55 research outputs found
An evaluation of contralateral hand involvement in the operation of the Delft Self-Grasping Hand, an adjustable passive prosthesis.
No full textThe Delft Self-Grasping Hand is an adjustable passive prosthesis operated using the concept of tenodesis (where opening and closing of the hand is mechanically linked to the flexion and extension of the wrist). As a purely mechanical device that does not require harnessing, the Self-Grasping Hand offers a promising alternative to current prostheses. However, the contralateral hand is almost always required to operate the mechanism to release a grasp and is sometimes also used to help form the grasp; hence limiting the time it is available for other purposes. In this study we quantified the amount of time the contralateral hand was occupied with operating the Self-Grasping Hand, classified as either direct or indirect interaction, and investigated how these periods changed with practice. We studied 10 anatomically intact participants learning to use the Self-Grasping Hand fitted to a prosthesis simulator. The learning process involved 10 repeats of a feasible subset of the tasks in the Southampton Hand Assessment Procedure (SHAP). Video footage was analysed, and the time that the contralateral hand was engaged in grasping or releasing was calculated. Functionality scores increased for all participants, plateauing at an Index of Functionality of 33.5 after 5 SHAP attempts. Contralateral hand involvement reduced significantly from 6.47 (first 3 attempts) to 4.68 seconds (last three attempts), but as a proportion of total task time remained relatively steady (increasing from 29% to 32%). For 9/10 participants most of this time was supporting the initiation of grasps rather than releases. The reliance on direct or indirect interactions between the contralateral hand and the prosthesis varied between participants but appeared to remain relatively unchanged with practice. Future studies should consider evaluating the impact of reliance on the contralateral limb in day-to-day life and development of suitable training methods
Abstract B076: TRIM24 degradation counteracts adaptation to androgen receptor inhibition in prostate cancer
No full textThe androgen receptor (AR) is the primary therapeutic target in prostate cancer. While androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSi) are effective, the disease eventually progresses to fatal castration-resistant prostate cancer (CRPC). That said, little is known about the mechanisms in residual disease that initiates tumor relapse upon ADT/ARSi. Here, we discover a crucial role for TRIM24 in supporting the survival of residual cell clusters primed for tumor relapse in vivo. Consequently, reducing TRIM24 with bifunctional degraders (dTRIM24) significantly delays or even prevents the emergence of CRPC in the context of AR reactivation and lineage plasticity in vivo. dTRIM24 not only inhibits further AR signaling under ADT/ARSi but also counteracts adaptive pathways engaged by AR inhibition itself, such as STAT3 activation and EMT. Our findings underscore the potential of TRIM24 as an effective and druggable target for preventing prostate cancer progression under AR inhibition. Citation Format: Daniela Bossi, Arianna Vallerga, Giuseppe Salfi, Nicolo Formaggio, Zhang Jichang, Tiziano Bernasocchi, Andrea Rinaldi, Lukas Bubendorf, Simone Mosole, Eva Corey, Marco Bolis, Matteo Pecoraro, Roger Geiger, Wouter Karthaus, Ricardo Pereira Mestre, Jinhua Wang, Jean-Philippe Paul. Theurillat. TRIM24 degradation counteracts adaptation to androgen receptor inhibition in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B076.UPKARTHAU
Abstract 4165: <i>SOX2</i> promotes lineage plasticity and antiandrogen resistance in <i>TP53</i> and <i>RB1</i> deficient prostate cancer
No full textAbstract
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. Here we show, using in vitro and in vivo prostate cancer models, that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR) dependent luminal epithelial cells to AR independent basal-like cells. This lineage plasticity is enabled by loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2 and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.
