Associations Between Prior Head Injury, Physical Functioning, and Frailty in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Older adults have the highest rates of head injury and are at the greatest risk for subsequent dysfunction, yet research on subsequent physical decline is limited. We sought to examine cross-sectional and prospective associations of head injury with physical functioning and frailty among older adults. METHODS: A total of 5 598 Atherosclerosis Risk in Communities Study participants from Visit 5 (2011-13) underwent assessments of physical functioning (Short Physical Performance Battery [SPPB], comprised of gait speed, chair stands, and balance) and frailty (defined using established criteria) were followed through Visit 7 (2018-19). Head injury was self-reported or based on ICD-9 codes. Adjusted linear and multinomial logistic regression models were used to estimate associations. Prospective models incorporated inverse probability of attrition weights to account for death or attrition. RESULTS: Participants were a mean age of 75 years, 58% were women, 22% were Black, and 27% had a prior head injury. Compared to individuals without head injury, individuals with head injury had worse physical functioning (SPPB total score, ß-coefficient = -0.22, 95% CI: -0.35 to -0.09) and were more likely to be pre-frail (OR = 1.19, 95% CI: 1.04 to 1.35) or frail (OR = 1.40, 95% CI: 1.08 to 1.80) compared to robust. Prospectively, head injury was associated with a 0.02 m/s greater decline (95% CI: -0.04 to -0.01) in gait speed over a median of 5 years. Among baseline robust individuals (n = 1 847), head injury was associated with increased odds of becoming pre-frail (OR = 1.32, 95% CI: 1.04 to 1.67) or frail (OR = 1.92, 95% CI: 1.05 to 3.51) compared to robust. CONCLUSIONS: Older adults with prior head injury had worse physical functioning and greater frailty at baseline and were more likely to become frail and walk slower over time, compared to individuals without head injury.

Concussion severity and functional outcome using biomarkers in children and youth involved in organized sports, recreational activities and non-sport related incidents.

This prospective multicenter study evaluated differences in concussion severity and functional outcome using glial and neuronal biomarkers glial Fibrillary Acidic (GFAP) and Ubiquitin C-terminal Hydrolase (UCH-L1) in children and youth involved in non-sport related trauma, organized sports, and recreational activities. Children and youth presenting to three Level 1 trauma centersfollowing blunt head trauma with a GCS 15 with a verified diagnosis of a concussion were enrolled within 6 hours of injury. Traumatic intracranial lesions on CT scan and functional outcome within 3 months of injury were evaluated. 131 children and youth with concussion were enrolled, 81 in the no sports group, 22 in the organized sports group and 28 in the recreational activities group. Median GFAP levels were 0.18, 0.07, and 0.39 ng/mL in the respective groups (p = 0.014). Median UCH-L1 levels were 0.18, 0.27, and 0.32 ng/mL respectively (p = 0.025). A CT scan of the head was performed in 110 (84%) patients. CT was positive in 5 (7%), 4 (27%), and 5 (20%) patients, respectively. The AUC for GFAP for detecting +CT was 0.84 (95%CI 0.75-0.93) and for UCH-L1 was 0.82 (95%CI 0.71-0.94). In those without CT lesions, elevations in UCH-L1 were significantly associated with unfavorable 3-month outcome. Concussions in the 3 groups were of similar severity and functional outcome. GFAP and UCH-L1 were both associated with severity of concussion and intracranial lesions, with the most elevated concentrations in recreational activities .

Evaluation of alpha-II-spectrin breakdown products as potential biomarkers for early recognition and severity of aneurysmal subarachnoid hemorrhage.

This study assessed whether cytoskeletal protein alpha-II spectrin breakdown products (SBDP150, SBDP145, and SBDP120) would identify the presence of aSAH and be associated with severity (GCS score, WFNS grade and survival to hospital discharge). This prospective case-control study, conducted at a tertiary care Level I trauma center, enrolled adult patients with angiography confirmed aSAH who underwent ventriculostomy placement for cerebrospinal fluid (CSF) drainage. There were 40 patients enrolled in the study, 20 with aSAH and 20 control subjects. Patients with aSAH were a mean age of 54 (SD15) and 75% were female. There were significant differences in SBDP150, SBDP145, and SBDP120 CSF levels between patients with and without aSAH (p < 0.001), even in those presenting with a GCS Score of 15 and a WFNS Grade 1. The AUC for distinguishing aSAH from control subjects was 1.0 for SBDP150 and SBDP145, and 0.95 for SBDP120. SBDP150 and SBDP145 both yielded sensitivities and specificities of 100% and SBDP120 was 90% and 100% respectively. Moreover, there were significantly higher levels of SBDP150 and SBDP145 in the non-survivors than in the survivors (p < 0.001). This study demonstrates the potential that SBDP's have as biomarkers for recognition and severity of aSAH. A larger prospective study is warranted.

Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus.

