Treatments for chronic pruritus outside of the box

Patients with chronic pruritus are in desperate need of novel treatment options, as current therapeutic possibilities are often not effective, have a poor level of evidence and are mostly off-label. In recent years, much effort has been put into the identification of potential targets for the treatment of chronic pruritus. More importantly, a number of promising new drugs that are aimed at treating pruritus in different conditions are currently in advanced stages of clinical trials. Here, current pharmacological developments leading to potential new drugs for the treatment of chronic pruritus within various conditions are summarized. Hopefully, these new approaches will result in effective and safe therapies for our patients with chronic pruritus associated with dermatological or non-dermatological diseases in the near future

Nanocoating with plant-derived pectins activates osteoblast response in vitro

Abstract: A new strategy to improve osseointegration of implants is to stimulate adhesion of bone cells, bone matrix formation, and mineralization at the implant surface by modifying surface coating on the nanoscale level. Plant-derived pectins have been proposed as potential candidates for surface nanocoating of orthopedic and dental titanium implants due to 1) their osteogenic stimulation of osteoblasts to mineralize and 2) their ability to control pectin structural changes. The aim of this study was to evaluate in vitro the impact of the nanoscale plant-derived pectin Rhamnogalacturonan-I (RG-I) from potato on the osteogenic response of murine osteoblasts. RG-I from potato pulps was isolated, structurally modified, or left unmodified. Tissue culture plates were either coated with modified RG-I or unmodified RG-I or – as a control – left uncoated. The effect of nanocoating on mice osteoblast- like cells MC3T3-E1 and primary murine osteoblast with regard to proliferation, osteogenic response in terms of mineralization, and gene expression of Runt-related transcription factor 2 (Runx2), alkaline phosphate (Alpl), osteocalcin (Bglap), α-1 type I collagen (Col1a1), and receptor activator of NF-κB ligand (Rankl) were analyzed after 3, 7, 14, and 21 days, respectively. Nanocoating with pectin RG-Is increased proliferation and mineralization of MC3T3-E1 and primary osteoblast as compared to osteoblasts cultured without nanocoating. Moreover, osteogenic transcriptional response of osteoblasts was induced by nanocoating in terms of gene induction of Runx2, Alpl, Bglap, and Col1a1 in a time-dependent manner – of note – to the highest extent under the PA-coating condition. In contrast, Rankl expression was initially reduced by nanocoating in MC3T3-E1 or remained unaltered in primary osteoblast as compared to the uncoated controls. Our results showed that nanocoating of implants with modified RG-I beneficially 1) supports osteogenesis, 2) has the capacity to improve osseointegration of implants, and is therefore 3) a potential candidate for nanocoating of bone implants

Increased periodontal attachment loss in patients with systemic sclerosis

Background: Patients with inflammatory rheumatic diseases and periodontitis share common pathogenetic characteristics, such as pro-inflammatory traits causative for tissue degradation and loss of function. Aim of the present case control study was to investigate the association between systemic sclerosis (SSc) and periodontitis. Methods: The association between SSc and periodontitis was examined in 58 SSc patients and 52 control patients, matched for age and gender. Periodontal examination included periodontal attachment loss, probing pocket depth, bleeding on probing, plaque index and gingival index. Potential risk factors of periodontitis were assessed through patients' questionnaires. Results: In unadjusted analyses, patients with SSc had a significant 0.61 mm higher periodontal attachment loss (95 % confidence interval (CI), 0.24 - 0.97; p = 0.002) when compared to controls. In a stepwise logistic regression, including SSc status, age, gender, education, smoking, alcohol consumption and BMI, only SSc status, age, and gender remained significantly associated with periodontitis. Adjusted for age and gender, patients with SSc had 0.52 mm higher periodontal attachment loss compared to controls (95 % CI, 0.16 - 0.88; p = 0.005). The strength of the association of SSc with periodontal attachment loss remained statistically significant after further adjustment for plaque index (0.44 mm; 95 % CI 0.02 - 0.86; p = 0.038) or gingival index (0.61 mm; 95 % CI, 0.24 - 0.97 p = 0.001). Conclusions: The study demonstrates higher periodontal clinical attachment loss in SSc patients, which remained significant following adjustment. The study indicates a possible relationship between SSc and periodontitis

A phenomenological approach to the simulation of metabolism and proliferation dynamics of large tumour cell populations

A major goal of modern computational biology is to simulate the collective behaviour of large cell populations starting from the intricate web of molecular interactions occurring at the microscopic level. In this paper we describe a simplified model of cell metabolism, growth and proliferation, suitable for inclusion in a multicell simulator, now under development (Chignola R and Milotti E 2004 Physica A 338 261-6). Nutrients regulate the proliferation dynamics of tumor cells which adapt their behaviour to respond to changes in the biochemical composition of the environment. This modeling of nutrient metabolism and cell cycle at a mesoscopic scale level leads to a continuous flow of information between the two disparate spatiotemporal scales of molecular and cellular dynamics that can be simulated with modern computers and tested experimentally.Comment: 58 pages, 7 figures, 3 tables, pdf onl

The anti-glucocorticoid receptor antibody clone 5E4: raising awareness of unspecific antibody binding

Unspecific antibody binding takes a significant toll on researchers in the form of both the economic burden and the disappointed hopes of promising new therapeutic targets. Despite recent initiatives promoting antibody validation, a uniform approach addressing this issue has not yet been developed. Here, we demonstrate that the anti-glucocorticoid receptor (GR) antibody clone 5E4 predominantly targets two different proteins of approximately the same size, namely AMP deaminase 2 (AMPD2) and transcription intermediary factor 1-beta (TRIM28). This paper is intended to generate awareness of unspecific binding of well-established reagents and advocate the use of more rigorous verification methods to improve antibody quality in the future

