Pharmacological stimulation of infralimbic cortex after fear conditioning facilitates subsequent fear extinction.

The infralimbic (IL) division of the medial prefrontal cortex (mPFC) is a crucial site for the extinction of conditioned fear memories in rodents. Recent work suggests that neuronal plasticity in the IL that occurs during (or soon after) fear conditioning enables subsequent IL-dependent extinction learning. We therefore hypothesized that pharmacological activation of the IL after fear conditioning would promote the extinction of conditioned fear.

From drosophila to humans: a journey through macrophage development.

Macrophages are fascinating immune cells involved in a variety of processes in both health and disease. Although they were first discovered and characterized by their functions as professional phagocytes and antigen-presenting cells, it is now clear that macrophages have multiple roles within embryonic development, tissue homeostasis, regulation of inflammation, and host response to pathogens and tissue insults. Interestingly, macrophages, or macrophage-like cells, exist in a variety of organisms, from echinoderms to humans, and are present also in species that lack an adaptive immune system or hematopoietic stem cells (HSCs).

A high-throughput lysosome trafficking assay guides ligand selection and elucidates differences in CD22-targeted nanodelivery.

Targeted nanoparticles offer potential to selectively deliver therapeutics to cells; however, their subcellular fate following endocytosis must be understood to properly design mechanisms of drug release. Here we describe a nanoparticle platform and associated cell-based assay to observe lysosome trafficking of targeted nanoparticles in live cells. The nanoparticle platform utilizes two fluorescent dyes loaded onto PEG-poly(glutamic acid) and PEG-poly(Lysine) block co-polymers that also comprise azide reactive handles on PEG termini to attach antibody-based targeting ligands.

A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.

Background & Aims: Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H) exchanger 3 (NHE3) accounts for a major component of intestinal Na absorption and is inhibited in most diarrheas.

Non-Viral Gene Delivery to Hepatocellular Carcinoma via Intra-Arterial Injection.

Purpose: Hepatocellular carcinoma (HCC) has limited treatment options, and modest survival after systemic chemotherapy or procedures such as transarterial chemoembolization (TACE). There is therefore a need to develop targeted therapies to address HCC. Gene therapies hold immense promise in treating a variety of diseases, including HCC, though delivery remains a critical hurdle.

Preschoolers' temperament and social functioning in novel and routine contexts.

Introduction: The centrality of social competence to children's short and long-term well-being has sparked interest in the factors that contribute to its development, including temperament, a set of biologically based dispositions. A large body of work documents two types of temperamental dispositions associated with young children's social functioning: reactivity and regulation. There is consensus about the detrimental effects of negative reactive tendencies, called negative affective reactivity (NA), and about the beneficial effects of regulatory tendencies, called effortful control (EC), on social functioning.

Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) develops predominantly in the inflammatory environment of a cirrhotic liver caused by hepatitis, toxin exposure, or chronic liver disease. A targeted therapeutic approach is required to enable cancer killing without causing toxicity and liver failure. Poly(beta-amino-ester) (PBAE) nanoparticles (NPs) were used to deliver a completely CpG-free plasmid harboring mutant herpes simplex virus type 1 sr39 thymidine kinase (sr39) DNA to human HCC cells.

Recent Advances in Gene Therapy for Cancer Theranostics.

There is great interest in developing gene therapies for many disease indications, including cancer. However, successful delivery of nucleic acids to tumor cells is a major challenge, and efficacy is difficult to predict. Cancer theranostics is an approach combining anti-tumor therapy with imaging or diagnostic capabilities, with the goal of monitoring successful delivery and efficacy of a therapeutic agent in a tumor.

Poly(beta-amino ester) nanoparticles enable tumor-specific TRAIL secretion and a bystander effect to treat liver cancer.

Despite initial promise, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based approaches to cancer treatment have yet to yield a clinically approved therapy, due to delivery challenges, a lack of potency, and drug resistance. To address these challenges, we have developed poly(beta-amino ester) (PBAE) nanoparticles (NPs), as well as an engineered cDNA sequence encoding a secretable TRAIL (sTRAIL) protein, to enable reprogramming of liver cancer cells to locally secrete TRAIL protein. We show that sTRAIL initiates apoptosis in transfected cells and has a bystander effect to non-transfected cells.

