PEG–Polypeptide Block Copolymers as pH-Responsive Endosome-Solubilizing Drug Nanocarriers

Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG–polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydride-based ring-opening polymerization with post-functionalization using azide–alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH-responsive manner under a range of biologically relevant conditions. The self-assembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model.Novartis Institutes of Biomedical ResearchNational Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant P30 CA14051)National Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02)National Science Foundation (U.S.). Graduate Research FellowshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship

Impact of Optimized Breastfeeding on the Costs of Necrotizing Enterocolitis in Extremely Low Birthweight Infants

To estimate risk of NEC for ELBW infants as a function of preterm formula and maternal milk (MM) intake and calculate the impact of suboptimal feeding on NEC incidence and costs

Changes in instrumentally and classically conditioned limb-flexion responses following inferior olivary lesions and olivocerebellar tractotomy in the cat

Lesions were placed in various parts of the inferior olivary nucleus and olivocerebellar tract in an attempt to define further the role of the inferior olive in the performance of a conditioned limb-flexion response (LFR) in cats. Thirty-two cats were trained to make an LFR using either classical or instrumental conditioning. The conditioned stimulus (CS) was a tone, and the unconditioned stimulus (US), a shock to the forelimb. Following training, lesions were placed in various parts of the inferior olivary nucleus in 20 animals (radio frequency lesions, 17; electrolytic lesions, 3). Midline section of the olivocerebellar tract was carried out in 12 animals. The degree of conditioned-response (CR) loss resulting from a given lesion was closely related to the precise locus of the lesion. Rostromedial olivary lesions, which included the spino- and cortico-olivary forelimb projection zones and the olivocerebellar projection area, resulted in varying degrees of CR loss (from partial to near total), deregulation of response latency, and a significant reduction of response amplitude. The CR deficit and degree of post-operative CR recovery were directly related to the extent of damage to this part of the rostromedial olive. Lesions restricted to the caudal olive or to caudal levels of the olivo- cerebellar tract resulted in no postoperative CR deficits. Animals with caudal lesions, however, showed more severe general motor deficits postoperatively than did those with rostromedial lesions and loss of the CR. Prolonged training of animals with the most complete CR deficits resulted in some relearning, but response patterns were typified by long-latency, low-amplitude CRs and a highly unstable response pattern.</jats:p

Spinal Angiolipomas: A Puzzling Case and Review of a Rare Entity

Patients with spinal epidural abscesses (SEAs) may have a variable presentation. Such an infection has a typical appearance on magnetic resonance imaging (MRI) and enhances with gadolinium. We present a case that was a diagnostic challenge where pre- and intra-operative findings resulted in conflicting impressions. The mimicker was a spinal angiolipoma (SAL). The authors then provide a thorough review of this rare spinal neoplasm. A 55-year-old man presented with back pain, paresis, paresthesia, and urinary retention. MRI was indicative of a longitudinal epidural thoracic mass with a signal homogeneous to nearby fat, curvilinear vessels, and lack of enhancement. Although at emergent surgery, the lesion was found to contain abundant purulent material. Microbiology was positive for methicillin-resistant Staphylococcus aureus and consistent with SEA without evidence of neoplasia. While the imaging features were suggestive of an angiolipoma, the findings at surgery made SEA more likely, which were validated histopathologically. The diagnosis of SEA is often clear-cut, and the literature has reported only a few instances in which it masqueraded as another process such as lymphoma or myelitis. The case highlights SEA masquerading as an angiolipoma, and further demonstrates to clinicians that obtaining tissue diagnosis plays a crucial role diagnostically and therapeutically. SALs, on the other hand, are slow-growing tumors that can be infiltrating or noninfiltrating. They typically present with chronic symptoms and T1-MRI shows an inhomogeneous picture. Complete surgical excision is standard of care and patients tend to do well afterward