Scientific Publications
Scientific publications and exciting articles where PreciPoint products and solutions were successfully used.
Silawal, Sandeep; Gögele, Clemens; Pelikan, Petr; Werner, Christian; Levidou, Georgia; Mahato, Raman; Schulze-Tanzil, Gundula
Study Uses PreciPoint Fritz Slide Scanner to Analyze CD55 Expression in SARS-CoV-2 Infected Lungs
In a recent study, the PreciPoint Fritz slide scanner was used to digitize histological slides for the analysis of lung tissue samples from patients infected with SARS-CoV-2. The research focused on investigating the expression of Complement Regulatory Protein CD55 in the infected lungs, as CD55 plays a crucial role in modulating the complement system and protecting cells from immune-mediated damage. By examining CD55\'s distribution and expression patterns, the study aimed to deepen the understanding of its role in the immune response to COVID-19 and its potential involvement in disease severity and progression. These findings from the research offer insights into the immune modulation in COVID-19 and may guide future therapeutic interventions.
Result: The Fritz slide scanner enabled the precise imaging of lung tissue, revealing a notable upregulation of CD55 in SARS-CoV-2-infected regions. This upregulation was predominantly observed in alveolar epithelial cells, suggesting a protective mechanism against complement-mediated injury. The increased expression of CD55 correlated with areas of severe inflammation, highlighting its potential role in mitigating immune damage in COVID-19-infected lungs.
@article{nokey,
title = {A Histological Analysis and Detection of Complement Regulatory Protein CD55 in SARS-CoV-2 Infected Lungs},
author = {Sandeep Silawal and Clemens Gögele and Petr Pelikan and Christian Werner and Georgia Levidou and Raman Mahato and Gundula Schulze-Tanzil },
url = {https://www.mdpi.com/2075-1729/14/9/1058},
doi = {10.3390/life14091058},
year = {2024},
date = {2024-08-23},
urldate = {2024-08-23},
journal = {Life},
volume = {14},
issue = {9},
pages = {1058},
abstract = {Background: A complement imbalance in lung alveolar tissue can play a deteriorating role in COVID-19, leading to acute respiratory distress syndrome (ARDS). CD55 is a transmembrane glycoprotein that inhibits the activation of the complement system at the intermediate cascade level, blocking the activity of the C3 convertase. Objective: In our study, lung specimens from COVID-19 and ARDS-positive COVID+/ARDS+ patients were compared with COVID-19 and ARDS-negative COVID–/ARDS– as well as COVID–/ARDS+ patients. Methods: Histochemical staining and immunolabeling of CD55 protein were performed. Results: The COVID–/ARDS– specimen showed higher expression and homogeneous distribution of glycosaminoglycans as well as compactly arranged elastic and collagen fibers of the alveolar walls in comparison to ARDS-affected lungs. In addition, COVID–/ARDS– lung tissues revealed stronger and homogenously distributed CD55 expression on the alveolar walls in comparison to the disrupted COVID–/ARDS+ lung tissues. Conclusions: Even though the collapse of the alveolar linings and the accumulation of cellular components in the alveolar spaces were characteristic of COVID+/ARDS+ lung tissues, evaluating CD55 expression could be relevant to understand its relation to the disease. Furthermore, targeting CD55 upregulation as a potential therapy could be an option for post-infectious complications of COVID-19 and other inflammatory lung diseases in the future.},
keywords = {Fritz},
pubstate = {published},
tppubtype = {article}
}
Stallmeyer, Birgit; Bühlmann, Clara; Stakaitis, Rytis; Dicke, Ann-Kristin; Ghieh, Farah; Meier, Luisa; Zoch, Ansgar; MacLeod, David MacKenzie; Steingröver, Johanna; Okutman, Özlem; Fietz, Daniela; Pilatz, Adrian; Riera-Escamilla, Antoni; Xavier, Miguel J.; Ruckert, Christian; Persio, Sara Di; Neuhaus, Nina; Gurbuz, Ali Sami; Şalvarci, Ahmet; May, Nicolas Le; McEleny, Kevin; Friedrich, Corinna; van der Heijden, Godfried; Wyrwoll, Margot J.; Kliesch, Sabine; Veltman, Joris A.; Krausz, Csilla; Viville, Stéphane; Conrad, Donald F.; & Frank Tüttelmann, Dónal O’Carroll
O8 Microscope and Scanner Uncovers Critical piRNA Pathway Gene Variants in Male Infertility and Spermatogenic Failure
PreciPoint O8 microscope and scanner was used in a study to investigate the role of piRNA pathway gene variants in male infertility, particularly in spermatogenic failure. The piRNA pathway is critical for maintaining genomic stability in the germline by silencing transposable elements, particularly during spermatogenesis. Dysfunctions in this pathway can lead to transposon de-repression, disrupting normal sperm development and potentially causing infertility. Previous studies have shown that mutations in piRNA-related genes can cause spermatogenic defects in animal models, but the implications for human fertility have been less clear. The study focused on identifying and analyzing biallelic variants in key piRNA pathway genes in a cohort of infertile men, to understand the genetic underpinnings of spermatogenic failure. Through comprehensive gene analysis and phenotype characterization, the study aimed to link specific genetic mutations to piRNA dysfunction, transposon activity, and male infertility.
