From the development of self-aggregating, scaffold-free multicellular spheroids to the inclusion of scaffold systems, 3D models have progressively increased in complexity to better mimic native ...tissues. The inclusion of a third dimension in cancer models allows researchers to zoom out from a significant but limited cancer cell research approach to a wider investigation of the tumor microenvironment. This model can include multiple cell types and many elements from the extracellular matrix (ECM), which provides mechanical support for the tissue, mediates cell-microenvironment interactions, and plays a key role in cancer cell invasion. Both biochemical and biophysical signals from the extracellular space strongly influence cell fate, the epigenetic landscape, and gene expression. Specifically, a detailed mechanistic understanding of tumor cell-ECM interactions, especially during cancer invasion, is lacking. In this review, we focus on the latest achievements in the study of ECM biomechanics and mechanosensing in cancer on 3D scaffold-based and scaffold-free models, focusing on each platform’s level of complexity, up-to-date mechanical tests performed, limitations, and potential for further improvements.
FAM46C is a non-canonical poly(A) polymerase uniquely mutated in up to 20% of multiple myeloma (MM) patients, implying a tissue-specific tumor suppressor function. Here, we report that FAM46C ...selectively stabilizes mRNAs encoding endoplasmic reticulum (ER)-targeted proteins, thereby concertedly enhancing the expression of proteins that control ER protein import, folding, N-glycosylation, and trafficking and boosting protein secretion. This role requires the interaction with the ER membrane resident proteins FNDC3A and FNDC3B. In MM cells, FAM46C expression raises secretory capacity beyond sustainability, inducing ROS accumulation, ATP shortage, and cell death. FAM46C activity is regulated through rapid proteasomal degradation or the inhibitory interaction with the ZZ domain of the autophagic receptor p62 that hinders its association with FNDC3 proteins via sequestration in p62+ aggregates. Altogether, our data disclose a p62/FAM46C/FNDC3 circuit coordinating sustainable secretory activity and survival, providing an explanation for the MM-specific oncosuppressive role of FAM46C and uncovering potential therapeutic opportunities against cancer.
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•In myeloma cells, FAM46C boosts ER growth and Ig secretion beyond sustainability•The ER-expanding activity of FAM46C requires its interaction with FNDC3 proteins•FAM46C abundance is tightly regulated by UPS-operated proteolysis•p62 compensates for UPS insufficiency by sequestering FAM46C away from the ER
Fucci et al. show that the poly(A) polymerase FAM46C acts as a multiple myeloma-specific tumor suppressor, increasing secretory capacity and antibody production beyond sustainability via its interaction with endoplasmic reticulum transmembrane FNDC3 proteins. Moreover, its activity is restricted through proteasomal degradation or p62-dependent aggregation and sequestration from FNDC3 proteins.
To cope with intrinsic and environmental stress, cancer cells rely on adaptive pathways more than non-transformed counterparts. Such non-oncogene addiction offers new therapeutic targets and ...strategies to overcome chemoresistance. In an attempt to study the role of adaptive pathways in acquired drug resistance in carcinoma cells, we devised a model of in vitro conditioning to three standard chemotherapeutic agents, cisplatin, 5-fluorouracil, and docetaxel, from the epithelial cancer cell line, HEp-2, and investigated the mechanisms underlying reduced drug sensitivity. We found that triple-resistant cells suffered from higher levels of oxidative stress, and showed heightened anti-stress responses, including the antioxidant Nrf2 pathway and autophagy, a conserved pleiotropic homeostatic strategy, mediating the clearance of aggregates marked by the adapter p62/SQSTM1. As a result, re-administration of chemotherapeutic agents failed to induce further accumulation of reactive oxygen species and p62. Moreover, autophagy proved responsible for chemoresistance through the avoidance of p62 accumulation into toxic protein aggregates. Indeed, p62 ablation was sufficient to confer resistance in parental cells, and genetic and pharmacological autophagic inhibition restored drug sensitivity in resistant cells in a p62-dependent manner. Finally, exogenous expression of mutant p62 lacking the ubiquitin- and LC3-binding domains, required for autophagic engulfment, increased chemosensitivity in TDR HEp-2 cells. Altogether, these findings offer a cellular system to investigate the bases of acquired chemoresistance of epithelial cancers and encourage challenging the prognostic and antineoplastic therapeutic potential of p62 toxicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper, we address the problem of energy conservation and optimization in residential environments by providing users with useful information to solicit a change in consumption behavior. ...Taking care to highly limit the costs of installation and management, our work proposes a Non-Intrusive Load Monitoring (NILM) approach, which consists of disaggregating the whole-house power consumption into the individual portions associated to each