Citation Format: Ping Mu, Zeda Zhang, Matteo Benelli, Wouter Karthaus, Elizebeth Hoover, Chi-Chao Chen, John Wongvipat, Sheng-Yu Ku, Dong Gao, Zhen Cao, Neel Shah, Elizabeth Adams, Wassim Abida, Philip Watson, Davide Prandi, Chun-Hao Huang, Elisa de Stanchina, Scott Lowe, Leigh Ellis, Himisha Beltran, Mark Rubin, David Goodrich, Francesca Demichelis, Charles L. Sawyers. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53 and RB1 deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4165. doi:10.1158/1538-7445.AM2017-4165</jats:p
Design of a 2-DOF wrist prosthesis
No full textAlthough a wide variety of upper limb prostheses is available, a large number of prostheses include wrist joints providing an insufficient amount of functionality. Compensatory movements have to be made in order to execute activities of daily living, causing fatigue and discomfort. This dissatisfaction amongst prosthetic users, which can result in rejection of the prosthesis. A 2-DOF prosthetic wrist is designed in which two curved hydraulic cylinders apply for flexion-extension and pronation-supination. The device is passively adjustable in a certain position by the sound hand and can be locked in any desired position. After a prototype is 3D printed, the wrist prosthesis is evaluated to validate if the wrist prosthesis has met the design requirements. With ROMs of 132 degrees for flexion-extension and 154 degrees for pronation-supination, the wrist prosthesis approached the functional mobility of a biological wrist. Requirements for the dimensions and mass have been met, with a diameter of 43 mm, length of 36 mm and mass of 43 g. Adjusting the wrist prosthesis can be executed with a maximal torque of 0.078 Nm. A static torque higher than 1.9 Nm causes leakage of the curved hydraulic cylinder. Although this does not meet the requirement, it enables lifting of an object up to 2.6 kg.Biomedical Engineerin
Abstract 992: Patient-derived tumor organoids of neuroendocrine prostate cancer
No full textAbstract
Background: The development of neuroendocrine prostate cancer (NEPC) is one mechanism of treatment resistance to androgen receptor (AR)-targeted therapies for a subset of patients with advanced prostate cancer. This is associated with transition from a prostate adenocarcinoma to small cell/NEPC histology, low AR signaling signaling, and expression of neuroendocrine markers as Chromogranin A (CGHA), Synaphophysin (SYP) and CD56). Patient derived preclinical models recapitulating the NEPC phenotype may be used to address NEPC pathogenesis and test emerging therapeutic targets.
Methods: Tumor organoids were developed according to protocols previously described (Gao et al, Cell 2015). Briefly the tissue biopsies (liver and bone biopsy) were washed, enzymatically digested and then seeded in Matrigel (BD) droplets. Organoids were characterized at genomic (WES), RNA and protein level (IHC) to confirm the expression of specific markers. Lentiviral infections were performed using shRNAs against EZH2 to knock down EZH2 in organoids. Organoids were also subcutaneously injected in NSG mice to generate patient derived xenografts (PDXs) for drug treatment in vivo.
Results: We developed and characterized two NEPC tumor organoids from tumor biopsies (liver and bone) of two patients both in vitro and in vivo (as PDXs). NEPC tumor organoid models retained the molecular and histological characteristic of their matched patient samples. We successfully manipulated the activity of the histone methyltransferase EZH2 by using a catalytic inhibitor and its expression by infecting organoids with shEZH2. We showed that the absence of EZH2 affects the expression of neuroendocrine-associated programs as stem cell and neuronal pathway. Moreover treatment with EZH2 inhibitor decreased tumor organoids viability and PDXs tumor volume. Drug screening approaches on NEPC organoids were used to discovery novel drug targets and combinations that could potentially benefit NEPC patients. Top single agent hits included previously identified targets such as EZH2, AURKA, as well as novel synergies.
Conclusions NEPC patient tumor organoids are clinically relevant tumor models to study the NEPC phenotype in advanced prostate cancer and may be used to elucidate novel drug targets.
Citation Format: Loredana Puca, Rohan Bareja, Reid Shaw, Wouter Karthaus, Dong Gao, Chantal Pauli, Juan Miguel Mosquera, Joanna Cyrta, Rachele Rosati, Rema Rao, Andrea Sboner, Carla Grandori, Giorgio Inghirami, Yu Chen, Mark A. Rubin, Himisha Beltran. Patient-derived tumor organoids of neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 992. doi:10.1158/1538-7445.AM2017-992</jats:p
Design and evaluation of carbon fibre-reinforced launch packages with segmented, copper and molybdenum fibre armatures
No full textFibre armatures have been studied both dynamically and statically to gain insight in their electrothermal and mechanical behaviour. In the first part of this paper, the results of launch experiments with single and multi-segment copper and molybdenum fibre armatures integrated in carbon-fibre reinforced launch packages are discussed. The launch experiments with Cu fibre armatures showed an improved reproducibility and a higher transition velocity. The poor results of the launch experiments with the Mo fibre armatures thus far, are explained with results of armature compliance and resistance measurements. In the second part, results are presented which are obtained from static experiments in an armature test bed. Using miniature B-dot probes and Rogowski coils, the magnetic field diffusion into monobloc and fibre armatures with identical geometry has been studied. The results show a significant difference in diffusion behaviour between the two types of armatures. It appears that the magnetic field diffuses faster into the fibre armature. The experimental data are compared with the results of calculations of the magnetic field distribution in both armatures based on 2D- and 3Dfinite element computer simulations. The results of the ID-simulations appear to confirm the measured results for monobloc and fibre armatures only qualitatively. The experimental results obtained with monobloc armatures agree with the results of the 3D-simulations in a quantitative sense. © 1997 IEEE