High-throughput evaluation of polymeric nanoparticles for tissue-targeted gene expression using barcoded plasmid DNA.

Successful systemic gene delivery requires specific tissue targeting as well as efficient intracellular transfection. Increasingly, research laboratories are fabricating libraries of novel nanoparticles, engineering both new biomaterial structures and composition ratios of multicomponent systems. Yet, methods for screening gene delivery vehicles directly in vivo are often low-throughout, limiting the number of candidate nanoparticles that can be investigated.

Proposing a new algorithm for premanipulative testing in physical therapy practice.

In the field of physical therapy, there is debate as to the clinical utility of premanipulative vascular assessments. Cervical artery dysfunction (CAD) risk assessment involves a multi-system approach to differentiate between spontaneous versus mechanical events. The purposes of this inductive analysis of the literature are to discuss the link between cervical spine manipulation (CSM) and CAD, to examine the literature on premanipulative vascular tests, and to suggest an optimal sequence of premanipulative testing based on the differentiation of a spontaneous versus mechanical vascular event.

Quantitative Assessment of Eosinophils in Dermatomyositis Skin Biopsies With Correlation of Eosinophils to Pruritus and Other Clinical Features.

The objective of this retrospective study was to analyze dermatomyositis skin biopsies for the presence of eosinophils and correlate this finding with other histopathologic and clinical characteristics. Cases of dermatomyositis evaluated in a single dermatologist's adult autoimmunity practice over a 2.5-year period were identified via ICD-10 diagnosis code.

Cancer-Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery.

Nucleic acids are a promising type of therapeutic for the treatment of a wide range of conditions, including cancer, but they also pose many delivery challenges. For efficient and safe delivery to cancer cells, nucleic acids must generally be packaged into a vehicle, such as a nanoparticle, that will allow them to be taken up by the target cells and then released in the appropriate cellular compartment to function. As with other types of therapeutics, delivery vehicles for nucleic acids must also be designed to avoid unwanted side effects; thus, the ability of such carriers to target their cargo to cancer cells is crucial.

Cancer-selective nanoparticles for combinatorial siRNA delivery to primary human GBM in vitro and in vivo.

Novel treatments for glioblastoma (GBM) are urgently needed, particularly those which can simultaneously target GBM cells' ability to grow and migrate. Herein, we describe a synthetic, bioreducible, biodegradable polymer that can package and deliver hundreds of siRNA molecules into a single nanoparticle, facilitating combination therapy against multiple GBM-promoting targets. We demonstrate that siRNA delivery with these polymeric nanoparticles is cancer-selective, thereby avoiding potential side effects in healthy cells.

Bioreducible Polymeric Nanoparticles Containing Multiplexed Cancer Stem Cell Regulating miRNAs Inhibit Glioblastoma Growth and Prolong Survival.

Despite our growing molecular-level understanding of glioblastoma (GBM), treatment modalities remain limited. Recent developments in the mechanisms of cell fate regulation and nanomedicine provide new avenues by which to treat and manage brain tumors via the delivery of molecular therapeutics. Here, we have developed bioreducible poly(β-amino ester) nanoparticles that demonstrate high intracellular delivery efficacy, low cytotoxicity, escape from endosomes, and promotion of cytosol-targeted environmentally triggered cargo release for miRNA delivery to tumor-propagating human cancer stem cells.

Biodegradable Polymeric Nanoparticles for Therapeutic Cancer Treatments.

Polymeric nanoparticles have tremendous potential to improve the efficacy of therapeutic cancer treatments by facilitating targeted delivery to a desired site. The physical and chemical properties of polymers can be tuned to accomplish delivery across the multiple biological barriers required to reach diverse subsets of cells. The use of biodegradable polymers as nanocarriers is especially attractive, as these materials can be designed to break down in physiological conditions and engineered to exhibit triggered functionality when at a particular location or activated by an external source.

A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer.

Background: Mucin 1 antigen, highly expressed by epithelial ovarian cancer (EOC), is a potential target for immunotherapy. A previous successful phase 1 trial was conducted in patients with adenocarcinoma who were injected with Cvac, autologous monocyte-derived dendritic cells (DCs) incubated with mannosylated mucin 1 protein (M-FP). The present study was a phase 2 trial of Cvac in patients with advanced EOC.