device. State of the art NILM algorithms need monitoring data sampled at high frequency, thus requiring high costs for data collection and management. In this paper, we propose an NILM approach that relaxes the requirements on monitoring data since it uses total active power measurements gathered at low frequency (about 1 Hz). The proposed approach is based on the use of Factorial Hidden Markov Models (FHMM) in conjunction with context information related to the user presence in the house and the hourly utilization of appliances. Through a set of tests, we investigated how the use of these additional context-awareness features could improve disaggregation results with respect to the basic FHMM algorithm. The tests have been performed by using Tracebase, an open dataset made of data gathered from real home environments.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A fundamental structural component of extracellular matrix in all connective and interstitial tissue, collagen is the most abundant protein in the human body. To date, mammalian collagens sources ...represent the golden standard for multiple biomedical applications, while marine-derived collagens have largely been used in industry (food, pharmaceutical, and cosmetic), with little use in research and clinical applications. Herein we demonstrate the effective use
jellyfish collagen, a source of biocompatible, sustainable collagen for 2D and 3D cell culture, addressing the global drive for technological developments that result in the replacement of animals and their derived products in research. Jellyfish collagen harbors similar structural features mammalian collagen type I, despite differing slightly in amino acid content. Jellyfish collagen supports ovarian cancer (OvCa) cell line proliferation, cellular morphology and expression of epithelial to mesenchymal transition markers, supporting the use of
as a non-mammalian collagen cell culture substrate. Furthermore,
collagen is effective in 3D device fabrication such as sponges where it mimics tissue architecture complexity. OvCa cells migrated and differentiated within the
collagen 3D scaffolds confirming its suitability for advanced cell culturing applications, providing an excellent alternative to mammalian collagen sources for the culture of human cells.
Osteosarcoma (OS) is the most common bone tumor in pediatrics. After resection, allografts or metal endoprostheses reconstruct bone voids, and systemic chemotherapy is used to prevent recurrence. ...This urges the development of novel treatment options for the regeneration of bone after excision. We utilized a previously developed biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of chemotherapy. We also performed experiments to determine if human mesenchymal stem cells (hMSCs) seeded on MHA/Coll scaffold migrate less toward OS cells, suggesting that hMSCs will not contribute to tumor growth and therefore the potential of oncologic safety in vitro. Also, hMSCs seeded on MHA/Coll had increased expression of osteogenic genes (BGLAP, SPP1, ALP) compared to hMSCs in the 2D condition, even when exposed to chemotherapeutics. This is the first study to demonstrate that a highly osteogenic scaffold can potentially be oncologically safe because hMSCs on MHA/Coll tend to differentiate and lose the ability to migrate toward tumor cells. Therefore, hMSCs on MHA/Coll could potentially be utilized for bone regeneration after OS excision.
The mechanical homeostasis of tissues can be altered in response to trauma or disease, such as cancer, resulting in altered mechanotransduction pathways that have been shown to impact tumor ...development, progression, and the efficacy of therapeutic approaches. Specifically, ovarian cancer progression is parallel to an increase in tissue stiffness and fibrosis. With in vivo models proving difficult to study, tying tissue mechanics to altered cellular and molecular properties necessitate advanced, tunable, in vitro 3D models able to mimic normal and tumor mechanic features. First, we characterized normal human ovary and high-grade serous (HGSC) ovarian cancer tissue stiffness to precisely mimic their mechanical features on collagen I-based sponge scaffolds, soft (NS) and stiff (MS), respectively. We utilized three ovarian cancer cell lines (OVCAR-3, Caov-3, and SKOV3) to evaluate changes in viability, morphology, proliferation, and sensitivity to doxorubicin and liposomal doxorubicin treatment in response to a mechanically different microenvironment. High substrate stiffness promoted the proliferation of Caov-3 and SKOV3 cells without changing their morphology, and upregulated mechanosensors YAP/TAZ only in SKOV3 cells. After 7 days in culture, both OVCAR3 and SKOV3 decreased the MS scaffold storage modulus (stiffness), suggesting a link between cell proliferation and the softening of the matrix. Finally, high matrix stiffness resulted in higher OVCAR-3 and SKOV3 cell cytotoxicity in response to doxorubicin. This study demonstrates the promise of biomimetic porous scaffolds for effective inclusion of mechanical parameters in 3D cancer modeling. Furthermore, this work establishes the use of porous scaffolds for studying ovarian cancer cells response to mechanical changes in the microenvironment and as a meaningful platform from which to investigate chemoresistance and drug response.