Result: Using the O8 microscope and scanner, biallelic variants in piRNA pathway genes were identified in infertile men, confirming the significant role of piRNA dysfunction in human spermatogenic failure. Variants in genes such as PIWIL1 and TDRD1 were directly linked to impaired piRNA biogenesis and abnormal sperm production. The study also showed that transposon de-repression occurred in spermatogonia due to these genetic mutations.
@article{nokey,
title = {Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility},
author = {Birgit Stallmeyer and Clara Bühlmann and Rytis Stakaitis and Ann-Kristin Dicke and Farah Ghieh and Luisa Meier and Ansgar Zoch and David MacKenzie MacLeod and Johanna Steingröver and Özlem Okutman and Daniela Fietz and Adrian Pilatz and Antoni Riera-Escamilla and Miguel J. Xavier and Christian Ruckert and Sara Di Persio and Nina Neuhaus and Ali Sami Gurbuz and Ahmet Şalvarci and Nicolas Le May and Kevin McEleny and Corinna Friedrich and Godfried van der Heijden and Margot J. Wyrwoll and Sabine Kliesch and Joris A. Veltman and Csilla Krausz and Stéphane Viville and Donald F. Conrad and Dónal O’Carroll & Frank Tüttelmann},
url = {https://www.nature.com/articles/s41467-024-50930-9},
doi = {10.1038/s41467-024-50930-9},
issn = {2041-1723},
year = {2024},
date = {2024-08-09},
urldate = {2024-08-09},
journal = {Nature Communications},
volume = {15},
issue = {1},
abstract = {piRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.},
keywords = {O8},
pubstate = {published},
tppubtype = {article}
}
Shi, Wanwan; Li, Xunsheng; Wang, Zhen; Li, Chenguang; Wang, Datao; Li, Chunyi
M8 Microscope and Slide Scanner Highlights the Role of CCL3 in Macrophage Recruitment and Cutaneous Wound Healing in Mice
Using PreciPoint M8 digital microscope, this study investigates the role of C-C motif chemokine ligand 3 (CCL3) in cutaneous wound healing in mice. Skin, as the largest organ, requires efficient healing mechanisms to maintain its barrier function. The healing process involves inflammation, proliferation, and remodeling stages, with macrophages playing a crucial role by clearing debris and secreting cytokines. CCL3, known for recruiting inflammatory cells, is hypothesized to enhance wound healing through macrophage recruitment. The study compares healing in wild-type, CCL3 knockout (CCL3-/-), and CCL3-treated CCL3-/- mice. Understanding the function of CCL3 can provide insights into improving wound healing therapies. The presence of CCL3 potentially accelerates the transition from the inflammatory to the proliferative phase of healing. The research emphasizes the significance of chemokines in tissue regeneration. Advanced imaging provided by PreciPoint products ensures precise histological analysis, facilitating this investigation.
Result: The use of PreciPoint M8 digital microscope revealed that CCL3 knockout (CCL3-/-) mice exhibited delayed wound healing, with reduced reepithelialization and collagen deposition. Application of CCL3 improved healing rates in CCL3-/- mice by enhancing macrophage recruitment and increasing cytokine levels, such as TNF-α and TGF-β1. These findings highlight the critical role of CCL3 in promoting efficient wound healing and demonstrate the effectiveness of imaging technology in medical research from PreciPoint.
