Therapeutic Hope Research Articles

Developing Drugs for Leukemias

At present, available therapies are only partially effective in patients with leukemia and the vast majority of patients cannot be cured with current treatment strategies. Hence, there is an obvious need to develop more specific and effective drugs for the treatment of these diseases. In the last twenty years, significant progress in molecular and cellular biology has resulted in a better characterization and understanding of the molecular abnormalities in acute and chronic leukemia. These achievements have provided new opportunities for the development of innovative drugs, and leukemia mortality rates have begun to decline. Molecular-targeted drugs were first introduced for the treatment of hematological malignancies. Imatinib was the first small moleculetargeted drug successfully used for the treatment of chronic myeloid leukemia (CML), and rituximab was the first tumor-specific antibody to be introduced for the treatment of CD20-positive lymphomas and chronic lymphocytic leukemia (CLL). The introduction of imatinib and rituximab has changed the mortality rates associated with CML and B-cell lymphoid malignancies. In CML the availability of tyrosine kinase inhibitors (TKIs) changed the management and prognosis of this disease [1]. However, about 20% of CML patients do not achieve optimal response on imatinib treatment and they need alternative drugs. The availability of second generation TKIs, such as dasatinib and nilotinib, has provided new therapeutic hope for patients with imatinib resistance [2]. In addition, new molecules with different modes of action have demonstrated activity in patients with highly-resistant mutants such as MK0457 and danusertib, which exhibit inhibitory activity against Aurora kinases [3]. Current therapies are frequently inappropriate and unsuccessful for acute myeloid leukemia (AML), especially for older patients. For these patients, there is an obvious need to develop better strategies and new, more specific and active drugs. The search for new drugs in AML has led to the development of many new antileukemic agents potentially active in this form of leukemia [4]. Novel agents potentially useful in the treatment of patients with AML include monoclonal antibodies, molecular target drugs, newer nucleoside analogs and other drugs. These new agents seem unlikely to be curative when administered as monotherapy. They will rather have to be used in combination with other new agents or with more standard therapy. Nucleoside analogs are clinically important antileukemic drugs which compete with physiologic nucleosides and consequently, interact with a large number of intracellular targets. Recently, three novel nucleoside analogs, clofarabine, troxacitabine and sapacitabine, have been introduced into clinical trials in AML and shown promise. However, phase II and III randomized trials are necessary to verify whether these drugs confer an advantage in the treatment of this disease.

Human Spermatagonial Stem Cells: A Novel Therapeutic Hope for Cardiac Regeneration and repair?

Although the identification and characterization of human spermatogonial stem cells was reported nearly 50 years ago, great progress has been made only in the last few years. Spermatogonial stem cells attract a great deal of researchers' attention because of their unique characteristics, including the ability to be converted spontaneously into pluripotent germline stem cells with embryonic stem cell-like properties. Pluripotent stem cells are able to differentiate into any desired cell type in the body; therefore, they are the most promising cell source for organ regeneration. The advantages of pluripotent germline stem cells over other stem cells are that they maintain a high degree of DNA integrity and can resolve some ethical and immunological problems related to human embryonic stem cells. In this article we address the origin, characteristics and pluripotency of spermatogonial stem cells. Their contribution to stem cell-based organ regeneration therapy with special emphasis on cardiac regeneration and repair in the future is also discussed.

REVIEW: Robert A. Aronowitz. Unnatural History: Breast Cancer and American Society.

“Breast cancer is all around us.” This is how Robert Aronowitz, a medical doctor, opens his timely Unnatural History: Breast Cancer and American Society. We are all familiar with the truism that “one in eight American women” will develop invasive breast cancer over the course of her lifetime. The pink ribbon has come to symbolize both solidarity and hope. Mammograms and “Self-Breast Examination” have become part of women’s daily routine, if not a spectre haunting their daily lives. Yet the evidence remains contested and the therapeutic promise, the fear and hope associated with this “obstinate” disease as problematic as ever. Unnatural History weaves all these different elements, artifactual and natural, emotional and rational, vital and morbid, in the socio-historical narrative of breast cancer in the American context. In that sense, this is an “unnatural” history, a history of how “fear” and “risk” have been reshaping a disease, which continues to be as elusive as it was two centuries ago.

