Cultivating the next generation of leaders : How postdocs, principal investigators and institutes can nurture and select for leadership competencies.

The transition from postdoc to PI is the most challenging career step. Peer groups, PIs and research institution can help postdocs to acquire the necessary skills and experience. [Image: see text]

pSTAT3 Expression is Increased in Advanced Prostate Cancer in Post-Initiation of Androgen Deprivation Therapy.

Background: The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) plays a role in carcinogenesis and is involved in processes, such as proliferation, differentiation, drug resistance and immunosuppression. STAT3 can be activated by phosphorylation of tyrosine at position 705 (pSTAT3) or serine at 727 (pSTAT3). High expression levels of pSTAT3 are implicated in advanced stages of prostate cancer (PCa) and are known to interact with the androgen receptor signaling pathway.

Artificial intelligence for detection of prostate cancer in biopsies during active surveillance.

Objectives: To evaluate a cancer detecting artificial intelligence (AI) algorithm on serial biopsies in patients with prostate cancer on active surveillance (AS).

Patients And Methods: A total of 180 patients in the Prostate Cancer Research International Active Surveillance (PRIAS) cohort were prospectively monitored using pre-defined criteria. Diagnostic and re-biopsy slides from 2011 to 2020 (n = 4744) were scanned and analysed by an in-house AI-based cancer detection algorithm.

Development, Validation, and Clinical Utility of a Six-gene Signature to Predict Aggressive Prostate Cancer.

Background: Molecular signatures in prostate cancer (PCa) tissue can provide useful prognostic information to improve the understanding of a patient's risk of harbouring aggressive disease.

Objective: To develop and validate a gene signature that adds independent prognostic information to clinical parameters for better treatment decisions and patient management.

Design, Setting, And Participants: Expression of 14 genes was evaluated in radical prostatectomy (RP) tissue from an Irish cohort of PCa patients (n = 426).

Nuclear expression of pSTAT3 and pSTAT3 in the stromal compartment of localized hormone-naïve prostate cancer.

Background: The signal transducer and activator of transcription 3 (STAT3) is involved in the progression of different tumors including prostate cancer (PCa). The expression of STAT3 in benign and malignant epithelium has been described previously but it has not been described in the stromal compartment. The aim of the present study was to evaluate the nuclear expression and prognostic value of different forms of phosphorylated STAT3 in the stromal compartment of non-cancer and cancer areas of prostatic tissue.

The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types.

Background: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed.

Methods: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours.

An Artificial Intelligence-based Support Tool for Automation and Standardisation of Gleason Grading in Prostate Biopsies.

Background: Gleason grading is the standard diagnostic method for prostate cancer and is essential for determining prognosis and treatment. The dearth of expert pathologists, the inter- and intraobserver variability, as well as the labour intensity of Gleason grading all necessitate the development of a user-friendly tool for robust standardisation.

Objective: To develop an artificial intelligence (AI) algorithm, based on machine learning and convolutional neural networks, as a tool for improved standardisation in Gleason grading in prostate cancer biopsies.

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases.

Hemopexin (Hx) is a scavenger of labile heme. Herein, we present data defining the role of tumor stroma-expressed Hx in suppressing cancer progression. Labile heme and Hx levels are inversely correlated in the plasma of patients with prostate cancer (PCa).

Annexin A5 prevents amyloid-β-induced toxicity in choroid plexus: implication for Alzheimer's disease.

In Alzheimer's disease (AD) amyloid-β (Aβ) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood-cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy subjects. One of these proteins, annexin A5, was previously demonstrated implicated in blocking Aβ-induced cytotoxicity in neuronal cell cultures.

Reelin Immunoreactivity in the Adult Spinal Cord: A Comparative Study in Rodents, Carnivores, and Non-human Primates.

