Face perception in humans and nonhuman primates is accomplished by a patchwork of specialized cortical regions. How these regions develop has remained controversial. In sighted individuals, facial information is primarily conveyed via the visual modality. Early blind individuals, on the other hand, can recognize shapes using auditory and tactile cues. Here we demonstrate that such individuals can learn to distinguish faces from houses and other shapes by using a sensory substitution device (SSD) presenting schematic faces as sound-encoded stimuli in the auditory modality. Using functional MRI, we then asked whether a face-selective brain region like the fusiform face area (FFA) shows selectivity for faces in the same subjects, and indeed, we found evidence for preferential activation of the left FFA by sound-encoded faces. These results imply that FFA development does not depend on experience with visual faces per se but may instead depend on exposure to the geometry of facial configurations. Face perception is one of the most studied human skills because of its evolutionary relevance for survival –4. CompaOn the other hand, selectivity for face stimuli within the FFA develops gradually and becomes more finely tuned over the first decade of human development –36, suggAs facial information is predominantly conveyed through the visual modality in sighted humans, conveying facial information through another modality, such as hearing or touch in early blind (EB) individuals, could help to clarify the role experience plays in the specialization of the FFA. Visually deprived individuals thus offer a unique window into assessing how the morphological and functional architecture of the human brain develops and what role sensory experience plays in shaping the functional organization of the human brain.). Previous functional neuroimaging studies have shown activation in various extrastriate areas of the visual cortex with similar devices in blind and sighted individuals  for details).Six early blind (EB) and ten sighted controls (SC) were trained to identify sound-encoded schematic images of faces, houses, and geometrical shapes using a visual-to-auditory sensory substitution device (SSD) referred to as the PSVA . The visIn a further fMRI session , right, Six EB and ten SC participants completed the one-back PSVA task which comprised sound-encoded images of the schematic stimuli that were also used as one type of visual stimuli in the SC . Given oTen sighted controls took part in the visual one-back comparison task. The visual task incorporated photographs of real faces, houses or geometrical shapes as well as the visual version of the sound-encoded schematic stimuli (drawings) used in the PSVA task. These conditions were used as localizers for identifying the FFA region .right-sided activation of the fusiform gyrus (see upper part of left fusiform gyrus (see lower part of Whole-brain random effects (RFX) analyses using a corrected threshold of q-FDR < 0.05 (with p < 0.01 cluster-forming threshold) were performed in SC subjects. The contrast [Schematic Faces minus Rest] showed predominantly A 5-mm radius sphere  was created around the main voxel peak  located within the FFA, as identified by a functional  localizer in the SC, using the contrast [Schematic Faces minus Schematic Houses]  in the spherical FFA-ROI as a function of group  and condition/stimulus . Beta values for the schematic visual conditions in SC are provided as a reference on the left. In EB subjects, the Face condition was significantly above the baseline  and above the House condition . See , penultimate line, in bold). In SC, the same contrast, [Schematic Faces minus Schematic Houses], did not show a significant activation focus in the fusiform gyrus at the selected threshold.To visualize activation patterns and their specificity, whole-brain analyses were also performed. The contrast [Schematic Faces minus Schematic Houses] in the six EB subjects showed an activation focus in the left FFA  activates the fusiform gyrus (BA 37) in EB subjects, in a region identified as the left fusiform face area (FFA) in sighted subjects. The fact that the FFA is activated in the blind by sound-encoded patterns of faces suggests that the computational algorithms for the detection of faces can develop without experience in the visual domain. Training and testing with the SSD and subsequent brain imaging reveals the presence of face-specific modules that seem to resonate with the underlying geometry of the recipient structure.Our results are the first to document that a specific, prominent region of the ventral pathway, the FFA of the left cerebral hemisphere, shows a preference for the perception of sound-encoded schematic faces in EB subjects. Activation of the FFA observed in sighted individuals when they perceived the same schematic faces visually, corresponded to the same location that had previously been found to identify that cortical region .In the current study, only the left FFA in the EB group showed a preference for sound-encoded images of schematic faces. This is in line with previous evidence of left-hemispheric involvement in analytic processing of local facial parts or features, as opposed to configural or ‘holistic’ face perception, which engages mostly the right FFA, –64. InteAlthough there is strong evidence for the analytical processing of schematic faces, there is also evidence in favor of schematic faces that show holistic processing , demonstAnother study  focused What is obvious is that the left FFA makes a substantial contribution to face processing, so the assumption is warranted that, being able to process relational information about faces, blind participants using an SSD should be able to gain some semblance of face recognition as in haptic face processing . Whetherhttps://osf.io/ta8xw/), although this was not systematically tested. EB individuals spontaneously produce facial expressions of basic emotions that are very similar to those produced by sighted individuals in the same situations . These activation maps were used as inclusive masks in further analyses of the FFA. The maps were obtained using a corrected threshold of qFDR < 0.05 in combination with a cluster size threshold correction of p < 0.01. An activation focus was found in the left fusiform gyrus Click here for additional data file.S1 Filehttps://osf.io/ta8xw/).Recognition of schematic visual patterns by a blind volunteer using a sensory substitution device (SSD). The SSD converts two-dimensional visual images viewed through a head-mounted camera into audible signals modulated by scanning motions of the head. (Video can be downloaded from (MP4)Click here for additional data file.S1 TableParaHippo G: parahippocampal gyrus, Post CG: posterior cingulate gyrus, Med FG: median frontal gyrus, Mid FG: middle frontal gyrus, SFG, superior frontal gyrus, Prec G: precentral gyrus, IPL: inferior parietal lobule, FFA: fusiform face area, IFG: inferior frontal gyrus.(DOCX)Click here for additional data file.S2 TableSTG: superior temporal gyrus, Mid TG: middle temporal gyrus, SFG: superior frontal gyrus, Cing G: cingulate gyrus, ITG: inferior temporal gyrus, FFA: fusiform face area.(DOCX)Click here for additional data file.


