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- Lekka, E, et al.
(author)
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Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease
- 2022
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 7940-
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Journal article (peer-reviewed)abstract
- Lin28 RNA-binding proteins are stem-cell factors that play key roles in development. Lin28 suppresses the biogenesis of let-7 microRNAs and regulates mRNA translation. Notably, let-7 inhibits Lin28, establishing a double-negative feedback loop. The Lin28/let-7 axis resides at the interface of metabolic reprogramming and oncogenesis and is therefore a potential target for several diseases. In this study, we use compound-C1632, a drug-like Lin28 inhibitor, and show that the Lin28/let-7 axis regulates the balance between ketogenesis and lipogenesis in liver cells. Hence, Lin28 inhibition activates synthesis and secretion of ketone bodies whilst suppressing lipogenesis. This occurs at least partly via let-7-mediated inhibition of nuclear receptor co-repressor 1, which releases ketogenesis gene expression mediated by peroxisome proliferator-activated receptor-alpha. In this way, small-molecule Lin28 inhibition protects against lipid accumulation in multiple cellular and male mouse models of hepatic steatosis. Overall, this study highlights Lin28 inhibitors as candidates for the treatment of hepatic disorders of abnormal lipid deposition.
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- Munoz-Gama, Jorge, et al.
(author)
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Process mining for healthcare : Characteristics and challenges
- 2022
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In: Journal of Biomedical Informatics. - : Elsevier BV. - 1532-0464 .- 1532-0480. ; 127
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Journal article (peer-reviewed)abstract
- Process mining techniques can be used to analyse business processes using the data logged during their execution. These techniques are leveraged in a wide range of domains, including healthcare, where it focuses mainly on the analysis of diagnostic, treatment, and organisational processes. Despite the huge amount of data generated in hospitals by staff and machinery involved in healthcare processes, there is no evidence of a systematic uptake of process mining beyond targeted case studies in a research context. When developing and using process mining in healthcare, distinguishing characteristics of healthcare processes such as their variability and patient-centred focus require targeted attention. Against this background, the Process-Oriented Data Science in Healthcare Alliance has been established to propagate the research and application of techniques targeting the data-driven improvement of healthcare processes. This paper, an initiative of the alliance, presents the distinguishing characteristics of the healthcare domain that need to be considered to successfully use process mining, as well as open challenges that need to be addressed by the community in the future.
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- Hess, Timo, et al.
(author)
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Dissecting the genetic heterogeneity of gastric cancer
- 2023
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In: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Journal article (peer-reviewed)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
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- Kolsch, N., et al.
(author)
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Novel local shielding approach for the laser welding based additive manufacturing of large structural space components from titanium
- 2020
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In: Journal of laser applications. - : American Institute of Physics (AIP). - 1042-346X .- 1938-1387. ; 32:2
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Journal article (peer-reviewed)abstract
- The Advanced Telescope for High-ENergy Astrophysics (ATHENA) will observe “the hot and energetic universe,” which was determined as one of the most urgent scientific topics for a major future space mission by The European Space Agency (ESA). One of its three main components is the optical bench, a monolithic titanium structure that accommodates 678 mirror modules and keeps them accurately aligned. The immense but slender structure in the range of 2.5–3 m diameter at a height of 300 mm proves a challenge to manufacturing. A hybrid robot cell is developed using additive buildup via laser welding, combined with high-performance machining and the state of the art process and metrology monitoring and control. The present work focuses on the shielding of the laser induced melt pool, a key concern when processing titanium. The sensitive metal with unusual low heat conductivity requires a large area of high purity atmosphere to prevent embrittlement. However, the large hybrid system prohibits the use of a sealed enclosure, and therefore, a local shielding system is developed for the challenging case of the ATHENA optical bench’s hollow-chamber design. Since the present thin wall design poses a worst-case scenario in terms of heat dissipation and shielding flow for the shielding system, its effectiveness here can be applied to most other geometries enabling the flexibility for lot size one. The key features of the novel approach are the prevention of turbulence while keeping operation economical despite the large shielding area. The first is achieved by means of an integrated honeycomb screen and the latter by employing a layered flow with a higher velocity outer curtain and an air deflecting coflow. This system was numerically optimized, tested, and effectiveness proven by means of visual inspection, microstructural analysis, and measurement of material properties.
