreased 39%; by contrast, the death rate of cancer only decreased by 17% in spite of intensive research and improved therapeutics. The stagnation of conventional medicine and the complexity of cancer demand new therapeutic strategies. As an emerging approach, the use of nanomaterials as cancer diagnostic and therapeutic agents has shown promising results due to their unique physical and chemical properties. To date, more than two dozen nanoparticle-based products have been approved for clinical use and they show advantages over conventional therapeutics. However, translation of many other nanomaterials has been impeded due to concerns over toxicity and biodegradability. This dissertation presents the development of biodegradable luminescent porous silicon nanomaterials and their potential applications for imaging and treatment of cancer. After a brief introduction to nanomedicine and the biomedical applications of porous silicon, Chapter 2 presents a method of making silicon nanoparticles with porous structure and intrinsic luminescence (LPSiNPs). The low toxicity and biodegradability of LPSiNPs are demonstrated in vitro with human cancer cells and in vivo with mouse model. The in vivo clearance of intravenously injected LPSiNPs is studied by tracking the emission of the nanoparticles with fluorescence imaging. Chapter 3 presents a diagnostic application of LPSiNPs. Time-gated fluorescence imaging of tumors using LPSiNPs with long emission lifetime is developed. This technique can effectively eliminate interference from short-lived tissue autofluorescence and improve the detection sensitivity. Chapter 4--6 demonstrate the therapeutic applications of porous silicon nanomaterials. In Chapter 4, magnetically-guided delivery of anticancer drug to cancer cells in vitro is achieved using magnetic, luminescent porous Si microparticles. Chapter 5 demonstrates that porous silicon nanoparticles can be used as photosensitizer and generate cytotoxic singlet oxygen when irradiated by light. The phototoxicity of the nanoparticles against cancer cells is also studied. Finally, the use of LPSiNPs for immune activation is investigated in Chapter 6.

Meaning and challenges in the practice of multiple therapeutic massage modalities: a combined methods study.

PubMed

Porcino, Antony J; Boon, Heather S; Page, Stacey A; Verhoef, Marja J

2011-09-20

Therapeutic massage and bodywork (TMB) practitioners are predominantly trained in programs that are not uniformly standardized, and in variable combinations of therapies. To date no studies have explored this variability in training and how this affects clinical practice. Combined methods, consisting of a quantitative, population-based survey and qualitative interviews with practitioners trained in multiple therapies, were used to explore the training and practice of TMB practitioners in Alberta, Canada. Of the 5242 distributed surveys, 791 were returned (15.1%). Practitioners were predominantly female (91.7%), worked in a range of environments, primarily private (44.4%) and home clinics (35.4%), and were not significantly different from other surveyed massage therapist populations. Seventy-seven distinct TMB therapies were identified. Most practitioners were trained in two or more therapies (94.4%), with a median of 8 and range of 40 therapies. Training programs varied widely in number and type of TMB components, training length, or both. Nineteen interviews were conducted. Participants described highly variable training backgrounds, resulting in practitioners learning unique combinations of therapy techniques. All practitioners reported providing individualized patient treatment based on a responsive feedback process throughout practice that they described as being critical to appropriately address the needs of patients. They also felt that research treatment protocols were different from clinical practice because researchers do not usually sufficiently acknowledge the individualized nature of TMB care provision. The training received, the number of therapies trained in, and the practice descriptors of TMB practitioners are all highly variable. In addition, clinical experience and continuing education may further alter or enhance treatment techniques. Practitioners individualize each patient's treatment through a highly adaptive process. Therefore, treatment provision is likely unique to each practitioner. These results may be of interest to researchers considering similar practice issues in other professions. The use of a combined-methods design effectively captured this complexity of TMB practice. TMB research needs to consider research approaches that can capture or adapt to the individualized nature of practice.

Personologic alignment and the treatment of posttraumatic distress.

PubMed

Everly, G

2001-01-01

The therapeutic alliance is generally considered the sine qua non of successful psychotherapy. Yet, establishing the therapeutic alliance with patients suffering from syndromes of posttraumatic distress (including posttraumatic stress disorder) represents an unusual challenge. This paper describes the use of a personality-based approach to the establishment of the therapeutic alliance. This approach is referred to as personologic alignment and consists of alignment with preferential processes, as well as thematic belief systems. It represents an integration of the personology of Theodore Millon and the rhetoric of Aristotle.

Targeting active cancer cells with smart bullets.

PubMed

Martel, Sylvain

2017-03-01

Paul Ehrlich's 'magic bullet' concept has stimulated research for therapeutic agents with the capability to go straight to their intended targets. The 'magic bullet' concept is still considered the ultimate approach to maximize the therapeutic effects of a given therapeutic agent without affecting nontargeted tissues. But so far, there has never been a therapeutic agent or a delivery system that goes straight to the target in the body, and no approach has provided anything better than just a few percents of the total administered dose reaching the intended target sites. But engineering principles can transform systematically circulating vectors that so far were based primarily on physical characteristics and biochemical principles alone, as smart therapeutic agents with the required propulsion-navigation-homing capabilities to enable them to go straight to their intended targets.

Hypoallergenic Edible Peanut Protein Matrix to Enable Novel Functional Food & Immunotherapy

USDA-ARS?s Scientific Manuscript database

Peanut allergies can present life-threatening consequences; therefore, there is an intense interest in developing therapeutic strategies that could reduce the danger and severity of the allergic reaction in peanut sensitive patients. We have developed a unique technology to modify or mask allergenic...

Endocarditis caused by Rhodotorula infection.

PubMed

Simon, Matthew S; Somersan, Selin; Singh, Harjot K; Hartman, Barry; Wickes, Brian L; Jenkins, Stephen G; Walsh, Thomas J; Schuetz, Audrey N

2014-01-01

Rhodotorula is an emerging opportunistic fungal pathogen that is rarely reported to cause endocarditis. We describe a case involving a patient who developed endocarditis due to Rhodotorula mucilaginosa and Staphylococcus epidermidis, proven by culture and histopathology. The case illustrates the unique diagnostic and therapeutic challenges relevant to Rhodotorula spp.

Stomatitis associated with mammalian target of rapamycin inhibition: A review of pathogenesis, prevention, treatment, and clinical implications for oral practice in metastatic breast cancer.