@article{nokey,
title = {CCL3 Promotes Cutaneous Wound Healing Through Recruiting Macrophages in Mice},
author = {Wanwan Shi and Xunsheng Li and Zhen Wang and Chenguang Li and Datao Wang and Chunyi Li},
url = {https://journals.sagepub.com/doi/10.1177/09636897241264912},
doi = {10.1177/09636897241264912},
year = {2024},
date = {2024-07-30},
urldate = {2024-07-30},
journal = {SAGE Publications},
volume = {33},
abstract = {Wound healing is a complex process, which involves three stages: inflammation, proliferation, and remodeling. Inflammation is the first step; thus, immune factors play an important regulatory role in wound healing. In this study, we focused on a chemokine, C-C motif chemokine ligand 3 (CCL3), which is often upregulated for expression during wound healing. We compared cutaneous wound healing at the histological, morphological, and molecular levels in the presence and absence of CCL3. The results showed that the wound healing rate in the wild-type and CCL3-/- + CCL3 mice was faster than that of CCL3-/- mice (P < 0.01), and application of CCL3 to wounds increased the healing rate. In the process of wound healing, the degree of reepithelialization and the rate of collagen deposition in the wound of CCL3-/- mice were significantly lower than those of wild-type mice (P < 0.01). The number of macrophages and the expression levels of tumor necrosis factor(TNF)-α and transforming growth factor (TGF)-β1 in the wounds of wild-type mice were much higher than those of the CCL3-/- mice. Removal of macrophages and CCL3-/- mice share similar phenotypes. Therefore, we infer that the wound healing requires the participation of macrophages, and CCL3 may play an important regulatory role through recruiting macrophages to the wound sites.},
keywords = {M8},
pubstate = {published},
tppubtype = {article}
}
Hogrefe, Christin; Paul, Neelima; Boveleth, Lioba; Bolsinger, Marius; Flügel, Marius; Danner, Timo; Latz, Arnulf; Gilles, Ralph; Knoblauch, Volker; Wohlfahrt-Mehrens, Margret; Hölzle, Markus; Waldmann, Thomas
PreciPoint Digital Microscope Helps Investigate Lithium Redistribution in Si-Graphite Composite Electrodes
Researchers used custom-made PreciPoint digital microscope in a study involving lithium (Li) redistribution. It was found that Li redistribution is more pronounced at a higher C-rate of 0.5 C, indicating a preference for graphite over silicon (Si) lithiation. To analyze Li redistribution in Si-graphite composite (SiG) electrodes, various techniques were used. The methods employed included in situ and operando X-ray diffraction (XRD), ex situ light microscopy (LM), in situ optical microscopy of cross-sectioned full cells (CS-IOM), and 3D microstructure-resolved simulations. First, the lithiation behavior of graphite and SiG full cells (20.8 wt.% Si) was validated using XRD, LM, CS-IOM, and simulations. Then, Li redistribution between graphite and Si components was investigated. Operando XRD during charging showed higher lithiation in graphite, suggesting Li moves to Si during relaxation. In situ and ex situ optical microscopy confirmed this, observing the disappearance of the golden LiC6 phase over 24 hours. Simulations supported these findings, showing Li concentration variations in both graphite and Si.
Result: To gain a better understanding of the Li redistribution behavior of the SiG composite electrodes, a graphite electrode and a SiG electrode were compared, referred to as SiG20.8. Experts used a custom-made digital microscope from PreciPoint with a 40X objective to acquire one image every 60s, using the stacked image mode. For the graphite cells, 150 images in a distance of 0.25 μm were taken and merged into one image. Since graphite and Si exhibit different kinetic, electronic, and thermodynamic characteristics during lithiation, more pronounced differences in Li redistribution with higher C-rates were expected. Therefore, C-rates of 0.1 C and 0.5 C were chosen as 0.5 C still allows for a sufficient time-resolution in the operando XRD measurements.
@article{nokey,
title = {Lithium Redistribution Mechanism within SiliconGraphite Electrodes: Multi-Method Approach and Method Validation},
author = {Christin Hogrefe and Neelima Paul and Lioba Boveleth and Marius Bolsinger and Marius Flügel and Timo Danner and Arnulf Latz and Ralph Gilles and Volker Knoblauch and Margret Wohlfahrt-Mehrens and Markus Hölzle and Thomas Waldmann},
url = {https://iopscience.iop.org/article/10.1149/1945-7111/ad59c7},
year = {2024},
date = {2024-07-03},
urldate = {2024-07-03},
journal = {The Electrochemical Society},
volume = {171},
issue = {7},
pages = {070503},
abstract = {Li redistribution processes within Si-graphite composite (SiG) electrodes are analyzed using in situ and operando X-ray diffraction (XRD), ex situ light microscopy (LM), in situ optical microscopy of cross-sectioned full cells (CS-IOM), and 3D microstructure-resolved simulations of full cells. First, the lithiation behavior of graphite and SiG full cells (Si content 20.8 wt.-%) is analyzed. The results are used as validation of the methods (XRD, LM, CS-IOM, simulation). Second, the Li redistribution between the graphite component and Si component within SiG electrodes is investigated: By operando XRD measurements during charging in comparison with relaxed cells, a higher lithiation degree in the graphite component is found during charging compared to the relaxed state, indicating Li redistribution from graphite to Si during relaxation. The Li redistribution is directly observed by in situ and ex situ optical microscopy, where the golden LiC6 phase disappears during a 24 h relaxation period. The results are supported by simulations showing the variation in the Li concentration, not only in graphite but also within the Si component. Furthermore, all methods find that the Li redistribution is more pronounced at a higher C-rate of 0.5 C, suggesting a preference for graphite lithiation over Si lithiation.},