Advancements in modern medicine have bolstered the usage of home-based rehabilitation services for patients, particularly those recovering from diseases or conditions that necessitate a structured rehabilitation process. Understanding the technological factors that can influence the efficacy of home-based rehabilitation is crucial for optimizing patient outcomes. As technologies continue to evolve rapidly, it is imperative to document the current state of the art and elucidate the key features of the hardware and software employed in these rehabilitation systems. This narrative review aims to provide a summary of the modern technological trends and advancements in home-based shoulder rehabilitation scenarios. It specifically focuses on wearable devices, robots, exoskeletons, machine learning, virtual and augmented reality, and serious games. Through an in-depth analysis of existing literature and research, this review presents the state of the art in home-based rehabilitation systems, highlighting their strengths and limitations. Furthermore, this review proposes hypotheses and potential directions for future upgrades and enhancements in these technologies. By exploring the integration of these technologies into home-based rehabilitation, this review aims to shed light on the current landscape and offer insights into the future possibilities for improving patient outcomes and optimizing the effectiveness of home-based rehabilitation programs. The shoulder joint, renowned for its exceptional range of movement, plays a crucial role in enabling essential daily activities, such as reaching, lifting, or throwing . CoordinRecognized as an alternative or complementary approach to traditional care-unit-based therapy, home-based rehabilitation empowers patients by fostering autonomy and facilitating their recovery to regain their ability to perform daily tasks . This apMaintaining high-quality healthcare services in a home-based rehabilitation setting necessitates the use of medical devices capable of monitoring patients, complemented with periodic supervisions from healthcare professionals . Well-deWhile previous literature reviews have explored specific technological factors, applicable exercises, and their effectiveness in home-based shoulder rehabilitation ,17,18,19The present article is organized into five sections, each addressing specific aspects of home-based shoulder rehabilitation. In the realm of medical advancements, numerous devices are currently under development, with many designed for use in clinical or hospital settings due to their inherent complexity. However, certain devices and technologies offer relative simplicity in their operation, making them well suited for home use and enabling patients to regain autonomy and independence in their rehabilitation journey . Figure Within the realm of physical technologies, wearable devices, also known as wearables, have emerged as a transformative tool in modern medicine. These devices incorporate sensors, which gather data from the patient and/or the surrounding environment, facilitating continuous monitoring outside traditional healthcare settings. Through the utilization of advanced computational algorithms, wearables enable event prediction, prevention, and intervention, thus revolutionizing the field . NotablyThe integration of rehabilitation robots has been a pivotal aspect of therapy since the 1990s, serving as a valuable aid in administering treatment to patients. These robots employ computerized interfaces to assist individuals in completing tasks, offering not only physical support but also emotional encouragement and motivation. Numerous studies have demonstrated the positive impact of robot-assisted training on arm function and overall ability in daily activities ,28,29,30In the realm of virtual approaches to home-based rehabilitation, the integration of machine learning has revolutionized the automation of processes by harnessing artificial intelligence and pattern recognition capabilities . ThroughThe increasing adoption of virtual and augmented reality systems in recent years indicates a shift toward a more e-health-focused approach in both medical and social rehabilitation . These sA compelling concept, which has emerged in the realm of physical rehabilitation, is the use of serious games. These games combine educational, informational, and rehabilitative aspects with the entertaining and enjoyable elements of video games . The verWith the foundational technologies discussed in this section, the subsequent sections will delve deeper into their key features, providing illustrative examples and conducting in-depth analyses. By exploring the capabilities and applications of these technologies, we aim to offer valuable insights into the evolving landscape of home-based shoulder rehabilitation and equip researchers and practitioners with the knowledge needed to harness these advancements effectively.The physical branch of rehabilitation encompasses a range of technologies, which integrate robotics to enhance the treatment approaches for muscular, neuromuscular, and osseous conditions . This brWearable sensors play a crucial role in shoulder rehabilitation, particularly for individuals with neurological or musculoskeletal impairments. These sensors enable the assessment of motor abilities by extracting and analyzing kinematics data, facilitating rehabilitation follow-up and treatment of disorders . Table 1The outcomes of wearable applications in home-based shoulder rehabilitation have been predominantly positive, ensuring patient safety and yielding rehabilitation results comparable to those observed in a care unit ,55. For Over the past two decades, significant advancements in the fields of robotics and orthotics have positively impacted the telerehabilitation process and motor function recovery outcomes in physical therapy. These technical improvements have led to enhanced patient experiences and better therapeutic results . Some exThe integration of robotic and orthotic technologies has brought about several key benefits. Robotic devices can provide real-time feedback, enabling patients to receive immediate information about their movements and posture. This feedback enhances patients’ understanding and correction of their movements, leading to improved motor function recovery. Moreover, the feedback from robots can boost patient motivation and adherence to rehabilitation therapy, as it provides a sense of accomplishment and progress. Robotic devices also offer physical assistance, supporting patients in performing exercises and movements. By augmenting patients’ abilities, robots enable more intensive and targeted therapy, potentially leading to better motor function recovery outcomes. Furthermore, the combination of telecommunication technologies with robotics has facilitated telerehabilitation. Telerehabilitation allows patients to access therapy remotely, reducing the need for in-person visits. Patients can engage in rehabilitation exercises and receive guidance from healthcare professionals through video conferencing or other communication tools, while robotic devices aid them in performing the prescribed activities.While the use of robotic devices autonomously in home rehabilitation settings is possible, safety measures and guidelines must be followed. Robotic devices designed for home use incorporate safety features to prevent excessive force or unexpected movements. However, the level of supervision required may vary depending on the patient’s condition and the complexity of the device. Initial setup and training by healthcare professionals may be necessary, and regular check-ins or remote monitoring can ensure progress tracking and program adjustments .The technical improvements in the robotic and orthotic fields have significantly improved the telerehabilitation process and motor function recovery outcomes in physical therapy. These advancements have allowed patients to receive real-time feedback, physical assistance, and guidance from healthcare professionals remotely. While patients can use robotic devices autonomously in their homes, the level of supervision required depends on individual factors and should be determined in consultation with healthcare professionals to ensure safety and optimal outcomes.Exoskeletons are described as wearable robotic devices, designed with the intent of facilitating and enhancing the user’s physical activities in a safe way, normally applied in patients with reduced mobility, such as patients who suffered spinal cord injuries  or strokWhen applied in upper limb rehabilitation, exoskeletons are primarily used to sustain a proper and ergonomic posture and give a boost of strength to the shoulder . In ordeThe virtual branch of rehabilitation encompasses a wide array of informatics technologies, such as machine learning and its subfields, virtual and augmented reality, and serious games. These technologies are pivotal in simulating human cognitive capabilities and enabling the control of health management systems, thereby automating decision-making processes in clinical support systems . By harnOne of the key aspects of the virtual branch is the creation of immersive and interactive experiences. Through virtual and augmented reality technologies, patients can engage in rehabilitation activities within simulated environments, which closely resemble real-world scenarios. This immersive approach provides a controlled and safe space for patients