Reproductive component vaccine developments for contraceptive and non-contraceptive uses

Introduction: There has been no novel contraceptive development since ‘the Pill’, 50 years ago. Despite the subsequent steady increase in the use of contraceptives, the contraceptive needs of a significant proportion of the world population have not yet been met. The key need is for novel, effective, practical, long-lasting, affordable, non-steroidal contraceptives. Immunocontraception, based on vaccination against components of the reproductive system that do not affect other physiological systems, fulfils most of the criteria of such a contraceptive. To date, immunocontraceptives have been developed for animal use and the application to human contraception is an exciting proposition. In addition, immunocontraceptive research has provided a greater understanding of the vaccination against ‘self-antigens’ and has led to non-contraceptive developments for these vaccines.Areas covered: This review provides an understanding of the historic context of immunocontraceptives and the progress that has been made. In some cases, the contraceptive aspect has been abandoned, but the knowledge gained has enabled other therapeutic advances.Expert opinion: Reproductive research is still an important area and innovations continue to arise, which offer hope for new therapeutics in reproduction and related fields.

The allenic carotenoid fucoxanthin, a novel marine nutraceutical from brown seaweeds.

Obesity and type 2 diabetes are pathologies with rapidly growing prevalence throughout the world. A few molecular targets offer the most hope for anti-obesity and anti-diabetic therapeutics. One of the keys to success will be the induction of uncoupling protein 1 (UCP1) in abdominal white adipose tissue (WAT) and the regulation of cytokine secretions from both abdominal adipose cells and macrophage cells infiltrated into adipose tissue. Anti-obesity and anti-diabetic effects of fucoxanthin, a characteristic carotenoid found in brown seaweeds, have been reported. Nutrigenomic studies reveal that fucoxanthin induces UCP1 in abdominal WAT mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose levels through the regulation of cytokine secretions from WAT. The key structure of carotenoids for the expression of anti-obesity effect is suggested to be the carotenoid end of the polyene chromophore, which contains an allenic bond and two hydroxyl groups.

Ontological Structure and Complexity of Therapeutic Hope: A Multidimensional Perspective

Despite the daunting challenge to hope and hoping currently confronting millions of traumatized populations throughout the world, the psychology literature has largely been silent on the proper meaning of therapeutic hope, and how hope can be resuscitated in people demoralized by extreme hardships or unpredictable life events. This anomaly perhaps arises from the fact that in spite of several and honest acknowledgements found in Western scholarship, about the relevance of hope-healing in the human conditions of captivity or tragedy, a gap still exists as regards the multidimensional conceptualization of the ontology and epistemology of hope that should enable psychologists to have a firm grip not only on the multidimensional constituents of hope and hoping but also on how it lives and dies, how it heals and how we can enhance its positive component in people (individuals or groups) beleaguered by its over-determination by the negative component of hopelessness and other devastating conditions of existence. Through a selective review of the scattered literature on hope and hoping, some of them drawn from outside of the mainline psychology field, this paper draws attention to the ontological complexity of the hope construct and to the factors and forces that combine to promote its activation, healing value and endurance. The overall aim is to move towards a more informed multidimensional re-visioning of the construct. Copyright © 2011 John Wiley & Sons, Ltd.

Cytoskeletal alterations in Alzheimer’s disease: the “skeleton” of therapeutic hope?

Damage to and functional alteration of structures responsible for synaptic plasticity correlate with memory loss and cognitive decline in Alzheimer's disease. The results of recent research in the pathomechanism of Alzheimer's disease emphasize the significance of cytoskeletal changes. The changes in actin dynamics and its regulation by actin-binding proteins have been proven in Alzheimer's disease, which may have a key role in the conformation and alteration of synapses and dendritic spines. The most important proteins in the regulation of actin dynamics are ADF/cofilin, kinases and drebrin. In this review, we summarize the physiological functions and complex regulation of these cytoskeletal proteins and their alterations in Alzheimer's disease. Additionally, the effects of some psychopharmacons on the actin cytoskeleton and cytoskeletal changes induced by stress are also summarized.

