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Advanced Technology Composite Fuselage - Materials and Processes

The goal of Boeing's Advanced Technology Composite Aircraft Structures (ATCAS) program was to develop the technology required for cost and weight efficient use of composite materials in transport fuselage structure. This contractor report describes results of material and process selection, development, and characterization activities. Carbon fiber reinforced epoxy was chosen for fuselage skins and stiffening elements and for passenger and cargo floor structures. The automated fiber placement (AFP) process was selected for fabrication of monolithic and sandwich skin panels. Circumferential frames and window frames were braided and resin transfer molded (RTM'd). Pultrusion was selected for fabrication of floor beams and constant section stiffening elements. Drape forming was chosen for stringers and other stiffening elements. Significant development efforts were expended on the AFP, braiding, and RTM processes. Sandwich core materials and core edge close-out design concepts were evaluated. Autoclave cure processes were developed for stiffened skin and sandwich structures. The stiffness, strength, notch sensitivity, and bearing/bypass properties of fiber-placed skin materials and braided/RTM'd circumferential frame materials were characterized. The strength and durability of cocured and cobonded joints were evaluated. Impact damage resistance of stiffened skin and sandwich structures typical of fuselage panels was investigated. Fluid penetration and migration mechanisms for sandwich panels were studied.

Scholz, D. B.↗

Advanced in In Situ Inspection of Automated Fiber Placement Systems

Automated Fiber Placement (AFP) systems have been developed to help take advantage of the tailorability of composite structures in aerospace applications. AFP systems allow the repeatable placement of uncured, spool fed, preimpregnated carbon fiber tape (tows) onto substrates in desired thicknesses and orientations. This automated process can incur defects, such as overlapping tow lines, which can severely undermine the structural integrity of the part. Current defect detection and abatement methods are very labor intensive, and still mostly rely on human manual inspection. Proposed is a thermographic in situ inspection technique which monitors tow placement with an on board thermal camera using the preheated substrate as a through transmission heat source. An investigation of the concept is conducted, and preliminary laboratory results are presented. Also included will be a brief overview of other emerging technologies that tackle the same issue. Keywords: Automated Fiber Placement, Manufacturing defects, Thermography

Juarez, Peter D.↗

Automated Fiber Placement of Composite Wind Tunnel Blades: Process Planning and Manufacturing

The ability to accurately manufacture large complex shapes in a consistent and repeatable manner has led to Automated Fiber Placement (AFP) being the predominant mode of manufacturing for large composite aerospace structures today. Currently, AFP is being considered for medium- and small-scale parts. Composite wind tunnel blades have traditionally been fabricated by hand layup for pre-impregnated or dry fabrics with resin infusion. Though well proven, the traditional fabrication method is laborious and tedious, and hence expensive. The project described in this paper used the Integral Structural Assembly of Advanced Composites (ISAAC) facility at the NASA Langley Research Center to build a manufacturing demonstration unit (MDU) with a shape representative of a wind tunnel blade. This MDU is used to discuss tooling, process planning, and fabrication. Additionally, details of the generic manufacturing workflow are presented.

Harik, Ramy↗

TPSAS-NF1676L-18913-DND

Composite materials and structures are enabling technology for modern aerospace vehicles. Numerical-control manufacturing, including automated fiber placement (AFP), is widely used to fabricate these components. However, weight and performance requirements for the next generation of aerospace vehicles will push the state-of-art even further, and require development of more advanced materials, manufacturing, and structures technologies that are both affordable and efficient. The Integrated Structural Assembly of Advanced Composites (ISAAC) system is intended to address much of NASA?s critical research needs in advanced composites. The baseline ISAAC system, combining a commercial robot with multiple redundant degrees of freedom, a tool changer interface, and a special-purpose AFP end effector, enables precise and accurate additive manufacturing of composite structures, as well as development of advanced tow-steered structures with tailored load paths. The highly capable baseline system can quickly change end effectors, thus enabling further research for composites manufacturing. This extended system is similar to a high-speed machining center, where interchangeable cutters are used for different operations during metal structures fabrication. This capability enables future development, integration and assessment of new advanced manufacturing technologies, such as in-situ curing and NDE, and through-thickness reinforcements to reduce delaminations. End effectors with these advanced capabilities may be purchased, developed internally or with industry or academia, and then integrated onto the existing robotic platform to perform advanced manufacturing operations and develop new techniques and processes. Technologies, techniques and processes developed using this research-oriented system could then be transitioned to the broader composites industry.