Remodeling of the human bony skeleton is constantly occurring with up to 10% annual bone volume turnover from osteoclastic and osteoblastic activity. A shift toward resorption can result in ...osteoporosis and pathologic fractures, while a shift toward deposition is required after traumatic, or surgical injury. Spinal fusion represents one such state, requiring a substantial regenerative response to immobilize adjacent vertebrae through bony union. Autologous bone grafts were used extensively prior to the advent of advanced therapeutics incorporating exogenous growth factors and biomaterials. Besides cost constraints, these applications have demonstrated patient safety concerns. This study evaluated the regenerative ability of a nanostructured, magnesium-doped, hydroxyapatite/type I collagen scaffold (MHA/Coll) augmented by autologous platelet-rich plasma (PRP) in an orthotopic model of posterolateral lumbar spinal fusion. After bilateral decortication, rabbits received either the scaffold alone (Group 1) or scaffold with PRP (Group 2) to the anatomic right side. Bone regeneration and fusion success compared to internal control were assessed by DynaCT with 3-D reconstruction at 2, 4, and 6 weeks postoperatively followed by comparative osteogenic gene expression and representative histopathology. Both groups formed significantly more new bone volume than control, and Group 2 subjects produced significantly more trabecular and cortical bone than Group 1 subjects. Successful fusion was seen in one Group 1 animal (12.5%) and 6/8 Group 2 animals (75%). This enhanced effect by autologous PRP treatment appears to occur
via
astounding upregulation of key osteogenic genes. Both groups demonstrated significant gene upregulation compared to vertebral bone controls for all genes. Group 1 averaged 2.21-fold upregulation of RUNX2 gene, 3.20-fold upregulation of SPARC gene, and 3.67-fold upregulation of SPP1 gene. Depending on anatomical subgroup (cranial, mid, caudal scaffold portions), Group 2 had significantly higher average expression of all genes than both control and Group 1–RUNX2 (8.23–19.74 fold), SPARC (18.67–55.44 fold), and SPP1 (46.09–90.65 fold). Our data collectively demonstrate the osteoinductive nature of a nanostructured MHA/Coll scaffold, a beneficial effect of augmentation with autologous PRP, and an ability to achieve clinical fusion when applied together in an orthotopic model. This has implications both for future study and biomedical innovation of bone-forming therapeutics.
The adoption of virtualization technologies in networking is promoting a radical innovation in the way network services are managed and delivered. Indeed, some network services may be provisioned to ...cope with complex and unpredictable traffic demands by dynamically creating a sequence of Virtual Network Functions (VNFs) and steering traffic flows through them. In this context, the optimized deployment of network services, composed of VNFs that may be instantiated in multiple Data Centers (DCs), is one of the most challenging orchestration target. VNF placement is the problem of choosing the set of optimal locations for a chain of VNFs according to the service request and the current characteristics of available computing resources and network links. With respect to the state of the art, our original contribution reflects a multi-stakeholder perspective (subscriber, service providers, infrastructure providers) in a multi-DC environment. We thus consider the problem of placing VNFs to maximize primarily the number of accepted requests from a set of incoming requests and secondarily the satisfaction of subscribers’ preferences. Our model also allows to differentiate service requests in priority levels and guarantees that Quality of Service objectives for accepted service requests are fulfilled, including also a requirement on network service instantiation time. We provide an integer linear programming formulation of this problem that leverages a layered auxiliary graph built for each request in a set. Experimental evaluation is described in detail and an assessment of the proposed placement approach is performed along three main directions: (i) service acceptance ratio in online and offline placement, (ii) preferences’ satisfaction, and (iii) scalability expressed in terms of computational time. The performance of the approach is also compared to a greedy heuristic.
The rational use and management of energy is considered a key societal and technological challenge. Home energy management systems (HEMS) have been introduced especially in private home domains to ...support users in managing and controlling energy consuming devices. Recent studies have shown that informing users about their habits with appliances as well as their usage pattern can help to achieve energy reduction in private households. This requires instruments able to monitor energy consumption at fine grain level and provide this information to consumers. While the most existing approaches for load disaggregation and classification require high-frequency monitoring data, in this paper we propose an approach that exploits low-frequency monitoring data gathered by meters (i.e., Smart Plugs) displaced in the home. Moreover, while the most existing works dealing with appliance classification delegate the classification task to a remote central server, we propose a distributed approach where data processing and appliance recognition are performed locally in the Home Gateway. Our approach is based on a distributed load monitoring system made of Smart Plugs attached to devices and connected to a Home Gateway via the ZigBee protocol. The Home Gateway is based on the OSGi platform, collects data from home devices, and hosts both data processing and user interaction logic.
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