Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) ...blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8
effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical ...challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans. In order to address this deficiency, ASL pH was measured in vivo in children using a novel luminescent technology integrated with fibre-optic probes. Here we show that ASL pH in children with CF is similar to that of children without CF. Findings were supported by highly controlled direct pH measurements in primary human airway epithelial cell culture models, which also suggest that the potential ASL pH gradient produced by defective apical ion transport is balanced out by paracellular shunting of acid/base. Thus, reduced baseline ASL pH is unlikely to be an important pathobiological factor in early CF lung disease.
Sarcopenia negatively affects skeletal muscle mass and function in older adults. Omega-3 (ω-3) fatty acid supplementation, with or without resistance exercise training (RET), is suggested to play a ...role as a therapeutic component to prevent or treat the negative effects of sarcopenia. A systematic review and meta-analysis were conducted on the impact of ω-3 fatty acid supplementation with or without RET on measures of muscle mass and function in older adults (≥55 y). The data sources included SPORTDiscus, PubMed, and Medline. All the study types involving ω-3 fatty acid supplementation on measures of muscle mass and function in older adults (without disease) were included. The mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals were calculated and pooled effects assessed. Sixteen studies (1660 females, 778 males) met our inclusion criteria and were included in the meta-analysis. ω-3 fatty acid supplementation did not impact lean tissue mass (SMD 0.09 -0.10, 0.28). Benefits were observed for lower body strength (SMD 0.54 0.33, 0.75), timed-up-and-go (MD 0.29 0.23, 0.35s), and 30-s sit-to-stand performance (MD 1.93 1.59, 2.26 repetitions) but not walking performance (SMD -0.01 -0.10, 0.07) or upper body strength (SMD 0.05 -0.04, 0.13). Supplementing with ω-3 fatty acids may improve the lower-body strength and functionality in older adults.
Two structurally related and photoresponsive cyanide-bridged Fe/Co square complexes, {Fe2Co2}, are reported: {(TpMe)Fe(CN)32Co(bpy)22(TpMe)Fe(CN)32}·12H2O (2) and {(TpMe)Fe(CN)32Co(bpy)22BPh42}·6MeCN ...(3), where TpMe and bpy are hydridotris(3-methylpyrazol-1-yl)borate and 2,2′-bipyridine, respectively. Through electrochemical and spectroscopic studies, the TpMe ligand appears to be a moderate σ donor in comparison to others in the NEt4(TpR)FeIII(CN)3 series where TpR = Tp, hydridotris(pyrazol-1-yl)borate; TpMe = hydridotris(3-methylpyrazol-1-yl)borate; pzTp = tetrakis(pyrazol-1-yl)borate; Tp* = hydridotris(3,5-dimethylpyrazol-1-yl)borate; Tp*Me = hydridotris(3,4,5-trimethylpyrazol-1-yl)borate. The spectroscopic, structural, and magnetic data of the {Fe2Co2} squares indicate that thermally-induced intramolecular electron transfer reversibly converts {FeII LS(μ-CN)CoIII LS} pairs into {FeIII LS(μ-CN)CoII HS} units near ca. 230 and 244 K (T 1/2) for 2 and 3, respectively (LS: low spin; HS: high spin). These experimental results show that 2 and 3 display light-induced {FeIII LS(μ-CN)CoII HS} metastable states that relax to thermodynamic {FeII LS(μ-CN)CoIII LS} ones at ca. 90 K. Ancillary TpR ligand donor strength appears to be the dominant factor for tuning electron transfer properties in these {Fe2Co2} complexes.
Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 ...RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.
•C9ORF72 repeat expansions cause age-, repeat-size-, and expression-dependent toxicity•Acquired toxicity, not loss of function, is a major contributor to C9orf72 disease•Absence of C9ORF72 in mice produces splenomegaly and enlarged cervical lymph nodes•ASO-induced decreases in repeat RNA mitigate C9ORF72-associated phenotypes in vivo
Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of ALS and FTD. Jiang et al. establish gain of toxicity from repeat-containing RNA, and not loss of C9ORF72 function, as a central disease mechanism and establish the feasibility of ASO-mediated therapy.
Current limitations to primary cell expansion led us to test whether airway epithelial cells derived from healthy children and those with asthma and cystic fibrosis (CF), co-cultured with an ...irradiated fibroblast feeder cell in F-medium containing 10 µM ROCK inhibitor could maintain their lineage during expansion and whether this is influenced by underlying disease status. Here, we show that conditionally reprogrammed airway epithelial cells (CRAECs) can be established from both healthy and diseased phenotypes. CRAECs can be expanded, cryopreserved and maintain phenotypes over at least 5 passages. Population doublings of CRAEC cultures were significantly greater than standard cultures, but maintained their lineage characteristics. CRAECs from all phenotypes were also capable of fully differentiating at air-liquid interface (ALI) and maintained disease specific characteristics including; defective CFTR channel function cultures and the inability to repair wounds. Our findings indicate that CRAECs derived from children maintain lineage, phenotypic and importantly disease-specific functional characteristics over a specified passage range.
Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT ...cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.
Abstract
All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies ...include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition.
Reducing avoidable healthcare-associated harm is a global health priority. Progress in evaluating the burden and aetiology of avoidable harm in prisons is limited compared with other healthcare ...sectors. To address this gap, this study aimed to develop a definition of avoidable harm to facilitate future epidemiological studies in prisons.
Using a sequential mixed methods study design we first characterised and reached consensus on the types and avoidability of patient harm in prison healthcare involving analysis of 151 serious prison incidents reported to the Strategic Executive Information System (StEIS) followed by in-depth nominal group (NG) discussions with four former service users and four prison professionals. Findings of the NG discussions and StEIS analysis were then synthesised and discussed among the research team and study oversight groups to develop an operational definition of avoidable harm in prison healthcare which was subsequently tested and validated using prison patient safety incident report data derived from the National Reporting and Learning System (NRLS).
Analysis of StEIS incident reports and NG discussions identified important factors influencing avoidable harm which reflected the unique prison setting, including health care delivery issues and constraints associated with the secure environment which limited access to care. These findings informed the development of a new working two-tier definition of avoidable harm using appropriate and timely intervention, which included an additional assessment of harm avoidability taking into the account the prison regime and environment. The definition was compatible with the NRLS incident report narratives and illustrated how the prison environment may influence identification of avoidable harm and judgements of avoidability.
We have developed a working definition of avoidable harm in prison health care that enables consideration of caveats associated with prison environments and systems. Our definition enables future studies of the safety of prison healthcare to standardise outcome measurement.
Abstract
The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that ...a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders R and 44 nonresponders NR). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-18Ffluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.
PDF