Extrinsic apoptotic pathways: A new potential "Target" for more sufficient therapy in a case of cutaneous anaplastic large CD30+ ALK-T--cell lymphoma

The primary cutaneous T-cell lymphomas (CTCL) represent a clonal T-lymphocyte proliferation infiltrating the skin. CD30+T-cell lymphomas present clinically as nodules with a diameter between 1 and 15 cm, mostly in elderly patients. The role of the CD30 molecule in patients suffering from T-cell lymphomas is not completely clear yet. The signal transduction pathway which includes CD30 seems to play a key role in tumor progression. In certain forms of T-cellular lymphomas, the interaction between CD30/CD30-ligand is able to provoke apoptosis of the “tumor lymphocytes”. The modern conceptions of the pathogenesis of T-cell lymphomas include disorders in the pathways involved in programmed cellular death and disregulation in the expression of certain of its regulatory molecules. We are presenting an unusual case of a female patient with a primary cutaneous form of CD30+/ALK− anaplastic large T-cell lymphoma. Upon the introduction of systemic PUVA, (psoralen plus ultraviolet light radiation) combined with beam therapy, a complete remission could be noticed. Eight months later, we observed a local recurrence, which was overcome by CHOP chemotherapy (Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Vincristin (Oncovin®), Predniso(lo)n). Six months later, new cutaneous lesions had been noticed again. A new therapeutic hope for the patients with anaplastic large CTCL is actually based on the influence of the activity of the different apoptotic pathways. Death ligands, including tumor necrosis factor (TNF)-α, CD95L/FasL, and TRAIL, mediate also some important safeguard mechanisms against tumor growth in patients with CD30+ cutaneous anaplastic large T-cell lymphomas and critically contribute to lymphocyte homeostasis.

Tweaking Dopamine Reception

Discovery of a binding site in the extracellular domain of a dopamine receptor offers hope for more selective therapeutics.

Molecular pathogenesis of spinocerebellar ataxia type 1 disease.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by ataxia and progressive motor deterioration. SCA1 is associated with an elongated polyglutamine tract in ataxin-1, the SCA1 gene product. As summarized in this review, recent studies have clarified the molecular mechanisms of SCA1 pathogenesis and provided direction for future therapeutic approaches. The nucleus is the subcellular site where misfolded mutant ataxin-1 acts to cause SCA1 disease in the cerebellum. The role of these nuclear aggregates is the subject of intensive study. Additional proteins have been identified, whose conformational alterations occurring through interactions with the polyglutamine tract itself or non-polyglutamine regions in ataxin-1 are the cause of SCA-1 cytotoxicity. Therapeutic hope comes from the observations concerning the reduction of nuclear aggregation and alleviation of the pathogenic phenotype by the application of potent inhibitors and RNA interference.

Chelated iron as an anti-Pseudomonas aeruginosabiofilm therapeutic strategy

Sir,The article by Musk and Hergenrother demonstratingthe effectiveness of iron-saturated iron-chelators directedagainst Pseudomonas aeruginosa biofilms is intriguing andoffers therapeutic hope to individuals with cystic fibrosis(CF) whose lives are foreshortened by infection with thisiron-requiring bacterium (Musk and Hergenrother 2008).However, as the authors highlight, there is a lack ofappropriate animal models in which to test their findingsbefore potential human studies can be considered. Anadditional factor is that while the data of Musk and Her-genrother clearly show that high iron concentrations(>50 lmol l

Targeting ERBB Receptors to Inhibit Metastasis: Old Hopes and New Certainties

The very early intuition of Paget about the molecular feature of metastasis has come in the field of therapeutic opportunities only in the last few years with the development of targeted therapy. However, to date the diagnosis of metastases is associated in the majority of cases with the loss of any therapeutic hope. According to present knowledge, metastatic spreading is considered as part of a long process in which tumor cells gain new properties in their cellular function, including invasion and adaptive survival. This gain of function is based on the expression of new molecular markers that may be potential therapeutic targets in blocking tumor dissemination. The epidermal growth factor receptor family comprises four members (ERBB) that are frequently upregulated in advanced tumor stages and have been associated with the metastatic potential of several tumors. ERBB receptor inhibitors are very effective against specific primary tumors and their use is frequently accompanied by toxicity problems, drug resistance and molecular desensitization. However, new studies indicate that ERBB inhibitors may provide a much-needed therapeutic option mainly for patients with metastases. In order to illustrate the potential of ERBB family members as therapeutic targets in blocking metastases we summarize the new molecular evidence and the observations from clinical trials.

