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Therapeutic Treatments (therapeutic + treatment)
Selected AbstractsTherapeutic Treatment for Benign Prostatic HyperplasiaBJU INTERNATIONAL, Issue 3 2007Robyn Webber No abstract is available for this article. [source] Diagnostic and therapeutic use of radioisotopes for bony disease in prostate cancer: Current practiceINTERNATIONAL JOURNAL OF UROLOGY, Issue 2 2007Nathan Lawrentschuk Abstract: Nuclear medicine techniques continue to be important non-invasive imaging tools assisting the diagnosis, monitoring and , in some cases , treatment of prostate cancer. Bone scintigraphy was the premier modality to have an extensive role in the staging of prostate cancer and has remained an integral tool for over three decades in the assessment of newly diagnosed disease or in follow-up staging. Therapeutic treatment and palliation of disseminated disease, particularly in the skeleton, has also been successful with several radioisotopes including strontium-89 chloride. Despite advances in nuclear medicine techniques and molecular imaging technology such as positron emission tomography and radioimmunoscintigraphy, bone scintigraphy still remains the gold standard in the assessment of osseous metastatic disease in prostate cancer. Thus, it is important to continually review the modalities that have remained important over time and not just to focus on newer technologies. This article summarizes the current diagnostic and therapeutic use of radioisotopes for bony disease in prostate cancer with particular reference to radionuclide bone scintigraphy and positron emission tomography. [source] IL-2 induces in vivo suppression by CD4+CD25+Foxp3+ regulatory T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2008Susan Brandenburg Abstract Interleukin-2 (IL-2) treatment is currently used to enhance T cell-mediated immune responses against tumors or in viral infections. At the same time, IL-2 is essential for the peripheral homeostasis of CD4+CD25+Foxp3+ regulatory T cells (Treg). In our study, we show that IL-2 is also an important activator of Treg suppressive activity in vivo. IL-2 treatment induces Treg expansion as well as IL-10 production and increases their suppressive potential in vitro. Importantly, in vivo application of IL-2 via gene-gun vaccination using IL-2 encoding DNA plasmids (pIL-2) inhibited naive antigen-specific T cell proliferation as well as a Th1-induced delayed type hypersensitivity response. The suppressive effect can be transferred onto naive animals by Treg from IL-2-treated mice and the suppression depends on the synergistic action of IL-10 and TGF-,. These data highlight that during therapeutic treatment with IL-2 the concomitant activation of Treg may indeed counteract the intended activation of cellular immunity. [source] Dynamic versus static models in cost-effectiveness analyses of anti-viral drug therapy to mitigate an influenza pandemicHEALTH ECONOMICS, Issue 5 2010Anna K. Lugnér Abstract Conventional (static) models used in health economics implicitly assume that the probability of disease exposure is constant over time and unaffected by interventions. For transmissible infectious diseases this is not realistic and another class of models is required, so-called dynamic models. This study aims to examine the differences between one dynamic and one static model, estimating the effects of therapeutic treatment with antiviral (AV) drugs during an influenza pandemic in the Netherlands. Specifically, we focus on the sensitivity of the cost-effectiveness ratios to model choice, to the assumed drug coverage, and to the value of several epidemiological factors. Therapeutic use of AV-drugs is cost-effective compared with non-intervention, irrespective of which model approach is chosen. The findings further show that: (1) the cost-effectiveness ratio according to the static model is insensitive to the size of a pandemic, whereas the ratio according to the dynamic model increases with the size of a pandemic; (2) according to the dynamic model, the cost per infection and the life-years gained per treatment are not constant but depend on the proportion of cases that are treated; and (3) the age-specific clinical attack rates affect the sensitivity of cost-effectiveness ratio to model choice. Copyright © 2009 John Wiley & Sons, Ltd. [source] Peripheral Atherectomy: A Critical ReviewJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 6 2007TROY A. BUNTING M.D. Atherectomy is experiencing increased interest from endovascular specialists as a therapeutic treatment in the peripheral arteries. Long studied in the coronary vasculature, atherectomy