Rob Martin↗

TPSAS-NF1676L-19134-DND

Composite materials and structures are state-of-art enabling technology for modern aerospace vehicles, reducing weight and maintenance requirements, and increasing performance and reliability. Numerical-control manufacturing systems, including automated fiber placement (AFP), are widely used to fabricate these components. However, the challenging weight and performance requirements necessary for the next generation of aerospace vehicles will push the composites state-of-art even further, and require development of even more advanced materials, manufacturing, and structures technologies that are more affordable and more efficient. The Integrated Structural Assembly of Advanced Composites (ISAAC) system is intended to address many of NASA's critical research needs in the field of advanced composites. The baseline ISAAC system, combining a commercial robot with multiple degrees of freedom, a tool changer interface, and a special-purpose AFP end effector, will enable very precise and accurate additive manufacturing of composite structures. One promising area of research enabled by the ISAAC system is advanced composite tow-steered structures that have tailored structural load paths. Several examples are presented that describe these tow-steered composite structures in more detail.

Brian K Stewart↗

Thermoplastic Aircraft Manufacturing Model

A manufacturing process to produce 80 single aisle sized thermoplastic composite aircraft a month is presented. Within the Hi-Rate Composite Aircraft Manufacturing (HiCAM) program a baseline aircraft fuselage was designed and modeled based on the Boeing 787 one-piece barrel build, but scaled down to a single aisle aircraft. Key Performance Parameters (KPPs) of recurring cost, non-recurring cost, and weight are calculated from the model. The outcome of this simulation indicated a prohibitively high non-recurring cost, so the thermoplastic team modeled the manufacturing flow for a panelized fuselage concept. The minimum success criteria is a 30% cost reduction and less than two percent increase in weight compared to the baseline aircraft. Automated Fiber Placement (AFP) is used to layup skins, stamp forming is used to make body frames, stringers, and passenger door surround parts. In the model, Co-Fusion was used to consolidate the skin while simultaneously welding on stringers to make stiffened panels. Additional welding technologies were considered to minimize fastener use and a vertical build concept was used for final assembly to reduce factory size. This manufacturing concept for a thermoplastic aircraft indicated a 39% cost and 12% weight savings compared to the baseline. Additional trade studies were conducted using Northrop Grumman’s Automated Stiffener Forming technology to make stringers and stamp forming instead of AFP to make skins.

thermoplastic composites↗

Thermoplastic Composite Aircraft Manufacturing Model

A manufacturing process to produce 80 single aisle sized thermoplastic composite aircraft a month is presented. Within the Hi-Rate Composite Aircraft Manufacturing (HiCAM) program a baseline aircraft fuselage was designed and modeled based on the Boeing 787 one-piece barrel build, but scaled down to a single aisle aircraft. Key Performance Parameters (KPPs) of recurring cost, non-recurring cost, and weight are calculated from the model. The outcome of this simulation indicated a prohibitively high non-recurring cost, so the thermoplastic team modeled the manufacturing flow for a panelized fuselage concept. The minimum success criteria is a 30% cost reduction and less than two percent increase in weight compared to the baseline aircraft. Automated Fiber Placement (AFP) is used to layup skins, stamp forming is used to make body frames, stringers, and passenger door surround parts. In the model, Co-Fusion was used to consolidate the skin while simultaneously welding on stringers to make stiffened panels. Additional welding technologies were considered to minimize fastener use and a vertical build concept was used for final assembly to reduce factory size. This manufacturing concept for a thermoplastic aircraft indicated a 39% cost and 12% weight savings compared to the baseline. Additional trade studies were conducted using Northrop Grumman’s Automated Stiffener Forming technology to make stringers and stamp forming instead of AFP to make skins.