Immunogenicity and Allogenicity: A Challenge of Stem Cell Therapy

As age progresses, the regenerative power of one's own pluripotent stem cells is often inadequate to sustain normal tissue function. Consequently, the incidence of chronic and degenerative diseases has significantly increased. The derivation of adult tissues and organs from a variety of stem cell sources represents the starting mark for regenerative medicine. It is currently considered a developing mean to repair, restore, maintain, or enhance organ functioning through life span. Recent advances in human embryonic stem cells (hESC) research, however, made the prospect of cell replacement therapy even more compelling and highlighted hESC as a fast track in the therapeutic hope. Among the hurdles which have been largely overlooked in the excitement over the expected benefit is the immunogenicity. Indeed, beyond the clear need to establish the safety of hESC and their derived tissues in terms of tumorogenicity and potential to transmit infections, the challenge is to overcome the immunological barriers to their transplantation.

Quelles nouveautés sur l’endométriose ?

Endometriosis concerns 6 to 10 % of the female population, and is responsible for severe pelvic pain and infertility. This estrogen dependant disease, is characterized by the presence of endometrial tissue outside of the uterus cavity. Although his physiopathology remains poorly understood, recent data have focused on angiogenesis, which could represent a key factor for the growing of lesions of endometriosis. New antiangiogenesis treatments represent a therapeutic hope, and have been tested in vitro or in vivo in mice. Those drugs have proven their efficacy on endometriotic lesions. Secondly, several hypothesis are discussed to explain infertility in endometriosis. In particular, a direct impact of peritoneal fluid from women with endometriosis on sperm DNA could be involved.

Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disorder, characterized by progressive cerebral demyelination cerebral childhood adrenoleukodystrophy (CCALD) or spinal cord neurodegeneration (adrenomyeloneuropathy, AMN), adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFA) in tissues. The disease is caused by mutations in the ABCD1 gene, which encodes a peroxisomal transporter that plays a role in the import of VLCFA or VLCFA-CoA into peroxisomes. The Abcd1 knockout mice develop a spinal cord disease that mimics AMN in adult patients, with late onset at 20 months of age. The mechanisms underlying cerebral demyelination or axonal degeneration in spinal cord are unknown. Here, we present evidence by gas chromatography/mass spectrometry that malonaldehyde-lysine, a consequence of lipoxidative damage to proteins, accumulates in the spinal cord of Abcd1 knockout mice as early as 3.5 months of age. At 12 months, Abcd1- mice accumulate additional proteins modified by oxidative damage arising from metal-catalyzed oxidation and glycoxidation/lipoxidation. While we show that VLCFA excess activates enzymatic antioxidant defenses at the protein expression levels, both in neural tissue, in ex vivo organotypic spinal cord slices from Abcd1- mice, and in human ALD fibroblasts, we also demonstrate that the loss of Abcd1 gene function hampers oxidative stress homeostasis. We find that the alpha-tocopherol analog Trolox is able to reverse oxidative lesions in vitro, thus providing therapeutic hope. These results pave the way for the identification of therapeutic targets that could reverse the deregulated response to oxidative stress in X-ALD.

海外論文紹介 : Rituximab and nephrotic syndrome: a new therapeutic hope?

海外論文紹介 : Rituximab and nephrotic syndrome: a new therapeutic hope?

The PPAR‐γ Agonist 15‐Deoxy‐Δ12,14‐Prostaglandin J2 Attenuates Microglial Production of IL‐12 Family Cytokines: Potential Relevance to Alzheimer′s Disease

Accumulation of amyloid-β peptide (Aβ) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Aβ deposits has been placed in strategies involving immunization against the Aβ peptide. Initial Aβ immunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Aβ. Specifically, CD4+ Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβ immunization in the treatment of AD. Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Aβ 1−42 synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-γ agonist 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2 suppressed the Aβ-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-γ agonists may be effective in modulating the development of AD.

