Nina F. Schor

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Understanding the mechanisms governing the switch between hypoxia-induced adaptive and pathological transcription may reveal novel therapeutic targets for stroke. Using an in vitro hypoxia model that temporally separates these divergent responses, we found apoptotic signaling was preceded by a decline in c/EBP-beta activity and was associated with markers of ER-stress including transient eIF2alpha phosphorylation, and the delayed induction of the bZIP proteins ATF4 and CHOP-10. Pretreatment with the eIF2alpha phosphatase inhibitor salubrinal blocked the activation of caspase-3, indicating that ER-related stress responses are integral to this transition. Delivery of either full-length, or a transcriptionally inactive form of c/EBP-beta protected cultures from hypoxic challenge, in part by inducing levels of the anti-apoptotic protein Bcl-2. These data indicate that the pathologic response in cortical neurons induced by hypoxia involves both the loss of c/EBP-beta-mediated survival signals and activation of pro-death pathways originating from the endoplasmic reticulum.

p75NTR-dependent modulation of cellular handling of reactive oxygen species.

Our previous studies demonstrated that p75NTR confers protection against oxidative stress‐induced apoptosis upon PC12 cells; however, the mechanisms responsible for this effect are not known. The present studies reveal decreased mitochondrion membrane potential and increased generation of reactive oxygen species (ROS) in p75NTR‐deficient PC12 cells as well as diminution of ROS generation after transfection of a full‐length p75NTR construct into these cells. They also show that p75NTR deficiency attenuates activation of the phosphatidylinositol 3‐kinase → phospho‐Akt/protein kinase B pathway in PC12 cells by oxidative stress or neurotrophic ligands and inhibition of Akt phosphorylation decreases the glutathione (GSH) content in PC12 cells. In addition, decreased de novo GSH synthesis and increased GSH consumption are observed in p75NTR‐deficient cells. These findings indicate that p75NTR regulates cellular handling of ROS to effect a survival response to oxidative stress.

Pharmacologic management of high-risk neuroblastoma in children.

Neuroblastoma is the most common extracranial solid tumor of childhood. It accounts for 15% of pediatric cancer deaths. Children with high-risk disease have a 3-year event-free survival rate of only 20%. Chemotherapy is the mainstay of treatment in children with advanced neuroblastoma.The aim of this article was to review and critically evaluate the pharmacotherapy of neuroblastoma, using peer reviewed and review literature from 2000–11. All peer reviewed, published human subject studies of therapy for neuroblastoma in children were included. Animal model and in vitro studies were included only if they added to the understanding of the mechanism of a proposed or existing human neuroblastoma therapy.Current therapeutic options for neuroblastoma involve insufficient differentiation of normal from neoplastic tissue. Critically needed new approaches will increasingly exploit targeting of therapy for unique characteristics of the neuroblastoma cell. Pharmacotherapy for neuroblastoma still suffers from an inadequate therapeutic window. Enhancement of toxicity for tumor and safety for normal tissues will entail innovation in targeting neuroblastoma cells and rescuing or protecting normal tissue elements.

Life at the interface: Adults with “pediatric” disorders of the nervous system

The increasing longevity of patients with congenital and developmental disorders of the nervous system reflects the palliative and social success of pediatrics in the past 2 decades. This success has resulted in an increasing number of adult patients with residua or sequelae of childhood disease and/or its treatment. It is critically important that residencies and subspecialty fellowships train a cadre of physicians to prepare patients and families for the transition of children with special health care needs to adulthood and to attend to their unique medical, psychological, and social concerns. Health services and education research must better define the needs of this growing population and the best ways to educate their physicians and families and empower them to become as independent as their fullest potential allows. Ann Neurol 2013;74:158–163

Comment: Autonomy vs beneficence

The dialogue between autonomy and beneficence is ages old. Doing what the patient wants is not always consonant with doing what one believes is good and right for the patient. Inner conflict for the physician lies on both sides of this issue. As illustrated by the articles by Ronan1 and Daly et al.,2 it is just as hard to live with giving the judgmentally competent patient the right not to be treated when the outcome of treatment is likely to be good as with doing everything possible for a patient, predicting or even promising a good outcome, only to have the actual outcome make one question the quality of that saved life. Part of physician discomfort with both of these situations derives from the notion that the medical community can correctly and unambiguously identify what is or is not good and right for a given patient. Several recent studies have generated results that fly in the face of that notion and the long-held concept that there is a core set of moral and ethical values that are independent of context.3–6 Given that culture, environment, professional domain, and personal and family history can influence that ethical core, it is perhaps not surprising that what their nonphysician patients chose to do or have done sometimes makes physicians feel uneasy in not having done what is in keeping with their own moral and ethical code.

