An engineered ultrahigh affinity bi-paratopic uPAR targeting agent confers enhanced tumor targeting.

Urokinase-type plasminogen activator receptor (uPAR) is overexpressed on tumor cells in multiple types of cancer and contributes to disease progression and metastasis. In this work, we engineered a novel bi-paratopic uPAR targeting agent by fusing the binding domains of two native uPAR ligands: uPA and vitronectin, with a flexible peptide linker. The linker length was optimized to facilitate simultaneous engagement of both domains to their adjacent epitopes on uPAR, resulting in a high affinity and avid binding interaction. Furthermore, the individual domains were affinity-matured using yeast surface display and directed evolution, resulting in a bi-paratopic protein with affinity in the picomolar to femtomolar range. This engineered uPAR targeting agent demonstrated significantly enhanced tumor localization in mouse tumor models compared to the native uPAR ligand and warrants further investigation as a diagnostic and therapeutic agent for cancer.

Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma.

Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvß3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment.

Identification of Secondary Metabolites from the Mangrove-Endophyte Lasiodiplodia iranensis F0619 by UPLC-ESI-MS/MS.

Lasiodiplodia is a widely distributed fungal genus, frequently found in tropical and subtropical regions where it can cause disease in important crops. It represents a promising source of active secondary metabolites with uses in chemical, pharmaceutical, and agrochemical processes. In this study, the strain Lasiodiplodia iranensis F0619 was isolated from the mangrove Avicennia ger-minans, collected from Sarigua National Park in the Republic of Panama. Fractions of crude extract were analyzed by UPLC-ESI-MS/MS, and five compounds, previously reported from Lasiodiplodia genus were identified, including 11,12-didehydro-7-iso-jasmonic acid (1), 4,5-didehydro-7-iso-jasmonic acid (2), cyclo-(L-Leu-L-Pro) (3), jasmonate-threonine (4), and abscisic acid (5). We describe and analyze their MS/MS fragmentation patterns to confirm the compounds 'chemical structures.

Translation of an evidence-based social skills intervention for children with prenatal alcohol exposure in a community mental health setting.

BACKGROUND: Children with prenatal alcohol exposure (PAE) have significant social skills deficits and are often treated in community mental health settings. However, it remains unclear whether these children can be effectively treated using manualized, evidence-based interventions that have been designed for more general mental health populations. METHODS: To shed light on this issue, the effectiveness of Children's Friendship Training (CFT) versus Standard of Care (SOC) was assessed for 85 children ages 6 to 12 years with and without PAE in a community mental health center. RESULTS: Children participating in CFT showed significantly improved knowledge of appropriate social skills, improved self-concept, and improvements in parent-reported social skills compared to children in the SOC condition. Moreover, results revealed that within the CFT condition, children with PAE performed as well as children without PAE. Findings indicated that CFT, an evidence-based social skills intervention, yielded greater gains than a community SOC social skills intervention and was equally effective for children with PAE as for those without PAE. CONCLUSIONS: Results suggest that children with PAE can benefit from treatments initiated in community settings in which therapists are trained to understand their unique developmental needs, and that they can be successfully integrated into treatment protocols that include children without PAE.

Causally-Rich Group Play: A Powerful Context for Building Preschoolers' Vocabulary.

This work explores whether the facilitative effect of causal information on preschoolers' word learning observed in the laboratory might be relevant to boosting children's vocabulary in a group-play context. Forty-eight 3- to 4-year-old children learned six novel words for novel tools introduced during a small group-play session. Half of the groups used the tools according to their specified function to construct a fruit salad. The remaining children used the same tools to decorate a castle of blocks. In this way, some children learned about the causal properties of the tools, while others did not. Although children in both conditions comprehended the novel words equally well when tested shortly after the play session, learning in the Causal condition was more robust. Children's comprehension scores in the Causal condition increased over time (a 7-20 day delay), such that children in this group performed better than children in the Non-Causal condition when tested in a follow-up session. These results demonstrate a striking benefit of causal enrichment to word learning in a context that could feasibly be implemented in preschool classrooms, playgroups, and individual households. Highlighting the causal properties of objects during playtime might offer a powerful approach to building children's vocabulary, thereby providing a stronger foundation for early literacy and success in school more generally speaking.

Conservative versus invasive stable ischemic heart disease management strategies: what do we plan to learn from the ISCHEMIA trial?

Over the past decade, landmark randomized clinical trials comparing initial management strategies in stable ischemic heart disease (SIHD) have demonstrated no significant reduction in 'hard' end points (all-cause mortality, cardiac death or myocardial infarction) with one strategy versus another. The main advantage derived from early revascularization is improved short-term quality of life. Nonetheless, questions remain regarding how best to manage SIHD patients, such as whether a high-risk subgroup can be identified that may experience a survival or myocardial infarction benefit from early revascularization, and if not, when should diagnostic catheterization and revascularization be performed. The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial is designed to address these questions by randomizing SIHD patients with at least moderate ischemia to an initial conservative strategy of optimal medical therapy or an initial invasive strategy of optimal medical therapy plus cardiac catheterization and revascularization.