has several theoretical advantages that make it uniquely suited for the peripheral circulation. In particular, infra-inguinal peripheral arterial disease experiences physiologic stresses and forces that have made traditional percutaneous coronary treatments such as angioplasty and stenting not as successful. Restenosis has been a major problem for angioplasty and stenting alone. The SilverHawk atherectomy device has favorable short-term data but important longer-term data are limited and need further study. Laser atherectomy also has favorable applications in niche patients but the number of studies is limited. Unfortunately, athero-ablative technologies for peripheral arterial disease require more definitive objective data regarding 12-month and longer-term outcomes in order to obtain widespread scientific acceptance. [source] Intratumoural chemotherapy of lung cancer for diagnosis and treatment of draining lymph node metastasisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2010Firuz Celikoglu Abstract Objectives Reviewed here is the potential effectiveness of cytotoxic drugs delivered by intratumoural injection into endobronchial tumours through a bronchoscope for the treatment of non-small cell lung cancer and the diagnosis of occult or obvious cancer cell metastasis to mediastinal lymph nodes. Key findings Intratumoural lymphatic treatment may be achieved by injection of cisplatin or other cytotoxic drugs into the malignant tissue located in the lumen of the airways or in the peribronchial structures using a needle catheter through a flexible bronchoscope. This procedure is termed endobronchial intratumoural chemotherapy and its use before systemic chemotherapy and/or radiotherapy or surgery may provide a prophylactic or therapeutic treatment for eradication of micrometastases or occult metastases that migrate to the regional lymph nodes draining the tumour area. Conclusions To better elucidate the mode of action of direct injection of cytotoxic drugs into tumours, we review the physiology of lymphatic drainage and sentinel lymph node function. In this light, the potential efficacy of intratumoural chemotherapy for prophylaxis and locoregional therapy of cancer metastasis via the sentinel and regional lymph nodes is indicated. Randomized multicenter clinical studies are needed to evaluate this new and safe procedure designed to improve the condition of non-small cell lung cancer patients and prolong their survival. [source] Allergen IgE-isotype-specific suppression by maternally derived monoclonal anti-IgG-idiotypeALLERGY, Issue 1 2010R. I. Tanasa Abstract Background:, The dramatic increase of IgE-mediated allergic diseases in western countries demonstrates the urgent need for new therapeutic or prophylactic approaches. In mice, a prophylactic long-lasting allergen-specific suppression of IgE responsiveness is induced by maternal IgG antibodies to allergens like ovalbumin, phospholipase A2 (bvPLA2) or ovomucoid. As neonatal application or maternally derived pathogen-reactive antibodies (idiotypes) as well as corresponding anti-idiotypes can induce anti-microbial protection, we probed the transgenerational IgE-suppressive mechanism with a syngeneic monoclonal anti-idiotypic antibody. Methods:, The monoclonal bee-venom-phospholipase A2 (bvPLA2)-reactive IgG antibody MS613 (idiotype) or the corresponding syngeneic anti-idiotype II/2-19 were injected during the first 2 days postpartum to the dams. Immunization of offspring with minute doses of IgE-inducing bvPLA2 was started at an adult age of 3½ months. Results:, The postnatal transfer of the anti-bvPLA2 idiotype MS613 or the corresponding anti-idiotype II/2-19 induced long-lasting allergen-specific IgE suppression in a dose-dependent manner, while the IgG response to the allergen developed normally. Quantitatively, the anti-idiotype was more effective than idiotype. Molecular modeling of the idiotype-anti-idiotype complex and its comparison with the bvPLA2 structure revealed that the anti-idiotype does not mimic bvPLA2 epitopes and thus can not be regarded as an internal image antibody and, consequently, does not function as a surrogate antigen. Conclusions:, Idiotypic network reactivity is at least one major factor for induction of transgenerational IgE suppression by maternal IgG antibodies. If applicable to humans, these data suggest the possibility of a prophylactic and possibly therapeutic treatment of IgE-mediated allergic diseases with anti-idiotypic antibodies. [source] Reversible posterior leukoencephalopathy syndrome in a patient with multiple system atrophy: A possible association with oral midodrine treatmentMOVEMENT