Metastasis is a multistep process during which cancer cells gain the ability to invade through the extracellular matrix (ECM) to disseminate to distant organs. Cancer cells can degrade ECM by forming invasive structures called invadopodia which concentrate protease activities to areas of the cell in contact with the ECM. Twist1 is a key transcription factor known to promote the epithelial mesenchymal transition (EMT) and tumor metastasis. We find that Twist1 promotes local invasion in metastasis by inducing invadopodia formation via transcriptional regulation of platelet-derived growth factor [alpha] (PDGFR[alpha]) and a disintegrin and metalloprotease 12 (ADAM12). We find that Twist1 is both necessary and sufficient for invadopodia formation and ECM degradation in multiple cell lines. Twist1 induces PDGFR[alpha] expression, which in turn activates Src, to promote invadopodia formation. We demonstrate that Twist1 and PDGFR[alpha] are central mediators of invadopodia formation in response to various EMT-inducing signals. Induction of PDGFR[alpha] and invadopodia is essential for Twist1 to promote tumor metastasis. Consistent with PDGFR[alpha] being a direct transcriptional target of Twist1, co-expression of Twist1 and PDGFR[alpha] predicts poor survival in breast tumor patients. Therefore, invadopodia-mediated matrix degradation is a key function of Twist1 in promoting tumor metastasis. Moreover, we find that the transmembrane metalloprotease ADAM12 is strongly induced by Twist1 and localizes to both invadopodia and focal adhesions. Knockdown of ADAM12 reduces both migration and invasion while increasing adhesion and focal adhesion number. We show that ADAM12 is required for formation of invadopodia and gelatin degradation. Using a series of ADAM12 mutants, we find that the disintegrin domain of ADAM12 is involved in both regulation of focal adhesions and invadopodia while the metalloprotease domain is specifically required for efficient invadopodia formation. Functionally, ADAM12 is required for efficient metastasis of tumor cells to the lung in a human xenograft breast cancer metastasis model in mice. Our work defines a novel role for Twist1 in regulating ECM degradation during tumor invasion and metastasis. These results could lead to new biomarkers and targeted therapeutics for invasive and metastatic breast cancer

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The current study investigated behavioral and neuroimaging evidence for orthographic influences on auditory word identification. To assess such influences, the proportion of similar sounding words (i.e. phonological neighbors) that were also spelled similarly (i.e., orthographic neighbors) was computed for each auditorily presented word as the Orthographic-to-Phonological Overlap Ratio (OPOR). Speech intelligibility was manipulated by presenting monosyllabic words in multi-talker babble at two signal-to-noise ratios: + 3 and + 10 dB SNR. Identification rates were lower for high overlap words in the challenging + 3 dB SNR condition. In addition, BOLD contrast increased with OPOR at the more difficult SNR, and decreased with OPOR under more favorable SNR conditions. Both voxel-based and region of interest analyses demonstrated robust effects of OPOR in several cingulo-opercular regions. However, contrary to prior theoretical accounts, no task-related activity was observed in posterior regions associated with phonological or orthographic processing. We suggest that, when processing is difficult, orthographic-to-phonological feature overlap increases the availability of competing responses, which then requires additional support from domain general performance systems in order to produce a single response.

OBJECTIVES: To evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that correlate with differences in MSC effects. METHODS: A literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints. RESULTS: Of 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral > intra-arterial > IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate > rat > mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs ≥ 24 hours poststroke; results were overall very similar. CONCLUSIONS: In preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans.

Although ischemic stroke is a major cause of morbidity and mortality, current therapies benefit only a small proportion of patients. Transplantation of mesenchymal stromal cells (MSC, also known as mesenchymal stem cells or multipotent stromal cells) has attracted attention as a regenerative therapy for numerous diseases, including stroke. Mesenchymal stromal cells may aid in reducing the long-term impact of stroke via multiple mechanisms that include induction of angiogenesis, promotion of neurogenesis, prevention of apoptosis, and immunomodulation. In this review, we discuss the clinical rationale of MSC for stroke therapy in the context of their emerging utility in other diseases, and their recent clinical approval for treatment of graft-versus-host disease. An analysis of preclinical studies examining the effects of MSC therapy after ischemic stroke indicates near-universal agreement that MSC have significant favorable effect on stroke recovery, across a range of doses and treatment time windows. These results are interpreted in the context of completed and ongoing human clinical trials, which provide support for MSC as a safe and potentially efficacious therapy for stroke recovery in humans. Finally, we consider principles of brain repair and manufacturing considerations that will be useful for effective translation of MSC from the bench to the bedside for stroke recovery.

In vivo sensors are an emerging field with the potential to revolutionize our understanding of basic biology and our treatment of disease. In this review, we highlight recent advances in the fields of in vivo electrochemical, optical, and magnetic resonance biosensors with a focus on recent developments that have been validated in rodent models or human subjects. In addition, we discuss major challenges in the development and translation of in vivo biosensors and present potential solutions to these problems. The field of nanotechnology, in particular, has recently been instrumental in driving the field of in vivo sensors forward. We conclude with a discussion of emerging paradigms and techniques for the development of future biosensors.