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| 8. |
- Schneider, J., et al.
(author)
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Additive manufacturing of a metallic optical bench—process development, material qualification and demonstration
- 2023
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In: CEAS Space Journal. - : Springer Nature. - 1868-2502 .- 1868-2510. ; 15:1, s. 55-68
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Journal article (peer-reviewed)abstract
- With the large-class science mission ATHENA, the European Space Agency (ESA) aims at exploring the hot and energetic universe with advanced X-Ray technology. As a central component of the telescope, hundreds of silicon pore optic (SPO) modules will be assembled in an optical bench with a diameter of about 2.5 m. Several approaches are under investigation for the manufacturing of this supporting structure, and for handling the challenging constraints with respect to size, geometry and material. In cooperation with ESA, the Fraunhofer IWS is currently investigating the manufacturing of the optical bench made from Ti-6Al-4 V by means of Additive Manufacturing using Laser Metal Deposition (LMD) followed by subtractive finishing. Several development steps have been covered in a holistic manner starting with the system engineering of the production site. The main focus of the activity was on the process development for the Additive Manufacturing as well as the subtractive finishing. Furthermore, the properties of the produced material were also investigated. Within the scope of this publication, a general overview is given about the project related developments, achievements, and flanking activities for solving various challenges. The suitability of the developed technologies and workflows are now being evaluated through the manufacture of a representative, large-scale breadboard.
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- Uijterwijk, Bas A., et al.
(author)
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Differences in Lymph Node Metastases Patterns Among Non-pancreatic Periampullary Cancers and Histologic Subtypes: An International Multicenter Retrospective Cohort Study and Systematic Review
- 2024
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In: Annals of Surgical Oncology. - : SPRINGER. - 1068-9265 .- 1534-4681.
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Research review (peer-reviewed)abstract
- Background: Standard lymphadenectomy for pancreatoduodenectomy is defined for pancreatic ductal adenocarcinoma and adopted for patients with non-pancreatic periampullary cancer (NPPC), ampullary adenocarcinoma (AAC), distal cholangiocarcinoma (dCCA), or duodenal adenocarcinoma (DAC). This study aimed to compare the patterns of lymph node metastases among the different NPPCs in a large series and in a systematic review to guide the discussion on surgical lymphadenectomy and pathology assessment. Methods: This retrospective cohort study included patients after pancreatoduodenectomy for NPPC with at least one lymph node metastasis (2010-2021) from 24 centers in nine countries. The primary outcome was identification of lymph node stations affected in case of a lymph node metastasis per NPPC. A separate systematic review included studies on lymph node metastases patterns of AAC, dCCA, and DAC. Results: The study included 2367 patients, of whom 1535 had AAC, 616 had dCCA, and 216 had DAC. More patients with pancreatobiliary type AAC had one or more lymph node metastasis (67.2% vs 44.8%; P < 0.001) compared with intestinal-type, but no differences in metastasis pattern were observed. Stations 13 and 17 were most frequently involved (95%, 94%, and 90%). Whereas dCCA metastasized more frequently to station 12 (13.0% vs 6.4% and 7.0%, P = 0.005), DAC metastasized more frequently to stations 6 (5.0% vs 0% and 2.7%; P < 0.001) and 14 (17.0% vs 8.4% and 11.7%, P = 0.015). Conclusion: This study is the first to comprehensively demonstrate the differences and similarities in lymph node metastases spread among NPPCs, to identify the existing research gaps, and to underscore the importance of standardized lymphadenectomy and pathologic assessment for AAC, dCCA, and DAC.
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- Uijterwijk, Bas A., et al.
(author)
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The road to tailored adjuvant chemotherapy for all four non-pancreatic periampullary cancers: An international multimethod cohort study
- 2024
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In: British Journal of Cancer. - : SPRINGERNATURE. - 0007-0920 .- 1532-1827.
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Journal article (peer-reviewed)abstract
- Background: Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. Patients and methods: Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). Results: The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). Discussion: Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.
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