PubMed

Chambers, Mark S; Rugo, Hope S; Litton, Jennifer K; Meiller, Timothy F

2018-04-01

Patients with metastatic breast cancer may develop oral morbidities that result from therapeutic interventions. Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a common adverse event (AE), secondary to mTOR inhibitor therapy, that can have a negative impact on treatment adherence, quality of life, and health care costs. A multidisciplinary team approach is important to minimize mIAS and to maximize treatment benefits to patients with breast cancer. In this review, we discuss the pathophysiology, diagnosis, and natural history of mIAS. Current and new management strategies for the prevention and treatment of mIAS are described in the context of fostering a coordinated team care approach to optimizing patient care. The authors conducted a PubMed search from 2007 through 2017 using the terms "stomatitis," "mIAS," "everolimus," "mTOR," "metastatic breast cancer," and "oral care." They selected articles published in peer-reviewed journals that reported controlled trials and evidence-based guidelines. mIAS can be distinguished from mucositis caused by cytotoxic chemotherapy or radiotherapy on the basis of cause, clinical presentation, and treatment paradigms. Specific preventive and therapeutic management strategies can be implemented across the continuum of patient oral health care. Oral health care providers are on the frontline of oral health care for patients with metastatic breast cancer and are uniquely positioned to provide patient education, advocate accurate reporting of mIAS, and support early identification, monitoring, and prompt intervention to mitigate the severity and duration of this manageable, potentially dose-limiting AE. Copyright © 2018 American Dental Association. Published by Elsevier Inc. All rights reserved.

Low-volume binary drug therapy for the treatment of hypovolemia.

PubMed

Bhattacharjee, Himanshu; Nadipuram, Asha; Kosanke, Stanley; Kiani, Mohammad F; Moore, Bob M

2011-06-01

The selective regulation of total peripheral circulation in hypovolemic crisis offers a unique approach for treating and preventing hemorrhagic shock. Ideally, such a therapeutic intervention would require targeting of the striated muscle vascular beds without altering the vascular resistance in vital organ vascular beds. We discovered that a combination of cannabinoid receptor agonist, THC (Δ-tetrahydrocannabinol), and cyclooxygenase 2 inhibitor, NS-398, caused selective microvascular constriction in the mouse cremaster muscle manifested by a pronounced and significant 27.4% ± 7.9% decrease in vessel diameter relative to control (P < 0.01). This observation, and the reported lack of microvascular response in the mesentery and brain, led us to hypothesize that the drug combination could favorably redistribute blood volume in hypovolemia and prolong survival. To test the hypothesis, male Sprague-Dawley rats were subjected to a pressure-controlled hemorrhage (mean arterial pressure reduced to 30 ± 13.73 mmHg) then randomly assigned to one of six treatment groups (n = 6 per group). The untreated, NS-398-treated, and THC-treated groups manifested an insignificant difference in survival between groups after shock. The group treated with a combination of THC and NS-398 manifested a significant increase in mean survival from 53 ± 12 to 227 ± 23 min after shock (P < 0.001). The drug combination significantly reduced IL-1α, IL-1β, IFN-γ, and IL-10 production compared with the group resuscitated with normal saline. In addition, histological evaluation indicated that the therapy protects the lungs and liver against hemorrhagic shock-induced damage. The combination of cannabinoid receptor agonist and cyclooxygenase 2 inhibitor represents a potentially new approach to low-volume therapeutic intervention for hypovolemia.

ABCA1 agonist peptides for the treatment of disease

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

Bielicki, John K.

Purpose of review The review summarizes information pertaining to the preclinical development of new apolipoprotein (apo) E mimetic peptides that stimulate cellular cholesterol efflux. Recent findings Small α-helical peptides based on the C-terminal domain of apoE have been developed for therapeutic applications. These peptides stimulate cellular cholesterol efflux via the ATP-binding cassette transporter A1 (ABCA1) with high potency, like native apolipoproteins on a molar basis. This potent activity has been related to the unique ability of these peptides to maintain α-helix structure upon dilution. Recent structure-activity studies improving the safety features of these mimetic peptides have greatly improved their potentialmore » for clinical use. Structural features of the class A α-helix motif that induce muscle toxicity and hypertriglyceridemia have been identified. These may have implications for the design of other HDL mimetic peptides. Summary ABCA1 is an integral membrane protein that plays a central role in biology. Its principal function is to mediate the efflux of cholesterol and phospholipid from cells to extracellular apo, preventing a build-up of excess cholesterol in membranes. This process generates HDL particles that perform a variety of functions to protect against disease. A number of these functions can be viewed as directly or indirectly supporting ABCA1 activity, thus constituting a positive feedback system to optimize cellular lipid efflux responses and disease prevention. Consequently, therapeutic approaches that mimic the activities of apos may prove highly effective to combat disease. One such approach involves the use of peptides. The broad biological relevance of ABCA1 suggests these apo mimetic peptides may be useful for the treatment of a number of diseases, such as atherosclerosis, diabetes, and Alzheimer's disease.« less

ABCA1 agonist peptides for the treatment of disease

DOE PAGES

Bielicki, John K.

2016-02-01

Purpose of review The review summarizes information pertaining to the preclinical development of new apolipoprotein (apo) E mimetic peptides that stimulate cellular cholesterol efflux. Recent findings Small α-helical peptides based on the C-terminal domain of apoE have been developed for therapeutic applications. These peptides stimulate cellular cholesterol efflux via the ATP-binding cassette transporter A1 (ABCA1) with high potency, like native apolipoproteins on a molar basis. This potent activity has been related to the unique ability of these peptides to maintain α-helix structure upon dilution. Recent structure-activity studies improving the safety features of these mimetic peptides have greatly improved their potentialmore » for clinical use. Structural features of the class A α-helix motif that induce muscle toxicity and hypertriglyceridemia have been identified. These may have implications for the design of other HDL mimetic peptides. Summary ABCA1 is an integral membrane protein that plays a central role in biology. Its principal function is to mediate the efflux of cholesterol and phospholipid from cells to extracellular apo, preventing a build-up of excess cholesterol in membranes. This process generates HDL particles that perform a variety of functions to protect against disease. A number of these functions can be viewed as directly or indirectly supporting ABCA1 activity, thus constituting a positive feedback system to optimize cellular lipid efflux responses and disease prevention. Consequently, therapeutic approaches that mimic the activities of apos may prove highly effective to combat disease. One such approach involves the use of peptides. The broad biological relevance of ABCA1 suggests these apo mimetic peptides may be useful for the treatment of a number of diseases, such as atherosclerosis, diabetes, and Alzheimer's disease.« less

Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs.

PubMed

Löscher, Wolfgang

2017-07-01

The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.

Comparison of exosomes and ferritin protein nanocages for the delivery of membrane protein therapeutics.