keywords = {M8},
pubstate = {published},
tppubtype = {article}
}
Schneider, Paul; Zhang, Heyang; Simic, Leon; Dai, Zhuqing; Schrörs, Barbara; Akilli-Öztürk, Özlem; Lin, Jian; Durak, Feyza; Schunke, Jenny; Bolduan, Vanessa; Bogaert, Bram; Schwiertz, David; Schäfer, Gabriela; Bros, Matthias; Grabbe, Stephan; Schattenberg, Jörn Markus; Raemdonck, Koen; Koynov, Kaloian; Diken, Mustafa; Kaps, Leonard; Barz, Matthias
Fritz Slide Scanner Enables Targeted siRNA Delivery via Multicompartment Polyion Complex Micelles for Antistromal Therapy in Hepatocellular Carcinoma
The PreciPoint Fritz Slide Scanner was pivotal in analyzing multicompartment polyion complex micelles (PICMs) used for siRNA delivery targeting cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). The study explores HCC\'s challenge as a chemoresistant tumor and the potential of antistromal therapy focusing on CAFs. CAFs, known to support tumor growth and neoangiogenesis, express microfibrillar-associated protein 5 (MFAP-5), a key target. Researchers developed biocompatible PICMs utilizing triblock copolymers, integrating anti-MFAP-5 siRNA and desloratadine to enhance endosomal escape. These PICMs were examined using the PreciPoint Fritz Slide Scanner, revealing promising antitumor effects by significantly reducing hepatic tumor burden. This novel RNA interference approach offers insights into future cancer therapies.
Result: The PreciPoint Fritz Slide Scanner helped researchers demonstrate that siMFAP-5/DES PICMs substantially reduced MFAP-5 expression in CAFs, leading to an 80% reduction in hepatic tumor burden. The scanner confirmed the PICMs\' precise targeting of CAFs, inhibiting tumor-related angiogenesis and enhancing therapeutic efficacy in the HCC mouse model.
@article{nokey,
title = {Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma},
author = {Paul Schneider and Heyang Zhang and Leon Simic and Zhuqing Dai and Barbara Schrörs and Özlem Akilli-Öztürk and Jian Lin and Feyza Durak and Jenny Schunke and Vanessa Bolduan and Bram Bogaert and David Schwiertz and Gabriela Schäfer and Matthias Bros and Stephan Grabbe and Jörn Markus Schattenberg and Koen Raemdonck and Kaloian Koynov and Mustafa Diken and Leonard Kaps and Matthias Barz},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/adma.202404784},
doi = {10.1002/adma.202404784},
year = {2024},
date = {2024-06-21},
urldate = {2024-06-21},
journal = {Wiley},
abstract = {Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π–π interaction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.},
keywords = {Fritz},
pubstate = {published},
tppubtype = {article}
}
Kuritcyn, Petr; Kletzander, Rosalie; Eisenberg, Sophia; Wittenberg, Thomas; Bruns, Volker; Evert, Katja; Keil, Felix; Ziegler, Paul K.; Bankov, Katrin; Wild, Peter; Eckstein, Markus; Hartmann, Arndt; Geppert, Carol I.; Benz, Michaela
M8 Microscope and Scanner Used in a Study to Achieve High Accuracy with Few-Shot Classification and Data Augmentation in Histopathology
Researchers used the M8 digital microscope and scanner to enhance artificial intelligence (AI) in histopathology, addressing image scarcity and data heterogeneity. They trained models with data from one scanner and site, achieving 90% accuracy on a multicenter database, matching primary data performance. EfficientNet B0 was the best for feature extraction. Prototypes from different scanners showed minimal accuracy deviation. Adapting to new tumor entities, the model classified urothelial carcinoma tissues with 93.6% accuracy using three annotations per subclass. This method supports an interactive AI system requiring few annotations and is adaptable to new tasks without extensive retraining. This demonstrates that few-shot classification with data augmentation can train robust models with minimal data. The approach allows for easy adaptation to new tasks, making it ideal for non-technical users. By reducing the need for extensive annotations and complex retraining, this method significantly improves efficiency and usability in histopathology AI applications.
Result: All tissue sections from the primary test set (30 slides) and adaptation set (9 slides) were digitized with four microscopic scanners including Precipoint’s M8 microscope and scanner. For manual digitization, a camera was mounted on a standard microscope and connected to a computer. The microscope stage was moved manually, systematically traversing the glass slide while the software stitched images from the video stream in real-time, resulting in one WSI representing the glass slide. The data set was included as a special challenge, with sub-optimal imaging conditions like saturation chosen during digitization. Each WSI was aligned to the WSI obtained by the primary scanner to transfer the annotations of the tissue classes to it.
