Citations

OBJECTIVEThe accessory nerve is frequently repaired or used for nerve transfer. The length of accessory nerve available is often insufficient or marginal (under tension) for allowing direct coaptation during nerve repair or nerve transfer (neurotization), necessitating an interpositional graft. An attractive maneuver would facilitate lengthening of the accessory nerve for direct coaptation. The aim of the present study was to identify an anatomical method for such lengthening.METHODSIn 20 adult cadavers, the C-2 or C-3 connections to the accessory nerve were identified medial to the sternocleidomastoid (SCM) muscle and the anatomy of the accessory nerve/cervical nerve fibers within the SCM was documented. The cervical nerve connections were cut. Lengths of the accessory nerve were measured. Samples of the cut C-2 and C-3 nerves were examined using immunohistochemistry.RESULTSThe anatomy and adjacent neural connections within the SCM are complicated. However, after the accessory nerve was “detethered” from within the SCM and following transection, the additional length of the accessory nerve increased from a mean of 6 cm to a mean of 10.5 cm (increase of 4.5 cm) after cutting the C-2 connections, and from a mean of 6 cm to a mean length of 9 cm (increase of 3.5 cm) after cutting the C-3 connections. The additional length of accessory nerve even allowed direct repair of an infraclavicular target (i.e., the proximal musculocutaneous nerve). The cervical nerve connections were shown not to contain motor fibers.CONCLUSIONSAn additional length of the accessory nerve made available in the posterior cervical triangle can facilitate direct repair or neurotization procedures, thus eliminating the need for an interpositional nerve graft, decreasing the time/distance for regeneration and potentially improving clinical outcomes.

Abstract The variable clinical success with immune checkpoint inhibitors in the treatment of solid tumors challenges us to further understand the regulatory mechanisms of immune cells infiltration – a critical step of tumor elimination – in a highly heterogenous tumor microenvironment (TME). Systemic analyses of the tumor-immune cell interface and interactions are of particular significance with direct clinical impact. We employed a multiplexed immunofluorescence (MxIF) method, a novel technology that allows in situ quantitative single cell characterization with high order protein multiplexing on whole tumor sections, to elucidate the key components in TME governing the immune cells' composition and function in metastatic melanoma lymph node metastases. Here, we show that the expression of tumor cell Human Leukocyte Antigen 1 (HLA-1) is highly heterogeneous both within the TME and between patients. The level of tumor HLA-1 expression directly correlates with the magnitude of cytotoxic T lymphocytes (CTLs) infiltration in the TME. In addition, decreased tumor HLA-1 expression is associated with accumulation of CD20+ cells at the edge of the tumor as well as an increased population of CD4+FOXP3+ cells. The association between tumor HLA-1 expression and immune cell distribution is highly consistent yet heterogenous across the entire tumor mass. Moreover, using quantitative single cell data, we developed algorithms for computational and spatial modeling of tumor-immune cell interfaces, allowing statistical comparison of cellular interactions in the context of tumor heterogeneity. Spatial analysis demonstrates that tumor HLA-1 expression favors CTL invasion, while lack of tumor HLA-1 expression results in CTL evasion. Furthermore, in a cohort of 166 Stage III melanoma patients, we confirm that CTLs infiltration is only present in regions with high tumor HLA-1 expressions, and that patients with tumors high in both tumor HLA-1 and CTLs have significantly improved progression free survival (PFS) compared with those with tumors low in HLA-1 and/or CTLs. Our study demonstrates that the heterogeneous tumor HLA-1 expression results in various immune cell distribution patterns in the TME, directly contributing to the varied antitumor immunities and ultimately influencing tumor outcomes. As part of the antigen presentation machinery, HLA-1 expression on tumors is necessary for CTLs infiltration and is indispensable for T cell mediated tumor elimination with direct clinical benefits. We also establish a novel platform for visualization and spatial representation of the cellular heterogeneity within the TME, providing data processing and modeling algorithms necessary for understanding the cellular interplay mediating tumor surveillance, which will ultimately improve therapeutic efficacy and clinical outcomes. Citation Format: Yiyi Yan, Alexey Leontovich, Thomas Flotte, Michael Gerdes, Fiona Ginty, Alberto Santamaria-Pang, Anup Sood, Keyur Desai, Chrystal Chadwick, Rong Zhang, Svetomir N. Markovic. Tumor HLA Class I expression influences immune cells infiltration in metastatic melanoma tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A71.

Abstract Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease ( CKD ) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end‐stage kidney disease ( ESKD ), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia‐induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia‐inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia‐induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF , TGF ‐β, Notch, PKC / ERK , PI 3K/Akt, NF ‐κB, Ang II / ROS and micro RNA s. Roles of molecules such as IL ‐6, IL ‐18, KIM ‐1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia‐responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD .

Liver vasculature is crucial for adequate hepatic functions. Global deletion of Notch signaling in mice results in liver vascular pathologies. However, whether Notch in endothelium is essential for hepatic vascular structure and function remains unknown. To uncover the function of endothelial Notch in the liver, we deleted Rbpj, a transcription factor mediating all canonical Notch signaling, or Notch1 from the endothelium of postnatal mice. We investigated the hepatic vascular defects in these mutants. The liver was severely affected within 2 weeks of endothelial deletion of Rbpj from birth. Two‐week old mutant mice had enlarged vessels on the liver surface, abnormal vascular architecture, and dilated sinusoids. Vascular casting and fluorosphere passage experiments indicated the presence of porto‐systemic shunts. These mutant mice presented with severely necrotic liver parenchyma and significantly larger hypoxic areas, likely resulting from vascular shunts. We also found elevated levels of VEGF receptor 3 together with reduced levels of ephrin‐B2, suggesting a possible contribution of these factors to the generation of hepatic vascular abnormalities. Deletion of Rbpj from the adult endothelium also led to dilated sinusoids, vascular shunts, and necrosis, albeit milder than that observed in mice with deletion from birth. Similar to deletion of Rbpj, loss of endothelial Notch1 from birth led to similar hepatic vascular malformations within 2 weeks. Conclusions: Endothelial Notch signaling is essential for the development and maintenance of proper hepatic vascular architecture and function. These findings may elucidate the molecular pathogenesis of hepatic vascular malformation and the safety of therapeutics inhibiting Notch. (Hepatology 2016;64:1302‐1316)

Spinal epidural arteriovenous fistulas (SEDAVFs) are rare complex lesions often presenting with protean clinical manifestations secondary to compressive symptoms or congestive myelopathy. The imaging manifestations of SEDAVFs on MR angiography/MRI include high T2 signal in the spinal cord, vascular engorgement of the epidural space, and prominent intradural vascular flow voids. Given the complexity of these lesions, they are best characterized anatomically on catheter angiography where careful inspection of arterial feeders and venous drainage patterns can be performed. The imaging hallmark of an SEDAVF on angiography is the presence of a dilated epidural venous pouch through which spinal and paraspinal veins are secondarily opacified. In the lower thoracic and lumbar spine, SEDAVFs are usually located in the ventral epidural space and fed mainly by the anteriorly coursing epidural arteries. In the cervical and upper thoracic spine, SEDAVFs and their feeding arteries are more typically located laterally in the spinal canal. Current treatment options include transarterial or transvenous endovascular embolization with liquid embolic agents or coils, and surgical resection/disconnection of the fistula. Further research is needed to better characterize how and why these lesions form and to identify the best treatment modalities.