Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling

The mitogen-activated protein kinase (MAPK) pathway plays a critical role in Toll-like receptor (TLR) signaling. MAPK phosphatase-1 (MKP-1) inhibits the MAPK pathway and decreases TLR signaling, but the regulation of MKP-1 is not completely understood. We now show that MKP-1 is acetylated, and that acetylation regulates its ability to interact with its substrates and deactivate inflammatory signaling. We found that LPS activates acetylation of MKP-1. MKP-1 is acetylated by p300 on lysine residue K57 within its substrate-binding domain. Acetylation of MKP-1 enhances its interaction with p38, thereby increasing its phosphatase activity and interrupting MAPK signaling. Inhibition of deacetylases increases MKP-1 acetylation and blocks MAPK signaling in wild-type (WT) cells; however, deacetylase inhibitors have no effect in cells lacking MKP-1. Furthermore, histone deacetylase inhibitors reduce inflammation and mortality in WT mice treated with LPS, but fail to protect MKP-1 knockout mice. Our data suggest that acetylation of MKP-1 inhibits innate immune signaling. This pathway may be an important therapeutic target in the treatment of inflammatory diseases.     

Prostate cancer: 1.5 T endo-coil dynamic contrast-enhanced MRI and MR spectroscopy—correlation with prostate biopsy and prostatectomy histopathological data

Purpose

To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data.

Materials and methods

43 patients, scheduled for radical prostatectomy, underwent prostate MR examination. Prostate cancer was identified by transrectal ultrasonographically (TRUS) guided sextant biopsy. MR examination was performed at 1.5T with an endorectal MR coil. Cancer localisation was performed on sextant-basis - for comparison between TRUS biopsy, MR techniques and histopathological findings on prostatectomy specimens.

Results

Prostate cancer was identified in all 43 patients by combination of the three MR techniques. The detection of prostate cancer on sextant-basis showed sensitivity and specificity: 50% and 91% for TRUS, 72% and 55% for T2WI, 49% and 69% for DCEMRI, and 46% and 78% for CSI.

Conclusion

T2WI, DCEMRI and CSI in combination can identify prostate cancer. Further development of MR technologies for these MR methods is necessary to improve the detection of the prostate cancer.     

Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis

Purpose  

Platelet-rich plasma (PRP) therapy is a simple, low-cost and minimally invasive method that provides a natural concentrate of autologous blood growth factors (GFs) that can be used to enhance tissue regeneration. In a previous analysis of a 12-month follow-up study, promising results were obtained when treating patients affected by knee degeneration with PRP intra-articular injections. The main purpose of this study was to investigate the persistence of the beneficial effects observed.     

Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study

Extensive bone loss is still a major problem in orthopedics. A number of different therapeutic approaches have been developed and proposed, but so far none have proven to be fully satisfactory. We used a new tissue engineering approach to treat four patients with large bone diaphysis defects and poor therapeutic alternatives. To obtain implantable three-dimensional (3D) living constructs, cells isolated from the patients' bone marrow stroma were expanded in culture and seeded onto porous hydroxyapatite (HA) ceramic scaffolds designed to match the bone deficit in terms of size and shape. During the surgical session, an Ilizarov apparatus or a monoaxial external fixator was positioned on the patient's affected limb and the ceramic cylinder seeded with cells was placed in the bone defect. Patients were evaluated at different postsurgery time intervals by conventional radiographs and computed tomography (CT) scans. In one patient, an angiographic evaluation was performed at 6.5 years follow-up. In this study we analyze the long-term outcome of these patients following therapy. No major complications occurred in the early or late postoperative periods, nor were major complaints reported by the patients. No signs of pain, swelling, or infection were observed at the implantation site. Complete fusion between the implant and the host bone occurred 5 to 7 months after surgery. In all patients at the last follow-up (6 to 7 years postsurgery in patients 1 to 3), a good integration of the implants was maintained. No late fractures in the implant zone were observed. The present study shows the long-term durability of bone regeneration achieved by a bone engineering approach. We consider the obtained results very promising and propose the use of culture-expanded osteoprogenitor cells in conjunction with porous bioceramics as a real and significant improvement in the repair of critical-sized long bone defects.     

Optical Properties of Site-Selectively Grown InAs/InP Quantum Dots with Predefined Positioning by Block Copolymer Lithography

The InAs/InP quantum dots (QDs) are investigated by time-integrated (PL) and time-resolved photoluminescence (TRPL) experiments. The QDs are fabricated site-selectively by droplet epitaxy technique using block copolymer lithography. The estimated QDs surface density is ∼1.5 × 10¹⁰ cm⁻². The PL emission at T=300K is centered at 1.5 μm. Below T=250K, the PL spectrum shows a fine structure consisting of emission modes attributed to the multimodal QDs size distribution. Temperature-dependent PL reveals negligible carrier transfer among QDs, suggesting good carrier confinement confirmed by theoretical calculations and the TRPL experiment. The PL intensity quench and related energies imply the presence of carrier losses among InP barrier states before carrier capture by QD states. The TRPL experiment highlighted the role of the carrier reservoir in InP. The elongation of PL rise time with temperature imply inefficient carrier capture from the reservoir to QDs. The TRPL experiment at T=15K reveals the existence of two PL decay components with strong dispersion across the emission spectrum. The decay times dispersion is attributed to different electron-hole confinement regimes for the studied QDs within their broad distribution affected by the size and chemical content inhomogeneities.     

Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity

Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells.     

Definition and classification of early osteoarthritis of the knee

With the emerging interest in regenerative medicine and tissue engineering, new treatment modalities being developed for joint disorders including joint surface lesions and articular cartilage defects. The clinical outcome of these novel approaches appears rather unpredictable and is due to many reasons but definitely also linked to the patient profile. As a typical example, symptomatic articular cartilage lesions can be presented in an otherwise normal joint, or associated with several other joint tissue alterations including meniscal lesions and abnormalities of the underlying bone. The outcome of novel treatments may well be influenced by the status of the whole joint, and the potential to develop osteoarthritis. To better identify the patients at risk and responders to certain treatments, it is of use to define and most importantly classify patients with “early osteoarthritis”. Here, classification criteria for this group of patients are presented, allowing a more defined and accurate inclusion in clinical trials in the future.     

Second-generation arthroscopic autologous chondrocyte implantation for the treatment of degenerative cartilage lesions

Purpose

Degenerative cartilage lesions present a negative joint environment, which may have a negative effect on the process of cartilage regeneration. The aim of this study is to analyze the clinical outcome obtained with the treatment for isolated degenerative knee cartilage lesions by second-generation arthroscopic autologous chondrocyte implantation (ACI).

Methods

Fifty-eight consecutive patients affected by focal degenerative chondral lesions of the femoral condyles and trochlea were treated by second-generation arthroscopic ACI. The mean age at surgery was 34.7?±?9.1?years and the average defect size was 2.3?±?0.9?cm². The patients were prospectively evaluated with IKDC, EQ-VAS, and Tegner scores preoperatively, at 2 and 6?years.

Results

A statistically significant improvement was observed in all scores from the basal evaluation to the final follow-up. The IKDC subjective score improved from 39.3?±?13.6 to 68.8?±?22.7 and 68.5?±?23.9 at the 2- and 6-year follow-ups, respectively, with a significant improvement (P?Conclusions Despite a significant improvement, the results were lower with respect to the outcome reported in different study populations, and the number of failures was markedly higher, too. Tissue-engineered cartilage implantation is a promising approach for the treatment of degenerative chondral lesions, but graft properties, besides mechanical and biochemical joint environment, have to be improved.

Level of evidence

Case series, Level IV.