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Wound healing is a complex process initiated by the formation of fibrin fibers and endothelialization. Normally, this process is triggered in a wound by thrombin cleavage of fibrinopeptides on fibrinogen molecules, which allows them to self spontaneously-assemble into large fibers that provide the support structure of the clot and promote healing. We have found that the fibrous structures can also form without thrombin on most polymer or metal surfaces, including those commonly used for stents. We show that the relatively hydrophobic E and D regions of the fibrinogen molecule are adsorbed on these surfaces, exposing the αC domains, which in turn results in the formation of large fiber structures that promote endothelial cell adhesion. We show that the entire process can be suppressed when stents or other substrates are coated with polymers that are functionalized to bind the αC domains, leading to the development of potentially nonthrombogenic implant materials.

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We investigated direct interactions between the human immunodeficiency virus (HIV)-trans-activator of transcription (Tat) protein and amyloid β peptide. Amyloid β-Tat complexes are readily formed extracellularly in the brain. In vitro studies showed that in the presence of Tat, the uniform amyloid fibrils turned into double twisted fibrils followed by populations with thick unstructured filaments and aggregated large patches in a dose-dependent manner. The fibers became more rigid and mechanically resistant. Tat attached externally to fibrils, causing their lateral aggregation into thick multifibrilar structures. These present growth in β sheet and enhanced adhesion. The neurotoxic properties of Tat and amyloid β aggregates were strongly synergistic when complexed together in vitro and in animal models. These data suggest that the increased rigidity and mechanical resistance of the amyloid β-Tat complexes coupled with stronger adhesion due to the presence of Tat in the fibrils accounted for the increased damage, likely through pore formation in membranes.

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Background.-Colorectal neuroendocrine tumors are a rare malignancy, yet their incidence appears to be increasing. The optimal treatment for the high-grade subset of these tumors remains unclear. We aimed to examine the relationship between different treatment modalities and outcomes for patients with high-grade neuroendocrine carcinomas (HGNECs) of the colon and rectum. Methods.-The National Cancer Database (2004-2015) was used to identify patients diagnosed with colorectal HGNECs. The primary outcome was overall survival. A Cox Proportional hazard model was used to identify risk factors for survival. Results.-Overall, 1208 patients had HGNECs; 452 (37.4%) patients had primary tumors of the rectum, and 756 (62.5%) patients had primary tumors of the colon. A total of 564 (46.7%) patients presented with stage IV disease. The median survival was 9.0 months [95% confidence interval (CI) 8.2-9.8]. In multivariable analysis, surgical resection [hazard ratio (HR) 0.54, 95% CI0.44-0.66; p < 0.001], chemotherapy (HR 0.74, 95% CI0.69-0.79; p < 0.001), and rectum as the primary site of tumor (HR 0.62, 95% CI 0.51-0.76; p < 0.001) were associated with better overall survival, while older age (HR1.01, 95% CI 1.00-1.01; p = 0.02) and the presence of metastatic disease (HR 3.34, 95% CI 2.69-4.15; p < 0.001) were associated with worse survival. Conclusions.-Patients with colorectal HGNECs selected for chemotherapy and surgical resection of the primary tumor demonstrated better overall survival than those managed without resection. Patients who were able to undergo systemic chemotherapy may benefit from potentially curative resection of the primary tumor. AUTHOR CONTRIBUTIONS All authors made substantial contributions to the design of the work, drafted the work, approved the final version submitted for publication, and agreed to be accountable for all aspects of the work. Adam C. Fields and Pamela Lu MD were co-first authors on this work. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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