PubMed

Cho, Eunji; Nam, Gi-Hoon; Hong, Yeonsun; Kim, Yoon Kyoung; Kim, Dong-Hwee; Yang, Yoosoo; Kim, In-San

2018-06-10

Exosomes are small membrane vesicles secreted by most cell types that play an important role in intercellular communication. Due to the characteristic of transferring their biomacromolecules, exosomes have potential as a new alternative for delivering protein therapeutics. Here, we investigate whether exosomes provide crucial advantages over other nanoparticles, in particular protein nanocage formulations, as a delivery system for membrane protein therapeutics. We characterized membrane-scaffold-based exosomes and protein-scaffold-based ferritin nanocages, both harboring SIRPα (signal regulatory protein α), an antagonist of CD47 on tumor cells. The efficacy of these two systems in delivering protein therapeutics was compared by testing their ability to enhance phagocytosis of tumor cells by bone-marrow-derived macrophages and subsequent inhibition of in vivo tumor growth. These analyses allowed us to comprehensively conclude that the therapeutic index of exosome-mediated CD47 blockade against tumor growth inhibition was higher than that of the same dose of ferritin-SIRPα. The results of this analysis reveal the importance of the unique characteristics of exosomes, in particular their membrane scaffold, in improving therapeutic protein delivery compared with protein-scaffold-based nanocages. Copyright © 2018 Elsevier B.V. All rights reserved.

Therapeutic Vaccination for HPV Induced Cervical Cancers

PubMed Central

Brinkman, Joeli A.; Hughes, Sarah H.; Stone, Pamela; Caffrey, Angela S.; Muderspach, Laila I.; Roman, Lynda D.; Weber, Jeffrey S.; Kast, W. Martin

2007-01-01

Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence. PMID:17627067

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.

Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

PubMed Central

Viola, Joana R.; Rafael, Diana F.; Wagner, Ernst; Besch, Robert; Ogris, Manfred

2013-01-01

Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed. PMID:23634303

Rabies in the critical care unit: diagnostic and therapeutic approaches.

PubMed

Jackson, Alan C

2011-09-01

Worldwide, human rabies is prevalent where there is endemic dog rabies, but the disease may present unexpectedly in critical care units when suggestive clinical features have passed. In North America transmission from bats is most common and there is often no history of a bat bite or even contact with bats. Laboratory diagnostic evaluation for rabies includes serology plus skin biopsy, cerebrospinal fluid, and saliva specimens for rabies virus antigen and/or RNA detection. Rare patients have survived rabies, and most received rabies vaccine prior to the onset of illness. Therapeutic coma (midazolam and phenobarbital), ketamine, and antiviral therapies (dubbed the "Milwaukee Protocol") were given to a rabies survivor, but this therapy was likely not directly responsible for the favorable outcome. There have been many subsequent failures of similar therapeutic approaches. There is no scientific rationale for the use of therapeutic coma in human rabies. New approaches to treating human rabies need to be developed.

New cancer diagnostics and therapeutics from a ninth 'hallmark of cancer': symmetric self-renewal by mutated distributed stem cells.

PubMed

Sherley, James L

2013-11-01

A total of eight cellular alterations associated with human carcinogenesis have been framed as the 'hallmarks of cancer'. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics.

Surface-functionalized nanoparticles for biosensing and imaging-guided therapeutics

NASA Astrophysics Data System (ADS)

Jiang, Shan; Win, Khin Yin; Liu, Shuhua; Teng, Choon Peng; Zheng, Yuangang; Han, Ming-Yong

2013-03-01

In this article, the very recent progress of various functional inorganic nanomaterials is reviewed including their unique properties, surface functionalization strategies, and applications in biosensing and imaging-guided therapeutics. The proper surface functionalization renders them with stability, biocompatibility and functionality in physiological environments, and further enables their targeted use in bioapplications after bioconjugation via selective and specific recognition. The surface-functionalized nanoprobes using the most actively studied nanoparticles (i.e., gold nanoparticles, quantum dots, upconversion nanoparticles, and magnetic nanoparticles) make them an excellent platform for a wide range of bioapplications. With more efforts in recent years, they have been widely developed as labeling probes to detect various biological species such as proteins, nucleic acids and ions, and extensively employed as imaging probes to guide therapeutics such as drug/gene delivery and photothermal/photodynamic therapy.

Management of pediatric uveitis

PubMed Central

Wentworth, Bailey A.; Freitas-Neto, Clovis A.

2014-01-01

Pediatric uveitis is a topic of special interest not only because of the unique diagnostic and therapeutic challenges but also because of the lifetime burden of vision loss if the problem is not adequately treated, as well as the economic and psychological toll on the family. Often, uveitis in children is discovered as part of a routine eye exam; this silent, insidious inflammation can be difficult to treat and can lead to further complications if not handled skillfully. Corticosteroids have long been the mainstay of therapy; however, the significant associated side effects mandate a corticosteroid-sparing therapeutic regimen in pursuit of remission. In this review, we cover the therapeutic options for pediatric uveitis, specifically focusing on the most common non-infectious varieties, juvenile idiopathic arthritis-associated uveitis and pars planitis. PMID:24991418

Unique differentiation profile of mouse embryonic stem cells in rotary and stirred tank bioreactors.

PubMed

Fridley, Krista M; Fernandez, Irina; Li, Mon-Tzu Alice; Kettlewell, Robert B; Roy, Krishnendu

2010-11-01

Embryonic stem (ES)-cell-derived lineage-specific stem cells, for example, hematopoietic stem cells, could provide a potentially unlimited source for transplantable cells, especially for cell-based therapies. However, reproducible methods must be developed to maximize and scale-up ES cell differentiation to produce clinically relevant numbers of therapeutic cells. Bioreactor-based dynamic culture conditions are amenable to large-scale cell production, but few studies have evaluated how various bioreactor types and culture parameters influence ES cell differentiation, especially hematopoiesis. Our results indicate that cell seeding density and bioreactor speed significantly affect embryoid body formation and subsequent generation of hematopoietic stem and progenitor cells in both stirred tank (spinner flask) and rotary microgravity (Synthecon™) type bioreactors. In general, high percentages of hematopoietic stem and progenitor cells were generated in both bioreactors, especially at high cell densities. In addition, Synthecon bioreactors produced more sca-1(+) progenitors and spinner flasks generated more c-Kit(+) progenitors, demonstrating their unique differentiation profiles. cDNA microarray analysis of genes involved in pluripotency, germ layer formation, and hematopoietic differentiation showed that on day 7 of differentiation, embryoid bodies from both bioreactors consisted of all three germ layers of embryonic development. However, unique gene expression profiles were observed in the two bioreactors; for example, expression of specific hematopoietic genes were significantly more upregulated in the Synthecon cultures than in spinner flasks. We conclude that bioreactor type and culture parameters can be used to control ES cell differentiation, enhance unique progenitor cell populations, and provide means for large-scale production of transplantable therapeutic cells.