thermoplastic composites↗

A Machine Learning Approach to Improve Air Traffic Management Initiatives

Collaborating closely with commercial air carriers and related organizations, the Federal Aviation Administration(FAA) regulates air traffic and ensures the safety and efficiency of air operations. Air traffic controllers make strategic decisions, such as delaying, rerouting, or canceling flights, partly based on guidance provided by the FAA’s Air TrafficControl System Command Center (ATCSCC). The guidance includes, among other things, control measures known asTraffic Management Initiatives (TMIs) designed to enhance safety and improve operational efficiency. TMIs play a crucial role in managing the demand and capacity within the U.S. National Airspace System (NAS). Two major TMIs that are routinely used (primarily to mitigate the adverse effects of bad weather) are Ground Delay Programs (GDPs) andGround Stops (GSs). In a GDP, flights destined for airports facing thunderstorm activity experience delays at their origin airports. This proactive approach minimizes the risk of routing aircraft through hazardous weather conditions and also replaces (fuel burning) airborne delays with ground delays. In a GS, a temporary restriction is imposed on the departure or arrival of aircraft at a specific airport or within a designated airspace. Although other TMIs (e.g., miles-in-trail) are also implemented as part of (air) traffic flow management in the NAS, the focus of this work is on GDPs and GSs. Since TMIs, by design, lead to flight delays or cancellations, it is crucial to put in place the right set of parameters(e.g., scope and duration of the GDP). For example, when the end time of a GDP extends beyond what is necessary, it imposes unnecessary delays on departing flights. This situation could occur as a result of inaccurate prediction of the(required) duration of the GDP based on the weather forecast. On the other hand, if a GDP ends prematurely before the underlying capacity constraints are resolved at the destination airport, it may result in airborne holding. The delicate balance lies in matching the termination of the GDP precisely with the resolution of capacity constraints, avoiding both the imposition of unnecessary ground delays and the need for airborne holding due to premature program termination.Failing to specify the right parameters for TMIs also leads to flight delays, creating a significant obstacle in managing the increasing traffic volumes causing increased work load for the controllers. To address this issue, we propose the integration of Machine Learning (ML) models in the traffic flow management(TFM) pipeline. In current operations, decisions are made by human experts based on extensive training, historical patterns, available traffic and weather data. Since we have an abundance of data from past events that tell us the likely impact of various TMIs, by ingesting historical data, properly trained ML models can offer valuable insights and aid human decision-making. With the FAA increasingly exploring advanced analytics, ML emerges as a focal point for enhancing TFM within the National Airspace System (NAS). As a first step, this study aims to provide traffic controllers with decision-making support for the issuance and adjustment of TMIs. Data analytics and machine learning have been previously employed to address some of the challenges associated with TMIs. Numerous studies have concentrated on various facets of TMI issuance, exploring factors influencing TMI parameters, including arrival rate, airport capacity, and delay prediction. For example, using weather forecasts, several statistical methods were used to produce probabilistic capacity profiles which in conjunction with deterministic models provided insights into the GDP planning process [1–4]. The downside of using deterministic models is that they rely on fixed inputs and predetermined rules, which lack the ability to account for the inherent uncertainty and variability present in real-world scenarios. In a separate series of studies, researchers aimed to predict the occurrences of GDPs and GSs. The majority of these studies utilized various supervised learning methods, including Decision Trees, Naive Bayes, Support VectorMachines, and Random Forests to analyze the influence of weather conditions and arrival demand on TMI incidents[5–8]. However, these studies primarily focused on predicting the incidence of TMIs without explicitly addressing the scope of TMIs, including their duration and their geographical coverage. Furthermore, the emphasis of these studies was largely on GDPs, given their higher frequency and longer duration when compared to GSs. A limited number of studies focused on predicting the parameters of TMIs, specifically addressing their duration and extent. In one such study focusing on optimizing the TMI parameters at San Francisco International Airport (SFO),the authors utilized a probabilistic forecast of fog [9]. They simulated various capacity scenarios based on the (fog)burn-off forecasts, selecting GDP parameters that minimized airborne and overall ground delays. However, this approach exclusively emphasizes stratus (fog) burn-off as the primary determinant of GDP and GS, neglecting other influential factors like severe weather events, runway closures, lower capacity than traffic demand, and other important variables. Given the complexity of predicting the TMI and determining its scope, we seek a more holistic approach. We aim to consider all significant factors that could impact TMIs and their parameters. What sets this research apart is the fusion of all data sources