Opioid-Induced Hyperalgesic Priming in Single Nociceptors

Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E₂ (PGE₂) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and mitogen-activated protein kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel in vitro experiments were performed on small-diameter (<30 µm) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type II priming. Enhancement of the sensitizing effect of a low concentration of PGE₂ (10 nm), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4–) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE₂ (100 nm) was enhanced. The sensitizing effect of 10 nm PGE₂ was attenuated in weakly IB4+ and IB4– neurons cultured from rats whose OIHP was reversed in vivo. Thus, in vivo administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4– nociceptors that persists in vitro and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE₂ in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.SIGNIFICANCE STATEMENT Commonly used clinical opioid analgesics, such as fentanyl and morphine, can produce hyperalgesia and chronification of pain. To uncover the nociceptor population mediating opioid-induced hyperalgesic priming (OIHP), a model of pain chronification, and elucidate its underlying mechanism, at the cellular level, we established an in vitro model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E₂ (PGE₂) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE₂-induced sensitization was observed in vitro, with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4–)] nociceptors.     

SATB1 gene expression and breast cancer prognosis

Recently it has been shown that the genome organizer SATB1 plays an important role in breast cancer progression and predicts a poor prognosis. However its prognostic value compared to markers as the estrogen receptor is currently unclear. The expression levels of SATB1 mRNA from Affymetrix microarray in a cohort of 2058 breast cancer samples and its prognostic impact were analyzed. There was no significant difference in disease-free survival among ER negative cancers but instead a benefit for high SATB1 expression among ER positive tumors (p = 0.042). However, even in ER positive cancer no independent prognostic value in multivariate analysis with standard parameters was observed. Thus the use of SATB1 as target or prognostic marker for breast cancer should be viewed with caution and a possible confounding effect of the estrogen receptor status of the tumor should be taken into account when analysing new markers as SATB1.     

Current therapies in ischemic stroke. Part B. Future candidates in stroke therapy and experimental studies

Stroke still remains a major healthcare problem. The growing understanding of the mechanism of cell death in ischemia leads to new approaches in stroke treatment. The aim of neuroprotection is to reduce the post-stroke impairment and the overall costs that are accompanied in patients with severe disability. Despite encouraging data from experimental animal models, almost all neuroprotective therapies have, to date, not been established in clinical routine. In this part B of our review on stroke therapies we provide an overview on future candidates in stroke therapy and neuroprotective agents that are under investigation.     

Monotherapy with tocilizumab or TNF-alpha inhibitors in patients with rheumatoid arthritis: efficacy, treatment satisfaction, and persistence in routine clinical practice

This study aims to investigate the use of biological disease-modifying antirheumatic drugs (bDMARDs) as monotherapy in patients with rheumatoid arthritis (RA) in “real world” clinical settings and to compare tumor necrosis factor (TNF) inhibitors and tocilizumab monotherapy in terms of efficacy and patient and clinician satisfaction with treatment. This study made use of a retrospective, cohort-19 based study including included data from 254 patients (TNF inhibitors n?=?128; tocilizumab n?=?126) managed in 30 centers throughout Germany. Efficacy of monotherapy and patient and physician overall satisfaction with treatment were assessed at baseline, 3, and 6 months of monotherapy using a range of measures including Disease Activity Score 28 joint (DAS28), swollen joint count (SJC) and tender joint count (TJC), and visual analogue scales (VAS). Between 18 and 41 % of patients treated with bDMARDs received the agent as monotherapy. Intolerance to DMARDs, contraindications for combination therapy, and comorbidities were the most common reasons for introduction of bDMARD monotherapy. Mean DAS28 (erythrocyte sedimentation rate, ESR) was significantly lower at 3 and 6 months following tocilizumab vs. TNF inhibitors (p?≤?0.001). Joint counts improved from baseline to month 6 in both groups (SJC ?5.1 vs. ?3.7 and TJC ?5.6 vs. ?5.1, for tocilizumab and TNF inhibitors, respectively). Patient as well as physician satisfaction (VAS 100 mm scale) was significantly higher for tocilizumab vs. TNF inhibitors (75.3 vs. 66.8; p?=?0.001 and 74.9 vs. 67.1, p?=?0.003, respectively). Significantly more patients remained on tocilizumab monotherapy vs. TNF-inhibitor monotherapy (89.7 vs. 75.8 %; p?<?0.01). Monotherapy with bDMARDs is common in routine clinical practice. Tocilizumab monotherapy appeared to be superior over TNF-inhibitor monotherapy with respect to DAS28 and drug adherence.     

