Top PDF Treatment of Rheumatoid Arthritis by A “Tolerogenic Vaccination A”Using Sirna Modified Dendritic Cells.

Treatment of Rheumatoid Arthritis by A “Tolerogenic Vaccination A”Using Sirna Modified Dendritic Cells.

Treatment of Rheumatoid Arthritis by A “Tolerogenic Vaccination A”Using Sirna Modified Dendritic Cells.

Dendritic cells are main important APC’s .These cells on maturation combines with MHC molecules and co-receptors like CD-80, CD-40 activates T-cells and B-cells. This main action is regulated by IL-12gene in dendritic cells. Tolerogenic vaccination signifies exotic tool that is launched in to humans or domestic animals with an intention to enroot immunity and to generate immunological tolerance that is condition marked by stolidity to a specific antigen. Here in this critique we have cited applicability of RNA modified DC in treatment of Rheumatoid arthritis. By using the method of RNA interference using siRNA-IL12 treated DC we can treat RA by decreasing T- cell responses towards our own cells.
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TREATMENT OF RHEUMATOID ARTHRITIS BY A

TREATMENT OF RHEUMATOID ARTHRITIS BY A

Dendritic cells are main important APC’s .These cells on maturation combines with MHC molecules and co-receptors like CD-80, CD-40 activates T-cells and B-cells. This main action is regulated by IL-12gene in dendritic cells. Tolerogenic vaccination signifies exotic tool that is launched in to humans or domestic animals with an intention to enroot immunity and to generate immunological tolerance that is condition marked by stolidity to a specific antigen. Here in this critique we have cited applicability of RNA modified DC in treatment of Rheumatoid arthritis. By using the method of RNA interference using siRNA- IL12 treated DC we can treat RA by decreasing T-cell responses towards our own cells.
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A mouse model of adoptive immunotherapeutic targeting of autoimmune arthritis using allo-tolerogenic dendritic cells.

A mouse model of adoptive immunotherapeutic targeting of autoimmune arthritis using allo-tolerogenic dendritic cells.

Several studies have shown that multiple mechanisms are involved in the inhibitory abilities of auto-tDCs in vivo [26-28]. Our study has confirmed that allo-tDCs played a suppressive role in vivo by similar mechanisms, including modulation of cytokine secretion, prolonged inhibition of anti-CII antibodies and polarization of the Treg/Th17 balance. Following treatment with allo-tDCs, the serological levels of IFN- , TNF-α, IL-17 and IL-6 were reduced. By contrast, the levels of both IL-10 and TGF- were enhanced in CIA mice. In this regard, we suggest that a tolerant state was established with allo-tDC treatment in vivo, which was apt to promote Treg cell differentiation and proliferation, while limiting the differentiation of Th17 cells in vivo. As expected, it was found that there were increases in the number of Foxp3 + CD4 + T cells and decreases in the percent
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Terapêuticas biológicas na Artrite Idiopática Juvenil: Porquê e para quem?

Terapêuticas biológicas na Artrite Idiopática Juvenil: Porquê e para quem?

to traditional treatment regimes and are troubled by chronic pain and stiffness, disability, growth re- tardation, risk of irreversible joint damage in addi- tion to the emotional and psychosocial implica- tions of having a chronic disease. In many cases, methotrexate or alternative disease modifying drugs, are useful in controlling disease, but do not lead to remission, and may have unacceptable ad- verse effects. Instead of using broad spectrum im- munosuppression, it seems sensible to chose a particular molecular target thought to be impor- tant in causing or provoking inflammation, and create a antibody or molecule that blocks the acti- on of that target alone (immuno-modulation). In this way, it is hoped that the molecule will work di- rectly at the site of action, with increased efficacy and specificity and fewer adverse effects. Howe- ver, the target molecules are involved in many im- portant pathways, particularly in host defence, which can potentially lead to adverse effects.
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Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population

Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population

The goal of therapy for patients with RA is to control and reduce the rate of degenera- tion of the joints due to immunologic destruction by the host’s immune system (Agarwal, 2011a). In addition, quality of life and increased productivity are important milestones for treatment. Anti-TNF agents have been reported to reduce the rate of radiographic progression and improve short-term inflammatory symptoms (Bathon et al., 2000; Breedveld et al., 2006; Choy et al., 2012; Emery et al., 2009; Keystone et al., 2008; Keystone et al., 2009; Keystone et al., 2004; Klareskog et al., 2004; Maini et al., 1999; Moreland et al., 1999; St Clair et al., 2004; Van de Putte et al., 2004; Weinblatt et al., 2003; Weinblatt et al., 1999). Consequently, improvement in clinical outcomes has resulted in improved quality of life for RA patients. To date, there are five FDA-approved anti-TNF agents for RA: adalimumab (Humira ® ), certolizumab pegol (Cimzia ® ), etanercept (Enbrel ® ), golimumab (Simponi ® ), and infliximab (Remicade ® ) (Agarwal, 2011b).
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Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.

Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.

Tyrosine kinase inhibitors such as erlotinib are commonly used as a therapeutic agent against cancer due to its relatively low side-effect profile and, at times, greater efficacy. However, erlotinib resistance (ER) in non-small cell lung cancer is being recognized as a major problem. Therefore, understanding the mechanism behind ER and developing effective regimens are needed. Autophagy’s role in cancer has been controversial and remains unclear. In this study, we examined the effectiveness of low dose erlotinib-cisplatin combination in erlotinib resistant lung adenocarcinoma (ERPC9) cells and the role of autophagy in ER. ERPC9 cells were established from erlotinib sensitive PC9 cells. Appropriate treatments were done over two days and cell survival was quantified with Alamar Blue assay. LC3II and regulatory proteins of autophagy were measured by western blot. Small interfering RNA (siRNA) was utilized to inhibit translation of the protein of interest. In ERPC9 cells, combination treatment induced synergistic cell death and a significant decrease in autophagy. At baseline, ERPC9 cells had a significantly higher LC3II and lower p-mTOR levels compared to PC9 cells. The addition of rapamycin increased resistance and 3-methyladenine sensitized ERPC9 cells, indicating autophagy may be acting as a protective mechanism. Further examination revealed that ERPC9 cells harbored high baseline Atg3 levels. The high basal Atg3 was targeted and significantly lowered with combination treatment. siRNA transfection of Atg3 resulted in the reversal of ER; 42.0% more cells died in erlotinib-alone treatment with transfection compared to non-transfected ERPC9 cells. We reveal a novel role for Atg3 in the promotion of ER as the inhibition of Atg3 translation was able to result in the re-sensitization of ERPC9 cells to erlotinib-alone treatment. Also, we demonstrate that combination erlotinib-cisplatin is an effective treatment against erlotinib resistant cancer by targeting (down-regulating) Atg3 mediated autophagy and induction of apoptotic cell death.
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Reduction of Orc6 expression sensitizes human colon cancer cells to 5-fluorouracil and cisplatin.

Reduction of Orc6 expression sensitizes human colon cancer cells to 5-fluorouracil and cisplatin.

