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BackgroundIdiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments.MethodsWe searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework.ResultsWe identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (–88.35 to 411.12)), pirfenidone (2.47% (–0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty).Conclusion and relevanceFuture guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.

Background Accumulation of p25 is thought to be a causative risk factor for Alzheimer's disease (AD). As a cleaved product of p35, p25 binds to cyclin-dependent kinase 5 (Cdk5) and leads to the hyperactivity of Cdk5. Then, Cdk5/p25 phosphorylates many pathological substrates related to neurodegenerative diseases. p25 transgenic (Tg) mouse model recaptures some pathological changes of AD, including tau hyperphosphorylation, neurofibrillary tangles, neuroinflammation, and neuronal death, which can be prevented by transgenic expression of Cdk5 inhibitory peptide (CIP) before the insult of p25. Objective In the present study, we would like to know whether adeno-associated virus serotype-9 (AAV9)-mediated CIP can protect neurons after insult of p25 in p25Tg mice. Methods Administration of AAV9-CIP or control virus were delivered in the brain of p25Tg mice via intracerebroventricular infusions following the induction of p25. Western blotting, immunohistochemistry and immunofluorescence assessment, and animal behavioral evaluation were performed. Results Brain atrophy, neuronal death, tau phosphorylation and inflammation in the hippocampus, and cognitive decline were observed in p25Tg mice. Administration of CIP but not the control virus in p25Tg mice reduced levels of tau phosphorylation and inflammation in the hippocampus, which is correlated with inhibition of brain atrophy and neuronal apoptosis in the hippocampus, and improvement of cognitive decline. Conclusion Our results provide further evidence that the neurotoxicity of p25 can be alleviated by CIP.

Deemed as incurable, Alzheimer's disease (AD) research is becoming less convoluted as our understanding of its pathology increases. With current treatments focusing on merely mitigating the symptoms of AD, there have been many attempts to find a molecular culprit to serve as the single underlying cause and therapeutic target for clinical applications to approach the disease from its roots. Indeed, over the course of decades, the endless search for a singular target culprit in AD has uncovered a cascade of pathological defects, adding on to each other throughout the progression of the disease. The developmental patterns of amyloid-β (Aβ) oligomers have been studied as a means to discover the complex molecular interplay between various immune responses, genetic mutations, pathway disturbances, and regulating factors that disturb synapse homeostasis before disease manifestation. This new understanding has shifted the underlying goal of the research community from merely removing Aβ oligomers to finding methods that can predict high risk individuals and resorting to cocktail-drug treatments in an attempt to regulate multiple pathways that cumulatively result in the debilitating symptoms of the disease. By utilizing various assays from immuno-targeting to molecular biomarkers, we then interfere in the molecular cascades in an endeavor to avoid synapse dysfunction before disease maturity. Here, we review the current literature supporting the importance of synapses in AD, our current understanding of the molecular interactions leading up to clinical diagnoses, and the techniques used in targeted therapies.

Background: The outcome for children with Burkitt lymphoma (BL)has improved significantly but for patients who relapse, the prognosis is dismal due to chemo-immunotherapy resistance (Cairo et al, JCO, 2012, Cairo et al, Blood, 2007). NK cells are bone marrow-derived cytotoxic lymphocytes that play a major role in the rejection of tumors. A variety of activating and inhibitory receptors on the NK cell surface are engaged to regulate NK cell activities and to discriminate target cells from other healthy 'self' cells. However, NK therapy is limited by several factors, including small numbers of active NK cells in unmodified peripheral blood, lack of tumor targeting specificity, and multiple mechanisms of tumor escape of NK cell immunosurveillance. Our group has successfully modified expanded peripheral blood Natural Killer cells (exPBNK) with an anti-CD20 CAR to target rituximab sensitive/resistant CD20+ BL cells in vitro and in NSG mice (Chu/Cairo, et al, Can Imm Res 2015). However, the short lifespan/persistence of adoptively transferred NK cells has limited the therapeutic efficacy. ALT-803 (Altor BioScience Corporation) is a superagonist of an IL-15 variant bound to an IL-15Rα-Fc fusion with enhanced IL-15 biological activity (Zhu et al. 2009 J Immunol), longer half-life and increased potency (Han, et al. Cytokine. 2011). It is currently in several clinical trials in patients with variety of cancers such as refractory indolent non-Hodgkin's lymphoma (NCT02384954). Objective: We hypothesize that ALT-803, IL-15 superagonist complex, promotes exPBNK persistence and significantly enhances the cytotoxicity of anti-CD20 CAR exPBNK against CD20+ BL. Method: PBMCs were expanded with lethally irradiated K562-mbIL21-41BBL cells (Dean Lee et al, PLoS One, 2012). CD56+ CD3- exPBNK cells were isolated using Miltenyi NK cell isolation kit. Anti-CD20-4-1BB-CD3 ζ mRNA (CAR mRNA) was producedin vitro and nucleofected into exPBNK as we have previously described (Chu/Cairo, et al, Can Imm Res 2015). ALT-803 was provided by Altor BioScience Corporation. ExPBNK cells were cultured with 0.35ng/ml or 3.5ng/ml ALT-803. NK proliferation was monitored with MTS assays. NK receptors expression and cytotoxicity were examined by flow cytometry (Chu/Cairo, et al, ASH 2014). NK resistant BL cells Raji and Daudi were used as target cells. Results: % CD56+ CD3- PBNK cells were significantly increased compared to media alone at day 14 (mean 81.85% vs 14.91%, n=3, p Different doses of ALT-803 or IgG were added to the culture medium of purified expanded exPBNK. Proliferation assays were performed at day 3, 7,11, and 17. ALT-803 significantly promoted exPBNK proliferation and persistence compared to IgG in vitro in a dose-dependent manner (A490 reading at 3.5ng/ml dose: ALT803 vs IgG=0.3383+0.009 vs 0.0987+0.0007, P And ALT-803 significantly enhanced exPBNK cytotoxicity against NK resistant BL cells: Raji (ALT803 vs IgG= 49.54%+2.7% vs 5.99+0.34%, p Further-more, we demonstrated ALT-803 significantly enhanced the cytotoxicity of anti-CD20 CAR modified exPBNK against Raji (CAR vs MOCK= 81.19%+0.35% vs 66.19+0.94%, p Conclusions: ALT-803 maintained the cytotoxicity of exPBNK and in vitro persistence and significantly enhanced anti-CD20 CAR exPBNK cytotoxicity against pediatric NK resistant BL. The in vivo effect of ALT-803 on CAR exPBNK using humanized NSG models is under investigation. Disclosures Wong: Altor BioScience Corporation: Employment, Other: stockholder of Altor Bioscience Corporation. Lee:Intrexon, Ziopharm, Cyto-Sen: Equity Ownership.