Detection of spontaneous CD4+ T-cell responses in melanoma patients against a tyrosinase-related protein-2-derived epitope identified in HLA-DRB1*0301 transgenic mice.

PURPOSE: The frequently expressed differentiation antigen tyrosinase-related protein-2 (TRP-2) has repeatedly been described as a target of spontaneous cytotoxic T-cell responses in melanoma patients, suggesting that it might be an ideal candidate antigen for T cell-based immunotherapy. As a prerequisite for immunization, T-cell epitopes have to be identified. Whereas a number of HLA class I-presented TRP-2-derived epitopes are known, information about HLA class II-presented antigenic ligands recognized by CD4+ T helper (Th) cells is limited. EXPERIMENTAL DESIGN: The search for TRP-2-derived Th epitopes was carried out by competitive in vitro peptide binding studies with predicted HLA-DRB1*0301 ligands in combination with peptide and protein immunizations of HLA-DRB1*0301 transgenic mice. In vivo selected candidate epitopes were subsequently verified for their immunogenicity in human T-cell cultures. RESULTS: This strategy led to the characterization of TRP-2(60-74) as an HLA-DRB1*0301-restricted Th epitope. Importantly, TRP-2(60-74)-reactive human CD4+ Th cell lines, specifically recognizing target cells loaded with recombinant TRP-2 protein, could be established by repeated peptide stimulation of peripheral blood lymphocytes from several HLA-DRB1*03+ melanoma patients. Even short-term peptide stimulation of patients' peripheral blood lymphocytes showed the presence of TRP-2(60-74)-reactive T cells, suggesting that these T cells were already activated in vivo. CONCLUSION: Peptide TRP-2(60-74) might be a useful tool for the improvement of immunotherapy and immune monitoring of melanoma patients.     

Multiscale Analogue Modelling of Clinching Process to Investigate Thickness Tolerance and Tool Misalignment

NEED—The effect of dimensional variability of sheet thickness (tolerance) and tool misalignment is poorly understood for the clinching process. Finite element analysis (FEA) is valuable but requires a lot of and is difficult to verify in this situation due to the asymmetrical geometry and nonlinear plasticity. OBJECTIVE—The objective of this work was to determine the effect of thickness tolerance, tool misalignment and sheet placement (top vs. bottom) in the clinching process, by use of analogue modelling with plasticine. METHOD—Experiments used a scaled-up punch and die, with plasticine as the analogue. Thickness tolerances were represented by sheet thicknesses of 11 and 7 mm, 12 and 8 mm, 8 and 12 mm and 13 and 9 mm for upper and lower sheets, respectively. Two types of lubricant were tested between sheets: glycerine and silicone oil. Angular variability was also introduced. Measured parameters were interlock (also called undercut) and neck thickness. Analogue results for deformation were compared with microscopy of metal clinching. FINDINGS—The results reveal that the multiscale analogue model is an efficient tool for studying the effect of dimensional deviation on a clinch joint. Thickness tolerance showed a critical relationship with interlock, namely a reduction to about half that of the nominal, for both maximum and least material conditions. Increased angular misalignment also reduced the interlock. Compared with glycerine, silicone oil tests showed reduced interlock, possibly the result of a lower coefficient of friction. ORIGINALITY—This work demonstrates the usefulness of analogue modelling for exploring process variability in clinching. The results also show that significant effects for sheet placement are ductility, lubricant (friction), thickness of samples and tool misalignment.     

Furan oligomers and beta-carbolines from terrestrial streptomycetes

2,5-Bis(hydroxymethyl)furan monoacetate (3) and 2,5-bis(hydroxymethyl)furan diacetate (4) were obtained as new natural products from an ethyl acetate extract of the terrestrial Streptomyces sp. isolate GW11/1695. Another Streptomyces isolate, GW21/1313, delivered a dimer (6) and a trimer (7) of (hydroxymethyl)furfural. The latter strain also produced 4-hydroxy-2-(5-(hydroxymethyl)furan-2-ylmethylene)-5-methylfuran-3-one (5), perlolyrin (8), and two new beta-carboline derivatives, 9 and 10. 2,5-Bis(hydroxymethyl)furan diacetate (4) exhibited weak cytotoxic activity against brine shrimp larvae.     