to practice various tasks, such as balance training, motor skill development, and functional movements. By replicating real-life situations, virtual environments allow patients to work on their rehabilitation goals in a dynamic and engaging manner. Furthermore, the virtual branch of rehabilitation offers personalized interventions, which cater to individual patient needs. Machine-learning techniques are employed to analyze patient data, predict outcomes, and optimize treatment plans. By leveraging personalized data, rehabilitation programs can be tailored to specific patient characteristics, resulting in more targeted and effective interventions. The utilization of machine learning and its subfields empowers healthcare professionals to make data-driven decisions and adapt rehabilitation strategies based on individual progress and requirements.Intelligent data analysis is another significant aspect of the virtual branch. By employing advanced analytics and machine-learning algorithms, large datasets collected from patients can be processed and analyzed to derive meaningful insights. This data-driven approach aids in identifying patterns, trends, and correlations, which can inform clinical decision making, treatment protocols, and the development of evidence-based rehabilitation practices. The ability to extract valuable knowledge from vast amounts of data enhances the understanding of patient outcomes, therapy effectiveness, and the overall impact of rehabilitation interventions.The virtual branch of rehabilitation integrates informatics technologies, such as machine learning, virtual and augmented reality, and serious games, to revolutionize rehabilitation practices (these are further expanded on in the following subsections). Through immersive and interactive experiences, personalized interventions, and intelligent data analysis, this branch offers new possibilities for enhancing patient outcomes, advancing clinical decision making, and promoting evidence-based rehabilitation strategies.The incorporation of machine-learning algorithms in rehabilitation has gained significant attention over the past two decades. Much of the research in this field has focused on utilizing machine-learning algorithms for classification, prediction, and treatment planning ,73. The The adoption of rehabilitation systems integrating machine-learning techniques has further accelerated in the wake of the global COVID-19 outbreak. These systems offer several advantages, including remote access to patients’ exercise information without the need for direct physical contact, enabling health professionals to monitor their patients’ progress at any time . This reSince the early 1990s, there has been a growing development of physical rehabilitation interventions utilizing virtual reality (VR) technology, with laboratories and clinics promoting its use in healthcare . VR provThe use of VR and AR applications in the recovery of cognitive function and simulation of daily life activity has shown great promise in the field of home-based rehabilitation . These t® has been utilized by Xbox [® has offered a distinctive remote controller and accessories [® has been developed by PlayStation [® [® [® [Serious games have gained considerable attention from researchers as a promising component in clinical practice—particularly for the rehabilitation of motor dysfunctions—over the past three decades . These g by Xbox ,82; Nintessories ; and Plaation [® ,82 uses on [® [®  uses a wThe development of serious games has focused on tailoring the gaming environment to specific disease conditions, aiming to motivate patients to complete exercises and improve clinical outcomes . By creaIn the existing literature, a variety of methodologies and measuring parameters have been used to evaluate the effectiveness of auxiliary technologies in home-based shoulder rehabilitation ,86. ThesRandomized controlled trials are considered the gold standard for evaluating the effectiveness of medical interventions . In thesCase studies and observational studies, on the other hand, involve observing and documenting the experiences of individual patients or groups of patients using auxiliary technologies ,87. ThesIn terms of measuring parameters, a variety of metrics have been used to evaluate the performance of auxiliary technologies in home-based shoulder rehabilitation . These iIn addition to these objective measures, patient-reported outcome measures, such as quality of life and satisfaction with treatment, have also been used ,89. ThesFrom our experience, we believe that a comparison of the results obtained using different methodologies usually reveals some interesting trends and patterns. For example, randomized controlled trials tend to produce more consistent and reliable results than case studies or observational studies. However, these studies can be time consuming and expensive to conduct, and they may not always reflect real-world use of auxiliary technologies.In conclusion, home-based rehabilitation employs a variety of methodologies and measuring parameters. While randomized controlled trials are considered the gold standard for evaluating medical interventions, case studies and observational studies can also provide valuable insights. A range of metrics have been used to measure the performance of these technologies, including range of motion, strength, pain, and functional outcomes.Physical methods include the use of wearable devices, robots, and exoskeletons. Wearable devices incorporate sensors, which gather data from the patient and/or the surrounding environment, facilitating continuous monitoring outside traditional healthcare settings. Robots employ computerized interfaces to assist individuals in completing tasks, offering not only physical support but also emotional encouragement and motivation. Exoskeletons are wearable robotic units designed to augment and enhance human physical capabilities.Virtual methods include the use of machine learning, virtual and augmented reality, and serious games. Machine-learning techniques are employed to analyze patient data, predict outcomes, and optimize treatment plans. Virtual and augmented reality systems simulate realistic scenes, providing valuable support to individuals with disabilities throughout the rehabilitation process. Serious games combine educational, informational, and rehabilitative aspects with the entertaining and enjoyable elements of video games.Each method has its own advantages and disadvantages. Physical methods offer real-time feedback, physical assistance, and remote monitoring capabilities. However, they may require initial setup and training by healthcare professionals, and regular check-ins or remote monitoring may be necessary to ensure progress tracking and program adjustments. Virtual methods offer immersive and interactive experiences, personalized interventions, and intelligent data analysis. However, they may require specialized equipment or software, and their effectiveness may vary depending on individual factors, such as cognitive function or motivation.Enhancing shoulder functionality through physical rehabilitation is a crucial aspect of achieving effective recovery following injury or surgery. This process entails engaging in appropriate rehabilitation exercises, which target various movement planes to enhance motor function . By provWhen it comes to the exercises utilized in home-based rehabilitation, there are various approaches, which can be employed. One innovative approach involves incorporating games, which leverage augmented reality (AR) features, such as the color ball game, whack-a-mole , fruit nRange of motion exercises: These exercises aim to improve the flexibility and mobility of the shoulder joint. They include movements such as shoulder flexion (raising the arms forward and upward), shoulder abduction (raising the arms out to the sides), shoulder external rotation (rotating the arm outward), and shoulder internal rotation (rotating the arm inward). These exercises can be performed in standing or sitting positions, and they help increase the range of motion in the shoulder.Strengthening exercises: Strengthening exercises focus on building the muscles around the shoulder joint to enhance stability and support. Examples include scapular retraction (squeezing the shoulder blades together), wall push-ups , and shoulder rows (using resistance bands or weights to pull the hands toward the body). These exercises help improve the strength and endurance of the shoulder muscles.Alternatively, a more traditional approach uses common physiotherapy exercises, which can be divided based on their objective, namely improving the shoulder motion or increasing the shoulder muscles’ strength:These may entail the pre-recording of physiotherapists demonstrating how the exercises should be performed. In a home setting, patients can utilize a system, which provides feedback and guidance during the therapeutic exercises prescribed by a physical therapist while also generating progress reports on the exercises . This coGiven the complexity of shoulder movements, it becomes necessary to monitor various parameters during the execution of exercises. The commonly monitored parameters include shoulder flexion, shoulder adduction and abduction, and shoulder internal and external rotation . AdditioTo facilitate the monitoring of exercise execution, various systems employ different approaches. Inertial measurement units are commonly used, which