HSA als Co-Autor
UKW UMM KIT 2024: Nutzen der partizipatorischen Mitwirkung von PatientInnen an der Entwicklung einer dermatologischen Therapie-App – ein Bericht aus der Praxis.
Abstract
Approximately 2% of the German population suffer from psoriasis. HybridVITA has developed a mobile application (app) that enables psoriasis patients to independently document the progression of the disease and the current psychological stress at home. The HybridVITA app was created in close collaboration with user groups to ensure optimal adaptation to their needs. Two interactive workshops were held with the user groups and the technical developers of the app as a core element of the developmental process. The workshops identified the needs and suggestions for improvement of the various user groups and formulated user stories for the further development of the app using the Scrum method. The participatory approach of the workshop enabled the project team to gather valuable practical knowledge at an early stage of development. The team’s awareness of potential obstacles during the early stages of the project enabled them to proactively identify and address these issues prior to implementing the app in dermatological care. We are confident that a patient-centered and participatory approach to health app development can provide valuable insights for developers.
https://link.springer.com/article/10.1007/s00105-024-05326-7
https://publikationen.bibliothek.kit.edu/1000170026
https://doi.org/10.1007/s00105-024-05326-7
Modules Used
Charité 2024: Using Deep Learning to Distinguish Highly Malignant Uveal Melanoma from Benign Choroidal Nevi.
Abstract
Background: This study aimed to evaluate the potential of human–machine interaction (HMI) in a deep learning software for discerning the malignancy of choroidal melanocytic lesions based on fundus photographs.
Methods: The study enrolled individuals diagnosed with a choroidal melanocytic lesion at a tertiary clinic between 2011 and 2023, resulting in a cohort of 762 eligible cases. A deep learning-based assistant integrated into the software underwent training using a dataset comprising 762 color fundus photographs (CFPs) of choroidal lesions captured by various fundus cameras. The dataset was categorized into benign nevi, untreated choroidal melanomas, and irradiated choroidal melanomas. The reference standard for evaluation was established by retinal specialists using multimodal imaging. Trinary and binary models were trained, and their classification performance was evaluated on a test set consisting of 100 independent images. The discriminative performance of deep learning models was evaluated based on accuracy, recall, and specificity.
Results: The final accuracy rates on the independent test set for multi-class and binary (benign vs. malignant) classification were 84.8% and 90.9%, respectively. Recall and specificity ranged from 0.85 to 0.90 and 0.91 to 0.92, respectively. The mean area under the curve (AUC) values were 0.96 and 0.99, respectively. Optimal discriminative performance was observed in binary classification with the incorporation of a single imaging modality, achieving an accuracy of 95.8%. Conclusions: The deep learning models demonstrated commendable performance in distinguishing the malignancy of choroidal lesions. The software exhibits promise for resource-efficient and cost-effective pre-stratification.
https://www.mdpi.com/2077-0383/13/14/4141
https://doi.org/10.3390/jcm13144141
Modules Used
Ophthalmic Tumor detection in HSA KIT
UKE 2023: The classical pathway triggers pathogenic complement activation in membranous nephropathy
Abstract
Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy.
https://www.nature.com/articles/s41467-023-36068-0
https://doi.org/10.1038/s41467-023-36068-0
Modules Used
PLA Analysis
UKE 2022: Artificial Intelligence Assisted Quantification of Complement Convertases in Glomerulonephritis
Abstract
Introduction
C3 glomerulopathy (C3GP) is caused by persisting activity of the complement system and characterized by glomerular deposition of C3, demonstrated by immunohistochemistry. Also in most of the other forms of glomerulonephritis (GN) deposition of complement factors occurs. However, here the significance and predominant activation pathways are less clear.
Methods
We used proximity ligation assays (PLA) to visualize C3/C5 complement convertases in renal biopsies. Close proximity of C3b and Bb or C2 and C4b was interpreted as assembled alternative or classical/lectin C3/C5 convertases, respectively. For quantitative analysis we established a two-stage, deep learning, explainable artificial intelligence (xAI) based workflow for a) the detection of glomeruli and b) detection and quantification of PLA signals. Signal densities were calculated as numbers of signals per glomerular area [signals/sqmm]. We analyzed ten cases per disease group of C3GP, immune complex membranoproliferative GN (IC-MPGN), IgA nephropathy (IgAN), infection-related GN (IRGN), and membranous nephropathy (MN) in comparison with 10 cases of thin basement membrane disease as control group, in which no local complement activity is expected.