Orc6 is one of the six origin recognition complex protein in human cells. It functions as the initial assembly platform that is required for DNA replication. The roles of Orc6 in DNA replication have been investigated extensively in both yeast and Drosophila [1,2,3,4,5,6]. But there are limited information on human cancer [7,8]. It has been reported that in addition to its function as a DNA replication initiator protein, it also plays a key role in transcriptional gene silencing and heterochromatin formation [8]. However, it is not clear during the initiation complex assembly at which step that Orc6 participates [9]. It has been demonstrated elegantly by Prasanth et al. the dynamics of Orc6 localization during the entire cell cycle, including DNA replication, chromosome regregation, and cytokinesis. They also suggest Orc6 may function in signaling to cell cycle control [8]. Our interest in Orc6 stemmed from our previous studies with a comprehensive genomics analysis revealed that Orc6 is associated with 5-FU associated resistance in human colon cancer cell lines [10]. Our follow up study using colorectal patient samples further confirmed that the expression of Orc6 is highly elevated in human colorectal tumor tissues compared to paired normal specimens [11]. These results confirmed the clinical relevance of Orc6 leading to our hypothesis that Orc6 may be a key player that is involved in colorectal cancer. Its elevated level may also be a significant contributor to chemoresistance. p53 is one of the most frequently altered tumor suppressors in colorectal cancer and due to its critical function in cycle control [12,13]. In this study, we use
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Unravelling the Mystery Between Structure and Sustained Clinical Outcomes

Unravelling the Mystery Between Structure and Sustained Clinical Outcomes

The challenge for the manufacture of biosimilars is the lack of detailed, publicly available information regarding the manufacturing process of biologics. The synthesis of biologics often undergoes manufacturing changes over time for a variety of reasons, e.g. to upscale production; these manufacturing changes significantly differ from the biosimilarity exercise as for such small process changes, only quality and analytical studies are required to evaluate the product. The manufacture of biosimilars will have fundamental differences to biologics, such as a different cell-line and a knowledge gap in the synthesis process of the innovator. Regulators require comparative clinical studies to ensure that differences between biosimilars and the reference biologic do not translate into differences in efficacy and safety. 15
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Rev. Bras. Reumatol.  vol.53 número1 en v53n1a10

Rev. Bras. Reumatol. vol.53 número1 en v53n1a10

Idiopathic infl ammatory myopathies (IIM), which include dermatomyositis (DM) and polymyositis (PM), are chronic systemic diseases associated with high morbidity and functional disability. Current treatment is based on the use of glucocorticoids and immunosuppressive drugs, but a considerable number of patients is refractory to traditional therapy. That has led to the attempted use of biologics based on the physiopathogenesis of IIM. From the immunopathological viewpoint, PM and DM differ: the former is more related to cellular immunity, while the latter, to humoral immunity. In both, however, elevated concentrations of proinfl ammatory interleukins (TNF, IL-1, IL-6) and increased expression of molecules related to costimulation of T lymphocytes have been described; thus, the use of biologics in those conditions seems reasonable. Considering the biologics available, open-label studies are scarce, comprising mainly case reports and series. TNF blockers have yielded confl icting results, with no evidence of good response to treatment. The anti- CD20 therapy has the most promising results. Data on T lymphocyte costimulation blockade and anti-IL-6 therapy are extremely scarce, preventing any consideration. Thus, the use of biologics in IIM still remains an unconquered frontier. Biologics may have an important role in the management of IIM refractory to conventional therapy, but further prospec- tive studies based on objective parameters of response to treatment are needed. So far, anti-CD20 therapy seems to be the most promising treatment for refractory IIM.
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Artrite reumatóide: diagnóstico e tratamento.

Artrite reumatóide: diagnóstico e tratamento.

Adalimumab, a full y human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the A[r]

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Pleural Effusion and Differential Diagnosis in a Patient  with Rheumatoid Arthritis

Pleural Effusion and Differential Diagnosis in a Patient with Rheumatoid Arthritis

A 30-year-old woman who had been diagnosed rheumatoid arthritis many years ago and not treated since 2 years was referred to local the Department of Chest Diseases of State Hospital with a sudden onset of right lateral chest pain. The chest X-ray on admission showed pleural efusion on the right hemithorax. Thora- centesis was applied. Hemorrhagic pleural efusion was obtained. It was thought rheumatoid pleurisy with its clinical, radiological and laboratory indings. In this case report, we have presented the difuculties during diferential diagnosis of pleural efusion in rheumatoid arthritis patients and details accompanied by a literature review.
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Rev. Bras. Reumatol.  vol.53 número6 en v53n6a09