provide precise measurements of movement using sensors . AlternaIn a more traditional approach to rehabilitation and therapy, healthcare professionals, such as physiotherapists, typically evaluate the patient’s performance during exercises and make necessary adjustments to maximize rehabilitation outcomes . HoweverWhen assessing the execution of an exercise, various parameters can be measured. These include the superficial electromyography (EMG) of muscles in the shoulder and arm , range oWhen it comes to providing feedback to users, different rehabilitation systems adhere to varying guidelines. Some technologies offer visual correction of exercises, employing mirror rehabilitation therapy for the impaired arm based on superficial EMG and machine-learning results, as exemplified by the ReRebot system . AnotherProviding feedback to patients undergoing home-based shoulder rehabilitation has shown to be highly beneficial. It enhances outcomes by engaging and educating patients, offering support during targeted exercises, and enabling real-time correction of potential mistakes, thereby influencing motor learning and engagement in various ways ,110,111.The definition of progression criteria in rehabilitation is dependent on the specific pathology being targeted and the rehabilitation system being employed. In gamification-based approaches, progression is often determined by the scores achieved by patients during the game, reflecting their progress compared to previous scores. Patients strive to reach or surpass their highest previous score, continuously adjusting their performance based on past achievement ,82,112. While rehabilitation primarily takes place in a home-based setting using dedicated technologies, evaluation of the rehabilitation progress can still involve therapist involvement. Short training sessions may be conducted where the therapist evaluates the patient’s motor performance ,99. ThisUnderstanding the progression criteria provides clarity on how to manage the progression of rehabilitation. In gamification approaches, the difficulty of the game and exercises is adjusted based on the patient’s performance. If the exercises no longer present a challenge and there is potential for further improvement in the patient’s physical condition, the game difficulty is increased. Conversely, if the patient’s performance declines, the difficulty is lowered to allow for retraining and the reacquisition of any lost capabilities ,83. Furthermore, a combination of traditional rehabilitation techniques and home program exercises has shown effectiveness in allowing patients to work beyond their pain thresholds. This approach has demonstrated positive outcomes in rehabilitating shoulder stiffness . In geneIn the design and development of home-based rehabilitation systems, several factors must be considered to ensure that these systems are effective, user friendly, and ethically responsible. These factors include accuracy, reliability, scalability, user experience, and potential ethical concerns.Accuracy and reliability are critical factors in the design of home-based rehabilitation systems . These sScalability is another important factor in the design of home-based rehabilitation systems . These sUser experience is also a critical factor in the design of home-based rehabilitation systems . These sFinally, potential ethical concerns must also be considered in the design and development of home-based rehabilitation systems . These cIn conclusion, the design and development of home-based rehabilitation systems must take into account a range of factors to ensure that these systems are effective, user friendly, and ethically responsible. These factors include accuracy, reliability, scalability, user experience, and potential ethical concerns. By carefully considering these factors in the design process, it is possible to develop home-based rehabilitation systems, which support patients in achieving their rehabilitation goals while also providing a positive user experience.User-centric design: Prioritize user needs and preferences when designing the system interface. Create an intuitive and user-friendly interface, which accommodates individuals with varying technological proficiency, ensuring easy navigation and engagement during home-based rehabilitation sessions.Accessibility and inclusivity: Ensure that the system is accessible to a diverse range of users, including those with physical disabilities, visual impairments, and cognitive limitations. Incorporate features such as adjustable font sizes, voice guidance, and alternative input methods to enhance accessibility for all patients.Customization and adaptability: Provide options for customization and adaptation of the system to meet individual patients’ specific needs. Allow for adjustments in difficulty levels, exercise intensity, and duration based on the patient’s progress and capabilities.Real-time feedback and guidance: Incorporate mechanisms to provide real-time feedback and guidance during exercises. Utilize visual cues, auditory signals, or haptic feedback to help patients perform exercises correctly and optimize their rehabilitation progress.Comprehensive progress tracking: Develop a robust system for tracking and recording patients’ progress over time. Monitor metrics such as exercise completion rates, duration, intensity, and improvements in performance. Utilize these data to personalize future exercise plans and set realistic goals for patients.Safety measures and risk mitigation: Prioritize patient safety by integrating safety measures into the system. Use technologies such as motion sensors to detect incorrect movements or provide warnings when patients exceed safe ranges of motion. Implement risk mitigation strategies to prevent injury during exercises.Data privacy and security: Ensure that the system complies with data privacy regulations and incorporates robust security measures to protect patient information. Implement measures to safeguard sensitive data and provide patients with control over their data and their usage.Seamless integration with healthcare professionals: Enable seamless communication and data exchange between the home-based rehabilitation system and healthcare professionals involved in the patients’ care. Facilitate remote monitoring, feedback, and the ability to make informed adjustments to the rehabilitation program based on professional expertise.Artificial intelligence and machine-learning integration: Explore opportunities to integrate artificial intelligence or machine-learning algorithms into the home-based rehabilitation system. Leverage artificial intelligence capabilities to analyze patient data, identify patterns, and provide personalized recommendations for exercise progression, adapting the rehabilitation program based on individual needs and response to treatment.Scalability and compatibility: Design the system to be scalable and compatible with various devices and platforms. Accommodate different technologies and future advancements, ensuring flexibility and long-term viability of the home-based rehabilitation system.Developing effective home-based rehabilitation systems requires adherence to specific guidelines to ensure optimal user experience, safety, and positive rehabilitation outcomes. Below, we propose a set of guidelines, which should be followed during the development process:By adhering to these guidelines, researchers and developers can create effective home-based rehabilitation systems, which prioritize user needs, promote engagement, and improve rehabilitation outcomes. These systems contribute to the advancement of rehabilitation practices and enhance the overall well-being of patients undergoing home-based rehabilitation programs.Privacy and data security: Home-based rehabilitation systems often involve the collection and storage of sensitive personal health information. It is essential to ensure that robust data protection measures are in place to safeguard patient privacy and prevent unauthorized access or misuse of the data.Informed consent: Patients participating in home-based rehabilitation programs should be adequately informed about the purpose, risks, benefits, and potential limitations of the technology being used. Informed consent should be obtained, outlining the scope of data collection, potential risks, and the patient’s right to withdraw from the program at any time.Equity and accessibility: It is important to consider the equitable access and availability of home-based rehabilitation systems to ensure that all individuals, regardless of socioeconomic status or geographical location, have equal opportunities for rehabilitation and benefit from the technology.User autonomy and empowerment: Home-based rehabilitation systems should be designed to empower patients and promote their active involvement in their own care. The technology should support patient autonomy, allowing them to make informed decisions about their treatment and providing them with tools for self-management.Transparent and explainable AI: If machine-learning algorithms are integrated into the rehabilitation systems, there is a need for transparency and explainability. Patients should have a clear understanding of how AI is being used, what factors influence treatment recommendations, and the basis for any decisions made by the system.Clinical oversight and human interaction: While home-based rehabilitation systems offer the advantage of remote monitoring and