Well-defined single polymer nanoparticles for the antibody-targeted delivery of chemotherapeutic agents.

Aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of linear copolymers of N,N-dimethylacrylamide (DMA) and 2-hydroxyethylacrylamide (HEAm) with narrow D values over a molecular weight range spanning three orders of magnitude (103 to 106 Da). Trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted onto these scaffolds using carbodiimide chemistry catalyzed with DMAP. The resultant graft chain transfer agent (gCTA) was subsequently employed to synthesize polymeric brushes with a number of important vinyl monomer classes including acrylamido, methacrylamido, and methacrylate. Brush polymerization kinetics were evaluated for the aqueous RAFT polymerization of DMA from a 10 arm gCTA. Polymeric brushes containing hydroxyl functionality were further functionalized in order to prepare 2nd generation gCTAs which were subsequently employed to prepare polymers with a brushed-brush architecture with molecular weights in excess of 106 Da. These resultant single particle nanoparticles (SNPs) were employed as drug delivery vehicles for the anthracycline-based drug doxorubicin via copolymerization of DMA with a protected carbazate monomer (bocSMA). Cell-specific targeting functionality was also introduced via copolymerization with a biotin-functional monomer (bioHEMA). Drug release of the hydrazone linked doxorubicin was evaluated as function of pH and serum and chemotherapeutic activity was evaluated in SKOV3 ovarian cancer cells.

A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs.

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with critical functions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences. However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven by EWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, all of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGF signaling.

Recurrent spontaneous hemarthrosis associated with reflex sympathetic dystrophy.

Reflex sympathetic dystrophy is a mysterious entity with unclear pathogenesis. The diagnosis is largely clinical and based on signs and symptoms of pain and vasomotor dysfunction. Treatment is a challenge because the underlying mechanism remains unknown. Our patient is a 75-year-old woman 2 years after left total knee replacement who presented with her second spontaneous hemarthrosis in 3 months. After arthrocentesis, dusky discoloration, edema, hyperesthesia, and decreased range of motion of the left knee and entire distal extremity were noted. Despite analgesia and physical therapy her symptoms worsened. Radiographs of her left knee showed severe periprosthetic osteopenia and a triple phase bone scan was negative. Clinically, reflex sympathetic dystrophy was considered likely and a lumbar sympathetic block was performed. The patient improved and continued to do well after a series of blocks. This is the first reported case of recurrent atraumatic hemarthrosis associated with reflex sympathetic dystrophy.

Autonomic dysfunction as the presenting feature of Guillain-Barré syndrome.

Autonomic dysfunction has been demonstrated in various conditions associated with peripheral neuropathy such as acute intermittent porphyria, amyloidosis, and Guillain-Barré syndrome (GBS). In the latter, hypertension is an associated complication that typically occurs after neurological signs are already present. We report a case of a patient with autonomic dysfunction as the presenting feature who was admitted to the coronary unit with chest pain and hypertension. Subsequently, he developed progressive symmetric muscle, weakness, sensory changes, and areflexia. GBS was then diagnosed based on the clinical picture, albuminocytologic dissociation in the cerebrospinal fluid, and electrodiagnostic abnormalities suggestive of demyelinative polyneuropathy with conduction block. Few cases in the literature have reported autonomic dysfunction as the presenting feature of GBS, such as in this case. In a previously asymptomatic patient, acute onset of autonomic dysfunction should alert the physician to the possibility of an acute polyneuropathy, such as GBS.