Citations

There is no therapy that promotes maturation and functionality of a dialysis arteriovenous fistula (AVF). The search for such therapies largely relies on evaluation of vascular responses and putative therapies in experimental AVFs. We studied an AVF in mice with chronic kidney disease (CKD). We demonstrate numerous stressors in the vein of the AVF-CKD group, including pathological shear, mitogenic, inflammatory, and hypoxia-reoxygenation stress. Because stress promotes premature senescence, we examined whether senescence is induced in the vein of the AVF-CKD model. We demonstrate a senescence phenotype in the AVF-CKD model, as indicated by increased expression of p16Ink4a, p21Cip1, and p53 and expected changes for certain senescence-associated microRNAs. RNA-sequencing analysis demonstrated differential expression of ~10,000 genes, including upregulation of proinflammatory and proliferative genes, in the vein of the AVF-CKD group. The vein in the AVF-CKD group exhibited telomere erosion and increased senescence-associated β-galactosidase activity and staining. Senescence was induced in the artery of the AVF-CKD group and in the vein of the AVF without CKD. Finally, given the rapidly rising clinical interest in senolytics, we provide proof of concept of senolytics as a therapeutic approach by demonstrating that senolytics decrease p16Ink4a expression in the AVF-CKD model. This study introduces a novel concept underlying the basis for maturational and functional failure in human dialysis AVFs and identifies a new target for senolytic therapy.

Abstract Cohort studies have been central to the establishment of the known causes of cancer. To dissect cancer etiology in more detail—for instance, for personalized risk prediction and prevention, assessment of risks of subtypes of cancer, and assessment of small elevations in risk—there is a need for analyses of far larger cohort datasets than available in individual existing studies. To address these challenges, the NCI Cohort Consortium was founded in 2001. It brings together 58 cancer epidemiology cohorts from 20 countries to undertake large-scale pooling research. The cohorts in aggregate include over nine million study participants, with biospecimens available for about two million of these. Research in the Consortium is undertaken by >40 working groups focused on specific cancer sites, exposures, or other research areas. More than 180 publications have resulted from the Consortium, mainly on genetic and other cancer epidemiology, with high citation rates. This article describes the foundation of the Consortium; its structure, governance, and methods of working; the participating cohorts; publications; and opportunities. The Consortium welcomes new members with cancer-oriented cohorts of 10,000 or more participants and an interest in collaborative research. Cancer Epidemiol Biomarkers Prev; 27(11); 1307–19. ©2018 AACR.

Background: Lower extremity intercalary allograft reconstruction has traditionally been used to facilitate limb salvage. Combining the allograft with a free vascularized fibula graft has been described; however, there is a paucity of data comparing the outcome of these reconstructions. Methods: Twenty-nine pediatric patients (15 boys and 14 girls) underwent lower extremity limb salvage with the use of intercalary cadaveric allograft at a mean age of 12 years. The most common diagnosis was osteosarcoma (n = 18). Patients underwent reconstruction with an allograft alone (n = 11) or supplemented with a free vascularized fibula graft (n = 18). Results: The mean time to union of the allograft was 11 months, with 10 patients requiring additional bone grafting. There was no difference in the need for an additional bone graft (OR, 0.87; p = 1.0) between patients with a free vascularized fibula graft and those without. The allograft was revised in three patients because of fracture (n = 2) and fracture and infection (n = 1). In all of these patients, the allograft was not supplemented with a free vascularized fibula graft (p < 0.001). Five patients underwent an amputation, most commonly for disease recurrence. At last follow-up, the mean Mankin and Musculoskeletal Tumor Society rating was 90 percent, with 19 patients (66 percent) who achieved a “good” or “excellent” outcome according to the Mankin score. Conclusion: Use of an intercalary allograft to reconstruct a lower extremity provides a durable means of reconstruction; however, supplementation with a free vascularized fibula graft reduces the risk of allograft revision. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Breast cancer is the most common cancer in women, and accounts for ~30% of new cancer cases and 15% of cancer‐related deaths. Tumor relapse and metastasis are primary factors contributing to breast cancer‐related deaths. Therefore, the challenge for breast cancer treatment is to sustain remission. A driving force behind tumor relapse is breast cancer heterogeneity (both intertumor, between different patients, and intratumor, within the same tumor). Understanding breast cancer heterogeneity is necessary to develop preventive interventions and targeted therapies. A recently emerging concept is that intratumor heterogeneity is driven by cancer stem cells (CSCs) that are capable of giving rise to a multitude of different cells within a tumor. Studies have highlighted linkage of CSC formation with epithelial‐to‐mesenchymal transition (EMT). In this review, we summarize the current understanding of breast cancer heterogeneity, links between EMT and CSCs, regulation of EMT by Runx transcription factors, and potential therapeutic strategies targeting these processes.