Surface AMP deaminase 2 as a novel regulator modifying extracellular adenine nucleotide metabolism

Adenine nucleotides represent crucial immunomodulators in the extracellular environment. The ectonucleotidases CD39 and CD73 are responsible for the sequential catabolism of ATP to adenosine via AMP, thus promoting an anti-inflammatory milieu induced by the "adenosine halo". AMPD2 intracellularly mediates AMP deamination to IMP, thereby both enhancing the degradation of inflammatory ATP and reducing the formation of anti-inflammatory adenosine. Here, we show that this enzyme is expressed on the surface of human immune cells and its predominance may modify inflammatory states by altering the extracellular milieu. Surface AMPD2 (eAMPD2) expression on monocytes was verified by immunoblot, surface biotinylation, mass spectrometry, and immunofluorescence microscopy. Flow cytometry revealed enhanced monocytic eAMPD2 expression after TLR stimulation. PBMCs from patients with rheumatoid arthritis displayed significantly higher levels of eAMPD2 expression compared with healthy controls. Furthermore, the product of AMPD2-IMP-exerted anti-inflammatory effects, while the levels of extracellular adenosine were not impaired by an increased eAMPD2 expression. In summary, our study identifies eAMPD2 as a novel regulator of the extracellular ATP-adenosine balance adding to the immunomodulatory CD39-CD73 system

The Calcitonin and Glucocorticoids Combination: Mechanistic Insights into Their Class-Effect Synergy in Experimental Arthritis

PMCID: PMC3564948This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Prognostic Implications of MicroRNA-21 Overexpression in Invasive Ductal Carcinomas of the Breast

(miR-21) is known to act as an oncogene. The aim of this study was to investigate the significance of miR-21 expression level in relation with clinicopathological factors and prognosis in breast cancer. Methods: MicroRNA was extracted from cancer and normal breast tissue of 109 breast cancer patients who underwent surgery from 2002 to 2004 using the Taqman ® MicroRNA Assay. The correlation between miR-21 expression and clinicopathologic features was analyzed and the significance of miR-21 as a prognostic factor and its relationship with survival was determined. Results: MiR-21 expression was higher in cancer tissues than in normal tissues (p<0.0001). High miR-21 expression was associated with mastectomy, larger tumor size, higher stage, higher grade, estrogen receptor (ER) negative, human epidermal growth factor receptor 2 (HER2) positive, HER2 positive breast cancer subtype, high Ki-67 expression, and death. On multivariate analysis, prognostic factors for overall survival were ER and miR-21. High miR-21 expression was significantly related to lower overall survival (p = 0.031). Conclusion: This study supports the role of miR-21 as an oncogene and a biomarker for breast cancer with its high expression in cancer tissues and its relationship with other prognostic factors and survival

Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation

Background Successful preclinical transplantations of porcine hearts into baboon recipients are required before commencing clinical trials. Despite years of research, over half of the orthotopic cardiac xenografts were lost during the first 48 hours after transplantation, primarily caused by perioperative cardiac xenograft dysfunction (PCXD). To decrease the rate of PCXD, we adopted a preservation technique of cold non-ischemic perfusion for our ongoing pig-to-baboon cardiac xenotransplantation project. Methods Fourteen orthotopic cardiac xenotransplantation experiments were carried out with genetically modified juvenile pigs (GGTA1- KO/hCD46/hTBM) as donors and captive-bred baboons as recipients. Organ preservation was compared according to the two techniques applied: cold static ischemic cardioplegia (IC; n = 5) and cold non-ischemic continuous perfusion (CP; n = 9) with an oxygenated albumin-containing hyperoncotic cardioplegic solution containing nutrients, erythrocytes and hormones. Prior to surgery, we measured serum levels of preformed anti-non-Gal-antibodies. During surgery, hemodynamic parameters were monitored with transpulmonary thermodilution. Central venous blood gas analyses were taken at regular intervals to estimate oxygen extraction, as well as lactate production. After surgery, we measured troponine T and serum parameters of the recipient's kidney, liver and coagulation functions. Results In porcine grafts preserved with IC, we found significantly depressed systolic cardiac function after transplantation which did not recover despite increasing inotropic support. Postoperative oxygen extraction and lactate production were significantly increased. Troponin T, creatinine, aspartate aminotransferase levels were pathologically high, whereas prothrombin ratios were abnormally low. In three of five IC experiments, PCXD developed within 24 hours. By contrast, all nine hearts preserved with CP retained fully preserved systolic function, none showed any signs of PCXD. Oxygen extraction was within normal ranges; serum lactate as well as parameters of organ functions were only mildly elevated. Preformed anti-non-Gal-antibodies were similar in recipients receiving grafts from either IC or CP preservation. Conclusions While standard ischemic cardioplegia solutions have been used with great success in human allotransplantation over many years, our data indicate that they are insufficient for preservation of porcine hearts transplanted into baboons: Ischemic storage caused severe impairment of cardiac function and decreased tissue oxygen supply, leading to multi-organ failure in more than half of the xenotransplantation experiments. In contrast, cold non-ischemic heart preservation with continuous perfusion reliably prevented early graft failure. Consistent survival in the perioperative phase is a prerequisite for preclinical long-term results after cardiac xenotransplantation