New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

PubMed

Busquets-Garcia, Arnau; Maldonado, Rafael; Ozaita, Andrés

2014-08-01

Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hypotheses about the psychological benefits of horses.

PubMed

Kendall, Elizabeth; Maujean, Annick; Pepping, Christopher A; Wright, John J

2014-01-01

In the last few decades, therapeutic horse-riding has become recognized as a progressive form of therapy, particularly for people with disabilities. Although there is a substantial amount of literature that supports the physical benefit of therapeutic riding, only anecdotal evidence exists in relation to its psychological benefits. The purpose of this article is to develop hypotheses about the mechanisms by which therapeutic riding might have a beneficial psychological effect. These hypotheses can then be tested, leading to a more detailed knowledge base. PsychINFO, MEDLINE, PROQUEST, Scopus, Web of Science, and CINAHL. Data sources were searched for studies that (a) were related to the psychological effects of therapeutic horse-riding, (b) focused exclusively on therapeutic horse-riding, (c) described, explicitly or implicitly, the mechanism by which therapeutic riding had a beneficial psychological effect. Studies were limited to those published between 2008 and 2012. Data were extracted by two authors independently. Thirty articles met the inclusion criteria. Three potential hypotheses emerged from the literature, namely, (1) the psychological benefits of therapeutic riding are actually unrelated to the horse, (2) the horse provides a particularly positive context within which psychological gains are facilitated, and (3) the horse itself has specific therapeutic qualities that bring about unique changes not otherwise likely to occur. The challenge for researchers in this area is to design studies that adequately test these competing hypotheses. Copyright © 2014 Elsevier Inc. All rights reserved.

Recognition and Distance in Therapeutic Education: A Swedish Case Study on Ethical Qualities within Life Competence Education

ERIC Educational Resources Information Center

Irisdotter Aldenmyr, Sara

2013-01-01

Lately, in educational research and debate, there have been discussions on a trend sometimes named as a "therapeutic turn" in education. Mindfulness-oriented activities represent one therapeutic approach in education, aiming for virtues such as patience and trust. A large part of the critical viewpoints on therapeutic education among…

A Receptor-Grounded Approach to Teaching Nonsteroidal Antiinflammatory Drug Chemistry and Structure-Activity Relationships

PubMed Central

2009-01-01

Objective To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Design Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Assessment Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Conclusion Student performance on NSAID-focused quizzes and examinations documented the success of this approach. PMID:20221336

Magnetic nanoparticles based cancer therapy: current status and applications.

PubMed

Zhang, Huan; Liu, Xiao Li; Zhang, Yi Fan; Gao, Fei; Li, Ga Long; He, Yuan; Peng, Ming Li; Fan, Hai Ming

2018-04-01

Nanotechnology holds a promising potential for developing biomedical nanoplatforms in cancer therapy. The magnetic nanoparticles, which integrate uniquely appealing features of magnetic manipulation, nanoscale heat generator, localized magnetic field and enzyme-mimics, prompt the development and application of magnetic nanoparticles-based cancer medicine. Considerable success has been achieved in improving the magnetic resonance imaging (MRI) sensitivity, and the therapeutic function of the magnetic nanoparticles should be given adequate attention. This work reviews the current status and applications of magnetic nanoparticles based cancer therapy. The advantages of magnetic nanoparticles that may contribute to improved therapeutics efficacy of clinic cancer treatment are highlighted here.

The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries

PubMed Central

Sanchez, Gonzalo M.; Burridge, Alwyn L.

2010-01-01

Dating from the seventeenth century b.c. the Edwin Smith papyrus is a unique treatise containing the oldest known descriptions of signs and symptoms of injuries of the spinal column and spinal cord. Based on a recent “medically based translation” of the Smith papyrus, its enclosed treasures in diagnostic, prognostic and therapeutic reasoning are revisited. Although patient demographics, diagnostic techniques and therapeutic options considerably changed over time, the documented rationale on spinal injuries can still be regarded as the state-of-the-art reasoning for modern clinical practice. PMID:20697750

The Ocean as a Unique Therapeutic Environment: Developing a Surfing Program

ERIC Educational Resources Information Center

Clapham, Emily D.; Armitano, Cortney N.; Lamont, Linda S.; Audette, Jennifer G.

2014-01-01

Educational aquatic programming offers necessary physical activity opportunities to children with disabilities and the benefits of aquatic activities are more pronounced for children with disabilities than for their able-bodied peers. Similar benefits could potentially be derived from surfing in the ocean. This article describes an adapted surfing…

Treating People in Families: An Integrative Framework.

ERIC Educational Resources Information Center

Nichols, William C.

Directed at practitioners and students of family therapy, this book presents a treatment framework that is compatible with a wide variety of therapeutic techniques. Focusing on the development over time of the family life cycles--from marriages in formation to the "postparental couple"--this book explores the unique challenges and opportunities…

Cults and Satanism: Threats to Teens. A "Bulletin" Special.

ERIC Educational Resources Information Center

Rudin, Marcia R.

1990-01-01

Administrators, teachers, and counselors must learn to recognize the signs of cult or Satanic-influenced youngsters. The process and effects of mind-control are unique and cannot be understood in traditional psychiatric terms or treated by traditional therapeutic methods. Schools should hold preventive cult-education programs. The International…

Applying Person-Centered Counseling to Sexual Minority Adolescents

ERIC Educational Resources Information Center

Lemoire, S. Jim; Chen, Charles P.

2005-01-01

Drawing attention to the very unique and complex needs of stigmatized sexual minority youth, the authors explore the therapeutic potential of person-centered counseling in helping lesbian, gay, bisexual, transgender/sexual (LGBT) adolescents who are working toward the acceptance and disclosure of their sexual identity. They suggest that…

Theoretical Counseling Orientation: An Initial Aspect of Professional Orientation and Identity

ERIC Educational Resources Information Center

Jackson, James Lloyd, Jr.

2010-01-01

The literature on counselor development suggests that the development of a professional identity is a fundamental aspect of counselor training. The unique demands placed on counselors to integrate aspects of both personal and professional identity into the therapeutic process (Skovholt & Ronnestad, 1995) make development of a professional…

Endocarditis Caused by Rhodotorula Infection

PubMed Central

Simon, Matthew S.; Somersan, Selin; Singh, Harjot K.; Hartman, Barry; Wickes, Brian L.; Jenkins, Stephen G.; Walsh, Thomas J.