@article{nokey,
title = {M8 Microscope and Scanner Used in a Study to Achieve High Accuracy with Few-Shot Classification and Data Augmentation in Histopathology},
author = {Petr Kuritcyn and Rosalie Kletzander and Sophia Eisenberg and Thomas Wittenberg and Volker Bruns and Katja Evert and Felix Keil and Paul K. Ziegler and Katrin Bankov and Peter Wild and Markus Eckstein and Arndt Hartmann and Carol I. Geppert and Michaela Benz},
url = {https://www.sciencedirect.com/science/article/pii/S2153353924000270},
doi = {10.1016/j.jpi.2024.100388},
year = {2024},
date = {2024-06-06},
urldate = {2024-06-06},
journal = {Journal of Pathology Informatics},
abstract = {A vast multitude of tasks in histopathology could potentially benefit from the support of artificial intelligence (AI). Many examples have been shown in the literature and first commercial products with FDA or CE-IVDR clearance are available. However, two key challenges remain: (1) a scarcity of thoroughly annotated images, respectively the laboriousness of this task, and (2) the creation of robust models that can cope with the data heterogeneity in the field (domain generalization). In this work, we investigate how the combination of prototypical few-shot classification models and data augmentation can address both of these challenges. Based on annotated data sets that include multiple centers, multiple scanners, and two tumor entities, we examine the robustness and the adaptability of few-shot classifiers in multiple scenarios. We demonstrate that data from one scanner and one site are sufficient to train robust few-shot classification models by applying domain-specific data augmentation. The models achieved classification performance of around 90% on a multiscanner and multicenter database, which is on par with the accuracy achieved on the primary single-center single-scanner data. Various convolutional neural network (CNN) architectures can be used for feature extraction in the few-shot model. A comparison of nine state-of-the-art architectures yielded that EfficientNet B0 provides the best trade-off between accuracy and inference time. The classification of prototypical few-shot models directly relies on class prototypes derived from example images of each class. Therefore, we investigated the influence of prototypes originating from images from different scanners and evaluated their performance also on the multiscanner database. Again, our few-shot model showed a stable performance with an average absolute deviation in accuracy compared to the primary prototypes of 1.8% points. Finally, we examined the adaptability to a new tumor entity: classification of tissue sections containing urothelial carcinoma into normal, tumor, and necrotic regions. Only three annotations per subclass (e.g., muscle and adipose tissue are subclasses of normal tissue) were provided to adapt the few-shot model, which obtained an overall accuracy of 93.6%. These results demonstrate that prototypical few-shot classification is an ideal technology for realizing an interactive AI authoring system as it only requires few annotations and can be adapted to new tasks without involving retraining of the underlying feature extraction CNN, which would in turn require a selection of hyper-parameters based on data science expert knowledge. Similarly, it can be regarded as a guided annotation system. To this end, we realized a workflow and user interface that targets non-technical users.},
keywords = {M8},
pubstate = {published},
tppubtype = {article}
}
Gao, Jia; Ren, Jing; Ye, Hanjie; Chu, Wenhui; Ding, Xuankai; Ding, Lingzhi; Fu, Yongqian
M8 Microscope and Scanner Used in Research on ZIF-8 Sericin Hydrogel for Bone Regeneration Promoting Angiogenesis and Osteogenesis
A recent study used the M8 microscope and scanner to evaluate a novel bone regeneration scaffold. Designing scaffolds with optimal biodegradability, osteogenic potential, and angiogenic properties presents a significant challenge. Thymosin beta 10 (TMSB10), known for its roles in angiogenesis and osteogenic differentiation, faces activity preservation limitations. To address this, researchers engineered ZIF-8 as a carrier for TMSB10 (TMSB10@ZIF-8), integrating it into a self-assembled sericin hydrogel. Testing the composite in a rat cranial defect model revealed successful synthesis of TMSB10@ZIF-8 with an 88.21% encapsulation efficiency. The sustained release of TMSB10 from this composite significantly enhanced tube formation in HUVECs and promoted angiogenesis in the CAM model. Additionally, it notably improved osteogenic differentiation in MC 3 T3-E1 cells. Eight weeks post-implantation, the TMSB10@ZIF-8/Sericin hydrogel group demonstrated substantial bone healing (86.77 ± 8.91%), outperforming controls.
Result: Histological observation of the skulls was conducted using M8 microscope and scanner. The skulls were first decalcified, followed by dehydration using a graded series of ethanol. Subsequently, the samples were cleared in xylene and embedded in paraffin. Tissue slices were then obtained from the central area of each defect and subjected to staining with H&E, Masson\'s trichrome, and Sirius Red for microscopic evaluation. The approach enabled detailed examination and documentation of tissue morphology and composition within the bone defects, providing crucial insights into the efficacy of the TMSB10@ZIF-8/Sericin hydrogel scaffold in promoting bone regeneration.
