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Objective This study examines sex differences in social inferencing deficits after traumatic brain injury (TBI), and examines the odds of males and females being impaired while controlling for potential confounders. Design Cross-sectional survey. Setting Outpatient.USA and a University in Canada. Participants One hundred five participants with TBI (60 males, 45 females) and 105 healthy controls (HC; 57 males, 48 females). Interventions Not applicable. Main Outcome Measures The Awareness of Social Inference Test (TASIT), which includes 1) Emotional Evaluation Test (EET), 2) Social Inference-Minimal (SI-M) test, and 3) Social Inference-Enriched (SI-E) test. Results Within the HC sample, males and females performed similarly on all three TASIT subtests. Within the TBI group, males had significantly lower scores than females on EET (P = 0.03), SI-M (P=0.01) and SI-E (P=0.04). Using impairment cutoffs derived from the HC sample, significantly more males with TBI (30%) were impaired on the EET than females(16.7%); impairment was similar between males and females on SI-M and SI-E. When adjusting for executive functioning and education, the odds of being impaired on the EET did not significantly differ for males and females (OR = 0.47; 95% CI: 0.16 - 1.40; P = 0.18). Conclusions While more males with TBI have emotion perception deficits than females, the difference appears to be driven by education and executive functioning. Research is needed in larger samples with more definitive norms to better understand social inferencing impairments in males and females with TBI, and translation to interpersonal behaviors.

Aberrant overactivation/overexpression of NRF2 is implicated as a driving event in tumor progression, which has been attributed to its mutation or inactivation of the inhibitory protein, KEAP1. However, alternative mechanisms responsible for sustained activation of NRF2 are less understood.Human colon cancer cell lines and tissues obtained from colorectal cancer (CRC) patients were used. To examine the expression levels of ARD1 and NRF2, Western blot and immunofluorescence analyses were performed. To investigate the potential relevance of NRF2 and ARD1 to human CRC, NRF2 and ARD1 were individually silenced in human colon cancer cells (HCT-116) by transfection with their specific small interfering RNA (siRNA). To determine the functional role of ARD1 in NRF2 regulation, in situ proximate ligation, co-immunoprecipitation, nano-LC-ESI MS/MS, and in vitro acetylation assays were performed.ARD1 knockdown in human colon cancer cell lines significantly reduced the protein levels of NRF2 without affecting its mRNA expression; however, silencing of NRF2 did not alter ARD1 protein expression. In addition, these two proteins were co-localized and physically interacted with each other both in human colon cancer cells (HCT-116) and human colon tumor tissues. Mechanistically, ARD1 overexpression increased the acetylation levels of NRF2. Moreover, an in vitro acetylation assay and mass spectrometric analysis demonstrated that ARD1 could directly acetylate NRF2. Ectopic expression of mutant forms of ARD1 with defective acetyltransferase activity reduced the stability of NRF2.In conclusion, ARD1 may potentiate the oncogenic function of NRF2 in human colon cancer by stabilizing this transcription factor.

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products of cyclooxygenase-2-catalized arachidonic acid metabolism, has been shown to stimulate breast cancer cell proliferation and migration through Akt activation, but the underlying mechanisms remain poorly understood. In the present study, we investigated the effects of 15d-PGJ2 on the activity of PTEN, the inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt axis, in human breast cancer (MCF-7) cells. Since the α,β-unsaturated carbonyl moiety in the cyclopentenone ring of 15d-PGJ2 is electrophilic, we hypothesized that 15d-PGJ2-induced Akt phosphorylation might result from the covalent modification and subsequent inactivation of PTEN that has several critical cysteine residues. When treated to MCF-7 cells, 15d-PGJ2 bound to PTEN, and this was abolished in the presence of the thiol-reducing agent dithiothreitol. A mass spectrometric analysis by using recombinant and endogenous PTEN protein revealed that the cysteine 136 residue (Cys136) of PTEN is covalently modified upon treatment with 15d-PGJ2. Notably, the ability of 15d-PGJ2 to covalently bind to PTEN as well as to induce Akt phosphorylation was abolished in the cells expressing a mutant form of PTEN in which Cys136 was replaced by serine (C136S-PTEN). The present study demonstrates for the first time that electrophilic 15d-PGJ2 directly binds to cysteine 136 of PTEN and provides new insight into PTEN loss in cancer progression associated with chronic inflammation. These observations suggest that 15d-PGJ2 can undergo nucleophilic addition to PTEN, presumably at Cys136, thereby inactivating this tumor suppressor protein with concomitant Akt activation.