Reelin is a large extracellular matrix (ECM) glycoprotein secreted by several neuronal populations in a specific manner in both the developing and the adult central nervous system. The extent of Reelin protein distribution and its functional role in the adult neocortex is well documented in different mammal models. However, its role in the adult spinal cord has not been well characterized and its distribution in the rodent spinal cord is fragmentary and has not been investigated in carnivores or primates as of yet.

Expression of tSTAT3, pSTAT3 , and pSTAT3 in the epithelial cells of hormone-naïve prostate cancer.

Background: The signal transducer and activator of transcription 3 (STAT3) pathway is observed to be constitutively activated in several malignancies including prostate cancer (PCa). In the present study, we investigated the expression of total STAT3 (tSTAT3) and two forms of activated phosphorylated STAT3 (pSTAT3 and pSTAT3 ) in tissue microarrays (TMA) of two cohorts of localized hormone-naïve PCa patients and analyzed associations between the expression and disease outcome.

Methods: The expression of tSTAT3, pSTAT3 , and pSTAT3 was scored in the nuclei and cytoplasm of prostatic gland epithelial cells in two TMAs of paraffin-embedded prostatic tissue.

Proteogenomic Characterization of Patient-Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration-Resistant Prostate Cancer.

Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. We applied mass spectrometry-based proteomics to a unique set of 17 prostate cancer patient-derived xenografts (PDX) to characterize the effects of castration , and the proteome differences between NEPC and prostate adenocarcinomas.

Treatment with the WNT5A-mimicking peptide Foxy-5 effectively reduces the metastatic spread of WNT5A-low prostate cancer cells in an orthotopic mouse model.

Prostate cancer patients with high WNT5A expression in their tumors have been shown to have more favorable prognosis than those with low WNT5A expression. This suggests that reconstitution of Wnt5a in low WNT5A-expressing tumors might be an attractive therapeutic approach. To explore this idea, we have in the present study used Foxy-5, a WNT5A mimicking peptide, to investigate its impact on primary tumor and metastasis in vivo and on prostate cancer cell viability, apoptosis and invasion in vitro.

Expression of STAT3 in Prostate Cancer Metastases.

Unlabelled: STAT3 and its upstream activator IL6R have been implicated in the progression of prostate cancer and are possible future therapeutic targets. We analyzed 223 metastatic samples from rapid autopsies of 71 patients who had died of castration-resistant prostate cancer (CRPC) to study protein and gene expression of pSTAT3 and IL6R. Immunohistochemical analysis revealed that 95% of metastases were positive for pSTAT3 and IL6R, with varying expression levels.

The Prognostic Impact of NK/NKT Cell Density in Periampullary Adenocarcinoma Differs by Morphological Type and Adjuvant Treatment.

Background: Natural killer (NK) cells and NK T cells (NKT) are vital parts of tumour immunosurveillance. However, their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, has not yet been described.

Methods: Immune cell-specific expression of CD56, CD3, CD68 and CD1a was analysed by immunohistochemistry on tissue microarrays with tumours from 175 consecutive cases of periampullary adenocarcinoma, 110 of pancreatobiliary type (PB-type) and 65 of intestinal type (I-type) morphology.

Quantitative Time-Resolved Fluorescence Imaging of Androgen Receptor and Prostate-Specific Antigen in Prostate Tissue Sections.

Androgen receptor (AR) and prostate-specific antigen (PSA) are expressed in the prostate and are involved in prostate cancer (PCa). The aim of this study was to develop reliable protocols for reproducible quantification of AR and PSA in benign and malignant prostate tissue using time-resolved fluorescence (TRF) imaging techniques. AR and PSA were detected with TRF in tissue microarrays from 91 PCa patients.

The STAT3 Inhibitor Galiellalactone Effectively Reduces Tumor Growth and Metastatic Spread in an Orthotopic Xenograft Mouse Model of Prostate Cancer.