2014-01-01

Rhodotorula is an emerging opportunistic fungal pathogen that is rarely reported to cause endocarditis. We describe a case involving a patient who developed endocarditis due to Rhodotorula mucilaginosa and Staphylococcus epidermidis, proven by culture and histopathology. The case illustrates the unique diagnostic and therapeutic challenges relevant to Rhodotorula spp. PMID:24197888

Marathon Group Therapy: Potential for University Counseling Centers and Beyond

ERIC Educational Resources Information Center

Stanger, Thomas; Harris, Rafael S., Jr.

2005-01-01

A descriptive analysis of marathon group therapy was conducted, specifying issues of set-up, screening, preparation, start-up, introduction to group process, facilitating therapeutic moments throughout the weekend, termination, and follow-up. Factors and dynamics unique to this modality are outlined for marathon groups in university counseling…

78 FR 56720 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-13

...-valve replacement in high-risk patients. N Engl J Med. 2011 Jun 9;364(23):2187-98. [PMID 21639811... be activated upon demand to release the therapeutic agent at the desired site. The concurrent release... streamlined for high-throughput analysis. Quantitative molecular diagnostics. Unique microRNAs and/or mRNAs...

[siRNAs with high specificity to the target: a systematic design by CRM algorithm].

PubMed

Alsheddi, T; Vasin, L; Meduri, R; Randhawa, M; Glazko, G; Baranova, A

2008-01-01

'Off-target' silencing effect hinders the development of siRNA-based therapeutic and research applications. Common solution to this problem is an employment of the BLAST that may miss significant alignments or an exhaustive Smith-Waterman algorithm that is very time-consuming. We have developed a Comprehensive Redundancy Minimizer (CRM) approach for mapping all unique sequences ("targets") 9-to-15 nt in size within large sets of sequences (e.g. transcriptomes). CRM outputs a list of potential siRNA candidates for every transcript of the particular species. These candidates could be further analyzed by traditional "set-of-rules" types of siRNA designing tools. For human, 91% of transcripts are covered by candidate siRNAs with kernel targets of N = 15. We tested our approach on the collection of previously described experimentally assessed siRNAs and found that the correlation between efficacy and presence in CRM-approved set is significant (r = 0.215, p-value = 0.0001). An interactive database that contains a precompiled set of all human siRNA candidates with minimized redundancy is available at http://129.174.194.243. Application of the CRM-based filtering minimizes potential "off-target" silencing effects and could improve routine siRNA applications.

Cavopulmonary assist: (Em)powering the univentricular Fontan circulation

PubMed Central

Rodefeld, Mark D; Frankel, Steven H; Giridharan, Guruprasad A

2011-01-01

Since the Fontan/Kreutzer procedure was introduced, evolutionary clinical advances via a staged surgical reconstructive approach have markedly improved outcomes for patients with functional single ventricle. However, significant challenges remain. Early stage mortality risk seems impenetrable. Serious morbidities - construed as immutable consequences of palliation - have hardly been addressed. Late functional status is increasingly linked to pathophysiologic consequences of prior staged procedures. As more single ventricle patients survive into adulthood, Fontan failure is emerging as an intractable problem for which there is no targeted therapy. Incremental solutions to address these ongoing problems have not had a measurable impact. Therefore, a fundamental reconsideration of the overall approach is reasonable and warranted. The ability to provide a modest pressure boost (2-6 mmHg) to existing blood flow at the total cavopulmonary connection can effectively restore more stable biventricular status. This would impact not only treatment of late Fontan failure, but also facilitate early surgical repair. A realistic means to provide such a pressure boost has never been apparent. Recent advances are beginning to unravel the unique challenges which must be addressed to realize this goal, with promise to open single ventricle palliation to new therapeutic vistas. PMID:21444049

Accelerating Pediatric Cancer Drug Development: Challenges and Opportunities for Pediatric Master Protocols.

PubMed

Khan, Tahira; Stewart, Mark; Blackman, Samuel; Rousseau, Raphaël; Donoghue, Martha; Cohen, Kenneth; Seibel, Nita; Fleury, Mark; Benettaib, Bouchra; Malik, Raleigh; Vassal, Gilles; Reaman, Gregory

2018-01-01

Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer.

[The Relevance of MicroRNAs in Glioblastoma Stem Cells].

PubMed

Kleinová, R; Slabý, O; Šána, J

2015-01-01

Glioblastoma multiforme is the most common intracranial malignity of astrocyte origin in adults. Despite complex therapy consisting of maximal surgical resection, adjuvant concomitant chemoradiotherapy with temozolomide followed by temozolomide in monotherapy, the median of survival ranges between 12 and 15 months from dia-gnosis. This infaust prognosis is very often caused by both impossibility of achieving of sufficient radical surgical resection and tumor resistance to adjuvant therapy, which relates to the presence of glioblastoma stem cells. Similarly to normal stem cells, glioblastoma stem cells are capable of self -renewal, differentiation, and unlimited slow proliferation. Their resistance to conventional therapy is also due to higher expressions of DNA repair enzymes, antiapoptotic factors and multidrug transporters. Therefore, targeting these unique properties could be a novel promising therapeutic approach leading to more effective therapy and better prognosis of glioblastoma multiforme patients. One of the approaches how to successfully regulate above -mentioned properties is targeted regulation of microRNAs (miRNAs). These small noncoding RNA molecules posttranscriptionally regulate expression of more than 2/ 3 of all human genes that are also involved in stem cell associated signaling pathways. Moreover, deregulated expression of some miRNAs has been observed in many cancers, including glioblastoma multiforme.

Systems analysis of thrombus formation

PubMed Central

Diamond, Scott L.

2016-01-01

The systems analysis of thrombosis seeks to quantitatively predict blood function in a given vascular wall and hemodynamic context. Relevant to both venous and arterial thrombosis, a Blood Systems Biology approach should provide metrics for rate and molecular mechanisms of clot growth, thrombotic risk, pharmacological response, and utility of new therapeutic targets. As a rapidly created multicellular aggregate with a polymerized fibrin matrix, blood clots result from hundreds of unique reactions within and around platelets propagating in space and time under hemodynamic conditions. Coronary artery thrombosis is dominated by atherosclerotic plaque rupture, complex pulsatile flows through stenotic regions producing high wall shear stresses, and plaque-derived tissue factor driving thrombin production. In contrast, venous thrombosis is dominated by stasis or depressed flows, endothelial inflammation, white blood cell-derived tissue factor, and ample red blood cell incorporation. By imaging vessels, patient-specific assessment using computational fluid dynamics provides an estimate of local hemodynamics and fractional flow reserve. High dimensional ex vivo phenotyping of platelet and coagulation can now power multiscale computer simulations at the subcellular to cellular to whole vessel scale of heart attacks or strokes. Additionally, an integrated systems biology approach can rank safety and efficacy metrics of various pharmacological interventions or clinical trial designs. PMID:27126646

The language of risk: common understanding or diverse perspectives?

