We evaluated the ability of neonatal porcine islets to engraft and restore glucose control in pancreatectomized rhesus macaques. Although porcine islets transplanted into nonimmunosuppressed macaques were rapidly rejected by a process consistent with cellular rejection, recipients treated with a CD28-CD154 costimulation blockade regimen achieved sustained insulin independence (median survival, >140 days) without evidence of porcine endogenous retrovirus dissemination. Thus, neonatal porcine islets represent a promising solution to the crucial supply problem in clinical islet transplantation.

Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least twenty weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when non-covalently loaded with an unmodified drug.

Recent advances in human allogeneic islet transplantation have established b -cell replacement therapy as a potentially viable treatment option for individuals afflicted with Type 1 diabetes. Two recent successes, one involving neonatal porcine islet xenografts transplanted into diabetic rhesus macaques treated with a costimulation blockade-based regimen and the other involving diabetic cynomolgus monkeys transplanted with adult porcine islet xenografts treated with an alternative multidrug immunosuppressive regimen have demonstrated the feasibility of porcine islet xenotransplantation in nonhuman primate models. In the current study, we assessed whether transplantation of adult porcine islet xenografts into pancreatectomized macaques, under the cover of a costimulation blockade-based immunosuppressive regimen (CD28 and CD154 blockade), could correct hyperglycemia. Our findings suggest that the adult porcine islets transplanted into rhesus macaques receiving a costimulation blockade-based regimen are not uniformly subject to hyperacute rejection, can engraft (2/5 recipients), and have the potential to provide sustained normoglycemia. These results provide further evidence to suggest that porcine islet xenotransplantation may be an attainable strategy to alleviate the islet supply crisis that is one of the principal obstacles to large-scale application of islet replacement therapy in the treatment of Type 1 diabetes.

Blockade of the CD40/CD154 signaling pathway using anti-CD154 Abs has shown promise in attenuating the alloimmune response and promoting long-term graft survival in murine model systems, although side effects observed in humans have hampered its progression through clinical trials. Appropriately designed anti-CD40 Abs may provide a suitable alternative. We investigated two isoforms of a novel monoclonal rat anti-mouse CD40 Ab (7E1) for characteristics and effects mirroring those of anti-CD154: 7E1-G1 (an IgG1 isotype); and 7E1-G2b (an IgG2b isotype). In vitro proliferation assays to measure the agonist properties of the two anti-CD40 Abs revealed similar responses when plate bound. However, when present as a soluble stimulus, 7E1-G1 but not 7E1-G2b led to proliferation. 7E1-G2b was as effective as anti-CD154 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimerism and skin graft survival, whereas 7E1-G1 was not. The protection observed with 7E1-G2b was not due to depletion of CD40-bearing APCs. These data suggest that an appropriately designed anti-CD40 Ab can promote graft survival as well as anti-CD154, making 7E1-G2b an attractive substitute in mouse models of costimulation blockade-based tolerance regimens.

On page 4008, in the section titled "Synthesis of CDϪgraphene OrganicϪinorganic Hybrid Nanosheets and Pure Graphene", the sixth line reads "mixed with 20.0 mL of 80 mg/mL ␣-, ␤-, or ␥-CD aqueous solution" but should be changed to read "mixed with 20.0 mL of ␣-, ␤-, or ␥-CD (80 mg) aqueous solution".

Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature.Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control.Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo. Clin Cancer Res; 17(8); 2281-91. Ó2011 AACR.

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BACKGROUND: Lymph node extracapsular extension (ECE) is a known adverse prognostic factor in head and neck cancer and is an indication for adjuvant chemoradiation (CRT). However, the extent of ECE may provide additional prognostic information in the setting of adjuvant CRT. METHODS: This study included 350 patients with oral cavity cancer (72.6%) or bulky/nonfunctional laryngeal cancer (27.4%) who underwent initial surgical resection. Extent of ECE was graded from 0 to 4 based on the scale established by Lewis and colleagues. Multivariable analyses (MVA) were adjusted for primary site, pathologic risk factors, and adjuvant therapy. RESULTS: In univariate failure-free survival (FFS) analysis, there was no significant difference in FFS for patients with lymph nodepositive disease and no ECE (grade 0) versus patients with ECE grades 1 through 3. However, patients with ECE grade 4 had significantly worse FFS. In MVA for FFS, differences between ECE grades 0 through 3 and grade 4 did not remain significant. In MVA of overall survival, ECE grade 4 was significantly associated with higher risk of death compared with ECE grade 0 (hazard ratio, 0.46; P 5.02) and ECE grades 1 through 3 (HR, 0.41; P 5.01). CONCLUSIONS: Dichotomous evaluation of ECE is useful for determining appropriate adjuvant therapy but has limited additional prognostic value in the setting of adjuvant CRT. The detrimental effect of ECE grades 1 through 3 relative to no ECE is effectively mitigated with adjuvant CRT, but ECE grade 4 retains a poorer prognosis despite CRT with regard to overall survival. Patients with ECE grade 4 may be candidates for trials investigating novel methods of adjuvant therapy intensification. Cancer 2014;120:1499