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"Mayer, Sebastian"
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Feasibility of urinary microRNA detection in breast cancer patients and its potential as an innovative non-invasive biomarker
Background
Since recent studies revealed the feasibility to detect blood-based microRNAs (miRNAs, miRs) in breast cancer (BC) patients a new field has been opened for circulating miRNAs as potential biomarkers in BC. In this pilot study, we evaluated to our knowledge for the first time whether distinct pattern of urinary miRNAs might be also applicable as innovative biomarkers for BC detection.
Methods
Urinary miRNA expression levels of nine BC-related miRNAs (miR-21, miR-34a, miR-125b, miR-155, miR-195, miR-200b, miR-200c, miR-375, miR-451) from 24 untreated, primary BC patients and 24 healthy controls were quantified by realtime-PCR. The receiver operating characteristic analyses (ROC) and logistic regression were calculated to assess discriminatory accuracy.
Results
Significant differences were found in the expression of four BC-associated miRNAs quantified as median miRNA expression levels. Urinary miR-155 levels were significantly higher in BC patients compared to healthy controls (1.49vs.0.25; p < 0.001). In contrast, compared to healthy controls, BC patients exhibited significantly lower urinary expression levels of miR-21 (2.27vs.5.07; p < 0.001), miR-125b (0.71vs.1.62; p < 0.001), and miR-451 (0.02vs.0.59 p = 0.004), respectively. The ROC including all miRNAs as well as the group of the four significant deregulated miRNAs separated BC patients from healthy controls with a very high (area under the receiver operating characteristic curve [AUC] = 0.932) and high accuracy (AUC = 0.887), respectively.
Conclusions
We were able to demonstrate for the first time the feasibility to detect distinct BC-dependent urinary miRNA profiles. The expression levels of four urinary miRNAs were specifically altered in our cohort of BC patients compared to healthy controls. This distinct pattern offers the possibility for a specific discrimination between healthy women and primary BC patients. This sustains the potential role of urinary miRNAs as non-invasive innovative urine-based biomarkers for BC detection.
Journal Article
The Impact of HVAC on the Development of Autonomous and Electric Vehicle Concepts
Automation and electrification are changing vehicles and mobility. Whereas electrification is mainly changing the powertrain, automation enables the rethinking of the vehicle and its applications. The actual driving range is an important requirement for the design of automated and electric vehicles, especially if they are part of a fleet. To size the battery accordingly, not only the consumption of the powertrain has to be estimated, but also that of the auxiliary users. Heating Ventilation and Air Conditioning (HVAC) is one of the biggest auxiliary consumers. Thus, a variable HVAC model for vehicles with electric powertrain was developed to estimate the consumption depending on vehicle size and weather scenario. After integrating the model into a tool for autonomous and electric vehicle concept development, various vehicle concepts were simulated in different weather scenarios and driving cycles with the HVAC consumption considered for battery sizing. The results indicate that the battery must be resized significantly depending on the weather scenario to achieve the same driving ranges. Furthermore, the percentage of HVAC consumption is in some cases higher than that of the powertrain for urban driving cycles, due to lower average speeds. Thus, the HVAC and its energy demand should especially be considered in the development of autonomous and electric vehicles that are primarily used in cities.
Journal Article
Lung Function Trajectory in Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplant
The natural history of lung function in patients with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant is poorly characterized. Understanding the trajectory of lung function is necessary for prompt clinical recognition and treatment and also for the rational design of prospective studies.
To describe the longitudinal trajectory of lung function parameters, including FEV
, in patients with BOS after hematopoietic cell transplant.
Subjects with BOS defined by National Institutes of Health consensus guidelines criteria from a recent multicenter prospective trial of combination treatment with fluticasone, azithromycin and montelukast and a retrospective cohort from Fred Hutchinson Cancer Research Center were included. Longitudinal change in FEV
for each patient was calculated on the basis of available pulmonary function tests in three periods: pre-BOS, from BOS diagnosis to 6 months, and 6-18 months after diagnosis. The effect of treatment on FEV
trajectory was analyzed by univariate and multivariate linear regression. The Kaplan-Meier method was used to estimate survival.
