Therapeutic targeting of gastrointestinal cancer stem cells.

Gastrointestinal cancers remain a tremendous burden on society. Despite advances in therapy options, including chemotherapy and radiation, cancer mortality from recurrences and metastases occur frequently. Cancer stem cells (CSCs) drive disease recurrence and metastasis, as these cells are uniquely equipped to self-renew and evade therapy. Therefore, cancer eradication requires treatment strategies that target CSCs in addition to differentiated cancer cells. This review highlights current literature on therapies targeting CSCs in gastrointestinal cancer.

Regional Molecular Signature of the Symptomatic Atherosclerotic Carotid Plaque.

BACKGROUND: Many studies have explored molecular markers of carotid plaque development and vulnerability to rupture, usually having examined whole carotid plaques. However, there are regional differences in plaque morphology and known shear-related mechanisms in areas surrounding the lipid core. OBJECTIVE: To determine whether there are regional differences in protein expression along the long axis of the carotid plaque and how that might produce gaps in our understanding of the carotid plaque molecular signature. METHODS: Levels of 7 inflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12 p70, IFN-γ, and TNF-α) and caspase-3 were analyzed in prebifurcation, bifurcation, and postbifurcation segments of internal carotid plaques surgically removed from symptomatic and asymptomatic patients. Expression profiles of miRNAs and mRNAs were determined with microarrays for the rupture-prone postbifurcation segment for comparison with published whole plaque results. RESULTS: Expression levels of all proteins examined, except IL-10, were lowest in the prebifurcation segment and significantly higher in the postbifurcation segment. Patient group differences in protein expression were observed for the prebifurcation segment; however, no significant differences were observed in the postbifurcation segment between symptomatic and asymptomatic patients. Expression profiles from postbifurcation carotid plaques identified 4 novel high priority miRNAs differentially expressed between patient groups (miR-214, miR-484, miR-942, and miR-1287) and 3 high-confidence miRNA:mRNA targets, including miR-214:APOD, miR-484:DACH1, and miR-942:GPR56. CONCLUSION: The results demonstrate regional differences in protein expression for the first time and show that focus on the rupture-prone postbifurcation region leads to prioritization for further study of novel miRNA gene regulation mechanisms.

Advances in Chimeric Antigen Receptor T-Cell Therapies for Solid Tumors.

In 2017, the US Food and Drug Administration approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CARs), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed "living drugs" for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted. This state-of-the-art review will focus on the challenges, advances, and novel approaches being used to implement CAR T-cell immunotherapy for the treatment of solid tumors.

Comprehensive chronic laminar single-unit, multi-unit, and local field potential recording performance with planar single shank electrode arrays.

BACKGROUND: Intracortical electrode arrays that can record extracellular action potentials from small, targeted groups of neurons are critical for basic neuroscience research and emerging clinical applications. In general, these electrode devices suffer from reliability and variability issues, which have led to comparative studies of existing and emerging electrode designs to optimize performance. Comparisons of different chronic recording devices have been limited to single-unit (SU) activity and employed a bulk averaging approach treating brain architecture as homogeneous with respect to electrode distribution. NEW METHOD: In this study, we optimize the methods and parameters to quantify evoked multi-unit (MU) and local field potential (LFP) recordings in eight mice visual cortices. RESULTS: These findings quantify the large recording differences stemming from anatomical differences in depth and the layer dependent relative changes to SU and MU recording performance over 6-months. For example, performance metrics in Layer V and stratum pyramidale were initially higher than Layer II/III, but decrease more rapidly. On the other hand, Layer II/III maintained recording metrics longer. In addition, chronic changes at the level of layer IV are evaluated using visually evoked current source density. COMPARISON WITH EXISTING METHOD(S): The use of MU and LFP activity for evaluation and tracking biological depth provides a more comprehensive characterization of the electrophysiological performance landscape of microelectrodes. CONCLUSIONS: A more extensive spatial and temporal insight into the chronic electrophysiological performance over time will help uncover the biological and mechanical failure mechanisms of the neural electrodes and direct future research toward the elucidation of design optimization for specific applications.

Effects of caspase-1 knockout on chronic neural recording quality and longevity: insight into cellular and molecular mechanisms of the reactive tissue response.

Chronic implantation of microelectrodes into the cortex has been shown to lead to inflammatory gliosis and neuronal loss in the microenvironment immediately surrounding the probe, a hypothesized cause of neural recording failure. Caspase-1 (aka Interleukin 1ß converting enzyme) is known to play a key role in both inflammation and programmed cell death, particularly in stroke and neurodegenerative diseases. Caspase-1 knockout (KO) mice are resistant to apoptosis and these mice have preserved neurologic function by reducing ischemia-induced brain injury in stroke models. Local ischemic injury can occur following neural probe insertion and thus in this study we investigated the hypothesis that caspase-1 KO mice would have less ischemic injury surrounding the neural probe. In this study, caspase-1 KO mice were implanted with chronic single shank 3 mm Michigan probes into V1m cortex. Electrophysiology recording showed significantly improved single-unit recording performance (yield and signal to noise ratio) of caspase-1 KO mice compared to wild type C57B6 (WT) mice over the course of up to 6 months for the majority of the depth. The higher yield is supported by the improved neuronal survival in the caspase-1 KO mice. Impedance fluctuates over time but appears to be steadier in the caspase-1 KO especially at longer time points, suggesting milder glia scarring. These findings show that caspase-1 is a promising target for pharmacologic interventions.

Beta-adrenergic receptors in the lateral nucleus of the amygdala contribute to the acquisition but not the consolidation of auditory fear conditioning.

Beta-adrenergic receptors (ßARs) have long been associated with fear disorders and with learning and memory. However, the contribution of these receptors to Pavlovian fear conditioning, a leading behavioral model for studying fear learning and memory, is still poorly understood. The aim of this study was to investigate the involvement of ßAR activation in the acquisition, consolidation and expression of fear conditioning. We focused on manipulations of ßARs in the lateral nucleus of the amygdala (LA) because of the well-established contribution of this area to fear conditioning. Specifically, we tested the effects of intra-LA microinfusions of the ßAR antagonist, propranolol, on learning and memory for auditory Pavlovian fear conditioning in rats. Pre-training propranolol infusions disrupted the initial acquisition, short-term memory (STM), and long-term memory (LTM) for fear conditioning, but infusions immediately after training had no effect. Further, infusion of propranolol prior to testing fear responses did not affect fear memory expression. These findings indicate that amygdala ßARs are important for the acquisition but not the consolidation of fear conditioning.