Neurofascin as a novel target for autoantibody-mediated axonal injury

Axonal injury is considered the major cause of disability in patients with multiple sclerosis (MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics-based approach, we identified neurofascin-specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 (NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte-specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement-dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein–specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood–brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune-mediated axonal injury that can contribute to axonal pathology in MS

Spatial Cooperation: Incorporating Social Research into Conservation Planning

A systematic method of assessing and applying landowner stewardship values would assist land trusts in prioritizing privately-owned parcels for conservation. Land trusts are non-profit organizations, usually with limited financial resources, diverse conservation objectives, and diverse conservation processes. When a conservation group synthesizes social research and spatial planning techniques they may rank parcels for conservation by the likeliness that those parcels will later be converted to developed uses. Landowner surveys are a means by which to assess stewardship values. Derivable from the surveys is a stewardship index (SI): a measure of such factors as a landowner’s dependence on their land for income; and their intentions to subdivide or sell their land. SI may be tested with other variables (e.g. number of acres owned) to detect causal relationships. If a person’s attitudes and behaviors are shaped by his surrounding environment, then rural landowner stewardship values must be at least in part a reflection of the landscape in which they reside. Upon the identification of causal relationships, GIS and a wide availability of spatial data permit the extrapolation of SI to the parcels of landowners not included in the original written survey. Land trusts may overlay their target conservation areas in GIS, enabling them to make informed predictions about the fate of a parcel before time and monetary resources are allocated for its conservation. Conservation plans gleaned by the process described above should anticipate uncertainties in SI generalization, and would be better to provide room for flexibility in design, as was applied in a recent case study of Greenwood County, SC

IMMU-27. LONG TERM STABILIZATION OF RECURRENT HIGH-GRADE GLIOMA WITH PD-1 INHIBITOR PEMBROLIZUMAB IN TWO CASES

Abstract INTRODUCTION Despite PD-1 inhibition having success in many cancers, it has uncertain effects in brain tumors. We report two cases of recurrent high-grade gliomas that have remained stable for over one year since starting pembrolizumab. CASE REPORTS Case 1: A 59-year-old male was diagnosed with glioblastoma (GBM) without MGMT methylation or IDH mutation in late 2018 after surgery. He received radiation and temozolomide (TMZ) followed by adjuvant TMZ before tumor progression. He underwent second tumor debulking with recurrent GBM on pathology with negative PD-L1 expression. He started carboplatin. Progression was noticed after 7 to 8 cycles. Pembrolizumab was added. Tumor was stabilized. Carboplatin was completed after total 12 cycles and the patient has continued single agent of pembrolizumab for more than one year with stable brain MRIs. The patient has survived for 24 months since recurrence and 30 months since diagnosis. Case 2: A 53-year-old male had a brain tumor discovered on MRI in 2012 and received no treatment until resection in 2014. In 2016, he underwent second tumor debulking and was diagnosed with anaplastic oligodendroglioma with negative PD-L1 expression. He received radiation followed by PCV regimen. 17 months since diagnosis, he had first tumor progression on PCV. TMZ was started. 22 months since diagnosis, bevacizumab was initiated due to further growth. 33 months since diagnosis, pembrolizumab was added due to new lesions after 12-months of bevacizumab therapy. His tumor was stabilized. Bevacizumab was eventually discontinued. He has continued single agent pembrolizumab for 6 months so far. His tumor has been stable for 22 months since starting pembrolizumab. Survival has been 38 months from first recurrence and 7 years since tissue diagnosis. DISCUSSION These cases demonstrate the potential effects of anti-PD-1 immunotherapy in stabilizing recurrent high-grade glioma with combination of other treatment agents followed by single agent as maintenance therapy

IMMU-27. LONG TERM STABILIZATION OF RECURRENT HIGH-GRADE GLIOMA WITH PD-1 INHIBITOR PEMBROLIZUMAB IN TWO CASES

Abstract INTRODUCTION Despite PD-1 inhibition having success in many cancers, it has uncertain effects in brain tumors. We report two cases of recurrent high-grade gliomas that have remained stable for over one year since starting pembrolizumab. CASE REPORTS Case 1: A 59-year-old male was diagnosed with glioblastoma (GBM) without MGMT methylation or IDH mutation in late 2018 after surgery. He received radiation and temozolomide (TMZ) followed by adjuvant TMZ before tumor progression. He underwent second tumor debulking with recurrent GBM on pathology with negative PD-L1 expression. He started carboplatin. Progression was noticed after 7 to 8 cycles. Pembrolizumab was added. Tumor was stabilized. Carboplatin was completed after total 12 cycles and the patient has continued single agent of pembrolizumab for more than one year with stable brain MRIs. The patient has survived for 24 months since recurrence and 30 months since diagnosis. Case 2: A 53-year-old male had a brain tumor discovered on MRI in 2012 and received no treatment until resection in 2014. In 2016, he underwent second tumor debulking and was diagnosed with anaplastic oligodendroglioma with negative PD-L1 expression. He received radiation followed by PCV regimen. 17 months since diagnosis, he had first tumor progression on PCV. TMZ was started. 22 months since diagnosis, bevacizumab was initiated due to further growth. 33 months since diagnosis, pembrolizumab was added due to new lesions after 12-months of bevacizumab therapy. His tumor was stabilized. Bevacizumab was eventually discontinued. He has continued single agent pembrolizumab for 6 months so far. His tumor has been stable for 22 months since starting pembrolizumab. Survival has been 38 months from first recurrence and 7 years since tissue diagnosis. DISCUSSION These cases demonstrate the potential effects of anti-PD-1 immunotherapy in stabilizing recurrent high-grade glioma with combination of other treatment agents followed by single agent as maintenance therapy

Golgi Acidification by NHE7 Regulates Cytosolic pH Homeostasis in Pancreatic Cancer Cells.

Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium-hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC. SIGNIFICANCE: NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a "proton sink" for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth.See related commentary by Ward and DeNicola, p. 768.This article is highlighted in the In This Issue feature, p. 747

Golgi Acidification by NHE7 Regulates Cytosolic pH Homeostasis in Pancreatic Cancer Cells.

Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium-hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC. SIGNIFICANCE: NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a "proton sink" for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth.See related commentary by Ward and DeNicola, p. 768.This article is highlighted in the In This Issue feature, p. 747

Mitigating avian collision with power lines: a proof of concept for installation of line markers via unmanned aerial vehicle

Abstract: Avian collisions with overhead power lines are a global conservation concern. Collisions are mitigated primarily through marking power lines to increase the visibility of lines. Line marking is typically accomplished via an expensive and potentially dangerous process of hovering a helicopter within 1 m of a wire and installing line markers by hand. Unmanned Aerial Vehicles (UAVs) may offer a less dangerous, less costly alternative that is also less disturbing to wildlife. Herein we describe equipping a commercially available UAV with an installation arm designed in collaboration with the Colorado State University Department of Mechanical Engineering to install line markers on a power line. The UAV installed line markers within a 30 cm target window on a model power line. The proof of concept described here demonstrates the potential utility of UAVs in mitigating avian collision with overhead power lines.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author