OBJECTIVE: We investigated the mechanistic and pharmacological properties of anifrolumab, a fully human, effector-null, anti-type I interferon (IFN) alpha receptor 1 (IFNAR1) monoclonal antibody in development for SLE. METHODS: IFNAR1 surface expression and internalisation on human monocytes before and after exposure to anifrolumab were assessed using confocal microscopy and flow cytometry. The effects of anifrolumab on type I IFN pathway activation were assessed using signal transducer and activator of transcription 1 (STAT1) phosphorylation, IFN-stimulated response element-luciferase reporter cell assays and type I IFN gene signature induction. The ability of anifrolumab to inhibit plasmacytoid dendritic cell (pDC) function and plasma cell differentiation was assessed by flow cytometry and ELISA. Effector-null properties of anifrolumab were assessed in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays with B cells. RESULTS: Anifrolumab reduced cell surface IFNAR1 by eliciting IFNAR1 internalisation. Anifrolumab blocked type I IFN-dependent STAT1 phosphorylation and IFN-dependent signalling induced by recombinant and pDC-derived type I IFNs and serum of patients with SLE. Anifrolumab suppressed type I IFN production by blocking the type I IFN autoamplification loop and inhibited proinflammatory cytokine induction and the upregulation of costimulatory molecules on stimulated pDCs. Blockade of IFNAR1 suppressed plasma cell differentiation in pDC/B cell co-cultures. Anifrolumab did not exhibit CDC or ADCC activity. CONCLUSIONS: Anifrolumab potently inhibits type I IFN-dependent signalling, including the type I IFN autoamplification loop, and is a promising therapeutic for patients with SLE and other diseases that exhibit chronic dysfunctional type I IFN signalling.

Aptamer-conjugated and doxorubicin-loaded unimolecular micelles for targeted therapy of prostate cancer.

In the absence of effective therapy for prostate cancer, there is an immense need for developing improved therapeutic options for the management of this disease. This study has demonstrated that aptamer-conjugated unimolecular micelles can improve the in vivo tumor biodistribution of systemically administered anti-cancer drugs in prostate cancer expressing prostate-specific membrane antigen (PSMA). The aptamer-conjugated unimolecular micelles were formed by individual hyperbranched polymer molecules consisting of a hyperbranched H40 polymer core and approximately 25 amphiphilic polylactide-poly(ethlyene glycol) (PLA-PEG) block copolymer arms (H40-PLA-PEG-Apt). The unimolecular micelles with an average hydrodynamic diameter of 69 nm exhibited a pH-sensitive and controlled drug release behavior. The targeted unimolecular micelles (i.e., DOX-loaded H40-PLA-PEG-Apt) exhibited a much higher cellular uptake in PSMA positive CWR22Rν1 prostate carcinoma cells than non-targeted unimolecular micelles (i.e., DOX-loaded H40-PLA-PEG), thereby leading to a significantly higher cytotoxicity. The DOX-loaded unimolecular micelles up-regulated the cleavage of PARP and Caspase 3 proteins and increased the protein expression of Bax along with a concomitant decrease in Bcl2. These micelles also increased the protein expression of cell cycle regulation marker P21 and P27. In CWR22Rν1 tumor-bearing mice, DOX-loaded H40-PLA-PEG-Apt micelles (i.e., targeted) also exhibited a much higher level of DOX accumulation in the tumor tissue than DOX-loaded H40-PLA-PEG micelles (i.e., non-targeted). These findings suggest that aptamer-conjugated unimolecular micelles may potentially be an effective drug nanocarrier to effectively treat prostate cancer.

MAGE-C2 promotes growth and tumorigenicity of melanoma cells, phosphorylation of KAP1, and DNA damage repair.

Melanoma-associated antigen-encoding (MAGE) genes are expressed in melanoma and other cancers but not in normal somatic cells. MAGE expression is associated with aggressive tumor growth, poor clinical outcome, and resistance to chemotherapy, but the mechanisms have not been completely elucidated. In this study, we show that downregulation of MAGE-C2 in A375 melanoma cells and low-passage cultures from human metastatic melanomas (MRA cells) results in increased apoptosis and decreased growth of tumor xenografts in athymic nude mice. Previously, we showed that MAGE-C2 binds KAP1, a scaffolding protein that regulates DNA repair. Phosphorylation of KAP1-Serine 824 (Ser824) by ataxia-telangiectasia-mutated (ATM) kinase is necessary for repair of DNA double-strand breaks (DSBs); now we show that MAGE-C2 knockdown reduces, whereas MAGE-C2 overexpression increases, ATM kinase-dependent phosphorylation of KAP1-Ser824. We demonstrate that MAGE-C2 increases co-precipitation of KAP1 with ATM and that binding of MAGE-C2 to KAP1 is necessary for increased KAP1-Ser824 phosphorylation. Furthermore, ectopic expression of MAGE-C2 enhances repair of I-SceI endonuclease-induced DSBs in U-2OS cells. As phosphorylation of KAP1-Ser824 facilitates relaxation of heterochromatin, which is necessary for DNA repair and cellular proliferation, our results suggest that MAGE-C2 can promote tumor growth by phosphorylation of KAP1-Ser824 and by enhancement of DNA damage repair.