Plasmacytoid Dendritic Cell-driven Induction of Treg Is Strain Specific and Correlates With Spontaneous Acceptance of Kidney Allografts.

BACKGROUND: DBA/2J kidney allografts, but not heart allografts, are spontaneously accepted indefinitely in C57BL/6 (B6) mice, through regulatory tolerance mechanism dependent on Foxp3 cells. In contrast, B6 kidneys are rejected within a week in DBA/2J recipients. We hypothesized that the tolerogenic difference of the kidneys might be due to differences in number or function of plasmacytoid dendritic cells (pDCs), because these cells are potent inducers of Foxp3 cells. METHODS: pDCs from murine bone marrow, native kidneys, and spontaneously accepted kidney allografts were analyzed using flow cytometry and immunohistochemical staining. Naive T cells were cocultured with pDCs in specific strain combinations and analyzed for FoxP3 induction and functionality. MEK/ERK and NFκB inhibitors were used to assess the regulatory T-cell induction pathways. pDCs and T-cell cultures were adoptively transferred before heterotopic heart transplantation to assess allograft survival. RESULTS: DBA/2J pDCs were more potent in inducing Foxp3 in B6 T cells than the reverse combination, correlating with survival of the kidney allografts. Foxp3 induction by pDCs in vitro was dependent on pDC viability, immaturity, and class II MHC mismatch and blocked by MEK/ERK and NFκB inhibition. pDC-induced Foxp3 T cells suppressed proliferation of B6 T cells in vitro, and adoptive transfer into B6 recipients 2 weeks before heterotopic DBA/2J heart transplantation resulted in prolonged allograft survival. CONCLUSIONS: These data suggest that pDC-induced regulatory T cells are dependent on downstream signaling effects and on strain-dependent, MHC class II disparity with naive T cells, which may explain organ- and strain-specific differences in spontaneous tolerance.

Hepatic Cancers Overview: Surgical and Chemotherapeutic Options, How Do Y-90 Microspheres Fit in?

Hepatocellular cancer (HCC) is most common primary liver malignancy in adults. Treatment for HCC is a multispecialty undertaking, with surgical, locoregional, and systemic options available. Choice of treatment depends upon patient and disease factors. Surgical therapy, including resection and transplantation, is the primary curative treatment and is best suited to patients with early disease. More advanced disease may be amenable to locoregional therapies to "bridge" to transplantation, downstage disease, or as destination therapy for unresectable cases. These include percutaneous ablation, transarterial therapy, external radiation, and radioembolization with yttrium-90 conjugated beads. Patients with more advanced disease may benefit most from systemic chemotherapeutic or small molecule inhibitor options available, many of which have only been recently FDA approved. Immunotherapy is the newest component of HCC treatment. The Y-90 consultant should be familiar with all modalities of HCC treatment and the interplay between them.

Identification of miRNAs involved in DRG neurite outgrowth and their putative targets.

Peripheral neurons regenerate their axons after injury. Transcriptional regulation by microRNAs (miRNAs) is one possible mechanism controlling regeneration. We profiled miRNA expression in mouse dorsal root ganglion neurons after a sciatic nerve crush, and identified 49 differentially expressed miRNAs. We evaluated the functional role of each miRNA using a phenotypic analysis approach. To predict the targets of the miRNAs we employed RNA-Sequencing and examined transcription at the isoform level. We identify thousands of differentially expressed isoforms and bioinformatically associate the miRNAs that modulate neurite growth with their putative target isoforms to outline a network of regulatory events underlying peripheral nerve regeneration. MiR-298, let-7a, and let-7f enhance neurite growth and target the majority of isoforms in the differentially expressed network.

The role of radiosurgery to the tumor bed after resection of brain metastases.

BACKGROUND: Optimal postoperative management paradigm for brain metastases remains controversial. OBJECTIVE: To conduct a systematic review of the literature to understand the role of postoperative stereotactic radiosurgery after resection of brain metastases. METHODS: We performed a MEDLINE search of the literature to identify series of patients with brain metastases treated with stereotactic radiosurgery after surgical resection. Outcomes including overall survival, local control, distant intracranial failure, and salvage therapy use were recorded. Patient, tumor, and treatment factors were correlated with outcomes through the use of the Pearson correlation and 2-way Student t test as appropriate. RESULTS: Fourteen studies involving 629 patients were included. Median survival for all studies was 14 months. Local control was correlated with the median volume treated with radiosurgery (r = -0.766, P < .05) and with the rate of gross total resection (r = .728, P < .03). Mean crude local control was 83%; 1-year local control was 85%. Distant intracranial failure occurred in 49% of cases, and salvage whole-brain radiation therapy was required in 29% of cases. Use of a radiosurgical margin did not lead to increased local control or overall survival. CONCLUSION: Our systematic review supports the use of radiosurgery as a safe and effective strategy for adjuvant treatment of brain metastases, particularly when gross total resection has been achieved. With all limitations of comparisons between studies, no increase in local recurrence or decrease in overall survival compared with rates with adjuvant whole-brain radiation therapy was found.