56 research outputs found
EV-3, an endogenous human erythropoietin isoform with distinct functional relevance
No full textAbstractGeneration of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced EPO transcript characterized by deletion of exon 3 (hEPOΔ3). We show co-regulation of EPO and hEPOΔ3 in human diseased tissue. The expression of hEPOΔ3 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEPOΔ3 and EPO in response to hypoxic conditions was also observed in HepG2 cell cultures. Using LC-ESI-MS/MS, we provide first evidence for the existence of hEPOΔ3 derived protein EV-3 in human serum from healthy donors. Contrary to EPO, recombinant EV-3 did not promote early erythroid progenitors in cultures of human CD34+ haematopoietic stem cells. Repeated intraperitoneal administration of EV-3 in mice did not affect the haematocrit. Similar to EPO, EV-3 acted anti-apoptotic in rat hippocampal neurons exposed to oxygen-glucose deprivation. Employing the touch-screen paradigm of long-term visual discrimination learning, we obtained first in vivo evidence of beneficial effects of EV-3 on cognition. This is the first report on the presence of a naturally occurring EPO protein isoform in human serum sharing non-erythropoietic functions with EPO.</jats:p
PD-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue – prognostic implications and rationale for immunotherapy
No full textPathophysiologie der gastroösophagealen Refluxerkrankung: Was ist wichtig für den Chirurgen?
No full textMulti-task learning of a deep K-nearest neighbour network for histopathological image classification and retrieval.
No full textDeep neural networks have achieved tremendous success in image recognition, classification and object detection. However, deep learning is often criticised for its lack of transparency and general inability to rationalise its predictions. The issue of poor model interpretability becomes critical in medical applications: a model that is not understood and trusted by physicians is unlikely to be used in daily clinical practice. In this work, we develop a novel multi-task deep learning framework for simultaneous histopathology image classification and retrieval, leveraging on the classic concept of k-nearest neighbours to improve model interpretability. For a test image, we retrieve the most similar images from our training databases. These retrieved nearest neighbours can be used to classify the test image with a confidence score, and provide a human-interpretable explanation of our classification. Our original framework can be built on top of any existing classification network (and therefore benefit from pretrained models), by (i) combining a triplet loss function with a novel triplet sampling strategy to compare distances between samples and (ii) adding a Cauchy hashing loss function to accelerate neighbour searching. We evaluate our method on colorectal cancer histology slides and show that the confidence estimates are strongly correlated with model performance. Nearest neighbours are intuitive and useful for expert evaluation. They give insights into understanding possible model failures, and can support clinical decision making by comparing archived images and patient records with the actual case
Increased intraepithelial CD3+ T-lymphocytes and high PD-L1 expression on tumor cells are associated with a favorable prognosis in esophageal squamous cell carcinoma and allow prognostic immunogenic subgrouping.
No full textEsophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis and additional therapeutic strategies must be implemented to optimize ESCC treatment. Meanwhile, the important biologic role and potential prognostic and therapeutic implications of a tumors immunologic microenvironment (IM) have been recognized in various cancers.In order to investigate the contexture and the prognostic relevance of the IM in ESCC, we immunohistochemically evaluated the extent of overall/intraepithelial TILs (CD3+/CD8+) and of PD-1 / PD-L1 expression in a cohort of 125 therapy-naive ESCCs, additionally assessing PD-L1 copy number status via fluorescence in-situ hybridization.High intraepithelial CD3+ TILs (CD3ihigh) and high PD-L1 expression on tumor cells (PD-L1high) were each significantly associated with improved overall- (OS) (CD3+: p = 0.019; PD-L1: p = 0.028), disease specific- (DSS) (CD3+: p = 0.05; PD-L1: p = 0.006) and disease free survival (DFS) (CD3+: p = 0.009; PD-L1: p < 0.001). CD3ihigh- and PD-L1high cases were significantly associated with one another (p < 0.001). Subgrouping of ESCC revealed decreased OS (p = 0.031), DSS (p = 0.012) and DFS (p < 0.001) for CD3ilow/PD-L1low cancers.Our data not only associate CD3ihigh- and PD-L1high ESCC with a beneficial outcome, but also demonstrate PD-L1high- and CD3ihigh status to be closely intertwined. Furthermore, our study demarcates a prognostically unfavorable, "non-immunoreactive" CD3ilow / PD-L1low ESCC-subgroup, potentially forming the basis for an immune-based stratification of ESCC
Liposarcoma of the Thyroid: A Case Report with a Review of the Literature.