relevant to the issuance and adjustment of TMIs and it represents the first comprehensive attempt to optimize TMIs in this manner. Since this comprehensive solution involves various aspects, we break down the problem into smaller components and input all parameters into a unified model called the “TMI Adjuster”. Figure 1 shows the overall framework and the list of datasets used in each model. The objective of the TMI Adjuster module is to deliver reliable, consistent and expedited recommendations for the progression, adjustment, and termination of TMIs. The ML solution entails developing a pipeline capable of predicting the necessity of a TMI (e.g., GS or GDP) along with its various parameters. For example, in the case of a GS, this includes the scope of the GS either in terms of distance from the destination airport or based on pre-defined airspace sectors. Here, scope refers to those regions and departing airports that are subject to the GS. In this paper, we concentrate on the issuance of GSs in the three major airports in the New York area — LaGuardia(LGA), John F. Kennedy International (JFK), and Newark Liberty International (EWR). We fuse traffic, weather and other relevant aviation data from years 2017 to 2019 to train and validate the ML models. In particular, we use the following datasets: •Terminal Aerodrome Forecast (TAF): meteorological forecasts specific to each airport, issued four times a day, covering predefined time periods. •TMI data: includes all GSs and GDPs along with their respective parameters. •Aviation System Performance Metrics (ASPM): includes traffic related data such as aircraft delays, arrival, and departure rates. •Notices to Airmen (NOTAMs): utilized to extract runway closure data and manage interdependencies between terminals in close proximity. •Flight cancellation data •Airspace Flow Programs (AFP): includes information on flight airborne holdings caused by TMIs. The data preprocessing entails transforming ASPM, TMI, AFP, NOTAMs, and weather data into an hourly format and consolidating all datasets by merging them based on date and time as the primary key. The TMI Adjuster framework comprises two parallel models: one dedicated to GS and a second model focused on GDP. As previously mentioned, our specific focus is on the GS model as a multi-classification problem. In this framework, each data point of the GS model input summarizes ten hours of data. Specifically, the data loader for the GS model generates the input and output of the model as follows: at a given time step, the input includes the actual traffic, weather, and TMI data from the two-hour window before the time step, alongside the weather forecast and scheduled traffic for the next 8 hours starting from the time step. Based on this information, the output of the GS model for each time interval consists of three dimensions. The first dimension represents a binary decision on whether there should be a GS in place for the next hour or not. The second dimension is related to the scope of the GS in the United States, and the third dimension is related to the scope of the GS in Canada (i.e., to determine if the GS impacts airports in Canada).One of the challenges with TMI modeling is the sparsity of TMI events, particularly regarding its scope. To address this challenge in the scope of the GS model output, we implement grouping. The GS scope for the US region is defined based on a list of centers that should be included when the GS is in place. With 20 centers in the US, we utilized historical data to group them into 4 categories. In particular, we summarized our historical data in a graph format where nodes represent centers, and link weights are defined based on the co-occurrence of centers in the scope parameter ofTMIs. By identified strongly connected components in this graph, we were able to partition the centers into four groups. We consider two model structures for the GS Model. Firstly, a hierarchical classification model [10], where the human decision-making for a GS is of hierarchical nature. The decision-maker first decides whether there is a need fora GS, and if the answer is yes, determines the scope. A hierarchical classification model organizes the problem into a class hierarchy, typically a tree or a Directed Acyclic Graph (DAG) structure, and considers the dependency of the decision in the previous step to the next component [10]. Here, we employ the local classifier per level approach, which involves training one multi-class classifier for each level of the class hierarchy. The second structure is the independent structure. In this setting, as the name suggests, we do not consider the dependency of the decisions in the different dimensions of the output of the model. Instead, for each dimension, we train a multi-class classifier independently. Table 1 summarizes GS model statistics for training, validation and testing. The table documents the effect of limiting data to the time steps when there was actually a TMI in place or when a TMI had just terminated. This resulted in a more balanced distribution of the GS class(GS positive class)versus “No GS”(GS negative class), which might help the training process. While JFK and LGA follow very similar distributions, with 40% and 42% GS positive class respectively, EWR has proportionally fewer GS incidents at 28%. Our subsequent phase involves evaluating the performance of both hierarchical structure and independent structure using different state-of-the-art multi-class classifier models such as Random Forest, Decision Trees, K-nearest Neighbors, and Logistic Regression and forecast the duration and scope of the GSs.

