Improved Arousal and Motor Function Using Zolpidem in a Patient With Space‐Occupying Intracranial Lesions: A Case Report

Patients with disorders of consciousness (DOC) have profound functional limitations with few treatment options for improving arousal and quality of life. Zolpidem is a nonbenzodiazepine hypnotic used to treat insomnia that has also been observed to paradoxically improve arousal in those with DOC, such as the vegetative or minimally conscious states. Little information exists on its use in patients with DOC who have intracranial space‐occupying lesions. We present a case of a 24‐year‐old man in a minimally conscious state due to central nervous system lymphoma who was observed to have increased arousal and improved motor function after the administration of zolpidem.Level of EvidenceVPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147138/1/pmr2831.pd

Poster 228 Zolpidem for the Treatment of Neurologic Disorders: A Systematic Review

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146862/1/pmrjs234b.pd

Comments on Bilateral Neonatal Testicular Torsion

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66939/2/10.1177_000992289703601108.pd

Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism

Obesity is a multi-systemic disorder of energy balance. Despite intense investigation, the determinants of energy homeostasis remain incompletely understood, and efficacious treatments against obesity and its complications are lacking. Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase

An overt chemical protective garment reduces thermal strain compared with a covert garment in warm-wet but not hot-dry environments

© 2017 The Authors. Published by Frontiers Media. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.3389/fphys.2017.00913© 2017 Maley, Costello, Borg, Bach, Hunt and Stewart. Objectives: A commercial chemical, biological, radiological and nuclear (CBRN) protective covert garment has recently been developed with the aim of reducing thermal strain. A covert CBRN protective layer can be worn under other clothing, with equipment added for full chemical protection when needed. However, it is unknown whether the covert garment offers any alleviation to thermal strain during work compared with a traditional overt ensemble. Therefore, the aim of this study was to compare thermal strain and work tolerance times during work in an overt and covert ensemble offering the same level of CBRN protection. Methods: Eleven male participants wore an overt (OVERT) or covert (COVERT) CBRN ensemble and walked (4 km·h-1, 1% grade) for a maximum of 120 min in either a wet bulb globe temperature [WBGT] of 21, 30, or 37°C (Neutral, WarmWet and HotDry, respectively). The trials were ceased if the participants' gastrointestinal temperature reached 39°C, heart rate reached 90% of maximum, walking time reached 120 min or due to self-termination. Results: All participants completed 120 min of walking in Neutral. Work tolerance time was greater in OVERT compared with COVERT in WarmWet (P 0.05). Conclusion: Those dressed in OVERT experienced lower thermal strain and longer work tolerance times compared with COVERT in a warm-wet environment. However, COVERT may be an optimal choice in a hot-dry environment. These findings have practical implications for those making decisions on the choice of CBRN ensemble to be used during work.This project is financially supported by the Australian Government, managed by the National Security Science and Technology Centre within the Defence Science and Technology Organization, and the US Government through the Technical Support Working Group within the Combating Terrorism Technical Support Office.Published versio

A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma

Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI‐PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose‐expansion study of patients with argininosuccinate synthetase (ASS1)‐deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m(2)) and Cis (75 mg/m(2)) every 3 weeks plus weekly intramuscular ADI (36 mg/m(2)), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1‐deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression‐free survival of 3.0 months (range, 1.3–8.1) and a median overall survival of 11.5 months (range, 3.2–36.9). Despite anti‐ADI‐PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re‐expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti‐metabolite strategies

A Phase 1 Study of ADI-PEG20 (Pegargiminase) Combined with Cisplatin and Pemetrexed in ASS1-Negative Metastatic Uveal Melanoma

Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI-PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose-expansion study of patients with argininosuccinate synthetase (ASS1)-deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m2 ) and Cis (75 mg/m2 ) every three weeks plus weekly intramuscular ADI (36 mg/m2 ), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1-deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression-free survival of 3.0 months (range, 1.3-8.1) and a median overall survival of 11.5 months (range, 3.2-36.9). Despite anti-ADI-PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re-expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional antimetabolite strategies

Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma.

Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation of ASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell lines. This adaptive transcriptional upregulation is blocked by neoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylated ASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquine accelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in a subset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpG island retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two key genes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate that methylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to arginine deprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for which we have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/brain barrier

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma

Background Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy. Methods Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic “hits” were validated by qPCR, ELISA, and LC/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM. Results We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1α in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1α-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model. Conclusions Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers