Biodistribution and Clearance of Stable Superparamagnetic Maghemite Iron Oxide Nanoparticles in Mice Following Intraperitoneal Administration.

Nanomedicine is an emerging field with great potential in disease theranostics. We generated sterically stabilized superparamagnetic iron oxide nanoparticles (s-SPIONs) with average core diameters of 10 and 25 nm and determined the in vivo biodistribution and clearance profiles. Healthy nude mice underwent an intraperitoneal injection of these s-SPIONs at a dose of 90 mg Fe/kg body weight. Tissue iron biodistribution was monitored by atomic absorption spectroscopy and Prussian blue staining. Histopathological examination was performed to assess tissue toxicity. The 10 nm s-SPIONs resulted in higher tissue-iron levels, whereas the 25 nm s-SPIONs peaked earlier and cleared faster. Increased iron levels were detected in all organs and body fluids tested except for the brain, with notable increases in the liver, spleen, and the omentum. The tissue-iron returned to control or near control levels within 7 days post-injection, except in the omentum, which had the largest and most variable accumulation of s-SPIONs. No obvious tissue changes were noted although an influx of macrophages was observed in several tissues suggesting their involvement in s-SPION sequestration and clearance. These results demonstrate that the s-SPIONs do not degrade or aggregate in vivo and intraperitoneal administration is well tolerated, with a broad and transient biodistribution. In an ovarian tumor model, s-SPIONs were shown to accumulate in the tumors, highlighting their potential use as a chemotherapy delivery agent.

PSMA Expression Correlates with Improved Overall Survival and VEGF Expression in Glioblastoma.

BACKGROUND: Glioblastomas are the most common and fatal primary brain malignancy in adults. There is a growing interest in identifying the molecular mechanisms of these tumors to develop novel treatments. Glioblastoma neo-angiogenesis is driven by VEGF, and another potential molecule linked to angiogenesis is PSMA. Our study suggests the potential for an association between PSMA and VEGF expression in glioblastoma neo-vasculature. METHODS: Archived IDH1/2 wild-type glioblastomas were accessed; demographic and clinical outcomes were recorded. PSMA and VEGF expression by IHC were examined. Patients were dichotomized into PSMA expression high (3+) and low (0-2+) groups. The association between PSMA and VEGF expression was evaluated using Chi2 analysis. OS in PSMA high and low expression groups were compared using multi-linear regression. RESULTS: In total, 247 patients with IDH1/2 wild-type glioblastoma with archival tumor samples (between 2009-2014) were examined. PSMA expression correlated positively with VEGF expression (p = 0.01). We detected a significant difference in median OS between PSMA vascular endothelial expression high and low groups-16.1 and 10.8 months, respectively (p = 0.02). CONCLUSION: We found a potential positive correlation between PSMA and VEGF expression. Secondly, we showed a potential positive correlation between PSMA expression and overall survival.

Tissue biomarker panel as a surrogate marker for squamous subtype of pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been recently classified into four subtypes based on the gene expression levels, with squamous subtype having worst prognostic outcomes. However, gene expression analysis for each individual patient is not clinically feasible due to very high associated cost. We previously reported that levels of three biomarkers (S100A4, Ca-125 and Mesothelin) can be used to classify PDAC patients based on their survival outcomes. This project aimed to determine if this novel biomarker panel can be used as a surrogate to identify squamous PDAC subtype. METHODS: Using the Nanostring gene expression platform, tumor tissue from 24 PDAC patients were analysed for our novel biomarkers and markers associated with four PDAC subtypes. RESULTS: Gene expression of our biomarker panel (S100A4, Ca-125 and Mesothelin) closely clustered together with markers for squamous PDAC subtype. CONCLUSION: These results highlight the potential of our biomarkers to be utilized for identification of squamous PDAC subtype.

Lateralisation of projections from the rostral ventrolateral medulla to sympathetic preganglionic neurons in the rat.

Spinally projecting sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM), synapse with sympathetic preganglionic neurons (SPN) and regulate the activity of sympathetic nerves that control the heart, blood pressure and the adrenal medulla (AM). However, the degree of lateralization of the bulbospinal projections to SPN innervating specific targets is poorly understood. Three approaches were used in this study. Anterograde tracer was iontophoresed into a pressor site in the RVLM (left or right) and retrograde tracer injected into the superior cervical ganglion (SCG, right) and the AM (left). Close appositions between anterogradely labelled axons and retrogradely labelled SCG- or AM-SPN were counted. Projections to the SCG were bilateral. Projections to the AM were markedly ipsilateral. In the second part, retrograde tracers were injected unilaterally into the region of the intermediolateral cell column at spinal segment T2 or T8 on one side and the number of labelled neurons in the RVLM counted. The results from each level of injection were similar showing that approximately 63-64% of the neurons were ipsilateral. Responses to glutamate microinjection into the RVLM on adrenal nerve (left) and superior cervical nerve (left) activity were measured. The ratio of the nerve responses was the same even when different sides of the RVLM were injected. The anterograde data strongly suggest that the RVLM projections to AM-SPN are predominantly ipsilateral. Although other experimental approaches also attempted to investigate lateralization, the retrograde data target different and functionally heterogeneous pools of SPN that may mask the ipsilateral projection to the AM. Similarly, chemical stimulation of the RVLM will excite not only monosynaptic projections but also polysynaptic projections that may also mask the predominant ipsilateral monosynaptic projection to AM.

Maps of cardiovascular and respiratory regions of rat ventral medulla: focus on the caudal medulla.

The ventral medulla oblongata is critical for cardiorespiratory regulation. Here we review previous literature relating to sites within the ventral medulla that have been identified as having a 'cardiovascular' or 'respiratory' function. Together with the maps generated here, of sites from which cardiovascular and respiratory responses were evoked by glutamate microinjection, specific 'cardiovascular' regions have been defined and delineated. Commonly investigated regions, including the vasopressor rostral ventrolateral medulla (RVLM) and vasodepressor caudal ventrolateral medulla (CVLM), or areas only described by others, such as the medullary cerebral vasodilator area, are included for completeness. Emphasis is given to the caudal medulla, where three pressor regions, the caudal pressor area (CPA), the intermediate pressor area (IPA) and the medullo-cervical pressor area (MCPA), caudal to the vasodepressor CVLM were defined in the original data provided. The IPA is most responsive under pentobarbitone rather than urethane anaesthesia clearly delineating it from both the rostrally located CPA and the caudally located MCPA. The description of these multiple pressor areas appears to clarify the confusion that surrounds the identification of the 'CPA'. Also noted is a vasopressor region adjacent to the vasodepressor CVLM. Apart from the well described ventral respiratory column, a region medial to the pre-Bötzinger is described, from which increases in both phrenic nerve frequency and amplitude were evoked. Limitations associated with the technique of glutamate microinjection to define functionally specific regions are discussed. Particular effort has been made to define and delineate the regions with respect to ventrally located anatomical landmarks rather than the commonly used ventral surface or dorsal landmarks such as the obex or calamus scriptorius that may vary with the brain orientation or histological processing. This should ensure that a region can easily be defined by all investigators. Study of defined regions will help expedite the identification of the role of the multiple cell groups with diverse neurotransmitter complements that exist even within each of the regions described, in coordinating the delivery of oxygenated blood to the tissues.