Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence
. Patient-derived CAR T cells have demonstrated remarkable efficacy ...against a range of B-cell malignancies
, and the results of early clinical trials suggest activity in multiple myeloma
. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low
. Unlike the mechanisms that result in complete and permanent antigen loss
, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.
In January 2017, the Dutch cervical cancer screening programme transitioned from cytomorphological to primary high-risk HPV (hrHPV) DNA screening, including the introduction of self-sampling, for ...women aged between 30 and 60 years. The Netherlands was the first country to switch to hrHPV screening at the national level. We investigated the health impact of this transition by comparing performance indicators from the new hrHPV-based programme with the previous cytology-based programme.
We obtained data from the Dutch nationwide network and registry of histo- and cytopathology (PALGA) for 454,573 women eligible for screening in 2017 who participated in the hrHPV-based programme between 1 January 2017 and 30 June 2018 (maximum follow-up of almost 21 months) and for 483,146 women eligible for screening in 2015 who participated in the cytology-based programme between 1 January 2015 and 31 March 2016 (maximum follow-up of 40 months). We compared indicators of participation (participation rate), referral (screen positivity; referral rate) and detection (cervical intraepithelial neoplasia (CIN) detection; number of referrals per detected CIN lesion).
Participation in the hrHPV-based programme was significantly lower than that in the cytology-based programme (61% vs 64%). Screen positivity and direct referral rates were significantly higher in the hrHPV-based programme (positivity rate: 5% vs 9%; referral rate: 1% vs 3%). CIN2+ detection increased from 11 to 14 per 1000 women screened. Overall, approximately 2.2 times more clinical irrelevant findings (i.e. ≤CIN1) were found in the hrHPV-based programme, compared with approximately 1·3 times more clinically relevant findings (i.e. CIN2+); this difference was mostly due to a national policy change recommending colposcopy, rather than observation, of hrHPV-positive, ASC-US/LSIL results in the hrHPV-based programme.
This is the first time that comprehensive results of nationwide implementation of hrHPV-based screening have been reported using high-quality data with a long follow-up. We have shown that both benefits and potential harms are higher in one screening round of a well-implemented hrHPV-based screening programme than in an established cytology-based programme. Lower participation in the new hrHPV programme may be due to factors such as invitation policy changes and the phased roll-out of the new programme. Our findings add further to evidence from trials and modelling studies on the effectiveness of hrHPV-based screening.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle?
In this study, 4.6% more live births were observed in ...the scratch group, with a likely certainty range between -0.7% and +9.9%.
Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes.
The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate.
Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%).
After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 95% CI 0.96-1.59). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI).
This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%.
The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials.
This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work.
Registered in the Netherlands Trial Register (NL5193/NTR 5342).
31 July 2015.
26 January 2016.
Shelter metrics can be used by shelters for self-assessment to optimise the health of their animal population and to identify risk factors for disease outbreaks. However, there is a need for a wider ...scope of these shelter metrics, as evidenced by the interest from shelters in the benchmarking of shelter progress and the development of national best practices. For the first time, Dutch shelter data were used retrospectively to signal trends using potentially reliable metrics for the analysis of shelter data. The aims of this study were to apply relevant metrics describing the different phases of shelter management for shelter cats (i.e., intake, stay and outcome) and a retrospective analysis of shelter data over the period between 2006 and 2021. Seven of the approximately 120 Dutch animal shelters participated in this study. Quantitative data on the intake of more than 74,000 shelter cats (e.g., stray cats, cats surrendered by their owners and cats obtained from other sources) and their outcomes (i.e., cats rehomed, returned to their owners, deceased, or otherwise lost) have been analysed. Metrics such as rehoming rate, return to owner rate, rates for mortality and euthanasia, length of stay and risk-based live release rate were determined. The main findings of the study during this 16-year period were that, over time, the number of cats per 1000 residents admitted to Dutch shelters was reduced by 39%, the number of feline euthanasia cases decreased by approximately 50%, the length of stay showed a reducing trend, while the return to owner and the risk-based live release rate increased. The shelter metrics examined in this study could be helpful in monitoring and evaluating the management, consequent health, and well-being of cats in shelters and eventually measuring progress of shelters both in the Netherlands and at a European level.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The knowledge and skills that are required for radiological image interpretation are not well documented, even though medical imaging is gaining importance. This study aims to develop a comprehensive ...framework of knowledge and skills, required for two-dimensional and multiplanar image interpretation in radiology. A mixed-method study approach was applied. First, a literature search was performed to identify knowledge and skills that are important for image interpretation. Three databases, PubMed, PsycINFO and Embase, were searched for studies using synonyms of
image interpretation skills
or
visual expertise
combined with synonyms of
radiology.
Empirical or review studies concerning knowledge and skills for medical image interpretation were included and relevant knowledge and skill items were extracted. Second, a preliminary framework was built and discussed with nine selective experts in individual semi-structured interviews. The expert team consisted of four radiologists, one radiology resident, two education scientists, one cognitive psychologist and one neuropsychologist. The framework was optimised based on the experts comments. Finally, the framework was applied to empirical data, derived from verbal protocols of ten clerks interpreting two-dimensional and multiplanar radiological images. In consensus meetings adjustments were made to resolve discrepancies of the framework with the verbal protocol data. We designed a framework with three main components of image interpretation: perception, analysis and synthesis. The literature study provided four knowledge and twelve skill items. As a result of the expert interviews, one skill item was added and formulations of existing items were adjusted. The think-aloud experiment showed that all knowledge items and three of the skill items were applied within all three main components of the image interpretation process. The remaining framework items were apparent only within one of the main components. After combining two knowledge items, we finally identified three knowledge items and thirteen skills, essential for image interpretation by trainees. The framework can serve as a guideline for education and assessment of two- and three-dimensional image interpretation. Further validation of the framework in larger study groups with different levels of expertise is needed.