@article{nokey,
title = {Thymosin beta 10 loaded ZIF-8/sericin hydrogel promoting angiogenesis and osteogenesis for bone regeneration},
author = {Jia Gao and Jing Ren and Hanjie Ye and Wenhui Chu and Xuankai Ding and Lingzhi Ding and Yongqian Fu},
url = {https://www.sciencedirect.com/science/article/pii/S0141813024023675#s0075},
doi = {10.1016/j.ijbiomac.2024.131562},
year = {2024},
date = {2024-05-01},
journal = {International Journal of Biological Macromolecules},
volume = {267},
abstract = {Angiogenesis is pivotal for osteogenesis during bone regeneration. A hydrogel that promotes both angiogenesis and osteogenesis is essential in bone tissue engineering. However, creating scaffolds with the ideal balance of biodegradability, osteogenic, and angiogenic properties poses a challenge. Thymosin beta 10 (TMSB10), known for its dual role in angiogenesis and osteogenesis differentiation, faces limitations due to protein activity preservation. To tackle this issue, ZIF-8 was engineered as a carrier for TMSB10 (TMSB10@ZIF-8), and subsequently integrated into the self-assembled sericin hydrogel. The efficacy of the composite hydrogel in bone repair was assessed using a rat cranial defect model. Characterization of the nanocomposites confirmed the successful synthesis of TMSB10@ZIF-8, with a TMSB10 encapsulation efficiency of 88.21 %. The sustained release of TMSB10 from TMSB10@ZIF-8 has significantly enhanced tube formation in human umbilical vein endothelial cells (HUVECs) in vitro and promoted angiogenesis in the chicken chorioallantoic membrane (CAM) model in vivo. It has markedly improved the osteogenic differentiation ability of MC 3 T3-E1 cells in vitro. 8 weeks post-implantation, the TMSB10@ZIF-8/ Sericin hydrogel group exhibited significant bone healing (86.77 ± 8.91 %), outperforming controls. Thus, the TMSB10@ZIF-8/Sericin hydrogel, leveraging ZIF-8 for TMSB10 delivery, emerges as a promising bone regeneration scaffold with substantial clinical application potential.},
keywords = {M8},
pubstate = {published},
tppubtype = {article}
}
Fuentes, Mary Esmeralda; Lu, Xiaoyin; Flores, Natasha M.; Hausmann, Simone; Mazur, Pawel K.
M8 Microscope and Scanner Investigates High-Grade Pancreatic Neuroendocrine Tumors in Mice with MEN1, ATRX, and PTEN Deletion
M8 microscope and scanner was used in the research involving pancreatic neuroendocrine tumors (PanNETs) that are rare yet aggressive malignancies lacking effective therapies. Characterized by extensive heterogeneity, PanNETs often present at advanced stages, resulting in poor prognoses. Research efforts focusing on genomic landscapes have identified recurrent mutations in MEN1, ATRX, DAXX, and PTEN, critical in PanNET pathogenesis. The development of effective therapeutics is hindered by this heterogeneity and limited preclinical models. Notably, MEN1, ATRX, and PTEN deletions in mice mimic PanNET tumorigenesis, offering a promising model for translational research and therapeutic development. Understanding the roles of these mutations and associated pathways holds potential for targeted precision therapies in this challenging disease.
Result: Researchers used the M8 microscope and scanner to identify key genetic alterations in human PanNETs. They analyzed the GENIE v14.1 genomic sequencing database, revealing frequent mutations in MEN1, ATRX, DAXX, and PTEN. Co-occurring mutations in MEN1, PTEN, and ATRX or DAXX suggest their combined loss drives PanNET pathogenesis. Using MAP mutant mice (Men1LoxP/LoxP; AtrxLoxP/LoxP; PtenLoxP/LoxP; Pdx1-CreER), experts induced tumorigenesis and observed robust tumor development resembling intermediate-grade PanNETs with progressive malignancy. RNA sequencing confirmed elevated neuroendocrine and PanNET marker gene expression, aligning with human PanNET biology. Transcriptomic analysis revealed MAP model similarity to human PanNETs, distinct from other mouse models, highlighting its relevance for studying PanNET pathogenesis.