Estrogen receptor beta 2 is associated with poor prognosis in estrogen receptor alpha-negative breast carcinoma

Purpose

Our aim was to examine the prognostic significance of ERbeta1 and ERbeta2 expression in ERalpha-negative breast carcinomas.

Materials and methods

We evaluated nuclear and cytoplasmic expression of ERbeta1 and ERbeta2 by immunohistochemistry in a group of 95 patients with long follow-up. ERbeta1 and ERbeta2 status was correlated with clinicopathological parameters and disease outcome. Univariate and multivariate analyses of ERbeta1 and ERbeta2 as independent markers of disease-free survival (DFS) were carried out using the Cox proportional hazards model.

Results

Nuclear ERbeta1 (nERbeta1) and nERbeta2 status was positively correlated (p = 0.01). nERbeta1 positivity was associated with low histological grade (p = 0.01) in all patients and in the nERbeta2-positive subgroup (p = 0.03) but not in the nERbeta2-negative (p = 0.27). nERbeta2 positivity was associated with lymph node involvement and tumor relapse in all cases (p < 0.00 and p < 0.00, respectively) and in the nERbeta1-negative subgroup (p < 0.00 and p < 0.00, respectively) but not in the nERbeta1-positive (p = 0.09 and p = 0.20, respectively). nERbeta2 positivity was associated with poor DFS in all patients (log-rank p <0.00), in the post-menopausal patient subgroup (log-rank p = 0.02) and in the HER2-negative (triple-negative) subgroup (log-rank p = 0.04). Cox multivariate analysis including ERbeta1, ERbeta2 and established clinicopathological variables highlighted ERbeta2 as an independent marker of early disease recurrence (hazard ratio 4.87; 95 % confidence interval 1.07–22.3; p = 0.04).

Conclusion

High nERbeta2 is an independent marker of early relapse in ERalpha-negative breast carcinoma, and in particular, in the nERbeta1-negative, the post-menopausal patient and the triple-negative subgroups. These findings suggest that inhibition of expression and/or function of ERbeta2 could improve disease outcome.     

Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) are clonal disorders of hematopoietic stem cells (HSCs) characterized by ineffective hematopoiesis. MDSs are responsible for 1 or several peripheral cytopenias. The evidence accumulated in recent years demonstrates that in addition to HSC defects, a particular role is also played by stromal microenvironment dysfunctions, which mediate the direct contact with hematopoietic precursor cells (HPCs). These interactions help regulate different adhesion-related processes, such as progenitor cell proliferation, apoptosis, clonogenic growth, and maintenance in in vitro cultures. As previously reported, these interactions are responsible for altering the microenvironment in MDS. Herein, we present a novel selection protocol for obtaining a standards-compliant mesenchymal stromal cell (MSC) preparation. This method allowed us to comparatively analyze 2 subpopulations of bone marrow MSCs (BM-MSCs) in terms of their adhesion profiles and growth abilities: BM-MSCs selected from MDS settings and their normal counterparts. Functional assays revealed that the MSCs from MDS are intrinsically pathological, thus showing a continuous decline of proliferation and a reduced clonogenic capacity during 14 days of culture and in the absence of signals from hematopoietic cells. The MSC growth defects were significantly correlated with decreases in CD44 adhesion molecules and CD49e (α5-integrin).