The FEV
percent predicted value at diagnosis was 46% (interquartile range, 35-57%) for trial participants and 53% (interquartile range, 41-64%) for the retrospective cohort. There was a concomitant mild reduction in FVC, as well as a marked reduction in forced expiratory flow, midexpiratory phase, at diagnosis. While there was individual heterogeneity, the overall FEV
trajectory was characterized by a marked decline within 6 months prior to BOS diagnosis, followed by stability of FEV
early after diagnosis and a slow rate of decline beyond 6 months. The effect of the trial medications on FEV
trajectory after BOS diagnosis was a mean rate of change of 0.92% predicted per month (95% confidence interval, -0.53 to 2.37) compared with the retrospective cohort, but this was not statistically significant. Two-year overall survival rates were 76% and 72% for the study participants and the retrospective cohort patients, respectively. Earlier time to diagnosis after hematopoietic cell transplant and severity of FVC at diagnosis were significantly associated with reduced survival.
The FEV
trajectory in patients with BOS after hematopoietic cell transplant in a contemporary era of management follows a predominant pattern of rapid FEV
decline in the 6 months prior to diagnosis, followed by FEV
stabilization after diagnosis.
Journal Article
High-dose bendamustine and melphalan conditioning for autologous stem cell transplantation for patients with multiple myeloma
High-dose melphalan (MEL200) followed by autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma (MM). Bendamustine induces responses in MM resistant to other alkylators. Our prior Phase I trial adding bendamustine to MEL200 transplant conditioning resulted in no additional toxicity. We now report a single-arm, phase II study that evaluated the efficacy of bendamustine 225 mg/m2 with MEL200 conditioning for ASCT in 18 patients with newly diagnosed MM (NDMM) and 17 with relapsed or refractory MM (RRMM). The primary end point was the complete response (CR/sCR) rate at day+ 100. Sample size was determined according to Simon’s two-stage design. At stage 1, sixteen patients entered the study. As there were eight patients with CR/sCR, enrollment increased to 28 patients. Sixteen out of the first 28 evaluable patients achieved CR/sCR, meeting the design criteria. Enrollment was then expanded to a total of 35 patients. 51% achieved a CR/sCR. After a median follow-up of 65 months, 21 patients progressed, including 7 deaths. The median PFS for NDMM and RRMM was 48 and 45 months, respectively. Bendamustine/MEL200 conditioning resulted in excellent overall and depth of response as well as PFS, particularly in the RRMM patients, and is worthy of further investigation (NCT00916058).
Journal Article
Studying Evolutionary Solution Adaption by Using a Flexibility Benchmark Based on a Metal Cutting Process
We consider optimization for different production requirements from the viewpoint of a bio-inspired framework for system flexibility that allows us to study the ability of an algorithm to transfer solutions from previous optimization tasks, which also relates to dynamic evolutionary optimization. Optimizing manufacturing process parameters is typically a multi-objective problem with often contradictory objectives, such as production quality and production time. If production requirements change, process parameters have to be optimized again. Since optimization usually requires costly simulations based on, for example, the Finite Element method, it is of great interest to have a means to reduce the number of evaluations needed for optimization. Based on the extended Oxley model for orthogonal metal cutting, we introduce a multi-objective optimization benchmark where different materials define related optimization tasks. We use the benchmark to study the flexibility of NSGA-II, which we extend by developing two variants: (1) varying goals, which optimizes solutions for two tasks simultaneously to obtain in-between source solutions expected to be more adaptable, and (2) active–inactive genotype, which accommodates different possibilities that can be activated or deactivated. Results show that adaption with standard NSGA-II greatly reduces the number of evaluations required for optimization for a target goal. The proposed variants further improve the adaption costs, where on average, the computational effort is more than halved in comparison to the non-adapted baseline. We note that further work is needed for making the methods advantageous for real applications.