Farzan Masrour Shalmani↗

Design for Manufacturing of Structures with Automated Fiber Placement via Integration of Analysis and Process Planning

Under the Design for Manufacturing (DFM) task in the NASA HiCAM program, significant process has been made towards establishing a fully automated optimization process that spans the structural analysis, design, and manufacturing process planning for Automated Fiber Placement (AFP) structures. Previous efforts in this area established the data formats and mapping processes needed to exchange data between disciplines. The software tools used in the framework are HyperX (structural optimization), CAPP (process planning), and VCP (AFP path generation). The work has culminated with automation of data exchanges and an optimization process that drives the three software toward convergence. Within this framework, HyperX is used to generate mass-optimum composite designs which are iterated with VCP and CAPP to improve manufacturability of the designs. As the ply manufacturing process is adjusted by CAPP and VCP, HyperX continually re-assesses the structural integrity of the part and makes adjustments to the laminate as needed. For example, the position of fiber steering and tow overlaps/gaps can necessitate changes to the laminate design. Once the design converges, the end result is a stack of plies that meets both structural and manufacturing requirements. This paper presents the details of the framework and demonstrations the automated process on several parts with significant double-curvature.

HiCAM↗

ISAAC

This document describes the ISAAC (Integrated Structural Assembly of Advanced Composites) robotic system. ISAAC is a highly accurate, automated robotic platform used to support research on the design, analysis, manufacturing and evaluation of advanced composite materials and structures. ISAAC can build composite parts using automated fiber placement (AFP) and stitching through the thickness of dry fabric. The system is frequently upgraded to include new capabilities. ISAAC is located at the NASA Langley Research Center

carbon-epoxy↗

Implementation of Combinatorial Optimization Techniques for Automated Fiber Placement Through Thickness Defect Stack-Up Minimization

The Computer Aided Process Planning (CAPP) module was developed to facilitate and accelerate the process planning workflow for Automated Fiber Placement (AFP). CAPP assists process planners in identifying optimal starting point locations and layup strategies for each ply of a laminate. Ply optimization operates on measurement and scoring of geometry-based defects such as gaps, overlaps, angle deviation, and steering. This paper expands on the established framework for analyzing defect stack-up through thickness of a laminate. Four different combinatorial optimization algorithms are implemented and evaluated: (1) genetic algorithm, (2) differential evolution, (3) particle swarm, and (4) greedy search. The algorithms identify the optimal combination of ply-level layup strategies, by scoring potential laminates on defect stacking, using two different objective functions. A final optimization approach is also presented which trades some performance for a large gain in efficiency. These approaches are compared to a randomized combination using a complex tool surface in a virtual case study. The result is a streamlined methodology for comparing different laminate-level manufacturing strategies and minimizing the through thickness defect stack up.

CAPP↗

Leveraging Automated Fiber Placement Computer Aided Process Planning Framework for Defect Validation and Dynamic Layup Strategies

Process planning represents an essential stage of the Automated Fiber Placement (AFP) workflow. It develops useful and efficient machine processes based upon the working material, composite design, and manufacturing resources. The current state of process planning requires a high degree of interaction from the process planner and could greatly benefit from increased automation. Therefore, a list of key steps and functions are created to identify the more difficult and time-consuming phases of process planning. Additionally, a set of metrics must exist by which to evaluate the effectiveness of the manufactured laminate from the machine code created during the Process Planning stage. Layup strategies, in addition to dog ears, stagger shifts, steering constraints, and starting points, represented the group of functions labeled as process optimization and ranked the highest in terms of priority for automation. The laminates resulting from the selected parameters are evaluated through the occurrences of principal defect metrics such as fiber gaps, overlaps, angle deviation and steering violations. This document presents an automated software solution to the layup strategy and starting point selection phase of process planning. A series of ply scenarios are generated with variations of these ply parameters and evaluated according to a set of metrics entered by the Process Planner. These metrics are generated through use of the Analytical Hierarchy Process (AHP), where relative importance between each of the fiber features are defined. The ply scenarios are selected which reduce the overall fiber feature scores based on the defects the Process Planner wishes to minimize.