DISORDERS, Issue 7 2007Joong-Seok Kim MD Abstract We describe a 51-year-old man with a 3-year history of multiple system atrophy, who developed a reversible posterior leukoencephalopathy syndrome (RPLS) after receiving prescription midodrine for therapeutic treatment of orthostatic hypotension. Typical reversible magnetic resonance imaging findings, following treatment with midodrine, suggested a possible relationship between midodrine treatment, supine hypertension, and RPLS, although a cause-and-effect relationship cannot be confirmed. © 2007 Movement Disorder Society [source] Antiparkinson drug , Mucuna pruriens shows antioxidant and metal chelating activityPHYTOTHERAPY RESEARCH, Issue 1 2008Muralikrishnan Dhanasekaran Abstract Parkinson's disease is a neurodegenerative disorder for which no neurorestorative therapeutic treatment is currently available. Oxidative stress plays an important role in the pathophysiology of Parkinson's disease. The ancient Indian medical system, Ayurveda, traditionally uses Mucuna pruriens to treat Parkinson's disease. In our earlier studies, Mucuna pruriens has been shown to possess antiparkinson and neuroprotective effects in animal models of Parkinson's disease. The antioxidant activity of Mucuna pruriens was demonstrated by its ability to scavenge DPPH radicals, ABTS radicals and reactive oxygen species. Mucuna pruriens significantly inhibited the oxidation of lipids and deoxyribose sugar. Mucuna pruriens exhibited divalent iron chelating activity and did not show any genotoxic/mutagenic effect on the plasmid DNA. These results suggest that the neuroprotective and neurorestorative effect of Mucuna pruriens may be related to its antioxidant activity independent of the symptomatic effect. In addition, the drug appears to be therapeutically safe in the treatment of patients with Parkinson's disease. Copyright © 2007 John Wiley & Sons, Ltd. [source] In Vitro and In Vivo Relaxation of Corpus Cavernosum Smooth Muscle by the Selective Myosin II Inhibitor, BlebbistatinTHE JOURNAL OF SEXUAL MEDICINE, Issue 10 2009Xin-hua Zhang MD ABSTRACT Introduction., Blebbistatin (BLEB) is a small cell permeable molecule originally reported as a selective inhibitor of myosin II isoforms expressed by striated muscle and non-muscle cells (IC50 = 0.5,5 µM) with poor inhibition of turkey gizzard smooth muscle (SM) myosin II (IC50,80 µM). However, recently it was found that BLEB can potently inhibit mammalian arterial SM (IC50,5 µM). Aim., To investigate the effect of BLEB on corpus cavernosum SM (CCSM) tone and erectile function (EF). Methods., CC tissue obtained from penile implant patients along with CC, aorta and bladder from adult male rats were used for BLEB organ bath studies. Intracavernosal BLEB was administered to rats and EF was assessed via intracavernous pressure (ICP). Main Outcome Measures., Effects of BLEB on agonist-induced CCSM, aorta and bladder contraction in vitro and ICP in vivo. Results., BLEB completely relaxed human CCSM pre-contracted with phenylephrine (PE) in a dose-dependent manner decreasing tension by 76.5% at 10 µM. BLEB pre-incubation attenuated PE-induced contraction of human CC by ,85%. Human CC strips pre-contracted with endothelin-1 or KCl were almost completely relaxed by BLEB. Rat CCSM pre-contracted with PE showed BLEB relaxation comparable to human CCSM. BLEB inhibition was similar for rat aorta but slower for bladder. Both maximal ICP and ICP/mean arterial pressure were dose-dependently increased by BLEB intracavernous injections with full erection at 1 micromole. Conclusion., Our novel data reveals that BLEB nearly completely relaxes rat and human CCSM pre-contracted with a variety of potent agonists and exhibits tissue selectivity. Coupled with our in vivo data in which nanomole doses of BLEB significantly increase ICP, our data substantiates an important role for the SM contractile apparatus in the molecular mechanism for EF and suggests the possibility of BLEB binding at myosin II as a therapeutic treatment for ED by targeting SM contractile pathways. Zhang X, Aydin M, Kuppam D, Melman A, and DiSanto ME. In vitro and in vivo relaxation of corpus cavernosum smooth muscle by the selective myosin II inhibitor, blebbistatin. J Sex Med 2009;6:2661,2671. [source] Expression of HNFs and C/EBP, is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytesCANCER SCIENCE, Issue 9 2003Tadashi Ishiyama Objective assessment of the differentiation grade of hepatocellular carcinomas (HCCs) is important for evaluation of the pathological diagnosis, prognosis and therapeutic treatment. Differentiation of hepatocytes is reflected by their expression