Journal Article
Cord blood transplants supported by unrelated donor CD34+ progenitor cells
Alternative donor transplantation with the haplo-cord platform allows the use of a lower-dose single umbilical cord blood unit (CBU) by co-infusion of third-party CD34+-selected cells from a haploidentical relative, which provides early transient engraftment while awaiting durable CBU engraftment. In our experience, ~15% of patients lack a suitable haploidentical donor. Here we report 26 patients who underwent haplo-cord transplant using CD34+-selected partially matched unrelated donor grafts. Twenty-four were conditioned with fludarabine/melphalan +/− low-dose TBI (n = 16). Twenty-five received ATG and all received posttransplant tacrolimus and mycophenolate mofetil. Median time to neutrophil and platelet recovery was 11 and 18 days. CBU engraftment, with CD33 and CD3 >5% cord chimerism in the myeloid/lymphoid compartment by day +60, occurred in 20 of 24 patients (83%). Incidence of grade 2–4 acute graft-versus-host disease (GVHD) was 27% at day +100, and chronic GVHD was 4% at 1 year. Overall survival at 1 year was 54%. For patients in need of an alternative transplant who lack a haploidentical donor, haplo-cord transplantation using CD34+-selected partially matched unrelated donor grafts results in rapid engraftment with no increased rate of cord graft failure or GVHD.
Journal Article
Lossy DICOM conversion may affect AI performance
Many pathologies have started to digitize their glass slides. To ensure long term accessibility, it is desirable to store them in the DICOM format. Currently, many scanners initially store the images in vendor-specific formats and only provide DICOM converters, with only a few producing DICOM directly. However, such a conversion is not lossless for all vendors, and in the case of MRXS files even overlapping tile handling differs. The resulting consequences have not yet been investigated. We converted MRXS files depicting bladder, ovarian and prostate tissue into DICOM images using the 3D Histech/Sysmex converter and an open-source tool both using baseline JPEG for the re-compression. After conversion no human perceptible differences were present between the images, nevertheless they were not identical and had structure similarity indices (SSIM) of ~ 0.85 to ~ 0.96 on average, while the vendor specific converter in general achieved higher values. AI models based on CNNs and current foundation models could distinguish between the original and the converted images in most cases with an accuracy of up to 99.5%. And already trained AI models showed significant performance differences between the image formats in five out of 64 scenarios, mainly when only little data was used during AI training. So, if DICOM images are intended for a diagnostic use, all processes and algorithms must be (re-)evaluated with the converted files, as images are not identical. Nevertheless, the DICOM format is an excellent opportunity to ensure interoperability in future, as some first AI trainings with converted files did not result in systematically decreased performances.
Journal Article
Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prognostic and therapeutic implications
Background
Cancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
Methods
The reactivity pattern of various mAbs (6C1, MA454, M3H67, 57B, E978, GAGE #26 and NY-BR-1 #5) were assessed by immunohistochemistry in a tissue micro array series of 210 randomly selected primary invasive breast cancers in order to study the diversity of different CTAs (e.g. MAGE-A, NY-ESO-1, GAGE) and NY-BR-1. These expression data were correlated to clinico-pathological parameters and outcome data including disease-free and overall survival.
Results
Expression of at least one CTA was detectable in the cytoplasm of tumor cells in 37.2% of the cases. NY-BR-1 expression was found in 46.6% of tumors, respectively. Overall, CTA expression seemed to be linked to adverse prognosis and M3H67 immunoreactivity specifically was significantly correlated to shorter overall and disease-free survival (p=0.000 and 0.024, respectively).
Conclusions
Our findings suggest that M3H67 immunoreactivity could serve as potential prognostic marker in primary breast cancer patients. The exclusive expression of CTAs in tumor tissues as well as the frequent expression of NY-BR-1 could define new targets for specific breast cancer therapies.
Journal Article