HiCAM↗

Detection and Localization of a Fold, Twist, and Overlaps within Tow-Steered Composite Panels During Autoclave Cure

Because of the anisotropic properties of carbon fiber reinforced polymer (CRFP) composites, novel layup architectures, such as tow-steering, can be used to tailor mechanical properties of the composite structure to the loading condition during use. In this work, a tow-steered composite panel was de-signed, laid up using the Integrated Structural Assembly of Advanced Com-posites (ISAAC) automated fiber placement (AFP) machine located at the NASA Langley Research Center (LaRC), and cured while simultaneously be-ing inspected using an ultrasonic inspection system operating inside the auto-clave. The composite panel contained overlaps that are intrinsic to the tow-steered design and had intentionally introduced layup defects including folds, wrinkles, splices, tow twists, foreign object debris (FOD), gaps, and additional overlaps. The inspections during the cure cycle focused on the ar-ea within the laminate containing a fold, a twist, and intrinsic overlaps. The ultrasonic inspections performed during the cure cycle were analyzed and compared to post-cure ultrasonic inspections of the entire laminate.

Composites↗

Detection and Localization of a Fold, Twist, and Overlaps within Tow-Steered Composite Panels During Autoclave Cure

Because of the anisotropic properties of carbon fiber reinforced polymer (CRFP) composites, novel layup architectures, such as tow-steering, can be used to tailor mechanical properties of the composite structure to the loading condition during use. In this work, a tow-steered composite panel was de-signed, laid up using the Integrated Structural Assembly of Advanced Com-posites (ISAAC) automated fiber placement (AFP) machine located at the NASA Langley Research Center (LaRC), and cured while simultaneously be-ing inspected using an ultrasonic inspection system operating inside the auto-clave. The composite panel contained overlaps that are intrinsic to the tow-steered design and had intentionally introduced layup defects including folds, wrinkles, splices, tow twists, foreign object debris (FOD), gaps, and additional overlaps. The inspections during the cure cycle focused on the ar-ea within the laminate containing a fold, a twist, and intrinsic overlaps. The ultrasonic inspections performed during the cure cycle were analyzed and compared to post-cure ultrasonic inspections of the entire laminate.

Composites↗

Serum tumor markers and testicular germ cell tumors: a primer for radiologists

Serum tumor markers (STMs) play a critical role in the diagnosis, staging and follow-up of both seminomatous and nonseminomatous testicular germ cell neoplasms. Levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH), especially those measured after orchiectomy, also have implications for patient prognosis. Given that testicular germ cell tumors represent the most common solid tumor in men aged 20–34, radiologists must have familiarity with the clinical utilization and implications of these STMs. This article will review the classical patterns of STM elevation most commonly seen in pure seminomatous and nonseminomatous germ cell tumors while also providing case-based examples highlighting the importance of STM correlation with imaging. The role of STMs in clinical staging and disease surveillance will also be discussed.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Safety and Short-Term Efficacy of Irreversible Electroporation and Allogenic Natural Killer Cell Immunotherapy Combination in the Treatment of Patients with Unresectable Primary Liver Cancer

Purpose: This study aimed to investigate the safety and short-term efficacy of irreversible electroporation (IRE) combined with allogenic natural killer (NK) cell immunotherapy in the treatment of patients with unresectable primary liver cancer. Materials and Methods: Between October 2015 and December 2016, 40 patients were enrolled and randomly allocated to either the IRE group (n = 22) or the IRE–NK group (n = 18). All adverse events experienced by the patients were recorded; the changes in tumor biomarkers [AFP, CA 19-9, circulating tumor cells (CTCs)], lymphocyte number and function, quality of life, clinical response, progression-free survival (PFS) and overall survival (OS) were assessed. Results: Patients who received combination therapy exhibited significantly longer median PFS and OS than who just received IRE (PFS 15.1 vs. 10.6 months, P < 0.05, OS 17.9 vs. 23.2 months, P < 0.05). The combination therapy of IRE and NK cell immunotherapy significantly reduced CTCs and increased immune function and Karnofsky performance status. Conclusion: Our data suggest a novel, promising combination therapy using IRE and allogenic NK cell immunotherapy. Larger clinical trials are required to confirm these conclusions.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Cancer cell specific cytotoxic gene expression mediated by ARF tumor suppressor promoter constructs