PubMed

Clancy, Leonie; Happell, Brenda; Moxham, Lorna

2014-07-01

Risk as a concept now takes high priority in contemporary mental health services, with increasing pressure on mental health services to develop risk assessment and management practices. This focus on risk has been criticised for its over-reliance on measurement and management at the expense of therapeutic care and is perpetuated by the language of risk which reinforces power differentials and limits capacity for consumers and carers to influence discussions and debates. Furthermore, to date, most work in this area reflects adult settings with limited consideration of the unique needs of older people and the impact of risk assessment on the care they receive. A qualitative, exploratory approach was undertaken using individual interviews and focus groups to enhance understanding of how risk is conceptualised within an older persons' setting. Managers, clinicians, consumers, and carers from a large metropolitan service participated (n = 57). The language of risk was a major theme emerging from this work. This language, so familiar to providers of services, was not familiar to consumers and carers. A reframing of risk is necessary to reflect consumers' and carers' experiences and understandings. This approach will be essential in promoting consumer and carer participation within recovery-based services, reflecting significant goals of government policy.

Systematic review of the information and communication technology features of web- and mobile-based psychoeducational interventions for depression.

PubMed

Zhao, Danyang; Lustria, Mia Liza A; Hendrickse, Joshua

2017-06-01

To examine the information and communication technology (ICT) features of psychoeducational interventions for depression delivered via the Internet or via mobile technology. Web- and mobile-based psychoeducational intervention studies published from 2004 to 2014 were selected and reviewed by two independent coders. A total of 55 unique studies satisfied the selection criteria. The review revealed a diverse range of ICTs used to support the psychoeducational programs. Most interventions used websites as their main mode of delivery and reported greater use of communication tools compared to effective approaches like tailoring or interactive technologies games, videos, and self-monitoring tools. Many of the studies relied on medium levels of clinician involvement and only a few were entirely self-guided. Programs that reported higher levels of clinician involvement also reported using more communication tools, and reported greater compliance to treatment. Future experimental studies may help unpack the effects of technology features and reveal new ways to automate aspects of clinician input. There is a need to further examine ways ICTs can be optimized to reduce the burden on clinicians whilst enhancing the delivery of proven effective therapeutic approaches. Copyright © 2017 Elsevier B.V. All rights reserved.

Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development.

PubMed

Wang, Xiaowei; Searle, Amy Kate; Hohmann, Jan David; Liu, Ao Leo; Abraham, Meike-Kristin; Palasubramaniam, Jathushan; Lim, Bock; Yao, Yu; Wallert, Maria; Yu, Eefang; Chen, Yung-Chih; Peter, Karlheinz

2018-04-04

Abdominal aortic aneurysm (AAA) is an often deadly disease without medical, non-invasive treatment options. The upregulation of vascular cell adhesion molecule-1 (VCAM-1) on aortic endothelium provides an early target epitope for a novel biotechnological theranostic approach. MicroRNA-126 was used as a therapeutic agent, based on its capability to downregulate VCAM-1 expression in endothelial cells and thereby reduces leukocyte adhesion and exerts anti-inflammatory effects. Ultrasound microbubbles were chosen as carriers, allowing both molecular imaging as well as targeted therapy of AAA. Microbubbles were coupled with a VCAM-1-targeted single-chain antibody (scFv mVCAM-1 ) and a microRNA-126 mimic (M 126 ) constituting theranostic microbubbles (Targ MB -M 126 ). Targ MB -M 126 downregulates VCAM-1 expression in vitro and in an in vivo acute inflammatory murine model. Most importantly, using Targ MB -M 126 and ultrasound-guided burst delivery of M 126 , the development of AAA in an angiotensin-II-induced mouse model can be prevented. Overall, we describe a unique biotechnological theranostic approach with the potential for early diagnosis and long-sought-after medical therapy of AAA. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy.

PubMed

Cohen, Itay; Kayode, Olumide; Hockla, Alexandra; Sankaran, Banumathi; Radisky, Derek C; Radisky, Evette S; Papo, Niv

2016-05-15

Engineered protein therapeutics offer advantages, including strong target affinity, selectivity and low toxicity, but like natural proteins can be susceptible to proteolytic degradation, thereby limiting their effectiveness. A compelling therapeutic target is mesotrypsin, a protease up-regulated with tumour progression, associated with poor prognosis, and implicated in tumour growth and progression of many cancers. However, with its unique capability for cleavage and inactivation of proteinaceous inhibitors, mesotrypsin presents a formidable challenge to the development of biological inhibitors. We used a powerful yeast display platform for directed evolution, employing a novel multi-modal library screening strategy, to engineer the human amyloid precursor protein Kunitz protease inhibitor domain (APPI) simultaneously for increased proteolytic stability, stronger binding affinity and improved selectivity for mesotrypsin inhibition. We identified a triple mutant APPIM17G/I18F/F34V, with a mesotrypsin inhibition constant (Ki) of 89 pM, as the strongest mesotrypsin inhibitor yet reported; this variant displays 1459-fold improved affinity, up to 350 000-fold greater specificity and 83-fold improved proteolytic stability compared with wild-type APPI. We demonstrated that APPIM17G/I18F/F34V acts as a functional inhibitor in cell-based models of mesotrypsin-dependent prostate cancer cellular invasiveness. Additionally, by solving the crystal structure of the APPIM17G/I18F/F34V-mesotrypsin complex, we obtained new insights into the structural and mechanistic basis for improved binding and proteolytic resistance. Our study identifies a promising mesotrypsin inhibitor as a starting point for development of anticancer protein therapeutics and establishes proof-of-principle for a novel library screening approach that will be widely applicable for simultaneously evolving proteolytic stability in tandem with desired functionality for diverse protein scaffolds. © 2016 Authors; published by Portland Press Limited.

Core-shell iron oxide-layered double hydroxide: High electrochemical sensing performance of H2O2 biomarker in live cancer cells with plasma therapeutics.