independent practice, it is essential to maintain a balance between technology-driven interventions and the involvement of healthcare professionals. Regular clinical oversight and human interaction should be incorporated into the system to ensure patient safety, address individual needs, and provide timely support or intervention when required.As technology continues to advance in the field of home-based rehabilitation systems, it is crucial to address the ethical considerations associated with their use. The following ethical concerns should be taken into account when developing and implementing such systems:Addressing these ethical concerns is paramount to fostering trust, protecting patient rights, and ensuring the responsible and ethical implementation of home-based rehabilitation systems. By considering these ethical considerations, developers and healthcare professionals can work together to create systems, which prioritize patient well-being, privacy, and equitable access to high-quality rehabilitation care.This narrative review has several limitations, which should be acknowledged. Firstly, due to its narrative nature, there is a possibility of bias in the selection and interpretation of the included literature. The absence of a research protocol or predefined hypothesis may have influenced the data selection process. Additionally, this review did not adhere to established guidelines, such as those proposed by PRISMA, and the literature search was conducted in a limited database, which may have restricted the breadth of the included studies.While this narrative review successfully achieves its main objectives of providing an overview of home-based shoulder rehabilitation technologies and offering insights into prescribed exercises, it should be noted that the amount of information presented is limited. It is important to note that this overview does not include detailed information about the methodologies and measuring parameters used in the existing literature. This is partly because many of the referenced works do not share this information themselves. As such, the analysis presented in this study is limited to a general overview of the technologies and their potential applications, without a critical evaluation of their effectiveness based on empirical data. Future studies could benefit from a more comprehensive analysis, which includes a detailed review of the methodologies and measuring parameters used in the existing literature, where available. In addition, the discussion of each topic is approached theoretically and simplistically, making this review less suitable for researchers seeking in-depth, specific information on any of the technologies discussed.Future studies should consider addressing these limitations by incorporating a more comprehensive and rigorous approach. This could involve providing more detailed information on each technology or dividing the content into multiple specialized studies, allowing for a more focused exploration of specific aspects.By recognizing these limitations, we aim to provide transparency and encourage further research to expand upon the findings presented in this narrative review.The advancements in software and hardware industries have paved the way for the development of more engaging equipment and services used in shoulder home-based rehabilitation. These innovative rehabilitation systems are the result of a multidisciplinary approach, combining technologies from both the physical and virtual branches discussed in this review. However, it is crucial to acknowledge that the progress in rehabilitation would not be possible without the collaboration between technology and healthcare experts.To further advance the field of rehabilitation, it is essential to foster knowledge exchange and collaboration between professionals from the technology and healthcare sectors. This can be achieved by establishing partnerships and promoting interdisciplinary research within institutions dedicated to innovation and the advancement of rehabilitation practices.By bridging the gap between technology and healthcare, we can propel the state of the art in rehabilitation, unlocking new possibilities for effective shoulder rehabilitation in home-based settings. This collaboration holds great potential for enhancing patient outcomes and transforming the field of rehabilitation.In conclusion, the integration of technological advancements with healthcare expertise offers promising opportunities for improving shoulder home-based rehabilitation. By embracing collaboration and fostering innovation, we can drive the future development of rehabilitation systems and methods, ultimately benefiting patients and advancing the field as a whole.


Complications were not observed in either group. Conclusions: The results indicate that the clinical application of the ARSN system in PELD is effective and feasible.Background: The puncture procedure in percutaneous endoscopic lumbar discectomy (PELD) is non-visual, and the learning curve for PELD is steep. Methods: An augmented reality surgical navigation (ARSN) system was designed and utilized in PELD. The system possesses three core functionalities: augmented reality (AR) radiograph overlay, AR puncture needle real-time tracking, and AR navigation. We conducted a prospective randomized controlled trial to evaluate its feasibility and effectiveness. A total of 20 patients with lumbar disc herniation treated with PELD were analyzed. Of these, 10 patients were treated with the guidance of ARSN (ARSN group). The remaining 10 patients were treated using C-arm fluoroscopy guidance (control group). Results: The AR radiographs and AR puncture needle were successfully superimposed on the intraoperative videos. The anteroposterior and lateral AR tracking distance errors were 1.55 ± 0.17 mm and 1.78 ± 0.21 mm. The ARSN group exhibited a significant reduction in both the number of puncture attempts (2.0 ± 0.4 vs. 6.9 ± 0.5,  Percutaneous endoscopic lumbar discectomy (PELD) has become a favorable treatment option for lumbar disc herniation . PELD isTo address these issues, navigation and robotics-assisted surgical techniques have been adopted in clinical practice ,14. HoweAugmented Reality (AR) is a technology that overlays virtual information in the real-world environment, offering enhanced visualization capabilities . The intIn this study, a novel augmented reality surgical navigation (ARSN) system has been developed. The ARSN system is equipped with three functionalities including AR radiograph overlay, real-time AR puncture needle tracking, and AR navigation. The purposes of this study were to establish the standardized ARSN navigation surgical protocols for PELD and to further evaluate the feasibility and clinical effectiveness of the ARSN system through clinical trials.The study protocol was approved by the local institutional review board (2020-378-02). All patients signed an informed consent document. Between December 2020 and March 2021, a cohort of 20 patients diagnosed with lumbar disc herniation underwent PELD treatment. The patients were randomized into two groups using a random number table. In this setup, 10 patients received treatment facilitated by the ARSN system (ARSN group), while the other 10 were treated with the conventional C-arm fluoroscopy guidance (control group). The patient characteristics are listed in The inclusion criteria are as follows: (1) age 18–70 years; (2) clear clinical and radiological diagnosis of lumbar disc herniation; (3) inadequate response to conservative therapy; (4) consent to PELD surgery; (5) willingness and ability to comply with the study protocol.The exclusion criteria encompass (1) lumbar segmental instability or spondylolisthesis; (2) multi-segmental spinal canal stenosis; (3) active infection; (4) coagulation disorders; (5) pregnancy; (6) refusal to participate, as indicated by the patient.The ARSN system comprises a designed hardware system and a self-developed software platform (version V1.0). The hardware system consists of an infrared positioning device , two depth cameras , a workstation with a monitor, and a location kit . The locThe ARSN system possesses three functionalities: (1) AR radiograph overlay and AR visualization of spinal anatomy; (2) AR puncture needle real-time tracking; and (3) AR navigation. Prior to current clinical trials, the precision and reliability of these functionalities have been validated through animal experiments A. In theFor the ARSN group, the puncture procedure of PELD was performed with the guidance of the ARSN system. The standardized surgical protocols for the ARSN system in PELD are shown in Before surgery, a detailed preoperative layout was performed to ensure the optimal positioning of all equipment. Initially, the patient’s surgical side is determined. As shown in Considering the inconsistent positions of the infrared positioning device and the workstation, the system necessitates self-adaptive calibration before formal operation. The calibration process was conducted in the surgical area in both anteroposterior and lateral video views. First, the cameras’ video streams were activated. The fiducial markers were positioned at a designated location within the surgical area. When the recognition button was clicked, the infrared tracking device captured the three-dimensional (3D) spatial coordinates. Concurrently, the coordinates within the video scene were obtained. The 3D spatial coordinates and the