Microwave spectroscopy experiments have been performed on two quantum levels of a macroscopic superconducting loop with three Josephson junctions. Level repulsion of the ground state and first ...excited state is found where two classical persistent-current states with opposite polarity are degenerate, indicating symmetric and antisymmetric quantum superpositions of macroscopic states. The two classical states have persistent currents of 0.5 microampere and correspond to the center-of-mass motion of millions of Cooper pairs.
Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these ...CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
We report the first results of AS2UDS, an 870 m continuum survey with the Atacama Large Millimeter/Submillimeter Array (ALMA) of a total area of ∼50 arcmin2 comprising a complete sample of 716 ...submillimeter sources drawn from the SCUBA-2 Cosmology Legacy Survey (S2CLS) map of the UKIDSS/UDS field. The S2CLS parent sample covers a 0.96 degree2 field at 850 = 0.90 0.05 mJy beam−1. Our deep, high-resolution ALMA observations with 870 ∼ 0.25 mJy and a 0 15-0 30 FWHM synthesized beam, provide precise locations for 695 submillimeter galaxies (SMGs) responsible for the submillimeter emission corresponding to 606 sources in the low-resolution, single-dish map. We measure the number counts of SMGs brighter than S870 ≥ 4 mJy, free from the effects of blending and show that the normalization of the counts falls by 28% 2% in comparison with the SCUBA-2 published counts, but that the shape remains unchanged. We determine that 44 − 14 + 16 % of the brighter single-dish sources with S850 ≥ 9 mJy consist of a blend of two or more ALMA-detectable SMGs brighter than S870 ∼ 1 mJy (corresponding to a galaxy with a total-infrared luminosity of LIR 1012 L ), in comparison with 28% 2% for the single-dish sources at S850 ≥ 5 mJy. Using the 46 single-dish submillimeter sources that contain two or more ALMA-detected SMGs with photometric redshifts, we show that there is a significant statistical excess of pairs of SMGs with similar redshifts (<1% probability of occurring by chance), suggesting that at least 30% of these blends arise from physically associated pairs of SMGs.
Purpose
Chimeric antigen receptor (CAR) engineered T-cells occupy an increasing niche in cancer immunotherapy. In this context, CAR-mediated CD3ζ signaling is sufficient to elicit cytotoxicity and ...interferon-γ production while the additional provision of CD28-mediated signal 2 promotes T-cell proliferation and interleukin (IL)-2 production. This compartmentalisation of signaling opens the possibility that complementary CARs could be used to focus T-cell activation within the tumor microenvironment.
Methods
Here, we have tested this principle by co-expressing an ErbB2- and MUC1-specific CAR that signal using CD3ζ and CD28 respectively. Stoichiometric co-expression of transgenes was achieved using the SFG retroviral vector containing an intervening
Thosea asigna
peptide.
Results
We found that “dual-targeted” T-cells kill ErbB2
+
tumor cells efficiently and proliferate in a manner that requires co-expression of MUC1 and ErbB2 by target cells. Notably, however, IL-2 production was modest when compared to control CAR-engineered T-cells in which signaling is delivered by a fused CD28 + CD3ζ endodomain.
Conclusions
These findings demonstrate the principle that dual targeting may be achieved using genetically targeted T-cells and pave the way for testing of this strategy in vivo.
Extracting relevant biological information from large data sets is a major challenge in functional genomics research. Different aspects of the data hamper their biological interpretation. For ...instance, 5000-fold differences in concentration for different metabolites are present in a metabolomics data set, while these differences are not proportional to the biological relevance of these metabolites. However, data analysis methods are not able to make this distinction. Data pretreatment methods can correct for aspects that hinder the biological interpretation of metabolomics data sets by emphasizing the biological information in the data set and thus improving their biological interpretability.
Different data pretreatment methods, i.e. centering, autoscaling, pareto scaling, range scaling, vast scaling, log transformation, and power transformation, were tested on a real-life metabolomics data set. They were found to greatly affect the outcome of the data analysis and thus the rank of the, from a biological point of view, most important metabolites. Furthermore, the stability of the rank, the influence of technical errors on data analysis, and the preference of data analysis methods for selecting highly abundant metabolites were affected by the data pretreatment method used prior to data analysis.
Different pretreatment methods emphasize different aspects of the data and each pretreatment method has its own merits and drawbacks. The choice for a pretreatment method depends on the biological question to be answered, the properties of the data set and the data analysis method selected. For the explorative analysis of the validation data set used in this study, autoscaling and range scaling performed better than the other pretreatment methods. That is, range scaling and autoscaling were able to remove the dependence of the rank of the metabolites on the average concentration and the magnitude of the fold changes and showed biologically sensible results after PCA (principal component analysis).In conclusion, selecting a proper data pretreatment method is an essential step in the analysis of metabolomics data and greatly affects the metabolites that are identified to be the most important.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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