Next-Generation Modeling of Cancer Using Organoids
No full textIn the last decade, organoid technology has become a cornerstone in cancer research. Organoids are long-term primary cell cultures, usually of epithelial origin, grown in a three-dimensional (3D) protein matrix and a fully defined medium. Organoids can be derived from many organs and cancer types and sites, encompassing both murine and human tissues. Importantly, they can be established from various stages during tumor evolution and recapitulate with high accuracy patient genomics and phenotypes in vitro, offering a platform for personalized medicine. Additionally, organoids are remarkably amendable for experimental manipulation. Taken together, these features make organoids a powerful tool with applications in basic cancer research and personalized medicine. Here, we will discuss the origins of organoid culture, applications in cancer research, and how cancer organoids can synergize with other models of cancer to drive basic discoveries as well as to translate these toward clinical solutions.MACEUPKARTHAU
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Abstract 1245: The histone methyltransferase KMT2D mediates subtype-specific transcriptional regulation and therapeutic response in prostate cancer
No full textAbstract Primary prostate cancer is characterized by its dependence on androgen receptor (AR) and often has hyperactive PI3K signaling, most frequently through loss of PTEN. PI3K/AKT pathway inhibitors are in late-stage clinical development in combination with anti-AR therapy. Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, but the development of castration-resistant prostate cancer (CRPC) eventually occurs. CRPC remains largely dependent on AR for growth with a subset of CRPC that lose AR dependence. There is an urgent need to study the molecular pathways leading to AR activation and the loss of AR reliance in order to identify therapeutic targets. KMT2D is a histone methyltransferase and an important regulator of gene expression. Here we found that KMT2D establishes the chromatin competence necessary for the recruitment of AR and FOXA1 transcription factors (TFs) to activate AR-dependent transcription in AR-high prostate models. In AR-low models such as the stem cell-like (SCL) subtype, KMT2D controls residual AR-FOXA1 gene expression programs and AP-1 TFs such as FOSL1, a driver of the SCL subtype. In SCL, single cell RNA-seq and single cell chromatin assays confirm a key role for KMT2D in the maintenance of a mixed lineage cell state through the regulation of AP-1 and FOXA1 TFs. Combined suppression of PI3K/AKT and KMT2D reduces cell proliferation in prostate cancer cells and patient derived organoids, providing a rationale for epigenetically informed combination therapies with PI3K/AKT inhibitors in PTEN-deficient prostate cancer. Together, these data establish KMT2D as a major mediator of subtype-specific chromatin accessibility and transcriptomic landscape in CRPC, required for prostate cancer growth and therapeutic response. Citation Format: Srushti Kittane, Erik Ladewig, Taibo Li, Jillian Love, Amaia Arruabarrena-Aristorena, Xinyu Guo, Mirna Sallaku, Liliana Garcia-Martinez, Ryan Blawski, Javier Carmona Sanz, Christopher Simpkins, Wanlu Chen, Bujamin Vokshi, Peihua Zhao, Nachiket Kelkar, Laura Baldino, Ingrid Kalemi, Pau Castel, Emiliano Cocco, Lluis Morey, Charles Sawyers, Hongkai Ji, Maurizio Scaltriti, Alexis Battle, Christina Leslie, Wouter Karthaus, Eneda Toska. The histone methyltransferase KMT2D mediates subtype-specific transcriptional regulation and therapeutic response in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1245
SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.
No full textSome cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching
Organoid culture systems for prostate epithelial and cancer tissue
No full textThis protocol describes a strategy for the generation of 3D prostate organoid cultures from healthy mouse and human prostate cells (either bulk or FACS-sorted single luminal and basal cells), metastatic prostate cancer lesions and circulating tumor cells. Organoids derived from healthy material contain the differentiated luminal and basal cell types, whereas organoids derived from prostate cancer tissue mimic the histology of the tumor. We explain how to establish these cultures in the fully defined serum-free conditioned medium that is required to sustain organoid growth. Starting with the plating of digested tissue material, full-grown organoids can usually be obtained in ∼2 weeks. The culture protocol we describe here is currently the only one that allows the growth of both the luminal and basal prostatic epithelial lineages, as well as the growth of advanced prostate cancers. Organoids established using this protocol can be used to study many different aspects of prostate biology, including homeostasis, tumorigenesis and drug discovery
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