Clients' Perceptions of the Therapeutic Process

Recently researchers in the family therapy field have encouraged a focus on aspects of therapy common across all models that are important to therapeutic change. The purpose of this study was to build on the “common factors” literature by exploring clients' perspectives of what was useful to their therapeutic experience. Quantitative and qualitative measures were used to collect data from 41 clients who participated in therapy at a university-based family therapy clinic. Quantitative results indicated that therapeutic relationship, client motivation, extratherapeutic factors, and hope and expectancy accounted for 49% of the variance of clients' perception of change and 73% of the variance of clients' perceptions of therapy helpfulness. Qualitative results indicated the therapeutic relationship to be the most helpful aspect of clients' therapeutic experience.

Rituximab and nephrotic syndrome: a new therapeutic hope?

Nephrotic syndrome (NS) remains a therapeutic challenge to nephrologists, despite trials of different ranges of therapeutic regimens. Treatment of NS secondary to either primary glomerulonephritis (GN) or recurrence in renal transplantation remains controversial, as various immunosuppression and plasma exchange regimes have been advocated, with variable success and risk of severe toxic effects [1–17]. Rituximab (RIT) is a chimeric monoclonal antibody that acts by inhibiting CD20-mediated B-cell proliferation and differentiation. The CD20 antigen is a membranous protein found on B cells as well as on malignant cells such as in non-Hodgkin’s lymphoma (NHL). It was first introduced in the late 1990s for the treatment of B cell NHL [18,19]. Since then, it has been used in over half a million patients with haematological malignancies, as first line and maintenance treatment. We reviewed the current literature to investigate the use of RIT in NS. We searched Pubmed with the key words, ‘rituximab’, ‘nephrotic syndrome’, and ‘glomerulonephritis’. Patients with lupus nephritis and cryoglobulinaemia were excluded. Systematic review was performed to analyse all the articles. Demographics including age, sex, clinical presentation and renal diagnosis; therapeutic regimens used in treating refractory NS and biochemical parameters such as serum albumin, creatinine, immunoglobulins, proteinuria and CD19 count were recorded. Success and side effects of treatment and duration of follow-up were also recorded. In total there were 13 case reports [3–9,11–13,15,17,20], three case series [10,14,16] and one prospective study [1,2] (see Table 1 ). RIT was used in NS affecting 20 patients with primary GN and 10 renal transplant patients (all with recurrence of their GN). Of the 20 primary GN, there were 10 idiopathic membranous glomerulonephritis (IMGN), 7 minimal change glomerulonephritis (McGN) and 3 focal segmental glomerulosclerosis (FSGS). Nine out of ten of the recurrence in renal transplantation were secondary to

What therapeutic hope for a subjective mind in an objectified body?

This is an article based on a presentation given at the United Kingdom Council of Psychotherapy (UKCP) conference 2004. Our modern attempt to re-include the body in psychotherapy brings with it the inevitable danger that we import the culturally dominant objectifying construction of the body into a field which may represent one of the last bastions of subjectivity, authenticity, and intimacy in an increasingly virtual world. The paper addresses the question how embodied subjectivity can be found within a relational matrix pervaded by disembodiment and self-objectification. The ubiquitous objectification of the body in our culture and in the field of psychotherapy is illustrated in the paper. It is described as a manifestation of an underlying experience of dis-embodiment. Two ways of re-including the body in psychotherapy are then distinguished: one based on a “third-person” “medical model” stance and the other on a “first-and-second-person” “intersubjective-relational” model. By formulating these two contradictory and complementary ways of using the body in terms of the therapist's implicit relational stance, attention is drawn to what is considered an underlying paradox inherent in all types of psychotherapy. I am hoping that practitioners from across the approaches will be able to recognize and relate to both sides of the dilemma, and through this to both ways of re-including the body in psychotherapy. As the medical model stance was the prevalent default position of what we may therefore call traditional body psychotherapy, and the relational one has become available only in the last decade, a case illustration is used to trace some of my own development as a therapist through the shadow aspects and pitfalls of an exclusive reliance on the first towards an integration of the two and to an appreciation of their necessarily conflicted co-existence in the paradoxical core of the therapeutic position.