of hepatic functional proteins in the mouse embryo, and liver-enriched transcription factors (LETFs) have been shown to regulate hepatic functional genes strictly. Previous reports demonstrated that the level of LETF expression is altered in HCC or preneoplastic nodules compared with noncancerous tissues. Therefore, LETF expression levels might be useful as a measure of HCC maturation. In this study, to clarify the correlation between the expression of LETFs and the differentiation grade of HCCs, we performed a quantitative analysis of the mRNA expressions of HNFs and C/EBP, using real-time reverse-transcription PCR and immunocytochemical analysis for hepatic functional proteins in twelve cell lines. Furthermore, we examined orthotopic transplantations of the HCC cell lines in C.B-17/Icrj-scid/scid mice and characterized the histologic and cytologic differentiation of the tumors that developed. Our results showed that comprehensive expressions of HNF-3,, HNF-4,, HNF-1,, and C/EBP, were specific to HCCs with well-differentiated function and morphology. Furthermore, among these four transcription factors, HNF-4, and HNF-1, expressions showed synchronism and had a close relation with HCC differentiation. These in vitro results were confirmed in tumors developed in SCID mice in vivo. These findings suggested that HNF-4, and HNF-1, are useful markers to assess the degree of HCC differentiation, which we suggest could be evaluated objectively by the quantitative analysis of HNFs and C/EBP, in HCCs. [source] Managing sexually abused and/or abusing children in substitute careCHILD & FAMILY SOCIAL WORK, Issue 2 2003Elaine Farmer ABSTRACT This paper reports on research on the characteristics, management and therapeutic treatment of sexually abused and/or abusing children in substitute care. Of the 40 sexually abused and/or abusing young people aged 10 or over in the interview sample, two-thirds showed sexual behaviours in the placement studied but one-third did not. The range of sexual behaviours shown by the young people is described. Analysis of the findings shows that four key components of effective management are supervision, adequate sex education, modification of inappropriate sexual behaviour and therapeutic attention to the needs that underlie such behaviour. Supervision includes planning for safe care before placement, preparing other children in the setting, teaching young people how to keep themselves safe when out on their own, and careful monitoring of contact with birth family members. The need for a proactive approach to sex education is stressed. Effective management approaches to masturbation, sexualized behaviour and sexually abusing behaviour are discussed but the processes of denial and minimization of sexual abuse and the development of high thresholds for action when looked after children are abused or at risk are shown to present obstacles to effective care. Finally, the importance of addressing children's deeper needs is emphasized, including the importance of regular review of their need for counselling. At the end of the article two case examples from the study are given. [source] AMPK-dependent hormonal regulation of whole-body energy metabolismACTA PHYSIOLOGICA, Issue 1 2009N. L. Dzamko Abstract AMP-dependent protein kinase (AMPK) is an evolutionarily conserved serine/threonine protein kinase central to the regulation of energy balance at both the cellular and whole-body levels. In its classical role as an intracellular metabolic stress-sensing kinase, AMPK switches on fatty acid oxidation and glucose uptake in muscle, while switching off hepatic gluconeogenesis. AMPK also has a broader role in metabolism through the control of appetite. Regulation of AMPK activity at the whole-body level is coordinated by a growing number of hormones and cytokines secreted from adipose tissue, skeletal muscle, pancreas and the gut including leptin, adiponectin, insulin, interluekin-6, resistin, TNF-, and ghrelin. Understanding how these secreted signalling proteins regulate AMPK activity to control fatty acid oxidation, glucose uptake, gluconeogenesis and appetite may yield therapeutic treatments for metabolic disorders such as diabetes, insulin resistance and obesity. [source] Evidence-based medicine: Review of guidelines and trials in the prevention of secondary stroke,JOURNAL OF HOSPITAL MEDICINE, Issue S4 2008David J. Likosky MD Abstract Transient ischemic attack (TIA) carries a substantial short-term risk for stroke, which is a leading cause of disability and death in the United States. Despite the existing evidence-based guidelines for secondary prevention of stroke, variability