Phagocytosis of pathogens by macrophages is crucial for the successful resolution of inflammation induced by microbial infection. Taurine chloramine (TauCl), an endogenous anti-inflammatory and antioxidative substance, is produced by reaction between taurine and hypochlorous acid by myeloperoxidase activity in neutrophils under inflammatory conditions. In the present study, we investigated the effect of TauCl on resolution of acute inflammation caused by fungal infection using a zymosan A-induced murine peritonitis model. TauCl administration reduced the number of the total peritoneal leukocytes, while it increased the number of peritoneal monocytes. Furthermore, TauCl promoted clearance of pathogens remaining in the inflammatory environment by macrophages. When the macrophages isolated from thioglycollate-treated mice were treated with TauCl, their phagocytic capability was enhanced. In the murine macrophage-like RAW264.7 cells treated with TauCl, the proportion of macrophages clearing the zymosan A particles was also increased. TauCl administration resulted in elevated expression of heme oxygenase-1 (HO-1) in the peritoneal macrophages. Pharmacologic inhibition of HO-1 activity or knockdown of HO-1 in the murine macrophage RAW264.7 cells abolished the TauCl-induced phagocytosis, whereas the overexpression of HO-1 augmented the phagocytic ability of macrophages. Moreover, peritoneal macrophages isolated from HO-1 null mice failed to mediate TauCl-induced phagocytosis. Our results suggest that TauCl potentiates phagocytic activity of macrophages through upregulation of HO-1 expression.

Research Objectives To explore the benefits versus harms of amantadine in the treatment of irritability and aggression. Design Parallel-group, randomized, double-blind, placebo-controlled trial of amantadine versus placebo. Setting Outpatient. Participants 168 individuals with chronic TBI and irritability (amantadine n=82 versus placebo n=86). Interventions Amantadine 100 mg or placebo equivalent two times daily. Main Outcome Measures Number-Needed-To-Treat (NNT) and Number-Needed-to-Harm (NNH). NNT was calculated using number of individuals with improvement as indicated by Clinical Global Impressions – Global Improvement scale. NNH was calculated using 3 definitions of adverse outcome: number of participants with GI indicating worsening, number of participants with serious adverse events, and number of participants with adverse events. Results Based on clinician ratings, for every 6 patients treated with amantadine, 1 patient more than placebo would be expected to improve. More participants in the placebo group worsened than in the amantadine group. For every 27 patients treated, 1 more than the placebo would be expected to experience serious adverse events. More participants in the placebo group experienced adverse events of any severity than in the amantadine group. Conclusions Clinician ratings suggest moderate benefit with low risk to appropriately selected patients. Thus, amantadine should be considered a treatment option for the experienced brain injury clinician. These data may support treatment decisions when a pharmaceutical agent is being considered to control irritability/aggression. Author(s) Disclosures Dr. Hammond serves on the Avanir Scientific Advisory Committee.

This study describes the characterisation of a new angiotensin I-converting enzyme (ACE) inhibitory peptide from the fruiting body of Pleurotus cornucopiae which could be used as a functional food or nutraceutical compounds. After purification of the ACE inhibitor in an ultrafiltration, Sephadex G-25 column chromatography, successively C 18 and SCX solid-phase extraction and reverse-phase HPLC, two types of the purified ACE inhibitors with IC 50 values of 0.46 and 1.14 mg/ml were obtained. The two purified ACE inhibitors were analysed, showing two types of oligopeptides. The amino acid sequences of the two purified oligopeptides were found to be RLPSEFDLSAFLRA and RLSGQTIEVTSEYLFRH. The molecular mass of the purified ACE inhibitors was estimated to be 1622.85 and 2037.26 Da, respectively. Water extracts of P. cornucopiae fruiting body showed a clear antihypertensive effect on spontaneously hypertensive rats at a dosage of 600 mg/kg.