Engineering Tumor Stroma Morphogenesis Using Dynamic Cell-Matrix Spheroid Assembly.

The tumor microenvironment consists of resident tumor cells organized within a compositionally diverse, three-dimensional (3D) extracellular matrix (ECM) network that cannot be replicated in vitro using bottom-up synthesis. We report a new self-assembly system to engineer ECM-rich 3D MatriSpheres wherein tumor cells actively organize and concentrate microgram quantities of decellularized ECM dispersions which modulate cell phenotype. 3D colorectal cancer (CRC) MatriSpheres were created using decellularized small intestine submucosa (SIS) as an orthotopic ECM source that had greater proteomic homology to CRC tumor ECM than traditional ECM formulations such as Matrigel.

Camel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours.

Rational design of chimeric antigen receptor T (CAR-T) cells based on the recognition of antigenic epitopes capable of evoking the most potent CAR activation is an important objective in optimizing immune therapy. In solid tumors, the B7-H3 transmembrane protein is an emerging target that harbours two distinct epitope motifs, IgC and IgV, in its ectodomain. Here, we generate dromedary camel nanobodies targeting B7-H3 and demonstrate that CAR-T cells, based on the nanobodies recognizing the IgC but not IgV domain, had potent antitumour activity against large tumors in female mice.

An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma.

Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR.

Disruption of anthrax toxin receptor 1 in pigs leads to a rare disease phenotype and protection from senecavirus A infection.

Senecavirus A (SVA) is a cause of vesicular disease in pigs, and infection rates are rising within the swine industry. Recently, anthrax toxin receptor 1 (ANTXR1) was revealed as the receptor for SVA in human cells. Herein, the role of ANTXR1 as a receptor for SVA in pigs was investigated by CRISPR/Cas9 genome editing.

The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models.

Purpose: Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3-targeting antibody-drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line-derived xenograft (CDX) models.

Novel metabolic role for BDNF in pancreatic β-cell insulin secretion.

BDNF signaling in hypothalamic circuitries regulates mammalian food intake. However, whether BDNF exerts metabolic effects on peripheral organs is currently unknown. Here, we show that the BDNF receptor TrkB.

Antxr1, Which is a Target of Runx2, Regulates Chondrocyte Proliferation and Apoptosis.

Antxr1/Tem8 is highly expressed in tumor endothelial cells and is a receptor for anthrax toxin. Mutation of causes GAPO syndrome, which is characterized by growth retardation, alopecia, pseudo-anodontia, and optic atrophy. However, the mechanism underlying the growth retardation remains to be clarified.

Isolation of rabbit single domain antibodies to B7-H3 via protein immunization and phage display.

Single domain antibodies have certain advantages including their small size, high stability and excellent tissue penetration, making them attractive drug candidates. Rabbit antibodies can recognize diverse epitopes, including those that are poorly immunogenic in mice and humans. In the present study, we established a method to isolate rabbit VH single domain antibodies for potential cancer therapy.

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.

Purpose: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted.

Improving VEGF-targeted therapies through inhibition of COX-2/PGE2 signaling.

Antiangiogenic agents targeting the vascular endothelial growth factor A (VEGFA) pathway play an important role in current cancer treatment modalities but are limited by alternative angiogenesis mechanisms. Recent studies suggest that enhanced signaling through a COX-2/PGE2 axis contributes to VEGF-independent tumor angiogenesis. Thus, COX-2/PGE2 inhibition may potentiate VEGF therapies.

Cost-effectiveness of ambulatory blood pressure monitoring in the initial evaluation of hypertension in children.

Objective: The goal was to determine the cost-effectiveness of ambulatory blood pressure monitoring in the initial evaluation of stage 1 hypertension.

Methods: Retrospective chart review of data for children referred to Texas Children's Hospital hypertension clinic between January 2005 and August 2006 was performed. We compared the costs of standard evaluations versus the initial use of ambulatory blood pressure monitoring for children with clinic blood pressure measurements suggesting stage 1 hypertension.

Serial analysis of gene expression (SAGE): experimental method and data analysis.

Serial analysis of gene expression (SAGE) involves the generation of short fragments of DNA, or tags, from a defined point in the sequence of all cDNAs in the sample analyzed. This short tag, because of its presence in a defined point in the sequence, is typically sufficient to uniquely identify every transcript in the sample. SAGE allows one to generate a comprehensive profile of gene expression in any sample desired from as little as 100,000 cells or 1 microg of total RNA.

Inaccuracy in pediatric outpatient blood pressure measurement.

Objective: Hypertension is common in the pediatric population. There is increasing evidence for early hypertensive target organ damage that may lead to substantial long-term morbidity. Because a critical aspect of any screening program for hypertension is the ability to measure blood pressure accurately, we compared typical blood pressure measurements at a vital sign station with those that were obtained following recommendations set forth in "The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents.

Childhood hypertension is not a silent disease.

Early hypertension has generally been considered to be an asymptomatic condition; however, recent data show that many hypertensive children have evidence of end organ damage. We sought to determine if a spectrum of common symptoms is associated with early hypertension and whether those symptoms resolve with lowered blood pressure. Four hundred and nine consecutive children, 7-18 years old, examined in the Texas Children's Hospital Hypertension Clinic for new-onset high blood pressure (BP) completed a questionnaire, including the self-reporting of 15 symptoms potentially attributed to high blood pressure.

Stem cell factor inhibits erythroid differentiation by modulating the activity of G1-cyclin-dependent kinase complexes: a role for p27 in erythroid differentiation coupled G1 arrest.

Terminal erythroid differentiation is accompanied by decreased expression of c-Kit and decreased proliferation of erythroid progenitor cells. Using a newly established erythroleukemia cell line HB60-5, which proliferates in response to erythropoietin (Epo) and stem cell factor (SCF) and differentiates when stimulated with Epo alone, we characterized several events associated with the cell cycle during erythroid differentiation. Forty-eight h after SCF withdrawal and Epo stimulation, there was strong inhibition of cyclin-dependent kinase (cdk) 4 and cdk6 activities, associated with an increase in the binding of p27 and p15 to cdk6.

Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells.

Targeted disruption of the single mutant K-ras allele in two human colorectal carcinoma cell lines (DLD-1 and HCT-116) leads to loss of tumorigenic competence in nude mice with retention of ability to grow indefinitely in monolayer culture. Because expression of the mutant K-ras oncogene in these cell lines is associated with marked up-regulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), we sought to determine whether this potent angiogenesis inducer plays a role in K-ras-dependent tumorigenic competence. Transfection of a VEGF121 antisense expression vector into DLD-1 and HCT-116 cells resulted in suppression of VEGF/VPF production by a factor of 3- to 4-fold.

Reversal by hyaluronidase of adhesion-dependent multicellular drug resistance in mammary carcinoma cells.

Background: De novo or acquired resistance to chemotherapeutic drugs continues to be one of the most important obstacles hindering the successful treatment of cancer patients. Consequently, enhancing the efficacy of conventional chemotherapeutic drugs has become an important research goal. Our previous studies using the mouse EMT-6 mammary carcinoma selected for resistance to various alkylating agents in vivo demonstrated that such acquired drug resistance may be manifested in vitro only in cells growing in a three-dimensional configuration but not in conventional monolayer culture.