PubMed

Asif, Muhammad; Liu, Hongwei; Aziz, Ayesha; Wang, Haitao; Wang, Zhengyun; Ajmal, Muhammad; Xiao, Fei; Liu, Hongfang

2017-11-15

In this work, we develop a new type of multifunctional core-shell nanomaterial by controllable integration of CuAl layered double hydroxides (LDHs) over the surface of iron oxides (Fe 3 O 4 ) nanospheres (NSs) to fabricate (Fe 3 O 4 @CuAl NSs) hybrid material with interior tunability of LDH phase and explore its practical application in ultrasensitive detection of emerging biomarker, i.e., H 2 O 2 as cancer diagnostic probe. In addition, atmospheric pressure plasmas (APPs) have also been used as potential therapeutic approach for cancer treatment. Due to the synergistic combination of p-type semiconductive channels of LDHs with multi-functional properties, unique morphology and abundant surface active sites, the Fe 3 O 4 @CuAl NSs modified electrode exhibited attractive electrocatalytic activity towards H 2 O 2 reduction. Under the optimized conditions, the proposed biosensor demonstrated striking electrochemical sensing performances to H 2 O 2 including linear range as broad as 8 orders of magnitude, low real detection limit of 1nM (S/N = 3), high sensitivity, good reproducibility and long-term stability. Arising from the superb efficiency, the electrochemical biosensor has been used for in vitro determination of H 2 O 2 concentrations in human urine and serum samples prior to and following the intake of coffee, and real-time monitoring of H 2 O 2 efflux from different cancer cell lines in normal state and after plasma treatment. We believe that this novel nano-platform of structurally integrated core-shell nanohybrid materials combined with APPs will enhance diagnostic as well as therapeutic window for cancer diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia.

PubMed

Guo, Jianfeng; Cahill, Mary R; McKenna, Sharon L; O'Driscoll, Caitriona M

2014-12-01

Leukaemia is a bone marrow cancer occurring in acute and chronic subtypes. Acute leukaemia is a rapidly fatal cancer potentially causing death within a few weeks, if untreated. Leukaemia arises as a result of disruption to haematopoietic precursors, caused either by acquired gene fusions, gene mutations or inappropriate expression of the relevant oncogenes. Current treatment options have made significant progress, but the 5 year survival for acute leukaemia remains under 10% in elderly patients, and less than 50% for some types of acute leukaemia in younger adults. For chronic leukaemias longer survival is generally expected and for chronic myeloid leukaemia patients on tyrosine kinase inhibitors the median survival is not yet reached and is expected to exceed 10 years. Chemotherapy and haematopoietic stem cell transplantation (HSCT) for acute leukaemia provide the mainstay of therapy for patients under 65 and both carry significant morbidity and mortality. Alternative and superior therapeutic strategies for acute leukaemias are urgently required. Recent molecular-based knowledge of recurring chromosome rearrangements, in particular translocations and inversions, has resulted in significant advances in understanding the molecular pathogenesis of leukaemia. Identification of a number of unique fusion genes has facilitated the development of highly specific small interfering RNAs (siRNA). Although delivery of siRNA using multifunctional nanoparticles has been investigated to treat solid cancers, the application of this approach to blood cancers is at an early stage. This review describes current treatments for leukaemia and highlights the potential of leukaemic fusion genes as therapeutic targets for RNA interference (RNAi). In addition, the design of biomimetic nanoparticles which are capable of responding to the physiological environment of leukaemia and their potential to advance RNAi therapeutics to the clinic will be critically evaluated. Copyright © 2014 Elsevier Inc. All rights reserved.

Getting TRAIL back on track for cancer therapy

PubMed Central

Lemke, J; von Karstedt, S; Zinngrebe, J; Walczak, H

2014-01-01

Unlike other members of the TNF superfamily, the TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) possesses the unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. This exciting discovery provided the basis for the development of TRAIL-receptor agonists (TRAs), which have demonstrated robust anticancer activity in a number of preclinical studies. Subsequently initiated clinical trials testing TRAs demonstrated, on the one hand, broad tolerability but revealed, on the other, that therapeutic benefit was rather limited. Several factors that are likely to account for TRAs' sobering clinical performance have since been identified. First, because of initial concerns over potential hepatotoxicity, TRAs with relatively weak agonistic activity were selected to enter clinical trials. Second, although TRAIL can induce apoptosis in several cancer cell lines, it has now emerged that many others, and importantly, most primary cancer cells are resistant to TRAIL monotherapy. Third, so far patients enrolled in TRA-employing clinical trials were not selected for likelihood of benefitting from a TRA-comprising therapy on the basis of a valid(ated) biomarker. This review summarizes and discusses the results achieved so far in TRA-employing clinical trials in the light of these three shortcomings. By integrating recent insight on apoptotic and non-apoptotic TRAIL signaling in cancer cells, we propose approaches to introduce novel, revised TRAIL-based therapeutic concepts into the cancer clinic. These include (i) the use of recently developed highly active TRAs, (ii) the addition of efficient, but cancer-cell-selective TRAIL-sensitizing agents to overcome TRAIL resistance and (iii) employing proteomic profiling to uncover resistance mechanisms. We envisage that this shall enable the design of effective TRA-comprising therapeutic concepts for individual cancer patients in the future. PMID:24948009

EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases

PubMed Central

Urnauer, Sarah; Müller, Andrea M.; Schug, Christina; Schmohl, Kathrin A.; Tutter, Mariella; Schwenk, Nathalie; Rödl, Wolfgang; Morys, Stephan; Ingrisch, Michael; Bertram, Jens; Bartenstein, Peter; Clevert, Dirk-André; Wagner, Ernst; Spitzweg, Christine

2017-01-01

Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases. The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of 131I. For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)-specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using 18F-tetrafluoroborate (18F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18F-TFB application showed high tumoral levels (4.8±0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq 131I resulted in marked delay in metastases spread, which was associated with improved animal survival. In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease. PMID:29190908

Oral Delivery of Nanoparticles Loaded With Ginger Active Compound, 6-Shogaol, Attenuates Ulcerative Colitis and Promotes Wound Healing in a Murine Model of Ulcerative Colitis.

PubMed

Zhang, Mingzhen; Xu, Changlong; Liu, Dandan; Han, Moon Kwon; Wang, Lixin; Merlin, Didier

2018-01-24

Oral drug delivery is the most attractive pathway for ulcerative colitis [UC] therapy, since it has many advantages. However, this strategy has encountered many challenges, including the instability of drugs in the gastrointestinal tract [GT], low targeting of disease tissues, and severe adverse effects. Nanoparticles capable of colitis tissue-targeted delivery and site-specific drug release may offer a unique and therapeutically effective system that addresses these formidable challenges. We used a versatile single-step surface-functionalising technique to prepare PLGA/PLA-PEG-FA nanoparticles loaded with the ginger active compound, 6-shogaol [NPs-PEG-FA/6-shogaol]. The therapeutic efficacy of NPs-PEG-FA/6-shogaol was evaluated in the well-established mouse model of dextran sulphate sodium [DSS]-induced colitis. NPs-PEG-FA exhibited very good biocompatibility both in vitro and in vivo. Subsequent cellular uptake experiments demonstrated that NPs-PEG-FA could undergo efficient receptor-mediated uptake by colon-26 cells and activated Raw 264.7 macrophage cells. In vivo, oral administration of NPs-PEG-FA/6-shogaol encapsulated in a hydrogel system [chitosan/alginate] significantly alleviated colitis symptoms and accelerated colitis wound repair in DSS-treated mice by regulating the expression levels of pro-inflammatory [TNF-α, IL-6, IL-1β, and iNOS] and anti-inflammatory [Nrf-2 and HO-1] factors. Our study demonstrates a convenient, orally administered 6-shogaol drug delivery system that effectively targets colitis tissue, alleviates colitis symptoms, and accelerates colitis wound repair. This system may represent a promising therapeutic approach for treating inflammatory bowel disease [IBD]. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

IMGN779, a Novel CD33-Targeting Antibody-Drug Conjugate with DNA-Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML.