Rev. Bras. Reumatol. vol.53 número6 en v53n6a09

Results: A high proportion of RA patients are now established users of anti-TNF agents. Data from national registries in European countries of patients with RA treated with an- ti-TNF suggest that biological therapies are closely linked to sepsis. Although previous studies reported a higher risk of infections, there are now emerging data with longer duration of follow-up that suggested an adjusted hazard risk of 1.2. Elderly patients and those with longstanding disease may have a higher rate of serious infections compared to their counterparts who were younger with early disease. There are now emerging data to suggest that anti-TNF therapy is associated with the development of neutrope- nia shortly after the commencement of treatment. The biologic registries found that RA patients treated with monoclonal antibodies are at increased risk of tuberculosis (TB) compared to those on TNF receptor blockers. This risk of infection needs to be weighed against the established benei ts of TNF blockers.
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Complex dynamics of a stochastic discrete modified Leslie-Gower predator-prey model with Michaelis-Menten type prey harvesting

Complex dynamics of a stochastic discrete modified Leslie-Gower predator-prey model with Michaelis-Menten type prey harvesting

Deterministic nonlinear predator-prey models (ODE models) are widely used to understand the dynamics of the ecosystems (Rosenzweig and MacArthur, 1963; Clark, 1976; Steven, 1994; Srinivasu, 2001; Kondoh, 2003; Murdoch et al., 2003; Nedorezov and Sadykov, 2012). In recent years, there has been an increasing interest in Leslie-Gower type predator-prey model (Hsu and Huang, 1995; Li and Xiao, 2007; Liang and Pan, 2007; Song et al., 2009; Tian and Weng, 2011; Tian and Zhu, 2012). The local and global stability for a predator-prey model of modified Leslie-Gower and Holling-type II with time-delay has been considered by Lin and Ho (2006). Bifurcation analysis of a Leslie-Gower prey-predator model with Holling-type III functional response has been studied by Li and Xiao (2007). The global stability of a Leslie-Gower prey-predator model with proportional harvesting in both prey and predator has been studied by Zhang et al. (2011). By defining a suitable Lyapunov function, the global stability of the unique interior equilibrium of the system was shown, which means that suitable harvesting has no influence on the persistent property of the harvesting system. Mena-Lorca et al. (2007) studied the dynamics of the Leslie-Gower model subjected to the Allee effect with proportionate harvesting. The dynamical behavior of the periodic prey-predator model with a modified Leslie- Gower Holling-type II scheme and impulsive effect has been studied by Song and Li (2008). Phase portraits
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Using magnetic resonance imaging to evaluate dendritic cell-based vaccination.

Using magnetic resonance imaging to evaluate dendritic cell-based vaccination.

Dendritic cell (DC)-based vaccines can produce striking remissions of advanced disease [1,2], but the clinical response rate in most studies is less than 10% [3]. To improve the response rate to DC-based vaccination, there are numerous parameters yet to optimise, such as the process of ex-vivo generation, the antigen loading procedure, selecting the ideal subtype and activation state of the DCs, defining the best route of delivery, and defining the optimal dosing schedule. To investigate these factors, it is necessary to monitor the immune responses generated by vaccination. Although several types of assays exist, typically based on in vitro analysis of induced T cell responses, these procedures have not been applied in a standardised manner and have not been consistently correlated with clinical responses [4]. Further- more, many DC-based vaccination strategies utilize antigens in the form of whole tumour lysates or tumour-derived nucleic material, so that the precise antigens presented to T cells are not defined, making direct analysis of antigen-specific T cell responses difficult. Analysis of some parameters of DC-based vaccination may be expedited by development of simple strategies to assess the early cellular interactions required to generate successful immune responses. Following injection by the commonly used routes of delivery (subcutaneous, intradermal or intravenous), the DCs must migrate via the vascular or lymphatic networks to the local lymph nodes to present their antigens to T cells. Indeed, the ability of the
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A Method To Find The Area Of Sector Without The Usage Of Angle Made By The Chord

A Method To Find The Area Of Sector Without The Usage Of Angle Made By The Chord

Thus if we prove that ΔL/ΔF =(r+a)/(r-a) then the theorem is proved. Now let us consider a circle with centre at origin and radius ‘r’. Thus the equation of circle is x²+y²=r².The equation of the chord at ‘a’ distance from center is ax-ry- ar=0 or Y= a/r(x-r).

