Introduction: We sought to determine if prostate cancer (PCa) is associated with worse lower urinary tract symptoms (LUTS) than matched benign prostates, with attention to cancer characteristics, in ...a contemporary cohort.Methods: Using a single-institution database (January 1, 2009‒ June 30, 2013), men diagnosed with PCa on biopsy and controls with negative biopsies were matched 1:1 on age, prostate volume, and a propensity score predicting the probability of PCa diagnosis. International Prostate Symptom Score (IPSS) was compared between PCa cases and controls using paired statistics, stratifying on grade, cancer volume, stage, and D’Amico risk group. Sensitivity analyses were performed separately, repeating the match for highgrade, high-volume, and high-stage cancers only, and excluding users of benign prostatic hyperplasia medications.Results: In our cohort of 1330 men (665 with PCa), there were 284 (42.7%) Gleason 6 cancers (Grade Group 1), 315 (47.4%) Gleason 7 cancers (Grade Group 2‒3), and 66 (9.9%) Gleason 8‒10 cancers (Grade Group 4‒5). There was no difference in IPSS between PCa cases (median 6.5, interquartile range IQR 3‒12) and benign controls (median 7, IQR 3‒13; p=0.34). Subgroup analyses based on cancer grade, volume, or stage, showed no significant differences in IPSS between men with and without PCa, except among men with cT2b-cT4 PC (median 9, IQR 5‒16) vs. matched benign counterparts (median 8, IQR 3‒12; p=0.03). Sensitivity analyses supported these findings.Conclusions: Modern PCa does not appear to be associated with worse LUTS compared to benign prostates of the same size. Outlet obstruction is likely a late event in the natural history of PCa. This has implications for timely PCa detection, which should ideally be prior to the onset of LUTS.
We sought to determine if prostate cancer (PCa) is associated with worse lower urinary tract symptoms (LUTS) than matched benign prostates, with attention to cancer characteristics, in a contemporary ...cohort.
Using a single-institution database (January 1, 2009-June 30, 2013), men diagnosed with PCa on biopsy and controls with negative biopsies were matched 1:1 on age, prostate volume, and a propensity score predicting the probability of PCa diagnosis. International Prostate Symptom Score (IPSS) was compared between PCa cases and controls using paired statistics, stratifying on grade, cancer volume, stage, and D'Amico risk group. Sensitivity analyses were performed separately, repeating the match for high-grade, high-volume, and high-stage cancers only, and excluding users of benign prostatic hyperplasia medications.
In our cohort of 1330 men (665 with PCa), there were 284 (42.7%) Gleason 6 cancers (Grade Group 1), 315 (47.4%) Gleason 7 cancers (Grade Group 2-3), and 66 (9.9%) Gleason 8-10 cancers (Grade Group 4-5). There was no difference in IPSS between PCa cases (median 6.5, interquartile range IQR 3-12) and benign controls (median 7, IQR 3-13; p=0.34). Subgroup analyses based on cancer grade, volume, or stage, showed no significant differences in IPSS between men with and without PCa, except among men with cT2b-cT4 PC (median 9, IQR 5-16) vs. matched benign counterparts (median 8, IQR 3-12; p=0.03). Sensitivity analyses supported these findings.
Modern PCa does not appear to be associated with worse LUTS compared to benign prostates of the same size. Outlet obstruction is likely a late event in the natural history of PCa. This has implications for timely PCa detection, which should ideally be prior to the onset of LUTS.
A hippocampal neuron in primary culture stained with anti‐PIST (red) and anti‐neuroligin‐2 (green), a postsynaptic cell adhesion protein which is exclusively located at inhibitory synapses. The ...nucleus was stained with DAPI (blue). Note the typical distribution of neuroligin‐2 immunoreactivity reminiscent of inhibitory synapses at proximal dendrites and cell body, which is not matched by the PIST immunofluorescence signal. The latter is concentrated in the perikaryon in a juxtanuclear position and appears to be absent from postsynaptic sites. The Journal of Comparative Neurology, Volume 520, Number 5, pages 889–913.
Somatostatin (SOM) is a neuropeptide fulfilling numerous physiological and neuro-modulatory functions throughout the body and brain. Its actions are mediated through a family of G Protein-coupled ...receptors (GPCRs), designated sst1-5, which are differentially regulated. While in vitro studies have previously demonstrated that the co-expression of several SOM receptor subtypes in cell lines has influence over receptor regulation and trafficking, this has yet to be confirmed in situ. Moreover, SOM receptors carry on their C-terminal ends, PDZ-binding motifs that mediate dynamic interactions between the receptors and various scaffolding and accessory proteins that also contain PDZ-binding motifs. For example, the "Protein Interacting Specifically with Tc10", abbreviated PIST, is a Golgi-associated chaperone that has been implicated in the cell surface targeting of sst5. The goal of my Master's thesis is to clarify, in situ, the regional and sub-cellular distributions of the sst2a and sst5 receptors, as well as the PDZ protein PIST, in the rat Basal Forebrain (BF). In the first portion of my thesis, I set out to identify, using stereology based quantification methods, neuronal populations co-expressing sst2a and sst5. Within the BF, 72% of SOM receptor expressing neurons co-expressed both sst2a and sst5. However, when qualitatively analyzed at the sub-cellular level, sst2a and sst5 did not co-localize to the same organelle compartments. In the second part of my project, I semi-quantitatively examined the sub-cellular distribution of PIST in nuclei of the BF. I found that the majority of immuno-labeled neurons (57% within the Olfactory Tubercle, 84% in the Ventral Pallidum and 82% in the horizontal limb of the diagonal band of Broca) presented a dispersed and granular pattern of of PIST distribution, where the chaperone localized primarily to punctate organelles that were separate from markers for the Trans-Golgi. Finally, I employed stereology-based methods to quantify the proportions of sst5-containing neurons that co-express the PIST chaperone. Though sst5 and PIST were found co-expressed in 46% of immuno-labeled neurons of the BF, their sub-cellular distributions indicated no overt signs of co-localization at the organelle level. In summary, past in vitro studies have shown that the intracellular trafficking of SOM receptors may be regulated through the expression of multiple SOM receptor subtypes, as well as through interactions with PDZ-motif containing chaperones, like PIST. My anatomical project suggests that the regional and subcellular distributions of SOM receptors and PIST in situ may be conducive to these models of regulation.
La Somatostatine (SOM) est un neuropeptide ayant de nombreuses fonctions physiologiques et neuro-modulatrices dans tout le corps et le cerveau. Ses actions sont contrôlées par une famille de récepteurs couplés aux protéines-G (GPCR), désignés sst1-5, et qui sont régulés différemment. Alors que des études in vitro ont déjà démontré que la co-expression de plusieurs sous-types du récepteur SOM dans des lignées cellulaires a une influence sur la régulation et le trafic du récepteur, cela reste encore à être confirmé in situ. De plus, les récepteurs SOM contienent, aux C-terminaux, des motifs de liaison PDZ qui interviennent dans les interactions dynamiques entre les récepteurs et des protéines d'échafaudages, et des accessoires qui contiennent également des motifs de liaison PDZ. Par exemple, le chaperon «Protein Interacting Specifically with Tc10», PIST, une est protéine associée à l'appareil de Golgi, et impliqué dans le ciblage, au niveau de la surface-cellulaire, des récepteurs neuropeptidique, tel que le sst5. Le but de ma thèse de maîtrise est de clarifier in situ la répartition régionale et sous-cellulaire de sst2a et sst5, ainsi de que PIST, dans le cerveau antérieur basal (BF) chez le rat. Dans la première partie de ma thèse, j'ai identifié, en utilisant des méthodes de quantifications stéréologiques, les populations neuronales qui co-expriment sst2a et sst5. Dans le BF, 72% des neurones exprimant des récepteurs SOM ont co-exprimé sst2a et sst5. Cependant, quand ils ont été analysés qualitativement au niveau sous-cellulaire, sst2a et sst5 n'ont pas été trouvés co-localisés dans les mêmes organelles.Dans la deuxième partie de mon projet, j'ai examiné semi-quantitativement la distribution sous-cellulaire de PIST dans les noyaux du BF. J'ai trouvé que la majorité des neurones immuno-marqués (57% dans le tubercule olfactif, 84% dans le pallidum ventral et 82% dans la branche horizontale de la bande diagonale de Broca) ont présenté une distribution de PIST dispersée et granulaire qui ressemble à des compartiments vésiculaires et qui sont séparés des marqueurs du trans-Golgi. Finalement, j'ai employé des méthodes stéréologiques pour quantifier les proportions des neurones contenant le sst5 qui co-expriment le chaperon PIST. Bien que sst5 et PIST ont été trouvés co-exprimés dans 46% des neurones immuno-marqués de la BF, leurs distributions sous-cellulaires n'indiquent pas des signe de co-localisation au niveau des organelles. En résumé, des études precédentes in vitro ont montré que le trafic intracellulaire des récepteurs SOM peut être régulé par l'expression de plusieurs sous-types de récepteurs SOM, ainsi que par des interactions avec des chaperons-PDZ comme PIST. Mon projet anatomique in situ suggère que la répartition régionale et sous-cellulaire des récepteurs SOM et PIST favorise ces modèles de régulation.
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