PubMed

Kovtun, Yelena; Noordhuis, Paul; Whiteman, Kathleen R; Watkins, Krystal; Jones, Gregory E; Harvey, Lauren; Lai, Katharine C; Portwood, Scott; Adams, Sharlene; Sloss, Callum M; Schuurhuis, Gerrit Jan; Ossenkoppele, Gert; Wang, Eunice S; Pinkas, Jan

2018-06-01

The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo , IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML. Mol Cancer Ther; 17(6); 1271-9. ©2018 AACR . ©2018 American Association for Cancer Research.

Mesenchymal stem cell and regenerative medicine: regeneration versus immunomodulatory challenges

PubMed Central

Law, Sujata; Chaudhuri, Samaresh

2013-01-01

Mesenchymal Stem cells (MSC) are now presented with the opportunities of multifunctional therapeutic approaches. Several reports are in support of their self-renewal, capacity for multipotent differentiation, and immunomodulatory properties. They are unique to contribute to the regeneration of mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. In addition to promising trials in regenerative medicine, such as in the treatment of major bone defects and myocardial infarction, MSC has shown a therapeutic effect other than direct hematopoiesis support in hematopoietic reconstruction. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73(SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. Manufacturing of MSC for clinical trials is also an important aspect as their differentiation, homing and Immunomodulatory properties may differ. Their suppressive effects on immune cells, including T cells, B cells, NK cells and DC cells, suggest MSCs as a novel therapy for GVHD and other autoimmune disorders. Since the cells by themselves are non-immunogenic, tissue matching between MSC donor and recipient is not essential and, MSC may be the first cell type able to be used as an “off-the-shelf” therapeutic product. Following a successful transplantation, the migration of MSC to the site of injury refers to the involvement of chemokines and chemokine receptors of respective specificity. It has been demonstrated that cultured MSCs have the ability to engraft into healthy as well as injured tissue and can differentiate into several cell types in vivo, which facilitates MSC to be an ideal tool for regenerative therapy in different disease types. However, some observations have raised questions about the limitations for proper use of MSC considering some critical factors that warn regular clinical use. PMID:23671814

Therapeutic Recreation in the Community: An Inclusive Approach. Second Edition

ERIC Educational Resources Information Center

Carter, Marcia Jean; LeConey, Stephen P.

2004-01-01

The second edition of Therapeutic Recreation in the Community: An Inclusive Approach reflects the changing and evolving nature of recreation and health care services. A number of social, economic, and political directives and technological advancements have fostered recreation in the community for all individuals. Due in part to a rising awareness…

Current Therapeutic Approach to Hypertrophic Scars

PubMed Central

Mokos, Zrinka Bukvić; Jović, Anamaria; Grgurević, Lovorka; Dumić-Čule, Ivo; Kostović, Krešimir; Čeović, Romana; Marinović, Branka

2017-01-01

Abnormal scarring and its accompanying esthetic, functional, and psychological sequelae still pose significant challe nges. To date, there is no satisfactory prevention or treatment option for hypertrophic scars (HSs), which is mostly due to not completely comprehending the mechanisms underlying their formation. That is why the apprehension of regular and controlled physiological processes of scar formation is of utmost importance when facing hypertrophic scarring, its pathophysiology, prevention, and therapeutic approach. When treating HSs and choosing the best treatment and prevention modality, physicians can choose from a plethora of therapeutic options and many commercially available products, among which currently there is no efficient option that can successfully overcome impaired skin healing. This article reviews current therapeutic approach and emerging therapeutic strategies for the management of HSs, which should be individualized, based on an evaluation of the scar itself, patients’ expectations, and practical, evidence-based guidelines. Clinicians are encouraged to combine various prevention and treatment modalities where combination therapy that includes steroid injections, 5-fluorouracil, and pulsed-dye laser seems to be the most effective. On the other hand, the current therapeutic options are usually empirical and their results are unreliable and unpredictable. Therefore, there is an unmet need for an effective, targeted therapy and prevention, which would be based on an action or a modulation of a particular factor with clarified mechanism of action that has a beneficial effect on wound healing. As the extracellular matrix has a crucial role in cellular and extracellular events that lead to pathological scarring, targeting its components mostly by regulating bone morphogenetic proteins may throw up new therapeutic approach for reduction or prevention of HSs with functionally and cosmetically acceptable outcome. PMID:28676850

“All of Those Things We Don't Eat”: A Culture-Centered Approach to Dietary Health Meanings for Asian Indians Living in the United States

PubMed Central

Koenig, Christopher J.; Dutta, Mohan J.; Kandula, Namratha; Palaniappan, Latha

2015-01-01

This article applies a culture-centered approach to analyze the dietary health meanings for Asian Indians living in the United States. The data were collected as part of a health promotion program evaluation designed to help Asian Indians reduce their risk of chronic disease. Community members who used two aspects of the program participated in two focus groups to learn about their health care experiences and to engage them in dialogue about how culture impacts their overall health. Using constructionist grounded theory, we demonstrate that one aspect of culture, the discourses around routine dietary choice, is an important, but under-recognized, aspect of culture that influences community members’ experiences with health care. We theorize community members’ dietary health meanings operate discursively through a dialectic tension between homogeneity and heterogeneity, situated amid culture, structure, and agency. Participants enacted discursive homogeneity when they affirmed dietary health meanings around diet as an important means through which members of the community maintain a sense of continuity of their identity while differentiating them from others. Participants enacted discursive heterogeneity when they voiced dietary health meanings that differentiated community members from one another due to unique life-course trajectories and other membership affiliations. Through this dialectic, community members manage unique Asian Indian identities and create meanings of health and illness in and through their discourses around routine dietary choice. Through making these discursive health meanings audible, we foreground how community members’ agency is discursively enacted and to make understandable how discourses of dietary practice influence the therapeutic alliance between primary care providers and members of a minority community. PMID:22364189