in the assessment, diagnostic testing, and treatment of patients with TIA in actual clinical practice remains. Identification of stroke etiology via radiological examination is of paramount importance for the appropriate treatment of patients after TIA or stroke. Management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors (eg, hypertension, diabetes, and elevated cholesterol), and appropriate therapeutic treatments. Antiplatelet therapy is the cornerstone of secondary prevention of stroke; guidelines for its use for noncardioembolic cases have been developed from a solid evidence base. Additional therapeutic approaches include HMG-CoA reductase inhibitors (statins), antihypertensives, and anticoagulants. The results of ongoing large trials will further clarify the role of specific antiplatelet agents for the secondary prevention of stroke in patients with noncardioembolic ischemic stroke or TIA. Journal of Hospital Medicine 2008;3(4 Suppl):S6,S19. © 2008 Society of Hospital Medicine. [source] Using a Box,Cox transformation in the analysis of longitudinal data with incomplete responsesJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES C (APPLIED STATISTICS), Issue 3 2000S. R. Lipsitz We analyse longitudinal data on CD4 cell counts from patients who participated in clinical trials that compared two therapeutic treatments: zidovudine and didanosine. The investigators were interested in modelling the CD4 cell count as a function of treatment, age at base-line and disease stage at base-line. Serious concerns can be raised about the normality assumption of CD4 cell counts that is implicit in many methods and therefore an analysis may have to start with a transformation. Instead of assuming that we know the transformation (e.g. logarithmic) that makes the outcome normal and linearly related to the covariates, we estimate the transformation, by using maximum likelihood, within the Box,Cox family. There has been considerable work on the Box,Cox transformation for univariate regression models. Here, we discuss the Box,Cox transformation for longitudinal regression models when the outcome can be missing over time, and we also implement a maximization method for the likelihood, assumming that the missing data are missing at random. [source] Immunogenicity of CIGB-230, a therapeutic DNA vaccine preparation, in HCV-chronically infected individuals in a Phase I clinical trialJOURNAL OF VIRAL HEPATITIS, Issue 3 2009L. Alvarez-Lajonchere Summary., Hepatitis C virus (HCV) is a worldwide health problem. No vaccine is available against this pathogen and therapeutic treatments currently in use are of limited efficacy. In the present study, the immunogenicity of the therapeutic vaccine candidate CIGB-230, based on the mixture of pIDKE2, a plasmid expressing HCV structural antigens, with a recombinant HCV core protein, Co.120, was evaluated. CIGB-230 was administered by intramuscular injection on weeks 0, 4, 8, 12, 16 and 20 to 15 HCV-chronically infected individuals, non-responders to previous treatment with interferon (IFN) plus ribavirin. Interestingly, following the final immunization, neutralizing antibody responses against heterologous viral pseudoparticles were modified in eight individuals, including six de novo responders. In addition, 73% of vaccinees exhibited specific T cell proliferative response and T cell IFN-gamma secretory response 24 weeks after primary immunization with CIGB-230. Furthermore, 33.3% of individuals developed de novo cellular immune response against HCV core and the number of patients (46.7% at the end of treatment) with cellular immune response against more than one HCV structural antigen increased during vaccination (P = 0.046). In addition, despite persistent detection of HCV RNA, more than 40% percent of vaccinated individuals improved or stabilized liver histology, particularly reducing fibrosis, which correlated with cellular immune response against more than one HCV antigen (P = 0.0053). In conclusion, CIGB-230 is a promising candidate for effective therapeutic interventions based on its ability for enhancing the immune response in HCV chronically infected individuals. [source] A concise update on the status of liver transplantation for hepatitis B virus: The challenges in 2002LIVER TRANSPLANTATION, Issue 1 2002Hugo E. Vargas Significant improvements in both patient and graft survival after orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver failure have been made during the last decade. Recurrence of HBV infection has decreased, even in high-risk patients. Despite ongoing progress, challenges remain for the next millennium, including the determination