Multimodal treatment of lymphatic malformations continues to expand as new information about the biology and genetics of these lesions is discovered, in addition to knowledge gained from clinical practice. A patient-centered approach should guide timing and modality of treatment. Continued study of lymphatic malformations will increase and solidify a treatment algorithm for these complicated lesions.

Multimodal treatment of lymphatic malformations continues to expand as new information about the biology and genetics of these lesions is discovered, along with knowledge gained from clinical practice. A patient-centered approach, ideally provided by a multidisciplinary medical and surgical team, should guide timing and modality of treatment. Current treatment options include observation, surgery, sclerotherapy, radiofrequency ablation, and laser therapy. New medical and surgical therapies are emerging, and include sildenafil, propranolol, sirolimus, and vascularized lymph node transfer. The primary focus of management is to support and optimize these patients' quality of life. Researchers continue to study lymphatic malformations with the goal of increasing therapeutic options and developing effective clinical pathways for these complicated lesions.

SummaryProtein kinase C (PKC) is a heterogeneous family of serine ⁄ ⁄ threonine protein kinases that have different biological effects in normal and neoplastic melanocytes (MCs). To explore the mechanism behind their differential response to PKC activation, we analyzed the expression profile of all nine PKC isoforms in normal human MCs, HPV16 E6 ⁄ ⁄ E7 immortalized MCs, and a panel of melanoma cell lines. We found reduced PKCb and increased PKCf and PKCi expression at both the protein and mRNA levels in immortalized MCs and melanoma lines. We focused on PKCb as it has been functionally linked to melanin production and oxidative stress response. Re-expression of PKCb in melanoma cells inhibited colony formation in soft agar, indicating that PKCb loss in melanoma is important for melanoma growth. PKCbII, but not PKCbI, was localized to the mitochondria, and inhibition of PKCb significantly reduced UV-induced reactive oxygen species (ROS) in MCs with high PKCb expression. Thus alterations in PKCb expression in melanoma contribute to their neoplastic phenotype, possibly by reducing oxidative stress, and may constitute a selective therapeutic target.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with “microbubble” ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods : To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results : In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo . Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid on...

Introduction S. aureus is a major cause of morbidity globally, and in the United States it contributes significantly to both hospital admissions and in-hospital morbidity [1, 2]. The increasing incidence of antibiotic-resistant strains increases the urgency of understanding the mechanisms by which this infection exerts its toxic acute effects, as well as potential longterm impact on infected patients, especially those with comorbid conditions. The major virulent toxin secreted by S. aureus is α-hemolysin (Hla). A Disintegrin And Metalloproteinase domain-containing protein-10 (ADAM10), which is involved in ectodomain shedding, is the eukaryotic receptor for Hla [3-5], and mediates vascular injury caused by Hla [6]. Almost all isolates of S. aureus express Hla, including methicillinresistant strains [7]. Recently, Hla has been shown to mediate VE-cadherin degradation in endothelial cells (EC) via ADAM10, affecting permeability [6]. Importantly, the Notch1 and 2 receptors are known ADAM10 targets [8]. Notch proteins are highly evolutionarily conserved. In mammals, the Notch pathway is comprised of the Jagged and Delta-like ligands, and the receptors Notch1 through Notch4. Both ligands and receptors are membrane-bound: in order for activation to take place, the ligand and receptor must be expressed in adjacent cells. Notch ligands are cleaved at Site 1 (S1) and can be post-translationally modified by glycosyltransferases, such as Fringe. Upon