Highlights: • ARF promoter showed higher responsiveness to deregulated E2F activity than the E2F1 promoter. • ARF promoter showed higher cancer cell-specificity than E2F1 promoter to drive gene expression. • HSV-TK driven by ARF promoter showed higher cancer cell-specific cytotoxicity than that driven by E2F1 promoter. - Abstract: In current cancer treatment protocols, such as radiation and chemotherapy, side effects on normal cells are major obstacles to radical therapy. To avoid these side effects, a cancer cell-specific approach is needed. One way to specifically target cancer cells is to utilize a cancer specific promoter to express a cytotoxic gene (suicide gene therapy) or a viral gene required for viral replication (oncolytic virotherapy). For this purpose, the selected promoter should have minimal activity in normal cells to avoid side effects, and high activity in a wide variety of cancers to obtain optimal therapeutic efficacy. In contrast to the AFP, CEA and PSA promoters, which have high activity only in a limited spectrum of tumors, the E2F1 promoter exhibits high activity in wide variety of cancers. This is based on the mechanism of carcinogenesis. Defects in the RB pathway and activation of the transcription factor E2F, the main target of the RB pathway, are observed in almost all cancers. Consequently, the E2F1 promoter, which is mainly regulated by E2F, has high activity in wide variety of cancers. However, E2F is also activated by growth stimulation in normal growing cells, suggesting that the E2F1 promoter may also be highly active in normal growing cells. In contrast, we found that the tumor suppressor ARF promoter is activated by deregulated E2F activity, induced by forced inactivation of pRB, but does not respond to physiological E2F activity induced by growth stimulation. We also found that the deregulated E2F activity, which activates the ARF promoter, is detected only in cancer cell lines. These observations suggest that ARF promoter is activated by E2F only in cancer cells and therefore may be more cancer cell-specific than E2F1 promoter to drive gene expression. We show here that the ARF promoter has lower activity in normal growing fibroblasts and shows higher cancer cell-specificity compared to the E2F1 promoter. We also demonstrate that adenovirus expressing HSV-TK under the control of the ARF promoter shows lower cytotoxicity than that of the E2F1 promoter, in normal growing fibroblasts but has equivalent cytotoxicity in cancer cell lines. These results suggest that the ARF promoter, which is specifically activated by deregulated E2F activity, is an excellent candidate to drive therapeutic cytotoxic gene expression, specifically in cancer cells.

60 APPLIED LIFE SCIENCES↗

TRIM26 functions as a novel tumor suppressor of hepatocellular carcinoma and its downregulation contributes to worse prognosis

Hepatocellular carcinoma (HCC) is the one of the most common malignancies worldwide and its prognosis is extremely poor. Tripartite motif (TRIM) proteins play crucial roles in cancer cell biology but the function of tripartite motif 26 (TRIM26) has not been investigated. We demonstrated that low expression level of TRIM26 in tumor samples was significantly correlated with worse prognosis in HCC patients. We also demonstrated its expression level was associated with several clinicopathologic features such as AFP level and T stage of HCC patients. Furthermore, we validated that TRIM26 was significantly downregulated in HCC tissue compared with normal liver tissue. To further clarify the functional role of TRIM26 in HCC, We confirmed that TRIM26 silencing can promote cancer cell proliferation, colony forming, migration and invasion in vitro with HCC cell lines HepG2 and Bel-7402. Then we utilized bioinformatic tool to predict gene influenced by TRIM26, showing TRIM26 could modulate gene sets about cancer cell metabolism. In conclusion, we proved that TRIM26 is a novel tumor suppressor modulating multiple metabolism-related pathways in HCC. To our best knowledge, this is the first study to investigate the function of TRIM26 in cancer biology. Our findings provide useful insight into the mechanism of HCC origin and progression. Moreover, TRIM26 may represent a novel therapeutic target for HCC. - Highlights: • TRIM26 is down-regulated in liver cancer samples and functions as a novel tumor suppressor. • Down-regulation of TRIM26 is associated with worse prognosis of hepatocellular carcinoma (HCC). • Knockdown of TRIM26 promotes the proliferation and metastasis of HCC cells. • TRIM26 may function in abnormal metabolic progress of HCC.

60 APPLIED LIFE SCIENCES↗