coordinates within the video scene were then matched by singular value decomposition (SVD). Following the initial calibration, the fiducial markers were relocated to another spot within the surgical area, and the recognition button was clicked to initiate the second calibration. Calibration was performed at twenty distinct locations for both AP and lateral views. Ultimately, the coordinate systems of the infrared positioning device and the camera were aligned.Following preparation, the patient entered the operating room and was positioned in a prone position on the operating table. Using a custom-made radiolucent bracket, surface fiducial markers were horizontally and perpendicularly placed on the patient’s back and flank. The surgical table, along with the patient, was then advanced into the C-arm, ensuring the patient’s surgical area was within the C-arm’s imaging range A. RadiogThe surgical table, along with the patient, was then repositioned into the ARSN system until the camera range of the ARSN system was aligned with the surgical area. At this point, the fiducial markers on the patient’s body surface can be seen in the video A,B. The After the AR radiograph overlay, the surface fiducial markers were removed. The surgical target segment was identified in the AR radiographs. Utilizing the anatomical information from the AR radiographs, a Kirschner wire was positioned on the patient’s back to outline the puncture direction and identify the skin entry point. The Kirschner wire’s position was fine-tuned until its line intersected with the midpoint of the targeted intervertebral disc and the tip of the superior articular process, as seen in the AP overlaid radiograph A. The liThe puncture needle was affixed to a locator with markers, and its length was input into the ARSN system. This enabled the infrared tracking device to pinpoint the location of the puncture needle. Through calibration and coordinate transformation, the AR virtual puncture needle could be shown in the intraoperative video in real time. Before the puncture, an external test was conducted to validate the tracking precision. The real puncture needle was placed on the patient’s body. The location of the real puncture needle could be captured by the camera and shown in the video. Meanwhile, the AR virtual puncture needle was shown in the video. In both the AP and lateral views, the positions of the real puncture needle and the AR virtual puncture needle were recorded and compared at five different positions . The errUpon confirming the precision of AR tracking, the puncture procedure was performed under AR navigation. On the AR radiograph, the operator could identify the target . Following local anesthesia, the puncture needle was introduced into the body through the predetermined entry point. At this time, the operator could see the position of the AR virtual puncture needle inside the body from the screen . Based oIn the control group, traditional methods were employed for preoperative localization and intraoperative puncture procedures . The patFollowing the puncture procedure, patients in both groups underwent the subsequent steps of PELD. We evaluated the number of puncture attempts and fluoroscopies and the total operation time as intraoperative outcome measures. The Visual Analogue Scale (VAS), the Oswestry Disability Index (ODI), and the complication rates were assessed both one week and one month postoperatively. At the one-month postoperative follow-up, clinical outcomes were also assessed using the modified Macnab criteria.p-value less than 0.05 in two-tailed tests was considered statistically significant.Data were presented as the mean ± standard error (SE). The independent samples t-test and Fisher’s exact test were employed for statistical analyses. The age, BMI, number of puncture attempts, number of fluoroscopies, operation time, VAS score, and ODI score were compared using the independent samples t-test. The gender, operative level, and modified Macnab scores were compared using Fisher’s exact test. All analyses were carried out using SPSS software . A PELD was successfully performed on patients in both the ARSN and control groups. For the ARSN group, AR radiographs were successfully acquired and superimposed onto the body surface for all patients. The preoperative localization process was entirely accomplished using AR radiographs. The skin entrance point chosen based on the AR radiographs was accurate; no adjustments were needed during surgery. The accuracy of the AR real-time puncture needle was assessed through the external test before puncture. The AP average tracking distance error was 1.55 ± 0.17 mm, the lateral average tracking distance error was 1.78 ± 0.21 mm, the AP average tracking angle error was 1.06 ± 0.13°, and the lateral average tracking angle error was 0.88 ± 0.11°.p = 0.000). The overall number of fluoroscopies in the ARSN group was significantly lower than that in the control group . In the ARSN group, preoperative localization predominantly utilized the AR radiograph, eliminating the need for a C-arm. However, the process of obtaining the AR radiograph did require X-ray imaging. Thus, the number of fluoroscopies used to capture the AR radiograph was counted in the number of localization fluoroscopies. No significant differences were found in the number of localization fluoroscopies between the groups . However, the ARSN group exhibited a significant reduction in the number of puncture fluoroscopies  compared to the control group. There were no significant differences in the operation time between the two groups (p = 0.91).The comparison of intraoperative data between the two groups is listed in The postoperative follow-up data are listed in Although the PELD procedure is minimally invasive and offers various advantages, it also presents certain challenges, particularly during the puncture and localization steps. Centro Médico Teknon et al. reported that a learning curve of 72 cases was necessary to achieve the target of 90% good/excellent outcomes for PELD . The chaCurrently, the puncture procedure in PELD is conducted under the guidance of a C-arm. Surgeons can determine the position of the needle tip from both the AP and lateral radiographic views. The AP view reveals the needle tip’s distance to the midline, while the lateral view reveals the depth of needle penetration. The puncture needle is repeatedly adjusted manually based on the position in the X-ray until it reaches the target site. This process is highly dependent on the surgeon’s expertise, and for beginners, it might necessitate numerous repetitive adjustments. Frequent adjustments of the puncture may result in various issues, including increased soft tissue damage, prolonged surgical time, and potential radiation hazards from excessive fluoroscopy. Iprenburg M et al. reported that during a surgeon’s initial experience with PELD, both the patient and the surgeon are likely to be exposed to elevated levels of radiation .AR technology integrates digital information into the real-world environment. Currently, it has been widely used in various fields, such as entertainment, education, and healthcare. In the realm of spinal surgery, AR is being gradually explored for its potential to assist in vertebroplasty , pedicleIn this study, the ARSN system was constructed. The ARSN system possesses three functionalities: (1) AR radiograph overlay and AR visualization of spinal anatomy; (2) AR puncture needle real-time tracking; and (3) AR navigation. The overlaid AR radiograph allows the surgeon to directly observe the structure and position of the patient’s lumbar spine in the surgical area. This enables the surgeon to clearly see the target and to directly determine the puncture entry point and direction during preoperative positioning and intraoperative puncturing. We previously conducted animal experiments to verify the accuracy of the AR radiograph overlay, which can achieve a level of 1 mm . In clinAR real-time tracking of the puncture needle is as crucial as visualizing the patient’s AR vertebrae internally. While the needle is visible externally, its position becomes invisible to the surgeon once it penetrates the patient’s body. The AR Spinal Navigation (ARSN) system could track the needle’s position and display it on the video in real time. The tracking precision was demonstrated to be high before penetration. With the integration of AR radiograph overlay and AR needle tracking, AR navigation becomes achievable. The surgeon can adjust the AR needle in real time towards the target displayed on the AR radiograph. The ARSN system provides continuous guidance without necessitating ongoing fluoroscopy. In contrast, traditional C-Arm guidance is typically intermittent to mitigate excessive radiation exposure. Barbara Carl et al. reported the AR incorporation of 3D anatomical structures overlay in spinal microscopic surgeries but found that the superimposition of 3D structures sometimes obstructed a clear view of the surgical field . AccuratIn the study, AR guidance was used to direct the puncture needle to the area near the target, and radiographs were still required to verify and adjust the position of the puncture needle. Since PELD surgery is performed under local anesthesia, patients might shift due to pain during the operation. Additionally, the patient’s breathing can also affect the accuracy of the puncture. In this case, even if the error of AR tracking is zero, the accuracy can