Results
In C3GP and IRGN a clear predominance of the alternative convertase (mean 8410 and 14483 signals/sqmm) was detected as compared to the control group (mean 798 signals/sqmm) whereas IC-MPGN and MN cases showed higher densities of the classical/lectin convertase (3039 signals/sqmm and 5015 signals/sqmm) as compared to the control group (mean 176 signals/sqmm). Interestingly, cases with IgAN revealed increased densities for the alternative convertase (mean 2088 signals/sqmm) but only very slightly increased densities for the classical/lectin convertase (225 signals/sqmm). IgAN cases with mesangial and endocapillary hypercellularity had higher values for the alternative convertase than cases without hypercellularity.
Conclusions
Our work shows the applicability of a combined xAI based convertase detecting analysis to quantify and type local complement activity in renal biopsies. The results reveal insights into the pathogenesis of different forms of glomerulonephritis. The clear predominance of C3bBb signals in IgAN and IRGN suggests a direct activation of the alternative pathway rather than an immune complex mediated activation via the classical pathway in these two entities. Moreover, this approach opens up the possibility to assess the local complement activity in individual patients also with regard to novel anti-complement agents being under clinical investigation.
https://www.sciencedirect.com/science/article/pii/S2468024922013171
https://www.kireports.org/article/S2468-0249(22)01317-1/fulltext
https://doi.org/10.1016/j.ekir.2022.04.040
Modules Used
PLA Analysis
KIT IMT 2022: Resemblance-Ranking Peptide Library to Screen for Binders to Antibodies on a Peptidomic Scale
Abstract
A novel resemblance-ranking peptide library with 160,000 10-meric peptides was designed to search for selective binders to antibodies. The resemblance-ranking principle enabled the selection of sequences that are most similar to the human peptidome. The library was synthesized with ultra-high-density peptide arrays. As proof of principle, screens for selective binders were performed for the therapeutic anti-CD20 antibody rituximab. Several features in the amino acid composition of antibody-binding peptides were identified. The selective affinity of rituximab increased with an increase in the number of hydrophobic amino acids in a peptide, mainly tryptophan and phenylalanine, while a total charge of the peptide remained relatively small. Peptides with a higher affinity exhibited a lower sum helix propensity. For the 30 strongest peptide binders, a substitutional analysis was performed to determine dissociation constants and the invariant amino acids for binding to rituximab. The strongest selective peptides had a dissociation constant in the hundreds of the nano-molar range. The substitutional analysis revealed a specific hydrophobic epitope for rituximab. To show that conformational binders can, in principle, be detected in array format, cyclic peptide substitutions that are similar to the target of rituximab were investigated. Since the specific binders selected via the resemblance-ranking peptide library were based on the hydrophobic interactions that are widespread in the world of biomolecules, the library can be used to screen for potential linear epitopes that may provide information about the cross-reactivity of antibodies
https://www.mdpi.com/1422-0067/23/7/3515
https://doi.org/10.3390/ijms23073515
FZI 2021: Neuromorphic Vision mit Spiking Neural Networks zur Sturzerkennung im betreuten Wohnen
Abstract
Zur schnellen Erkennung von gefährlichen Stürzen in betreuten Wohnsituationen können klassische Kameras kombiniert mit künstlichen neuronalen Netzen (Artificial Neural Networks) verwendet werden. Solche Lösungen haben allerdings eine hohe elektrische Leistungsaufnahme und erfordern daher eine dauerhafte Stromversorgung. Dies macht die Integration in bestehende Räume aufwendig. Im Rahmen des Projekts EmbeddedNeuroVision wird daher eine extrem energieeffiziente Lösung basierend auf neuromorphen Kameras und Spiking Neural Networks erforscht, die die elektrische Leistungsaufnahme um mehrere Größenordnungen senken kann. Die energieeffiziente Verarbeitung schafft neue Möglichkeiten für batteriebetriebene Visionssysteme, die nicht nur im betreuten Wohnen, sondern auch in industriellen und Smart-City-Anwendungen flexibler eingesetzt werden können.
