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Myeloid-derived suppressor cells are a major mechanism of tumor-induced immune suppression in cancer. Arginase I-producing myeloid-derived suppressor cells deplete l-arginine (L-Arg) from the microenvironment, which arrests T cells in the G0–G1 phase of the cell cycle. This cell cycle arrest correlated with an inability to increase cyclin D3 expression resulting from a decreased mRNA stability and an impaired translation. We sought to determine the mechanisms leading to a decreased cyclin D3 mRNA stability in activated T cells cultured in medium deprived of L-Arg. Results show that cyclin D3 mRNA instability induced by L-Arg deprivation is dependent on response elements found in its 3′-untranslated region (UTR). RNA-binding protein HuR was found to be increased in T cells cultured in medium with L-Arg and bound to the 3′-untranslated region of cyclin D3 mRNA in vitro and endogenously in activated T cells. Silencing of HuR expression significantly impaired cyclin D3 mRNA stability. L-Arg deprivation inhibited the expression of HuR through a global arrest in de novo protein synthesis, but it did not affect its mRNA expression. This alteration is dependent on the expression of the amino acid starvation sensor general control nonderepressible 2 kinase. These data contribute to an understanding of a central mechanism by which diseases characterized by increased arginase I production may cause T cell dysfunction.

Tobacco smoking predisposes the development of diseases characterized by chronic inflammation and T cell dysfunction. In this study, we aimed to determine the direct effects of cigarette smoke on primary T cells and to identify the corresponding molecular mediators. Activated T cells cultured in the presence of cigarette smoke extract (CSE) displayed a dose-dependent decrease in cell proliferation, which associated with the induction of cellular apoptosis. T cell apoptosis by CSE was independent of caspases and mediated through reactive oxygen and nitrogen species endogenously contained within CSE. Additional results showed that exposure of T cells to CSE induced phosphorylation of the stress mediator eukaryotic-translation-initiation-factor 2 alpha (eIF2 ). Inhibition of the phosphorylation of eIF2 in T cells prevented the cellular apoptosis induced by CSE. Altogether, the results show the direct effects of CSE on T cells, which advance in the understanding of how cigarette smoking promotes chronic inflammation and immune dysfunction.

New treatments for adults with acute lymphoblastic T-cell leukemia (T-ALL) are urgently needed, as the current rate of overall remission in these patients is only about 40 percent. We recently showed the potential therapeutic benefit of the pegylated-human-arginase I (peg-Arg I) in T-ALL. However, the mechanisms by which peg-Arg I induces an anti-T-ALL effect remained unknown. Our results show the induction of T-ALL cell apoptosis by peg-Arg I, which associated with a global arrest in protein synthesis and with the phosphorylation of the eukaryotic-translation-initiation factor 2 alpha (eIF2α). Inhibition of eIF2α phosphorylation in T-ALL cells prevented the apoptosis induced by peg-Arg I, whereas the expression of a phosphomimetic eIF2α form increased the sensibility of T-ALL cells to peg-Arg I. Phosphorylation of eIF2α by peg-Arg I was mediated through kinases PERK and GCN2 and down-regulation of phosphatase GADD34. GCN2 and decreased GADD34 promoted T-ALL cell apoptosis after treatment with peg-Arg I, whereas PERK had an unexpected anti-apoptotic role. Additional results showed that phospho-eIF2α signaling further increased the anti-leukemic effects induced by peg-Arg I in T-ALL-bearing mice. These results suggest the central role of phospho-eIF2α in the anti-T-ALL effects induced by peg-Arg I and support its study as a therapeutic target.

OBJECTIVEFew studies have been published specifically examining intravenous drug abuse (IVDA)–associated spinal epidural abscesses (SEAs), an unfortunate sequela of the opioid crisis in the United States. Here, the authors examined a series of patients with IVDA-associated SEAs in order to shed light on this challenging disease entity.METHODSThis study is a retrospective chart review of patients presenting with IVDA-associated SEAs at the authors’ institution from 2013 to 2018, spanning the statewide implementation of opioid-prescribing restrictions.RESULTSA total of 45 patients presented with IVDA-associated SEAs; 46.5% presented with a neurological deficit. Thirty-one patients underwent surgery for neurological deficit, failure of medical therapy, or both. Nineteen surgical patients underwent a fusion procedure along with decompression. The complication rate was 41.9%, and the mortality rate was 6.7%. The average length of stay was 27.6 days. Patients who underwent surgery within 24 hours of onset of neurological symptoms trended toward more improvement in their American Spinal Cord Association Impairment Scale grade than those who did not (0.5 vs −0.2, p = 0.068). Methicillin-resistant Staphylococcus aureus was isolated as the causative pathogen in 57.8% of patients. Twenty-three patients (51.5%) kept their scheduled clinic follow-up appointments. Of the fusion patients with adequate follow-up, 5 showed bony arthrodesis and 3 had pseudarthrosis. The rate of IVDA-associated SEAs increased after opioid-prescribing restrictions were put in place, from 0.54 cases per month to 1.15 cases per month (p = 0.017).CONCLUSIONSPatients with IVDA-associated SEAs are challenging to treat, with high complication rates and poor follow-up. This disease is increasing in frequency, and opioid-prescribing restrictions did not slow that rise. Community outreach to promote prevention, early medical attention, and medication compliance would benefit this largely publicly funded patient population.