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Modified vaccinia virus Ankara exerts potent immune modulatory activities in a murine model.

Modified vaccinia virus Ankara exerts potent immune modulatory activities in a murine model.

Several poxviral vector systems are under clinical evaluation for vaccine development against infectious diseases and cancer. One of these vectors is based on the highly attenuated modified vaccinia virus Ankara (MVA) that was originally obtained by attenuation over more than 500 passages in chicken embryo fibroblast cultures [1,2]. During its attenuation, MVA lost ,15% of its parental genome, including genes that regulate viral host range and evasion of host immune response. The replication in most mammalian cells is extremely limited and in non-permissive human cell lines only immature viral particles are formed [2,3,4,5]. Therefore, dissemination within the host is precluded in most species, including humans. MVA also showed an excellent safety record when administered during the smallpox eradication campaign in approximately 150,000 individuals, including many persons at risk for the conventional pox vaccines [6,7,8]. Recombinant MVA (rMVA) expressing immunogens from a variety of infectious agents (e.g., HIV, Plasmodium falciparum) or tumor-associated antigens (Ags) have been success- fully tested in phase I and II clinical trials [9,10,11,12,13,14,15]. In spite of this, most commercial vaccines are based on formulations encompassing purified Ag(s) and adjuvant(s). Thus, considering the fact that the immune system has evolved to respond to ‘‘danger’’ and that molecules delivering such a ‘‘danger’’ signal(s) (e.g., pathogen associated molecular patterns)
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A role for angiogenesis in rheumatoid arthritis

A role for angiogenesis in rheumatoid arthritis

into the synovium. Similar peptides prevent inflammation in delayed-type hypersensitiv- ity reactions through this mechanism (54). However, it is noteworthy that these linear peptide antagonists have broad specificity, and actually inhibit integrin avß3-depen- dent adhesion at lower concentrations than, for example, integrin a5ß1-mediated adhe- sion (55). This raises the possibility that some of the observed anti-arthritic activity resulted from anti-angiogenic effects. In or- der to address these types of questions, an- tagonists with higher specificity/selectivity will be required. Since the principal target of novel cyclic av antagonists used in tumor studies appears to be endothelial cells ex- pressing avß3, these compounds may be amenable to future studies on RA (46). The success of alternative, toxin-based anti-an- giogenic strategies such as taxol (14) or de- rivatives of the fungal metabolite fumagillin (15) validates targeting endothelial cell-me- diated pathology in RA. Together, these stud- ies provide an excellent rationale to pursue development of integrin-based anti-angio- genic strategies as a viable approach to con- trol RA.
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Indirect costs of rheumatoid arthritis in Brazil

Indirect costs of rheumatoid arthritis in Brazil

A second important limitation of our study is with regard to data collection and accuracy. Productivity losses information collected in our study was based on patient’s report and took into account periods up to 1 month or 1 year before the interview as a reference for recording data. Official absenteeism records, dis- ability, and medical retirement benefits are considered better sources to ensure the reliability of indirect cost estimates. Nevertheless, the obstacles to obtaining this information are significant. Access to all sources of payment of salaries and benefits is not easily available and the economic feasibility of conducting such a study is questionable. Interestingly, a comparative analysis of data taken from patient reports and from payment sources performed by Merkesdal et al. has revealed striking consistency between the two methods to assess indirect costs and suggests that RA patients tend to properly report productivity losses in a period up to 3 months before data collection [41]. Our study included information regarding the previous 12 months, a period long enough to allow memory lapses and less accuracy in data collection. As an alter- native, shorter periods such as 4 weeks, or even daily reports, can increase the accuracy of the data collected in economic analyses [41,42]. Using only the data for productivity loss for the month before the interview, the monthly RA-related indirect cost estimated in the present study would be US$42,445.31 per month or US$221.15 per patient per month.
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A systems approach to rheumatoid arthritis.

A systems approach to rheumatoid arthritis.

Among these 108 candidates (Table S1) and the 19 TFs selected above (Table S2), we further selected two sets of molecular candidates. The first set of 15 known candidates were identified as the ones (Table 2); 1) that are currently being used as therapeutic targets in RA treatments or whose efficacy has been previously reported in RA, and 2) for which the agents modulating their activities are available. If there were multiple candidates in the same module, the candidate with the smallest P value was chosen with a high priority. The list includes TNF-a whose inhibition is highly efficacious, as well as CXCR4, PTPRC, and CD19 that have been previously proposed as promising drug targets [53,54,55]. Interestingly, PTPRC mutations have been reported to be associated with responses to anti-TNF-a therapy in RA [55]. Although the listed candidates are known as potential therapeutic targets, most of their inhibitors have neither been tested nor proven effective by a clinical study. Our network analysis further indicates that the inhibitors of these targets could be tested singly or in combination with other drugs. We further identified the second set of candidates (Table 3) that have never been reported as diagnostic markers or therapeutic targets of RA though they represent RA-associated cellular processes (Figure 1C). We showed above that ‘pannus formation’ related processes (cell cycle, cell migration and adhesion, angiogenesis, and ECM organization) were specifically enriched by RA-dominant RAGs (Figure 1C). Thus, we selected nine candidates representing these processes. The candidates have been implicated in RA-related diseases, such as multiple sclerosis and lymphoma, (Figure 1D), but their roles in RA have never been reported and thus should be confirmed in vitro and in vivo .
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B cells contribute to heterogeneity of IL-17 producing cells in rheumatoid arthritis and healthy controls.

B cells contribute to heterogeneity of IL-17 producing cells in rheumatoid arthritis and healthy controls.

following optimally pre-titrated fluorochrome-conjugated monoclonal antibodies: anti-CDγ-FITC, anti-CD8-PerCP, anti- CD56-Alexa700, anti-IFN- -PE-Cy7 (BD, Heidelberg, Germany), anti-CD4-Pacific- Blue, anti-CDβ5-APC-Cy7, anti- CDβ8-APC, anti-CD56-Alexa700, anti-CD19-PerCP, anti- CD11b-PE, anti-CD14-PE-Cy7, anti-CD19-BV4β1, anti-CDβ0- BV570,anti-CDβ4-PE-Cy7, anti-CDβ7-BV605, anti-CDγ8- BV711, anti-IgD-FITC (BioLegend, Biozol, Eching, Germany), anti-CDγ-Q.655 (Invitrogen Life Technologies, Karlsruhe, Germany) and anti-CDβ0-FITC (Immunotools, Friesoythe, Germany). In each sample, dead cells were discriminated from live cells by the addition of ethidium monoazide (EMA, Invitrogen, Karlsruhe, Germany). Before specific surface labelling, human immunoglobulin Gamunex (Bayer, Leverkusen, Germany) was added to each sample for Fc- receptor blockade. Subsequently, cells were washed, fixed and permeabilized using Cytofix/Cytoperm reagent (BD, Heidelberg, Germany) for intracellular analysis of IL-17 applying anti-IL-17-PE (Invitrogen, Karlsruhe, Germany) or anti-IL-17-PerCP-Cy5.5 (eBioscience, Frankfurt, Germany). All events (at least 10 5 cell events) were acquired directly after
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