https://dl.gi.de/items/f27e40ad-d9d6-426f-b258-32e88f08b768
https://doi.org/10.18420/informatik2021-103
Modules Used
AI-Vision with HSA-TRAC
UKE 2020: In situ Visualization of C3/C5 Convertases to Differentiate Complement Activation
Abstract
Deregulated complement activation contributes to or drives the pathogenesis of various kidney diseases. Targeting complement is a therapeutic option.1,2 Inhibition on the level of C5 is an established therapy in atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria, and myasthenia gravis, and novel drugs targeting other components of the complement cascade are being developed.3,4 Currently, the diagnosis of complement activation in kidney diseases is based primarily on immunohistochemical detection of deposited complement activation products in tissue and the detection of consumption of complement components in plasma.5
To date, a method to directly identify, localize, quantify, and differentiate complement convertases in tissue has been lacking. We therefore established an in situ method to detect and localize assembled C3/C5 convertases of the classical/lectin and alternative pathways (Figure 1; Supplementary Methods; Supplementary Figures S1–S4). We utilized a bright field proximity ligation assay6,7 because (i) the microanatomic context is preserved, allowing, for example, selection of preserved glomeruli and the exact localization of the signals, and (ii) the signals are stable and easily quantifiable. Close proximity of C2 and C4b was used to identify assembled classical/lectin C3/C5 convertases, and of C3b and Bb, the fragment of factor B, to identify the alternative C3/C5 convertase.
https://pubmed.ncbi.nlm.nih.gov/32518877/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271008/
https://doi.org/10.1016/j.ekir.2020.03.009
HSA KIT Als Werkzeug
Bayer AG 2024: Preclinical Efficacy of a PSMA-Targeted Actinium-225 Conjugate (225Ac-Macropa-Pelgifatamab): A Targeted Alpha Therapy for Prostate Cancer
Abstract
Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs.
The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line– and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide.
Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi; all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line– (22Rv1) and patient-derived (ST1273) xenograft models.
These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase I study has been initiated (NCT06052306).
https://aacrjournals.org/clincancerres/article-abstract/30/11/2531/745373/Preclinical-Efficacy-of-a-PSMA-Targeted-Actinium?redirectedFrom=fulltext
https://doi.org/10.1158/1078-0432.CCR-23-3746
Modules Used
Membran-Detektion mit HSA KIT Software
Bayer AG 2023: Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model
Abstract
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15–30% of breast cancers but has low expression in normal tissue, making it attractive for targeted alpha therapy (TAT). HER2-positive breast cancer typically metastasizes to bone, resulting in incurable disease and significant morbidity and mortality. Therefore, new strategies for HER2-targeting therapy are needed. Here, we present the preclinical in vitro and in vivo characterization of the HER2-targeted thorium-227 conjugate (HER2-TTC) TAT in various HER2-positive cancer models. In vitro, HER2-TTC showed potent cytotoxicity in various HER2-expressing cancer cell lines and increased DNA double strand break formation and the induction of cell cycle arrest in BT-474 cells. In vivo, HER2-TTC demonstrated dose-dependent antitumor efficacy in subcutaneous xenograft models. Notably, HER2-TTC also inhibited intratibial tumor growth and tumor-induced abnormal bone formation in an intratibial BT-474 mouse model that mimics breast cancer metastasized to bone. Furthermore, a match in HER2 expression levels between primary breast tumor and matched bone metastases samples from breast cancer patients was observed. These results demonstrate proof-of-concept for TAT in the treatment of patients with HER2-positive breast cancer, including cases where the tumor has metastasized to bone.