Why our patients (and we) need basic science research

In times of fiscal austerity, the tendency is to seek instant, inexpensive gratification. In the case of biomedical research, this means the shortest path to practical clinical implementation. But fueling the translational pipeline with discovery depends critically on allowing the biomedical research community to follow their science where it takes them. Fiscal constraints carry with them the risk of squelching creativity and forfeiting the power of serendipity to provide the substrate for the translational engine in the future.

Aiming at Neuroblastoma and Hitting Other Worthy Targets

Neuroblastoma is, at once, the most common and deadly extracranial solid tumor of childhood. Efforts aimed at targeting the neural characteristics of these tumors have taught us much about neural crest cell biology, apoptosis induction in the nervous system, and neurotrophin receptor signaling and intracellular processing. But neuroblastoma remains a formidable enemy to the oncologist and an enigmatic target to the neuroscientist.

Abstract B22: Antitumor effects of selective PRMT1 inhibitors on neuroblastoma in vitro and in vivo

The MYC family of transcription factors is one of the most frequently overexpressed oncogenes in human malignancies, including tumors that are derived from the nervous system. MYCN plays a causative role in neuroblastoma, a common and fatal childhood cancer of the developing sympathetic nervous system. Thus, the MYC family has been considered as a promising cancer target; however, so far, no small molecules can directly target MYC or MYCN in vivo. We have recently reported that PRMT1 functions as a key regulator of the stability and oncogenicity of MYCN. In this study, we have performed the structure-activity relationship analysis of diamidine-related PRMT1-seletive inhibitors. In correlation with their inhibition against PRMT1 in biochemical assays, these compounds showed remarkable anticancer properties both in neuroblastoma cell lines in vitro and in a preclinical mouse model of neuroblastoma in vivo. Mechanistically, these potent PRMT1 inhibitors destabilized MYCN, caused cell cycle arrest, and restored normal developmental signals of the developing sympathetic neuroblast precursors. Together, our results demonstrate that PRMT1-seletive inhibitors are promising anti-neuroblastoma agents and may represent a general strategy to target certain MYC/MYCN-driven cancers. Citation Format: Jeanne N. Hansen, Louis T. Lotta, Allison Eberhardt, Yujun George Zheng, Sen Ji, Shengyong Yang, Nina F. Schor, Xingguo Li. Antitumor effects of selective PRMT1 inhibitors on neuroblastoma in vitro and in vivo [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B22.

Chance juxtapositions and (un)biased methods in science More efficient at inefficiency

A recent article in Neurology® hammered home several points made all the more cogent by proposals relative to the Federal budget and allegations made during the 2016 Presidential campaign. Shepheard et al.1 demonstrated that the extracellular domain (ECD) of the low-affinity neurotrophin receptor, p75NTR, is found in higher-than-normal concentration in the urine of patients with amyotrophic lateral sclerosis (ALS). This urinary excess of p75ECD varies in magnitude in proportion to other more cumbersome and more expensive measures of nerve loss and muscle dysfunction. This may make measurement of urinary p75ECD a practical and reliable method for monitoring progression of ALS and response of patients with ALS to experimental therapeutics.

Clinical and ethical judgment: A profound dilemmaAuthor Response

I read with interest the article by Daly et al.1 on clinical and ethical judgment. When making ethically charged clinical decisions, the other variable between the extremes of autonomy and beneficence is the moral center of the physician. The treating physician should have a subjective line drawn over which he or she will not cross, even if the patient and the majority-driven respect for autonomy demand it.nnEvery physician has the right to exercise his or her own conscience. As Schor2 implies, part of a physicians role is to identify …