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Information into Interfacial and also Bulk Carry Phenomena Affecting Proton Change Tissue layer Drinking water Electrolyzer Functionality with Ultra-Low Iridium Loadings.
002). Patients with mixed progressive/pseudoprogressive lesions were in between at 53% (25 months). The blood prediction-model (LDH+S100) achieved an AUC=0.71. CID755673 Higher LDH/S100 values indicated a low chance of pseudoprogression. Volume-based models AUC=0.72 (TP1) and AUC=0.80 (delta-volume between TP0/TP1). Radiomics-models (including/excluding volume-related features) AUC=0.79/0.78. Combined blood/volume-model AUC=0.79. Combined blood/radiomics-model (including volume-related features) AUC=0.78. The combined blood/radiomics-model (excluding volume-related features) performed best AUC=0.82. CONCLUSIONS Non-invasive PET/CT-based radiomics, especially in combination with blood parameters, are promising biomarkers for early differentiation of pseudoprogression, potentially avoiding added toxicity or delayed treatment switch. Copyright ©2020, American Association for Cancer Research.PSMA radioligand therapy is a promising new class of therapy for prostate cancer. Heterogeneity of PSMA expression are important factors explaining variability in clinical results. The ability to visualise the target with theranostics provides unique mechanistic insights. Potential clinically-applicable strategies to improve patient selection and optimise therapeutic efficacy are discussed. Copyright ©2020, American Association for Cancer Research.Although the last two decades have seen a broad improvement in overall survival, colorectal cancer (CRC) is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their CRC. Consequently, many patients present with metastatic CRC, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of CRC tumors and are associated with uninhibited cell proliferation, reduced apoptosis and resistance to standard therapeutic options. In CRC, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared to tumors with wildtype BRAF. Success in treating other BRAFV600E-mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic CRC. Consequently, combination therapy with inhibitors of BRAF, MEK, and epidermal growth factor receptor, which overcomes the innate treatment-resistant characteristics of BRAFV600E-mutant CRC, is now recommended by treatment guidelines. Copyright ©2020, American Association for Cancer Research.PURPOSE Only a minority of patients with advanced non-small-cell lung cancer (NSCLC) truly benefit from single-agent PD-1 checkpoint blockade, and more robust predictive biomarkers are needed. EXPERIMENTAL DESIGN We assessed tumor samples from 67 immunotherapy-treated NSCLC cases represented in a tissue microarray, 53 of whom had pre-treatment samples and received monotherapy. Using GeoMx Digital Spatial Profiling system (NanoString), we quantified 39 immune parameters simultaneously in four tissue compartments defined by fluorescence co-localization (tumor [panCK+], leucocytes [CD45+], macrophages [CD68+], and non-immune stroma). RESULTS 156 protein variables were generated per case. In the univariate unadjusted analysis, we found 18 markers associated with outcome in spatial context, 5 of which remained significant after multiplicity adjustment. In the multivariate analysis, high levels of CD56 and CD4 measured in the CD45 compartment were the only markers that were predictive for all clinical outcomes, including progression-free survival (PFS) (HR 0.24, p = 0.006; and HR 0.31, p = 0.011, respectively), and overall survival (OS) (HR 0.26, p = 0.014; and HR 0.23, p = 0.007, respectively). Then, using an orthogonal method based on multiplex immunofluorescence and cell counting (inForm), we validated that high CD56+ immune cell counts in the stroma were associated with PFS and OS in the same cohort. CONCLUSIONS This pilot scale discovery study shows the potential of the DSP technology in the identification of spatially-informed biomarkers of response to PD-1 checkpoint blockade in NSCLC. We identified a number of relevant candidate immune predictors in spatial context that deserve validation in larger independent cohorts. Copyright ©2020, American Association for Cancer Research.PURPOSE The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5FU) chemoradiation (CRT) in patients with locally advanced rectal cancer (LARC). EXPERIMENTAL DESIGN Stage II/III rectal cancer patients were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the maximum tolerated dose (MTD). Following a 5-day trametinib lead-in, with pre- and post-treatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5FU 225 mg/m2/day and 28 daily fractions of 1.8 Gy (total 50.4Gy). The primary endpoint was to identify the MTD and recommended phase 2 dose. Immunohistochemistry (IHC) staining for phosphorylated -ERK (pERK) and genomic profiling was performed on the tumor samples. RESULTS Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well-tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathological complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. CONCLUSIONS The combination of trametinib with 5FU-CRT is safe and well-tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population. Copyright ©2020, American Association for Cancer Research.OBJECTIVES The aim of this clustered, randomised controlled trial was to assess the effectiveness of a lumbopelvic postural feedback device for changing postural behaviour in a group of healthcare workers. We hypothesised that workers exposed to auditory postural feedback would reduce the number of times forward bending posture is adopted at work. METHODS This was a participant and assessor blinded, randomised, sham-controlled trial with blocked cluster random allocation. We recruited healthcare workers from aged care institutions. Healthcare sites were randomly allocated to the feedback or sham group (SG). A postural monitoring and feedback device was used to monitor and record lumbopelvic forward bending posture, and provided audio feedback whenever the user sustained lumbopelvic forward bending posture that exceeded predefined thresholds. The primary outcome measure was postural behaviour (exceeding thresholds). We used a robust variant of repeated measures mixed-effect model for assessing within-group and between-group differences in postural behaviour. RESULTS We recruited 19 sites, and 130 healthcare workers participated. There were no within-group changes on the number of times postural threshold was exceeded at 1-week follow-up (feedback group -0.7, 95% CI -2.61 to 0.72; SG -0.3, -1.65 to 0.98), and no differences (0.05, 95% CI -1.83 to 1.94) between SG and feedback group. CONCLUSIONS Findings from this trial indicate that audio feedback provided by a postural monitor device did not reduce the number of times healthcare workers exceeded the postural threshold. TRIAL REGISTRATION NUMBER ACTRN12616000449437. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (β-D-N4-hydroxycytidine-5'-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses. Copyright © 2020, American Association for the Advancement of Science.Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http//group.bmj.com/group/rights-licensing/permissions.Whether cell death caused by T lymphocytes and natural killer (NK) cells would be immunogenic per se has been a matter of intense debate. Two back-to-back papers from the Melero's and Pardo's groups have now resolved this conundrum, demonstrating that T and NK cell-mediated cytotoxicity represents indeed a bona fide variant of immunogenic cell death. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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