| 1. |
|
|
| 2. |
- Hermsen, Meyke, et al.
(författare)
-
Convolutional Neural Networks for the Evaluation of Chronic and Inflammatory Lesions in Kidney Transplant Biopsies
- 2022
-
Ingår i: American Journal of Pathology. - : ELSEVIER SCIENCE INC. - 0002-9440 .- 1525-2191. ; 192:10, s. 1418-1432
-
Tidskriftsartikel (refereegranskat)abstract
- In kidney transplant biopsies, both inflammation and chronic changes are important features that predict long-term graft survival. Quantitative scoring of these features is important for transplant diagnostics and kidney research. However, visual scoring is poorly reproducible and labor intensive. The goal of this study was to investigate the potential of convolutional neural networks (CNNs) to quantify inflammation and chronic features in kidney transplant biopsies. A structure segmentation CNN and a lymphocyte detection CNN were applied on 125 whole-slide image pairs of periodic acid-Schiff- and CD3-stained slides. The CNN results were used to quantify healthy and sclerotic glomeruli, interstitial fibrosis, tubular atrophy, and inflammation within both nonatrophic and atrophic tubuli, and in areas of interstitial fibrosis. The computed tissue features showed high correlation with Banff lesion scores of five pathologists (A.A., A.Dend., J.H.B., J.K., and T.N.). Analyses on a small subset showed a moderate correlation toward higher CD3+ cell density within scarred regions and higher CD3+ cell count inside atrophic tubuli correlated with long-term change of estimated glomerular filtration rate. The presented CNNs are valid tools to yield objective quantitative information on glomeruli number, fibrotic tissue, and inflammation within scarred and non-scarred kidney parenchyma in a reproducible manner. CNNs have the potential to improve kidney transplant diagnostics and will benefit the community as a novel method to generate surrogate end points for large-scale clinical studies. (Am J Pathol 2022, 192: 1418-1432; https://doi.org/10.1016/j.ajpath.2022.06.009)
|
|
| 3. |
|
|
| 4. |
- Luna-Marco, Clara, et al.
(författare)
-
Endoplasmic Reticulum Stress and Metabolism in Hepatocellular Carcinoma
- 2023
-
Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 193:10, s. 1377-1388
-
Forskningsöversikt (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for 85% to 90% of all liver cancer cases. It is a hepatocyte-derived primary tumor, causing 550,000 deaths per year, ranking it as one of the most common cancers worldwide. The liver is a highly metabolic organ with multiple functions, including digestion, detoxification, breakdown of fats, and production of bile and cholesterol, in addition to storage of vitamins, glycogen, and minerals, and synthesizing plasma proteins and clotting factors. Due to these fundamental and diverse functions, the malignant transformation of hepatic cells can have a severe impact on the liver's metabolism. Furthermore, tumorigenesis is often accompanied by activation of the endoplasmic reticulum (ER) stress pathways, which are known to be highly intertwined with several metabolic pathways. Because HCC is characterized by changes in the metabolome and by an aberrant activation of the ER stress pathways, the aim of this review was to summarize the current knowledge that links ER stress and metabolism in HCC, thereby focusing on potential therapeutic targets.
|
|
| 5. |
- Macchi, Chiara, et al.
(författare)
-
Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9 - The Role of STAT3
- 2020
-
Ingår i: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 190:11, s. 2226-2236
-
Tidskriftsartikel (refereegranskat)abstract
- In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokines levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of signal transducer and activator of transcript 3 (STAT3). In HepG2 cells, leptin and resistin upregulated PCSK9 gene and protein expression as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knock-down of STAT3 did not affect the expression of leptin and resistin receptors as well as that of PCSK9. The analysis of human PCSK9 promoter region showed that the two adipokines raise PCSK9 promoter activity via the involvement of sterol regulatory element motif. In healthy male, a positive association between circulating leptin and PCSK9 levels was found only when BMI was < 25 kg/m2. In conclusion, our study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.
|
|
| 6. |
- Mairinoja, L., et al.
