Expression of STAT3 in Prostate Cancer Metastases

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. Bone metastases showed significantly higher expression of both pSTAT3 and IL6R in comparison to lymph node and visceral metastases. STAT3 mRNA levels were significantly higher in bone than in lymph node and visceral metastases, whereas no significant difference in IL6R mRNA expression was observed. Our study strongly supports the suggested view of targeting STAT3 as a therapeutic option in patients with metastatic CRPC. Patient summary We studied the levels of two proteins (pSTAT3 and IL6R) in metastases from patients who died from castration-resistant prostate cancer. We found high levels of pSTAT3and IL6R in bone metastases, suggesting that these proteins could be used as targets for new anticancer drugs

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

In Alzheimer's disease (AD) amyloid-beta (A beta) 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 A beta -induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on A beta toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse A beta accumulation, cell death and annexin A5 levels compared with control subjects. Choroid plexus cell cultures from rats were used to analyse annexin A5 effects on A beta -induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased A beta accumulation and cell death as disease stage was higher. On the other hand, annexin A5 levels in CSF from patients were found progressively increased as the disease stage increased in severity. In choroid plexus primary cultures, A beta administration reduced endogenous annexin A5 levels in a time-course dependent manner and simultaneously increased annexin A5 levels in extracellular medium. Annexin A5 addition to choroid plexus cell cultures restored the A beta -induced impairments on autophagy flux and apoptosis in a calcium-dependent manner. We propose that annexin A5 would exert a protective role in choroid plexus and this protection is lost as A beta accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised

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. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns.Findings: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR (95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59 (1.49-8.62)) associations of the tumour stroma fraction with survival.Interpretation: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance.</p

Peripheral pain mechanisms and their modulation by neurotrophic factors

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

In-vivo PRESS spectroscopy reveals changes in osmolite and phospholipid turnover anticipating those observed by MRI in a model of LPS-induced cerebral inflammation

Trabajo presentado al 29th Annual Scientific Meeting of European Society for Magnetic Resonance In Medicine and Biology, celebrado en Lisboa (Portugal) del 4 al 6 de Octubre de 2012.Peer Reviewe

Early increases in Glu/Gln, Tau and TCho 1H MRS resonances in vivo, anticipate later imaging repercussions of the cerebral inflammatory response in a mouse model of LPS-induced endotoxemia

Trabajo presentado al 21th Annual Meeting & Exhibition of International Society for Magnetic Resonance in Medicine, celebrado en Salt Lake City (US) del 20 al 26 de Abril de 2013.Cerebral inflammation underlies the most morbid and prevalent neurological disorders, including cancer, ischemia or neurodegeneration. However, the inflammatory component remains difficult to differentiate from the intrinsic pathology by most bioimaging methods, since in-vivo biomarkers of the inflammatory phenotype have not been characterized. With this aim, we report a longitudinal MRI and MRS characterization of the cerebral inflammatory component developed after systemic administration of LPS, an inflammation model devoid of additional intrinsic pathologies. Our results revealed that inflammation is characterized by early, severe, spectroscopic changes in Glu/Gln, tCho, Tau and Lac resonances, anticipating those detected later by multi-parametric MRI.Peer Reviewe

Cytokines and Janus kinase/signal transducer and activator of transcription signaling in prostate cancer : overview and therapeutic opportunities

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway was originally identified as a key cellular mechanism mediating the action of cytokines, interferons, and growth factors for the control of gene expression. Extracellular signals mediated by cytokines are thus transduced through this pathway into transcriptional programs that regulate cell growth, differentiation, proliferation, invasion, survival, and inflammation. In prostate cancer, an aberrant or persistent activation of the JAK/STAT signaling is related to tumor growth and disease progression, making this pathway an ideal therapeutic target. Here, we review the most recent literature on this topic, and we summarize the latest advances and future challenges in therapeutically targeting the JAK/STAT pathway in prostate cancer

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. To gain insight into which neuronal populations and specific circuits may be influenced by Reelin in the adult spinal cord, we have conducted light and confocal microscopy study analysis of Reelin-immunoreactive cell types in the adult spinal cord. Here, we describe and compare Reelin immunoreactive cell type and distribution in the spinal cord of adult non-human primate (macaque monkeys, Macaca mulatta), carnivore (ferret, Mustela putorius) and rodent (rat, Rattus norvegicus). Our results show that in all three species studied, Reelin-immunoreactive neurons are present in the intermediate gray matter, ventricular zone and superficial dorsal horn and intermedio-lateral nucleus, while positive cells in the Clarke nucleus are only found in rats and primates. In addition, Reelin intermediolateral neurons colocalize with choline acetyltransferase (ChAT) only in macaque whilst motor neurons also colocalize Reelin and ChAT in macaque, ferret and rat spinal cord. The different expression patterns might reflect a differential role for Reelin in the pathways involved in the coordination of locomotor activity in the fore- and hind limbs