of cost-effective dosing strategies, treatment of HBV infection in liver transplant recipients, and ramifications of the use of new antiviral agents, specifically, the appearance of resistant strains. This review summarizes the relevant history of OLT for chronic viral hepatitis B, details accepted preventive and therapeutic treatments, and discusses ongoing experimental trials. Emphasis also is placed on new approaches in transplantation as they impact on the care of HBV-infected patients. [source] Characterization of the Streptococcus sobrinus acid-stress response by interspecies microarrays and proteomicsMOLECULAR ORAL MICROBIOLOGY, Issue 5 2010A.R. Martinez Summary Streptococcus mutans and Streptococcus sobrinus are considered the primary organisms responsible for human dental caries. The ability to generate acids and to adapt to low pH conditions is directly associated with the cariogenic potential of these bacteria. To survive acidic conditions, both species have been shown to mount an acid-tolerance response (ATR). However, previous characterization of the S. sobrinus ATR identified critical differences in the mechanisms of acid adaptation between S. mutans and S. sobrinus. Here, interspecies microarray and proteomic approaches were used to identify novel, previously unrecognized genes and pathways that participate in the S. sobrinus acid-stress response. The results revealed that, among other things, metabolic alterations that enhance energy generation and upregulation of the malolactic fermentation enzyme activity constitute important acid-resistance properties in S. sobrinus. Some of these acid adaptive traits are shared by S. mutans and might be considered optimal targets for therapeutic treatments designed to control dental caries. [source] Matrix Metalloproteinase 2 in Reduced-Size Liver Transplantation: Beyond the MatrixAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010S. Padrissa-Altés We studied the contribution of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) to the beneficial effects of preconditioning (PC) in reduced-size orthotopic liver transplantation (ROLT). We also examined the role of c-Jun N-terminal kinase (JNK) and whether it regulates MMP2 in these conditions. Animals were subjected to ROLT with or without PC and pharmacological modulation, and liver tissue samples were then analyzed. We found that MMP2, but notMMP9, is involved in the beneficial effects of PC in ROLT. MMP2 reduced hepatic injury and enhanced liver regeneration. Moreover, inhibition of MMP2 in PC reduced animal survival after transplantation. JNK inhibition in the PC group decreased hepatic injury and enhanced liver regeneration. Furthermore, JNK upregulated MMP2 in PC. In addition, we showed that Tissue inhibitors of matrix metalloproteinases 2 (TIMP2) was also upregulated in PC and that JNK modulation also altered its levels in ROLT and PC. Our results open up new possibilities for therapeutic treatments to reduce I/R injury and increase liver regeneration after ROLT, which are the main limitations in living-donor transplantation. [source] An epidemiological survey on pigs showing symptoms of infectious enteric diseases and dyspepsia in JapanANIMAL SCIENCE JOURNAL, Issue 5 2009Kazunari USHIDA ABSTRACT Diarrhea in pigs has the potential to have a serious economic impact on the swine industry. Previously, we suggested that the likely cause of the presence of non-infectious diarrhea in pigs characterized by lactate accumulation was dyspepsia. In this experiment, the prevalence of enteropathogens and hyper-lactate accumulation in feces of piglets in 4 distinct growth stages was examined. The feces were collected when veterinarian experts recognized abnormalities in sporadic outbreaks. Prevalence of enteropathogens in diarrheal feces was 100% in fattening pigs (FP), 75% in weaning pigs (WP), 50% in suckling pigs (SP), and 42% in growing pigs (GP). Prevalence of enteropathogens in loose feces was 53% in WP, 50% in SP, 40% in FP, and 28% in GP. Prevalence of hyper-lactate accumulation in diarrheal feces was 33% in GP, 33% in SP, 25% in WP, and 25% in FP. Prevalence of hyper-lactate accumulation in loose feces was 40% in GP, 0% in SP, 7% in WP, and 5% in FP. Accordingly, non-infectious dyspepsia is frequent in growing pigs. In this period, pigs are potentially exposed to needless antimicrobial therapeutic treatments in sporadic cases. [source] Structural genomics of the SARS coronavirus: cloning, expression, crystallization and preliminary crystallographic study of the Nsp9 proteinACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2003Valérie Campanacci The aetiologic agent of