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Summary: Background: 68Ga‐labelled prostate‐specific membrane antigen (PSMA) is a promising PET ligand for the detection of prostate cancer. Little attention has been given to the ability of 68Ga‐PSMA PET/CT to detect malignant bone lesions and whether this approach is superior to existing bone imaging modalities. Aim: To review the existing data of 68Ga‐PSMA PET/CT for the diagnosis of bone metastases in prostate cancer. Methods: Systematic review of the peer‐reviewed literature. Results: Among 1858 papers in the original search, 37 papers were included in the analysis (six case reports and 31 case series). The vast majority of the studies were low‐level evidence studies. Most studies presented data on detection rates without a reference standard. All but two studies were of a retrospective nature. Several cohort studies showed bone metastasis in 5–60% of patients with prostate cancer, including in patients with very low‐PSA values. For primary staging, 68Ga‐PSMA PET/CT outperformed bone scans, while the superiority of 68Ga‐PSMA PET/CT compared with bone scans with respect to biochemical recurrence and metastatic castration‐resistant prostate cancer (mCRPC) remains to be demonstrated. Conclusion: 68Ga‐PSMA PET/CT has shown to be a promising technique for use in prostate cancer. 68Ga‐PSMA PET/CT shows more lesions than bone scans, but data on diagnostic performance are very limited and indicate improved diagnostic performance in primary staging but not in mCRPC. Properly designed studies are needed to clarify the diagnostic performance of 68Ga‐PSMA PET/CT as well as its superiority over existing methods before 68Ga‐PSMA PET/CT can be routinely used for bone imaging. [ABSTRACT FROM AUTHOR]

In horses, pathological healing with formation of exuberant granulation tissue (EGT) is a particular problem in limb wounds, whereas body wounds tend to heal without complications. Chronic inflammation has been proposed to be central to the pathogenesis of EGT. This study aimed to investigate levels of inflammatory acute phase proteins (APPs) in interstitial fluid from wounds in horses. A novel approach for absolute quantification of proteins, selected reaction monitoring (SRM)-based mass spectrometry in combination with a quantification concatamer (QconCAT), was used for the quantification of five established equine APPs (fibrinogen, serum amyloid A, ceruloplasmin, haptoglobin, and plasminogen) and three proposed equine APPs (prothrombin, α-2-macroglobulin, and α-1-antitrypsin). Wound interstitial fluid was recovered by large pore microdialysis from experimental body and limb wounds from five horses at days 1, 2, 7, and 14 after wounding and healing without (body) and with (limb) the formation of EGT. The QconCAT included proteotypic peptides representing each of the protein targets and was used to direct the design of a gene, which was expressed in Escherichia coli in a media supplemented with stable isotopes for metabolically labeling of standard peptides. Co-analysis of wound interstitial fluid samples with the stable isotope-labeled QconCAT tryptic peptides in known amounts enabled quantification of the APPs in absolute terms. The concentrations of fibrinogen, haptoglobin, ceruloplasmin, prothrombin, and α-1-antitrypsin in dialysate from limb wounds were significantly higher than in dialysate from body wounds. This is the first report of simultaneous analysis of a panel of APPs using the QconCAT-SRM technology. The microdialysis technique in combination with the QconCAT-SRM-based approach proved useful for quantification of the investigated proteins in the wound interstitial fluid, and the results indicated that there is a state of sustained inflammation in equine wounds healing with formation of EGT. [ABSTRACT FROM AUTHOR]

As in other fibroproliferative disorders, hypoxia has been suggested to play a key role in the pathogenesis of exuberant granulation tissue ( EGT). The purpose of this study was to investigate metabolism and blood flow locally in full-thickness wounds healing with (limb wounds) and without (body wounds) formation of EGT. Microdialysis was used to recover endogenous metabolites from the wounds, and laser Doppler flowmetry was used to measure blood flow. Measurements were performed before wounding and 1-28 days after wounding. Blood flow was consistently lower in limb wounds than in body wounds throughout the study period with no change over time. After wounding and throughout the study period, the glucose concentration was significantly lower in limb wounds than in body wounds, whereas the lactate level showed a significantly higher concentration in limb wounds. The lactate/glucose ratio displayed a significant difference between body and limb wounds. In conclusion, the metabolic disturbances may suggest an inadequate oxygen supply during the wound healing process in equine limb wounds healing with EGT. This may be related to the inherently decreased perfusion in the wound bed of limb wounds. [ABSTRACT FROM AUTHOR]