(författare)
-
Deep Learning-Based Image Analysis of Liver Steatosis in Mouse Models
- 2023
-
Ingår i: American Journal of Pathology. - 0002-9440. ; 193:8, s. 1072-1080
-
Tidskriftsartikel (refereegranskat)abstract
- The incidence of nonalcoholic fatty liver disease is a continuously growing health problem worldwide, along with obesity. Therefore, novel methods to both efficiently study the manifestation of nonalco-holic fatty liver disease and to analyze drug efficacy in preclinical models are needed. The present study developed a deep neural network-based model to quantify microvesicular and macrovesicular steatosis in the liver on hematoxylin-eosin-stained whole slide images, using the cloud-based platform, Aiforia Create. The training data included a total of 101 whole slide images from dietary interventions of wild-type mice and from two genetically modified mouse models with steatosis. The algorithm was trained for the following: to detect liver parenchyma, to exclude the blood vessels and any artefacts generated during tissue processing and image acquisition, to recognize and differentiate the areas of micro-vesicular and macrovesicular steatosis, and to quantify the recognized tissue area. The results of the image analysis replicated well the evaluation by expert pathologists and correlated well with the liver fat content measured by EchoMRI ex vivo, and the correlation with total liver triglycerides was notable. In conclusion, the developed deep learning-based model is a novel tool for studying liver steatosis in mouse models on paraffin sections and, thus, can facilitate reliable quantification of the amount of steatosis in large preclinical study cohorts. (Am J Pathol 2023, 193: 1072-1080; https://doi.org/ 10.1016/j.ajpath.2023.04.014)
|
|
| 7. |
- Müller, Catharina, et al.
(författare)
-
Protein signatures of remodeled airways in transplanted lungs with Bronchiolitis Obliterans Syndrome obtained using laser capture microdissection
- 2021
-
Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 191:8, s. 1398-1411
-
Tidskriftsartikel (refereegranskat)abstract
- Bronchiolitis obliterans syndrome (BOS), a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation. The histological correlate is progressive, fibrotic occlusion of small airways, obliterative bronchiolitis lesions, ultimately leading to organ failure. The molecular composition of these lesions is unknown. By laser-capture microdissection and optimized sample preparation protocols for mass spectrometry the protein composition of the lesions in explanted lungs from four end-stage BOS patients were analysed. Immunohistochemistry and immunofluorescence were used to determine the spatial distribution of commonly identified proteins on the tissue level, protein signatures for in total 14 OB-lesions were established. A set of 39 proteins identified in more than 75% of lesions included distinct structural proteins (collagen type IV and VI) and cellular components (actins, vimentin, tryptase). Each respective lesion exhibited a unique composition of proteins (on average n=66 proteins), thereby mirroring the morphological variation of the lesions. Antibody-based staining confirmed these MS-based findings. The 14 analyzed OB-lesions showed variations in their protein content, but also common features. This study provides molecular and morphological insights into the development of chronic rejection after lung transplantation. The protein patterns in the lesions were correlated to pathways of extracellular matrix organization, tissue development and wound healing processes.
|
|
| 8. |
- Pandita, Ankur, et al.
(författare)
-
Intussusceptive angiogenesis in human metastatic malignant melanoma. : Intussusception in human melanoma
- 2021
-
Ingår i: The American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 191:11, s. 2023-2038
-
Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. The limited effect may be explained by an additional, less vascular endothelial growth factor-driven, form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered BRAF-induced, PTEN-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cell infiltration were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, invitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation invitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.
|
|
| 9. |
|
|
| 10. |
- Pham, Tuan D., et al.
(författare)
-
Tensor Decomposition of Largest Convolutional Eigenvalues Reveals Pathologic Predictive Power of RhoB in Rectal Cancer Biopsy
- 2023
-
Ingår i: American Journal of Pathology. - : ELSEVIER SCIENCE INC. - 0002-9440 .- 1525-2191. ; 193:5, s. 579-590
-
Tidskriftsartikel (refereegranskat)abstract
- RhoB protein belongs to the Rho GTPase family, which plays an important role in governing cell signaling and tissue morphology. Its expression is known to have implications in pathologic processes of diseases. In particular, the role of RhoB in rectal cancer is not well understood. Investigation in the regulation and communication of this protein, detected by immunohistochemical staining on the mi-croscope, can help gain insightful information leading to optimal disease treatment options. Herein, deep learning-based image analysis and the decomposition of multiway arrays were used to study the predictive factor of RhoB in two cohorts of patients with rectal cancer having survival rates of <5 and >5 years. The results show distinctions between the tensor decomposition factors of the two cohorts. (Am J Pathol 2023, 193: 579-590; https://doi.org/10.1016/j.ajpath.2023.01.007)
|
|