@article{nokey,
title = {Combined deletion of MEN1, ATRX and PTEN triggers development of high-grade pancreatic neuroendocrine tumors in mice},
author = {Mary Esmeralda Fuentes and Xiaoyin Lu and Natasha M. Flores and Simone Hausmann and Pawel K. Mazur},
url = {https://www.nature.com/articles/s41598-024-58874-2},
doi = {10.1038/s41598-024-58874-2},
year = {2024},
date = {2024-04-12},
urldate = {2024-04-12},
journal = {Scientific Reports},
volume = {14},
issue = {1},
abstract = {Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET, but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, ATRX, and PTEN, tumor suppressors commonly mutated in human PanNETs, triggers the development of high-grade pancreatic neuroendocrine tumors in mice. Histopathological evaluation and gene expression analyses of the developed tumors confirm the presence of PanNET hallmarks and significant overlap in gene expression patterns found in human disease. Thus, we postulate that the presented novel genetically defined mouse model is the first clinically relevant immunocompetent high-grade PanNET mouse model.},
keywords = {M8},
pubstate = {published},
tppubtype = {article}
}
Porth, Isabel
M8 Microscope and Scanner and ViewPoint Software Used to Study Trastuzumab\'s Long-term Effects in HER2-positive Advanced Gastric or Gastroesophageal Adenocarcinoma
A study, conducted with the help of M8 microscope and scanner and ViewPoint software, identified biomarkers distinguishing HER2-positive gastric cancer patients with long-term versus short-term responses to trastuzumab plus chemotherapy. Genetic analyses revealed two non-synonymous mutations in ERBB2, occurring exclusively in long-term responders. However, neither HER2 gene copy number nor other genetic alterations correlated with treatment response. Notably, patients with homogeneous HER2 protein expression had improved progression-free survival on trastuzumab-containing therapy. Evaluating PD-L1, long-term responders exhibited higher PD-L1 combined positive scores, correlating positively with progression-free survival across the cohort. PD-L1 positivity (combined positive score ≥1) was associated with enhanced progression-free survival on trastuzumab-based treatment. Bioinformatics analysis linked increased PD-L1 scores to elevated CD4+ memory T-cell levels. While genetic mutations in ERBB2 were specific to long-term responders, a homogeneous HER2 expression pattern and PD-L1 positivity emerged as potential biomarkers for improved treatment outcomes in HER2-positive gastric cancer, emphasizing the clinical importance of PD-L1 in this setting.
Result: The study used M8 microscope and scanner and ViewPoint software to identify that the PD-L1 combined positive score (CPS) is higher in long-term responders compared to short-term responders, suggesting a potential biomarker for predicting the efficacy of trastuzumab in these patients. The PD-L1 CPS was also positively correlated with progression-free survival (PFS), highlighting its potential as a prognostic marker for better outcomes under trastuzumab-based therapy. The study found that the copy number variations (CNVs) of the HER2 gene (ERBB2) did not significantly distinguish between long-term and short-term responders. However, patients with a homogeneous HER2 expression pattern showed improved PFS, suggesting that the uniformity of HER2 expression might be an important factor in the effectiveness of trastuzumab therapy. The CD4+ memory T-cells were found in higher levels in PD-L1 positive patients. Overall, the thesis suggests that PD-L1 expression and the immune cell landscape, particularly the presence of CD4+ memory T-cells, hold significant potential as indicators for better clinical outcomes in HER2-positive gastric and gastroesophageal junction cancers.
@mastersthesis{nokey,
title = {Long-term response to trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma},
author = {Isabel Porth},
url = {https://archiv.ub.uni-heidelberg.de/volltextserver/34645/1/Thesis%20Isabel%20Porth%20final.pdf},
doi = {10.11588/heidok.00034645},
year = {2024},
date = {2024-04-11},
urldate = {2024-04-11},
school = {Heidelberg University Library},
abstract = {Gastric cancer is the fifth most prevalent cancer type, with the fourth highest cancer-related mortality worldwide. Since 2010, the HER2-targeting agent trastuzumab has been approved as a first-line therapy in combination with chemotherapy for HER2-positive advanced/metastatic gastric or gastroesophageal junction cancer. However, despite improvement of overall survival through trastuzumab treatment, the survival remains low with only about one year. However, a subgroup of patients with long-term response to trastuzumab has been observed in small studies and case reports. Genetic alterations and the level of HER2 gene amplification have been proposed to identify patients with trastuzumab long-term response. Despite this, a biomarker for superior response to trastuzumab remains elusive. This study aimed to identify a biomarker that could distinguish between HER2-positive gastric cancer patients with long-term and short-term response to trastuzumab plus chemotherapy. FFPE tumor samples and follow-up data of 19 patients with HER2-positive advanced/metastatic gastric or gastroesophageal junction cancer who underwent trastuzumab-containing therapy were retrospectively collected from four German clinical centers. The patients were divided into long-term (n=7) and short-term responding groups (n=12) according to progression-free survival on trastuzumab-containing therapy (PFS≥12 months vs. PFS<12 months). A comprehensive genetic and gene expression analysis was performed. In addition, established biomarkers HER2, PD-L1 and MSI were analyzed. An automated analysis pipeline was developed to detect genetic alterations such as somatic single nucleotide variants and copy number alterations. The copy number of the HER2 gene, ERBB2, could not distinguish between trastuzumab long-term and short-term response in gastric cancer patients. However, two somatic non-synonymous mutations were detected in ERBB2, and both mutations occurred in patients with long-term response to trastuzumab. Other genetic alterations and the tumor mutational burden were not correlated with response to trastuzumab. The HER2 protein expression pattern was also evaluated, and the results showed that patients with homogeneous HER2 expression pattern had improved progression-free survival on trastuzumab-containing therapy.