Background/Aims The purpose of the present pilot study was to investigate the feasibility of combining large pore dermal microdialysis with shotgun proteomic analysis in human skin. Methods Dialysate was recovered from human skin by 2000 kDa microdialysis membranes from one subject at three different phases of the study; trauma due to implantation of the dialysis device, a post implantation steady-state period, and after induction of vasodilatation and plasma extravasation. For shotgun proteomics, the proteins were extracted and digested with trypsin. Peptides were separated by capillary and nanoflow HPLC systems, followed by tandem mass spectrometry ( MS/ MS) on a Quadrupole- TOF hybrid instrument. The MS/ MS spectra were merged and mapped to a human target protein database to achieve peptide identification and protein inference. Results Results showed variation in protein amounts and profiles for each of the different sampling phases. The total protein concentration was 1.7, 0.6, and 1.3 mg/ mL during the three phases, respectively. A total of 158 different proteins were identified. Immunoglobulins and the major classes of plasma proteins, including proteases, coagulation factors, apolipoproteins, albumins, and complement factors, make up the major load of proteins in all three test conditions. Conclusion Shotgun proteomics allowed the identification of more than 150 proteins in microdialysis samples from human skin. This highlights the opportunities of LC- MS/ MS to study the complex molecular interactions in the skin. [ABSTRACT FROM AUTHOR]

As there is evidence for an anti-inflammatory efficacy of histamine H receptor (H4R) selective antagonists, we aimed at testing the efficacy of the H4R antagonists JNJ7777120 and JNJ28307474 in comparison with histamine H receptor (H1R) antagonists hydroxyzine and cetirizine for skin lesion prevention in a canine model of acute atopic dermatitis. Six atopic Maltese-beagle dogs experimentally sensitized to Dermatophagoides farinae (Df) house dust mites were selected for this study. Twenty-four hours after challenge by epicutaneous application of Df, erythematous skin lesions were scored. In this blinded, placebo and active controlled study, topical JNJ7777120 or JNJ28307474 was applied as a 1% solution before allergen challenge. The latter was also given orally at 15 mg/kg before and after allergen challenge. A 0.015% triamcinolone acetonide solution was used as a positive control. The H1R antagonists hydroxyzine and cetirizine were administered orally before challenge in a second experiment. Twenty-four hours after challenge, placebo-treated animals had a median lesional score of 2. Treatment with topical and oral JNJ28307474 resulted in a median score of 2.5. After topical administration of JNJ7777120, the median lesional score was 2. Hydroxyzine and cetirizine did also not reduce the median score of the placebo treatment. Triamcinolone acetonide prevented all dogs from having any lesions. Determination of histamine in lesions revealed that only during the initiation increased concentrations of histamine were detected. In conclusion, the preventive administration of H1R or H4R antagonists has no impact on the development of acute skin lesions in this experimental canine atopic dermatitis model. [ABSTRACT FROM AUTHOR]

In vitro data have suggested that the skin is a significant lactate source. The purpose of the present study was to measure lactate and glucose concentrations in intact human skin in vivo using the microdialysis technique. Microdialysis fibres of 216 μm were inserted intradermally and perfused at a rate of 3 μl min[sup –1]. In the first experimental protocol, dialysis fibres were calibrated by the method of no net flux in eight subjects. Skin lactate concentrations of 2·48 ± 0·17 mmol l[sup –1] were significantly greater than lactate concentrations of 0·84 ± 0·15 mmol l[sup –1 ]in venous plasma (P<0·01). Glucose concentrations in skin and venous plasma were similar (5·49 ± 0·18 vs. 5·26 ± 0·24 mmol l[sup –1]). In the second experimental protocol, changes in lactate and glucose levels were studied in 10 subjects after an oral glucose tolerance test (OGTT). After the OGTT, plasma glucose and lactate levels increased by 54% and 39% to peak levels at 30 and 60 min respectively. In comparison, skin glucose and lactate increased by 41% and 18% at 60 and 90 min. No changes in skin blood flow were observed during the OGTT. The data suggest that resting skin is a significant lactate source with no significant lactate production during OGTT. The cellular source of lactate in the skin remains undetermined to date. [ABSTRACT FROM AUTHOR]

Objective: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA., Methods: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study., Results: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%)., Conclusion: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.