https://www.mdpi.com/2072-6694/15/13/3419
https://doi.org/10.3390/cancers15133419
Modules Used
Membran-Detektion mit HSA KIT Software
Bayer AG 2023: A Targeted Thorium-227 Conjugate Demonstrates Efficacy in Preclinical Models of Acquired Drug Resistance and Combination Potential with Chemotherapeutics and Antiangiogenic Therapies
Abstract
Targeted alpha therapies (TAT) are an innovative class of therapies for cancer treatment. The unique mode-of-action of TATs is the induction of deleterious DNA double-strand breaks. Difficult-to-treat cancers, such as gynecologic cancers upregulating the chemoresistance P-glycoprotein (p-gp) and overexpressing the membrane protein mesothelin (MSLN), are promising targets for TATs. Here, based on the previous encouraging findings with monotherapy, we investigated the efficacy of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) both as monotherapy and in combination with chemotherapies and antiangiogenic compounds in ovarian and cervical cancer models expressing p-gp. MSLN-TTC monotherapy showed equal cytotoxicity in vitro in p-gp–positive and -negative cancer cells, while chemotherapeutics dramatically lost activity on p-gp–positive cancer cells. In vivo, MSLN-TTC exhibited dose-dependent tumor growth inhibition with treatment/control ratios of 0.03–0.44 in various xenograft models irrespective of p-gp expression status. Furthermore, MSLN-TTC was more efficacious in p-gp–expressing tumors than chemotherapeutics. In the MSLN-expressing ST206B ovarian cancer patient-derived xenograft model, MSLN-TTC accumulated specifically in the tumor, which combined with pegylated liposomal doxorubicin (Doxil), docetaxel, bevacizumab, or regorafenib treatment induced additive-to-synergistic antitumor efficacy and substantially increased response rates compared with respective monotherapies. The combination treatments were well tolerated and only transient decreases in white and red blood cells were observed. In summary, we demonstrate that MSLN-TTC treatment shows efficacy in p-gp–expressing models of chemoresistance and has combination potential with chemo- and antiangiogenic therapies.
https://aacrjournals.org/mct/article/22/9/1073/728677/A-Targeted-Thorium-227-Conjugate-Demonstrates
https://doi.org/10.1158/1535-7163.MCT-22-0808
Modules Used
gH2AX Analyzer for pharmaceutical research
Bayer AG 2023: Enhanced Antitumor Efficacy of Radium-223 and Enzalutamide in the Intratibial LNCaP Prostate Cancer Model
Abstract
Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. In vitro experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy. The combination of radium-223 and enzalutamide also demonstrated enhanced in vivo antitumor efficacy, as determined by measuring serum PSA levels in the intratibial LNCaP model. A decreasing trend in the total area of tumor-induced abnormal bone was associated with the combination treatment. The serum levels of the bone formation marker PINP and the bone resorption marker CTX-I were lowest in the combination treatment group and markedly decreased compared with vehicle group. Concurrent administration of enzalutamide did not impair radium-223 uptake in tumor-bearing bone or the ability of radium-223 to inhibit tumor-induced abnormal bone formation. In conclusion, combination treatment with radium-223 and enzalutamide demonstrated enhanced antitumor efficacy without compromising the integrity of healthy bone. The results support the ongoing phase 3 trial of this combination.
https://www.mdpi.com/1422-0067/24/3/2189
https://doi.org/10.3390/ijms24032189
Modules Used
Membran-Detektion mit HSA KIT Software
Bayer AG 2023: Targeted thorium-227 conjugates as treatment options in oncology
Abstract
Targeted alpha therapy (TAT) is a promising approach for addressing unmet needs in oncology. Inherent properties make α-emitting radionuclides well suited to cancer therapy, including high linear energy transfer (LET), penetration range of 2–10 cell layers, induction of complex double-stranded DNA breaks, and immune-stimulatory effects. Several alpha radionuclides, including radium-223 (223Ra), actinium-225 (225Ac), and thorium-227 (227Th), have been investigated. Conjugation of tumor targeting modalities, such as antibodies and small molecules, with a chelator moiety and subsequent radiolabeling with α-emitters enables specific delivery of cytotoxic payloads to different tumor types. 223Ra dichloride, approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-metastatic disease and no visceral metastasis, is the only approved and commercialized alpha therapy. However, 223Ra dichloride cannot currently be complexed to targeting moieties. In contrast to 223Ra, 227Th may be readily chelated, which allows radiolabeling of tumor targeting moieties to produce targeted thorium conjugates (TTCs), facilitating delivery to a broad range of tumors. TTCs have shown promise in pre-clinical studies across a range of tumor-cell expressing antigens. A clinical study in hematological malignancy targeting CD22 has demonstrated early signs of activity. Furthermore, pre-clinical studies show additive or synergistic effects when TTCs are combined with established anti-cancer therapies, for example androgen receptor inhibitors (ARI), DNA damage response inhibitors such as poly (ADP)-ribose polymerase inhibitors or ataxia telangiectasia and Rad3-related kinase inhibitors, as well as immune checkpoint inhibitors.
https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1071086/full
https://doi.org/10.3389/fmed.2022.1071086
Modules Used