No full textLiposarcomas of the thyroid gland are extremely rare tumors, and, to our knowledge, only 12 cases have been reported in the English literature. An accurate diagnosis is challenging due to the nonspecific clinical presentation of this cancer, frequently defined just by a swelling of the neck.We present an 82-year-old woman with liposarcoma of the thyroid, complaining of a fast-growing neck mass. MRI and neck ultrasound showed a large lipomatous mass, which corresponded to anodule in the thyroid scan. After performing a total thyroidectomy, the diagnosis of a well-differentiated liposarcoma of the thyroid gland was made, showing an MDM2 amplification in fluorescence in situ hybridization. Since neither a metastasis nor a residual tumor was found, no further adjuvant therapy was needed.We searched the literature for previous case reports and identified only 12 cases worldwide to form our database. A demographic as well as clinical and histopathological analysis was made. In most cases, the liposarcoma occurred in patients >60 years of age. All histological subtypes, such as well-differentiated and myxoid liposarcomas, and pleomorphic and dedifferentiated liposarcomas, were found in the literature. In only 38.46% of the cases, an infiltration of the adjacent organs was observed. Surgery was the most common treatment chosen.Our review provides clinical and histopathological features of a primary liposarcoma of the thyroid to enable the identifi-cation of this rare tumor entity and assist in the decision-making process regarding therapeutic options and tumor follow-up
PD-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue - prognostic implications and rationale for immunotherapy.
No full textTherapies targeting programmed death 1-(PD-1) or its ligand (PD-L1), promoting antitumor T-cell activity have been successfully introduced into clinical practice. Clinical response correlates with PD-L1 expression by tumor cells or immune cells within the tumor microenvironment. The PD-L1/PD-1 axis and tumor microenvironment has been rarely studied in high-grade sarcomas of soft tissue (hSTS), a group of rare, genetically heterogenous and clinically aggressive tumors. We examined PD-L1 protein and CD274/PD-L1 gene copy number variations in 128 primary resected, therapy-naive hSTS using immunohistochemistry and fluorescence-in-situ hybridization. Frequency of tumoral PD-L1 expression varied widely in different disease subentities, with highest rates of positivity (40%) seen in undifferentiated pleomorphic sarcomas (UPS) and rare positivity detected in synovial sarcomas (6%). Amplification of the CD274/PD-L1 gene occurred in 14% of UPS and was rare in other subtypes. PD-L1 protein expression was significantly more frequent in CD274/PD-L1 amplified cases (p = 0.015). The subgroup of UPS was further characterized regarding the interaction between PD-L1 and the immunologic tumor microenvironment. High density of CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) was significantly correlated with the presence of PD-L1 expression and seen more frequently in tumors with lower TNM stage (p = 0.024). Both, PD-L1 expression and high density lymphocytic infiltration were independent prognostic factors for a favorable overall (p = 0.001, HR 6.105 (2.041-8.258)), disease-specific (p = 0.003, HR 10.536 (2.186-50.774)) and disease-free survival (p = 0.020, HR 3.317 (1.209-9.106); values for CD8) in this particular subgroup of hSTS, whereas PD-L1 expression in TILs or CD274/PD-L1 gene amplification were not associated with outcome. These findings represent novel insights into the immune landscape of soft tissue sarcomas, in particular UPS and strengthen the rationale for immunotherapy, including targeting the PD-1/PD-L1 axis in these tumors
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