Astrocyte heterogeneity is increasingly recognized, but still little is known about juxtavascular astrocytes with their somata directly adjacent to blood vessels, despite their importance after brain injury. As juxtavascular astrocytes originate from common progenitor cells, that is, have a clonal origin, they may intrinsically differ from other, nonjuxtavascular astrocytes. To explore this, we examined the electrophysiological properties of these groups of astrocytes and the underlying ion channels. Using brain slices of BAC Aldh1l1-eGFP transgenic mice with astrocytes labeled by GFP expression, we compared juxtavascular and non-juxtavascular astrocytes in the somatosensory cortex by means of whole-cell patch-clamp recordings and immunohistochemical staining. Prior to injury, juxta-and non-juxtavascular astrocytes exhibit comparable electrophysiological properties with characteristic mostly passive conductance and a typical negative resting membrane potential. Immunohistochemical analysis of K + channels showed that all astrocytes were K ir 4.1 + , but revealed an intriguing difference for K v 4.3. The expression of K v 4.3 in sibling astrocytes (non-juxtavascular, juxtavascular and pial) was dependent on their ontogenetic origin with lowest levels in juxtavascular astrocytes located in upper cortical layers. After traumatic brain injury (TBI), we found profound changes in the electrophysiological type of astrocytes with a predominance of non-passive properties and this pattern was significantly enriched in juxtavascular astrocytes. This was accompanied by pronounced down-regulation of K ir 4.1 in proliferating astrocytes, which was significantly more in juxtavascular compared to non-juxtavascular astrocytes. Taken together, TBI induces profound differences in electrophysiological properties between juxtavascular and non-juxtavascular astrocytes that might be related to the preponderance of juxtavascular astrocyte proliferation.
M.M. and M.B. contributed equally to the present manuscriptWhat's known on the subject? and What does the study add?• Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between different Broders' grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet.• Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders' grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of 82% for CSS.
Objective• To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically treated squamous cell carcinoma of the penis (SCCP).
Patients and Methods• A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade.• The 5-year CSS for the entire study cohort was 62%.• Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036).• In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS.• The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741-0.898).
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