Unlabelled: Signal transducer and activator of transcription 3 (STAT3) is known to be involved in the progression of prostate cancer (PCa) and is a key factor in drug resistance and tumor immunoescape. As a result, it represents a promising target for PCa therapy. We studied the effects of the STAT3 inhibitor galiellalactone (GL) on tumor growth and metastatic spread in vitro and in vivo.

Expression of regulatory proteins in choroid plexus changes in early stages of Alzheimer disease.

Recent studies indicate that the choroid plexus has important physiologic and pathologic roles in Alzheimer disease (AD). To obtain additional insight on choroid plexus function, we performed a proteomic analysis of choroid plexus samples from patients with AD stages I to II (n = 16), III to IV (n = 16), and V to VI (n = 11) and 7 age-matched control subjects. We used 2-dimensional differential gel electrophoresis coupled with mass spectrometry to generate a complete picture of changes in choroid plexus protein expression occurring in AD patients.

Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease.

Elevated levels of amyloid beta (Aβ) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD.

Behavioral testing in rodent models of orofacial neuropathic and inflammatory pain.

Orofacial pain conditions are often very debilitating to the patient and difficult to treat. While clinical interest is high, the proportion of studies performed in the orofacial region in laboratory animals is relatively low, compared with other body regions. This is partly due to difficulties in testing freely moving animals and therefore lack of reliable testing methods.

Pathological alteration in the choroid plexus of Alzheimer's disease: implication for new therapy approaches.

Morphological alterations of choroid plexus in Alzheimer's disease (AD) have been extensively investigated. These changes include epithelial atrophy, thickening of the basement membrane, and stroma fibrosis. As a result, synthesis, secretory, and transportation functions are significantly altered resulting in decreased cerebrospinal fluid (CSF) turnover.

Assessing nociceptive sensitivity in mouse models of inflammatory and neuropathic trigeminal pain.

Chronic orofacial pain encompasses a range of debilitating conditions, however in contrast to other body regions, few animal models are available to investigate mechanisms and treatments in the trigeminal area. Particularly, there is a lack of reliable models and testing methods in mice. We have behaviourally tested C57BL/6 mice subjected to unilateral chronic constriction injury (CCI) of the infraorbital nerve (IoN) or unilateral injections of Complete Freunds Adjuvant (CFA) into the vibrissal pad region with the aid of von Frey filaments and air-puffs and the use of a newly designed restraining device.

DREAM regulates BDNF-dependent spinal sensitization.

Background: The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) controls the expression of prodynorphin and has been involved in the modulation of endogenous responses to pain. To investigate the role of DREAM in central mechanisms of pain sensitization, we used a line of transgenic mice (L1) overexpressing a Ca(2+)- and cAMP-insensitive DREAM mutant in spinal cord and dorsal root ganglia.

Results: L1 DREAM transgenic mice showed reduced expression in the spinal cord of several genes related to pain, including prodynorphin and BDNF (brain-derived neurotrophic factor) and a state of basal hyperalgesia without change in A-type currents.

Cot/tpl2 (MAP3K8) mediates myeloperoxidase activity and hypernociception following peripheral inflammation.

Cot/tpl2 (also known as MAP3K8) has emerged as a new and potentially interesting therapeutic anti-inflammatory target. Here, we report the first study of Cot/tpl2 involvement in acute peripheral inflammation in vivo. Six hours after an intraplantar injection of zymosan, Cot/tpl2(-/-) mice showed a 47% reduction in myeloperoxidase activity, concomitant with a 46% lower neutrophil recruitment and a 40% decreased luminol-mediated bioluminescence imaging in vivo.

Local caspase activity directs engulfment of dendrites during pruning.

Pruning is important for sculpting neural circuits, as it removes excessive or inaccurate projections. Here we show that the removal of sensory neuron dendrites during pruning in Drosophila melanogaster is directed by local caspase activity. Suppressing caspase activity prevented dendrite removal, whereas a global activation of caspases within a neuron caused cell death.