Biologie

Ohne Zusammenfassung     

Biochar Synthesis from Mineral- and Ash-Rich Waste Biomass,Part 1: Investigation of Thermal Decomposition Mechanism during Slow Pyrolysis

Synthesizing biochar from mineral- and ash-rich waste biomass (MWB), a by-product of human activities in urban areas, can result in renewable and versatile multi-functional materials, which can also cater to the need of solid waste management. Hybridizing biochar with minerals, silicates, and metals is widely investigated to improve parent functionalities. MWB intrinsically possesses such foreign materials. The pyrolysis of such MWB is kinetically complex and requires detailed investigation. Using TGA-FTIR, this study investigates and compares the kinetics and decomposition mechanism during pyrolysis of three types of MWB: (i) mineral-rich banana peduncle (BP), (ii) ash-rich sewage sludge (SS), and (iii) mineral and ash-rich anaerobic digestate (AD). The results show that the pyrolysis of BP, SS, and AD is exothermic, catalyzed by its mineral content, with heat of pyrolysis 5480, 4066, and 1286 kJ/kg, respectively. The pyrolysis favors char formation kinetics mainly releasing CO₂ and H₂O. The secondary tar reactions initiate from ≈318 °C (BP), 481 °C (SS), and 376 °C (AD). Moreover, negative apparent activation energies are intrinsic to their kinetics after 313 °C (BP), 448 °C (SS), and 339 °C (AD). The results can support in tailoring and controlling sustainable biochar synthesis from slow pyrolysis of MWB.     

Willingness to Self-Collect a Sample for HPV-Based Cervical Cancer Screening in a Well-Screened Cohort: HPV FOCAL Survey Results

Self-collection may provide an opportunity for innovation within population-based human papillomavirus (HPV) cervical cancer screening programs by providing an alternative form of engagement for all individuals. The primary objective was to determine willingness to self-collect a vaginal sample for primary HPV screening and factors that impact willingness in individuals who participated in the Human Papillomavirus For Cervical Cancer (HPV FOCAL) screening trial, a large randomized controlled cervical screening trial. A cross-sectional online survey was distributed between 2017 and 2018 to 13,176 eligible participants exiting the FOCAL trial. Bivariate and multivariable logistic regression assessed factors that influence willingness to self-collect on 4945 respondents. Overall, 52.1% of respondents indicated willingness to self-collect an HPV sample. In multivariable analysis, the odds of willingness to self-collect were significantly higher in participants who agreed that screening with an HPV test instead of a Pap test was acceptable to them (odds ratio (OR): 1.45 (95% confidence interval (CI): 1.15, 1.82), those who indicated that collecting their own HPV sample was acceptable to them (p < 0.001), and those with higher educational ascertainment (OR: 1.31, 95% CI: 1.12, 1.54). The findings offer insight into the intentions to self-collect in those already engaged in screening, and can inform cervical cancer screening programs interested in offering alternative approaches to HPV-based screening.     

Clinician perspectives on clinical decision support systems in lung cancer: Implications for shared decision‐making

BackgroundLung cancer treatment decisions are typically made among clinical experts in a multidisciplinary tumour board (MTB) based on clinical data and guidelines. The rise of artificial intelligence and cultural shifts towards patient autonomy are changing the nature of clinical decision‐making towards personalized treatments. This can be supported by clinical decision support systems (CDSSs) that generate personalized treatment information as a basis for shared decision‐making (SDM). Little is known about lung cancer patients'' treatment decisions and the potential for SDM supported by CDSSs. The aim of this study is to understand to what extent SDM is done in current practice and what clinicians need to improve it.ObjectiveTo explore (1) the extent to which patient preferences are taken into consideration in non‐small‐cell lung cancer (NSCLC) treatment decisions; (2) clinician perspectives on using CDSSs to support SDM.DesignMixed methods study consisting of a retrospective cohort study on patient deviation from MTB advice and reasons for deviation, qualitative interviews with lung cancer specialists and observations of MTB discussions and patient consultations.Setting and ParticipantsNSCLC patients (N = 257) treated at a single radiotherapy clinic and nine lung cancer specialists from six Dutch clinics.ResultsWe found a 10.9% (n = 28) deviation rate from MTB advice; 50% (n = 14) were due to patient preference, of which 85.7% (n = 12) chose a less intensive treatment than MTB advice. Current MTB recommendations are based on clinician experience, guidelines and patients'' performance status. Most specialists (n = 7) were receptive towards CDSSs but cited barriers, such as lack of trust, lack of validation studies and time. CDSSs were considered valuable during MTB discussions rather than in consultations.ConclusionLung cancer decisions are heavily influenced by clinical guidelines and experience, yet many patients prefer less intensive treatments. CDSSs can support SDM by presenting the harms and benefits of different treatment options rather than giving single treatment advice. External validation of CDSSs should be prioritized.Patient or Public ContributionThis study did not involve patients or the public explicitly; however, the study design was informed by prior interviews with volunteers of a cancer patient advocacy group. The study objectives and data collection were supported by Dutch health care insurer CZ for a project titled ‘My Best Treatment’ that improves patient‐centeredness and the lung cancer patient pathway in the Netherlands.