the recent epidemics of Severe Acute Respiratory Syndrome (SARS) is a positive-stranded RNA virus (SARS-CoV) belonging to the Coronaviridae family and its genome differs substantially from those of other known coronaviruses. SARS-CoV is transmissible mainly by the respiratory route and to date there is no vaccine and no prophylactic or therapeutic treatments against this agent. A SARS-CoV whole-genome approach has been developed aimed at determining the crystal structure of all of its proteins or domains. These studies are expected to greatly facilitate drug design. The genomes of coronaviruses are between 27 and 31.5,kbp in length, the largest of the known RNA viruses, and encode 20,30 mature proteins. The functions of many of these polypeptides, including the Nsp9,Nsp10 replicase-cleavage products, are still unknown. Here, the cloning, Escherichia coli expression, purification and crystallization of the SARS-CoV Nsp9 protein, the first SARS-CoV protein to be crystallized, are reported. Nsp9 crystals diffract to 2.8,Å resolution and belong to space group P61/522, with unit-cell parameters a = b = 89.7, c = 136.7,Å. With two molecules in the asymmetric unit, the solvent content is 60% (VM = 3.1,Å3,Da,1). [source] Structural analysis of caspase-1 inhibitors derived from TetheringACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 5 2005Bruce T. Fahr Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1, and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering® with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1, but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site. [source] Renal carcinogenesis: Genotype, phenotype and dramatypeCANCER SCIENCE, Issue 2 2003Okio Hino Cancer is a heritable disorder of somatic cells. Environment and heredity are both important in the carcinogenic process. The Eker rat model of hereditary renal carcinoma (RC) is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Forty years after the discovery of the Eker rat in Oslo, we and Knudson's group independently identified a germline retrotransposon insertion in the rat homologue of the human tuberous sclerosis (TSC2) gene. To our knowledge, this was the first isolation of a Mendelian dominantly predisposing cancer gene in a naturally occurring animal model. Recently, we discovered a new hereditary renal carcinoma in the rat. This rat was named the "Ninon''rat and its predisposing (Nihon) gene could be a novel renal tumor suppressor gene. This article will review the utility of these unique models for the study of problems in carcinogenesis; e.g., species-specific differences in tumorigenesis, cell stage and tissue/cell-type specific tumorigene-sis, multistep carcinogenesis, modifier gene(s) in renal carcinogenesis, cancer prevention and the development of therapeutic treatments which can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s). (Cancer Sci 2003; 94: 142,147) [source] 2135: Influence of Hsp90 and HDAC inhibition and tubulin acetylation on perinuclear protein aggregation in human retinal pigment epithelial cellsACTA OPHTHALMOLOGICA, Issue 2010K KAARNIRANTA Purpose Retinal pigment epithelial (RPE) cells are continually exposed to oxidative stress that contributes to protein misfolding, aggregation and functional abnormalities during aging. The protein aggregates formed at the cell periphery are delivered along the microtubulus network by dynein dependent retrograde trafficking to a juxtanuclear location. Methods Cellular organelles were analysed by transmission electron microscopy of ARPE-19 cells exposed 5 µM MG-132, 0.25 µM geldanamycin (GA), 1 µM trichostatin A (TSA), 1 µM taxol (TAX) or 5 µM nocodazole (NOC) for 24 hours. In addition, the cells were treated simultaneously with GA or TSA or TAX or NOC and MG-132 up to 24 hours. Ubiquitin, Hsp90, Hsp70, acetylated tubulin and Hsc70 protein levels were analyzed by western blotting. Results Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG-132 ,induced protein aggregation in a way that is an independent of HDAC inhibition, or the tubulin acetylation levels in ARPE-19 cells. However, the tubulin acetylation and polymerization state affects the localization of the proteasome-inhibitor ,induced aggregation. Conclusion Hsp90 inhibition is effectively related to regulation of protein aggregation that is independent of HDAC inhibition or tubulin acetylation levels in the RPE cells. Our findings open new perspectives for understanding the pathogenesis of protein aggregation in retinal cells and can be useful for the development of therapeutic treatments to prevent retinal cell deterioration. [source] | |||||||||||||||||||||||||||||||