Evaluation of the biomarker PD-L1 revealed a higher PD-L1 combined positive score in longterm responding patients, and a positive correlation between PD-L1 combined positive score and PFS in the overall study population. PD-L1 positivity, defined as a combined positive score ≥1, was associated with improved PFS on trastuzumab-based treatment. Furthermore, using bioinformatics methods, increased PD-L1 combined positive scores could be associated with a higher level of CD4+ memory T-cells.
In conclusion, genetic alterations and the tumor mutational burden were not correlated with response to a trastuzumab-containing therapy, while a homogeneous HER2 protein expression pattern and PD-L1 combined positive score were identified as potential biomarkers for improved progression-free survival. The findings highlight the clinical relevance of PD-L1 for the treatment of HER2-positive advanced gastric and gastroesophageal adenocarcinoma.
},
keywords = {M8, ViewPoint},
pubstate = {published},
tppubtype = {mastersthesis}
}
Evaluation of the biomarker PD-L1 revealed a higher PD-L1 combined positive score in longterm responding patients, and a positive correlation between PD-L1 combined positive score and PFS in the overall study population. PD-L1 positivity, defined as a combined positive score ≥1, was associated with improved PFS on trastuzumab-based treatment. Furthermore, using bioinformatics methods, increased PD-L1 combined positive scores could be associated with a higher level of CD4+ memory T-cells.
In conclusion, genetic alterations and the tumor mutational burden were not correlated with response to a trastuzumab-containing therapy, while a homogeneous HER2 protein expression pattern and PD-L1 combined positive score were identified as potential biomarkers for improved progression-free survival. The findings highlight the clinical relevance of PD-L1 for the treatment of HER2-positive advanced gastric and gastroesophageal adenocarcinoma.
Tang, Yuan-juan; Zhang, Zhen; Yan, Tong; Chen, Ken; Xu, Guo-fan; Xiong, Shi-qiang; Wu, Dai-qian; Chen, Jie; Jose, Pedro A.; & Jin-juan Fu, Chun-yu Zeng
M8 Microscope and Scanner Explores Irisin’s Impact on Type 1 Diabetic Cardiomyopathy
Research on diabetic cardiomyopathy (DCM) in type 1 diabetes mellitus (T1DM) was conducted with the assistance of an M8 microscope and scanner. Diabetes, particularly type 1 diabetes mellitus (T1DM), presents a significant global health challenge, with diabetic cardiomyopathy (DCM) posing a major threat to patients, characterized by cardiac dysfunction leading to morbidity and mortality. While apoptosis is recognized as a primary mechanism in DCM, recent evidence suggests a role for ferroptosis, a distinct form of cell death involving iron accumulation and lipid peroxidation. Despite emerging links between ferroptosis and DCM, understanding remains limited, especially in T1DM. Training has shown protective effects against DCM, and irisin, a myokine, has been implicated in cardiovascular protection and ferroptosis inhibition in other conditions. Investigating the role of ferroptosis in DCM pathogenesis, particularly in T1DM, and exploring whether irisin mitigates cardiac dysfunction through anti-ferroptotic mechanisms are crucial research aims.
Result: The study revealed lower irisin levels in the heart and serum of STZ-induced T1DM mice. Irisin supplementation improved cardiac function in diabetic cardiomyopathy (DCM) by inhibiting ferroptosis. This was shown by decreased cardiac MDA, restored GSH, and increased SLC7A11/GPX4 expression. The protective effect of irisin was demonstrated to be specific to ferroptosis, as erastin, a ferroptosis inducer, blocked irisin-mediated benefits. Mechanistically, irisin increased SIRT1 and decreased p53 K382 acetylation, leading to reduced p53 levels, upregulation of SLC7A11/GPX4, and ultimately decreasing ferroptosis and protecting cardiomyocytes from high glucose-induced injury.
@article{nokey,
title = {Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53},
author = {Yuan-juan Tang and Zhen Zhang and Tong Yan and Ken Chen and Guo-fan Xu and Shi-qiang Xiong and Dai-qian Wu and Jie Chen and Pedro A. Jose and Chun-yu Zeng & Jin-juan Fu},
url = {https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02183-5},
doi = {10.1186/s12933-024-02183-5},
year = {2024},
date = {2024-04-02},
urldate = {2024-04-02},
journal = {Cardiovascular Diabetology},
volume = {23},
issue = {1},
abstract = {Background
Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known.
Methods and results
T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose.
Conclusion
This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.},
keywords = {M8},
pubstate = {published},
tppubtype = {article}
}
Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known.
Methods and results
T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose.
Conclusion
This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.