still be affected. Therefore, achieving a one-time successful placement is challenging. However, the initial puncture managed to reach the vicinity of the articular process, and it could be easily adjusted to the target under the guidance of the C-arm. The results indicate that the utilization of ARSN can markedly reduce the number of punctures. This not only mitigates the injuries caused by multiple punctures but also decreases the number of fluoroscopies, thereby reducing radiation exposure risks. Additionally, the application of ARSN is not complicated. The results show that the employment of ARSN does not significantly increase the duration of the surgery. To guarantee the optimal functionality of ARSN, several details should be noted: (1) the video scope of ARSN should be accurately aligned with the surgical area to ensure precision and efficiency during the operation; (2) during the AR radiograph capture, it is crucial to include both the lumbar vertebrae of the surgical segment and the markers required for registration within the X-ray image; (3) once the real space and video space are calibrated and registered, and it is essential to maintain the absolute fixation of the infrared positioning device and the workstation to ensure consistent and accurate guidance; (4) after the AR radiograph overlay, patients should be instructed to avoid any movement.Besides reducing the number of punctures and intraoperative fluoroscopy, the results show that the application of ARSN during surgery is highly safe. Complications were not observed in either group. Moreover, patients in both groups experienced good relief one week and one month postoperatively. Ninety percent of patients in both groups achieved “excellent” or “good” recovery according to the modified Macnab criteria at the 1-month follow-up. To further enhance the safety of the ARSN system, several precautions should be taken into account: (1) during puncture, it is important to regard the AR guiding as a tool only, and the surgeon should still observe the direction of the puncture and judge the appropriateness; (2) in the course of surgery, reliance on the C-arm should not be entirely eliminated, as the C-arm can still be utilized to confirm the direction and position of the puncture needle, if needed; (3) throughout the puncture process, it is important to inquire about the patient’s lower limb sensations to monitor potential nerve damage.Implementing the above details, the ARSN group achieved favorable results, including fewer puncture attempts and fewer fluoroscopies, while ensuring good postoperative outcomes. Nonetheless, this study has certain limitations: the modest sample size and the fact that it was conducted at a single center limit the generalizability of our findings. A multi-center study with a larger sample size is needed for further validation. The existing ARSN systems lack movement tracking and correction capabilities, which should be further developed and improved in the future.In this study, we developed a novel ARSN system, equipped with functionalities including AR radiograph overlay, real-time AR puncture needle tracking, and AR navigation. The system facilitates the AR visualization of the lumbar spine structure and the puncture needle inside a patient’s body in real time, enhancing both preoperative positioning and intraoperative puncture procedures. The precision and reliability of these functionalities have been validated through animal experiments in our previous work, and the clinical effectiveness and the standardized surgical protocols for the ARSN system in PELD were further evaluated in the study. Our findings indicate that the ARSN system significantly minimizes the number of punctures and reduces the need for excessive fluoroscopy in PELD. The application of ARSN during surgery proved to be highly safe, with no observed complications and significant postoperative relief. The introduction of AR in spine navigation makes minimally invasive spinal surgeries more intuitive and visible. This technology has substantial potential. This was a preliminary study, and it should be continued. Further research such as the construction of an AR endoscope is anticipated in the future.


Partial androgen insensitivity syndrome is a rare X-linked disorder. While most cases are sporadic, familial cases are less frequent. The management of this syndrome follows a multidisciplinary approach involving hormone substitution, psychological counseling, and surgical procedures. We present a case series of three young siblings with familial partial androgen insensitivity syndrome who presented with a female phenotype. All of them were managed with hormonal treatment for 6 months followed by surgical reconstruction. The operative procedure involved phalloplasty and urethroplasty using amniotic membrane transplant, which is considered a novel technique in this group of patients. No intraoperative or postoperative complications were observed and good results were achieved within 2 years of follow-up. AR gene, which is located at Xq11–Xq12 on the X-chromosome. Most AIS cases are sporadic, resulting from new mutations in the AR gene, while familial cases are seen in only 10–15% of cases [Androgen insensitivity syndrome (AIS) is an X-linked disease caused by a defective androgen receptor (AR) and presents clinically in various phenotypes. The AIS phenotypic spectrum is related to the active ARs and ranges from a complete female phenotype to a male phenotype with undervirilization and/or infertility . The ARsof cases . In thisA 6-year-old female was admitted to the Urological Surgery Department due to a recently detected swelling in the right inguinal region. No pain, nausea, vomiting, or fever were reported. The patient had no medical or surgical history, or family or genetic disorders. On clinical examination, both the right and the left inguinal areas showed slight swelling. The palpation detected no cough impulse or signs of an inguinal hernia, but rather bilateral palpable soft masses in the inguinal canal. Examination of the external genital organs revealed a clitoromegaly with a primitive vestibule and blind vaginal stump . An abdoA 5-year-old female, a sibling of the first patient, was admitted to the Urological Surgery Department with the same manifestations. The examination showed a similar phenotypically female appearance. Furthermore, the investigations confirmed a PAIS with a male karyotype. The patient followed the same management strategy with multidisciplinary consultations, hormonal pretreatment, and subsequent two-staged reconstruction after 6 months. The patient showed no complications or psychological sequelae after a follow-up period of 2 years.During the treatment of the previously mentioned two patients, their mother became pregnant again. After delivery, the one-day-old newborn was brought for evaluation due to the parent’s concerns. Physical examination revealed female external genitalia . FurtherAR gene is located on the XqI1.12 chromosome and mediates the androgens’ activity in expressing the male phenotype [AR gene. On the other hand, familial cases are less frequent and result from inherited mutations, which may affect many members of the family, as in this case series. Familial AIS was reported in ~15 cases in the medical literature. All were related to mutations in the AR gene. McPhaul et al. analyzed the relevant coding segment in a family with a qualitative defect in the AR and confirmed the presence of the same genetic alterations in the family members [et al. reported 14 affected males in one large Chinese family and identified an Arg (840) Cys substitution in the AR gene [et al. identified four affected family members in India with a C 2754 to T transition in exon 6 of the AR gene [exon 7 of the AR gene [http://androgendb.mcgill.ca/) includes >600 mutations involved in AIS [AR gene are single base mutations, mostly missense mutations. Possible clinical indications of AIS can be possibly sustained by a positive X-linked family history [X-linked mutation of the AR gene that was passed to her male offspring. Patients with PAIS exhibit a broad spectrum of manifestations according to the extent of the AR gene mutation [AR gene mutations are found in 95% of CAIS patients, but less frequently with PAIS (28–50%) [AIS is an X-linked genetic disease, which is considered the most common cause of sex development disorders in 46 XY individuals . The synhenotype . Mutatiohenotype . Most ca members . Chu et  AR gene . Kota etd an Arg 40 Cys su history . Therefomutation . Internamutation . In addimutation . Some remutation , 18. Themutation . The hor(28–50%) . There a(28–50%) . The pat(28–50%) . Neverth(28–50%) . General(28–50%) . Surgica(28–50%) . After o(28–50%) . Some co(28–50%) . The fir(28–50%) . Previou(28–50%) . Numerou(28–50%) . In addi(28–50%) . AmniotiFamilial PAIS is an inherited disorder that makes the patient’s phenotype different from his genotype. Appropriate management requires multidisciplinary collaboration and the use of hormonal and surgical therapy. In this article, we presented a case series of three siblings with this syndrome and we reviewed the literature for uncommon familial presentations. The three patients underwent male transformation procedures using amniotic membrane allograft as a novel and advantageous way of covering the urethral defect. More studies are needed to evaluate the applicability of amniotic allografts in urethral reconstruction.


Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance.We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker.In vitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy.AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance.The funding detail can be found in the Acknowledgements section. PROTAC is an emerging therapeutic modality for cancer treatment. Several PROTAC compounds have been reported to target androgen receptor (AR) with demonstrated efficacies toward AR protein degradation and anti-proliferation of prostate tumors in animal studies. Significantly, the ongoing phase 2 clinical study of Arvinas ARV-110 has shown encouraging results of antitumor activity and benefit for patients with metastatic castration-resistant prostate cancer. Most reported AR PROTAC degrade only full-length AR protein. MTX-23 that is derived from a binder of AR DNA-binding domain (DBD), is reported to possess degradation ability towards both full-length and a truncated AR variant, AR-V7. Many preclinical and clinical evidence showed that truncated AR variants, which lack the hormone binding domain for regulation and remain constitutively active, accounts for the major mechanism underlying castration and second-generation anti-androgen drug resistance. Targeting the truncated AR variants has thus been considered an attractive approach to overcome therapy resistance. ESSA Pharma has recently reported AR degraders targeting the N-terminal domain (NTD), capable of inducing truncated AR degradation.We present PROTAC compounds targeting the AR NTD, which commonly exists in full length and all active truncated AR variants. These compounds effectively degrade both forms of AR including at least two species of the clinical relevant, truncated variants in a castration-resistant cell model. In animal studies, we further demonstrate ITRI-90 with a decent oral availability and a strong antitumor efficacy in a therapy-resistant prostate cancer model. Without hormone ablation, single use of ITRI-PROTAC is sufficient to greatly impair tumor growth. Given that compensating hormone synthesis in tumor niche occurs after standard hormone therapy and restrains the efficacies of androgen antagonist drugs, the ability of eliminating all active AR proteins regardless of high hormone environment is an efficient strategy to block AR signaling.AR NTD that governs the activities of all AR variants, has been considered challenging for conventional drug development. This preclinical study shows that PROTAC technology represents an ideal alternative approach to inhibit AR signaling via NTD targeting and subsequent degradation of all active AR forms. The ITRI-PROTAC is anticipated to provide advantages for the intervention of therapy-resistant prostate cancers.As of 2020, prostate cancer is the second most common malignancy and the 5th leading cause of cancer death in men worldwide.,,,,in vitro and shown to regulate a distinct transcriptional program contributing to CRPC and stem cell potential.,,Substantial pre-clinical and clinical evidence shows that expression of constitutively active AR variants (AR-V) that lack the ligand-binding domain (LBD) associates with anti-androgen resistance.,Proteolysis targeting chimeras (PROTAC) is a rapidly developing technology that has become a promising therapeutic modality for cancer treatment, and a number of PROTACs are being evaluated in clinical trials.3CN/H2O with 0.1% TFA or without TFA, flow rate 42 mL/min, UV254 nm). Mass spectra with electronic impact (MS) were recorded from Micromass Quattro triple quadrupole mass spectrometer . Solvents were reagent grade and, when necessary, they were purified and dried by standard methods. Concentration of the reaction solutions involved the use of rotary evaporator at reduced pressure.Starting materials, reagents and solvents were purchased from commercial suppliers  and were used as received without further purification. 1H spectra were obtained on Varian AS500 500 NMR-spectrometer in the indicated solvents. Chemical shifts are expressed in ppm (δ units) relative to TMS signal as internal standard. Flash column chromatography was performed on column packed with Merck silica gel 60 (0.063–0.200 μm). Preparative HPLC was carried out on a Jasco with a UV-975 detector  and KI (0.5 eq) in ACN (0.1 M) was stirred at reflux for overnight. The mixture was filtered with DCM, concentrated and purified by flash chromatography to get 3 or 3a. The structures of compounds 3 and 3a were verified by 1H-NMR (A mixture of 1 (1.0 eq), 2 or 2a (2.0 eq), Ky 1H-NMR .A solution of 3 or 3a (1.0 eq) in DCM/TFA (1/1) was stirred at room temperature for 2 h. Then the reaction solution was concentrated to dryness to give 4 or 4a without further purification.2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by reverse phase preparative HPLC to get ITRI-90 or ITRI-125.A mixture of 4 or 4a (1.0 eq) and VHL HCl salt (1.1 eq) in DMF (0.1 M) was added DIPEA (3.0 eq) and HATU (1.1 eq), the mixture was stirred at room temperature for 5 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by reverse phase preparative HPLC to get ITRI-126.A mixture of 4 (1.0 eq) and lenalidomide (1.1 eq) in DMF (0.1 M) was added DIPEA (3.0 eq) and HATU (1.1 eq), the mixture was stirred at room temperature for 5 h. The mixture was diluted with H1H-NMR : δ 7.10 , 6.85 , 4.31 , 3.99–3.96 , 3.58 , 3.21 , 3.00 , 2.80–2.72 , 1.95–1.85 , 1.82–1.76 , 1.72–1.62 , 1.47 .Yield = 66%. 1H-NMR : δ 7.11 , 6.85 , 4.32 , 3.95–3.93 , 3.52 , 3.23 , 3.01 , 2.82–2.73 , 1.97–1.80 , 1.79–1.76 , 1.73–1.61 , 1.48 , 1.47–1.42 .Yield = 51%. 1H-NMR : δ 8.66 , 7.36–7.32 , 7.18 , 7.10 , 6.83 , 4.72 , 4.57–4.53 , 4.49 , 4.34 , 4.09 , 3.97–3.89 , 3.62–3.56 , 3.21 , 3.02–2.95 , 2.79 , 2.50 , 2.14–2.09 , 2.00–1.92 , 1.86–1.78 , 1.71–1.63 , 1.25 , 0.94 . 13C-NMR , δ(ppm): 174.39, 172.04, 171.74, 161.59, 158.99, 152.80, 148.99, 147.84, 140.23, 138.78, 133.41, 131.48, 130.51, 130.35, 128.94, 128.67, 115.59, 72.61, 71.06, 70.75, 68.69, 60.88, 58.15, 58.09, 43.82, 42.87, 38.92, 37.22, 34.28, 27.39, 27.20, 26.92, 21.10, 17.94, 15.85. ESI-MS m/z:calculated for C45H57F3N9O6S 908.4103, found [M + H]+ = 908.4099.; Purity = 95.4%. LCMS [M + H]+ = 908.3.Yield = 34%. 1H-NMR : δ 8.83 , 7.44 , 7.40 , 7.11 , 6.80 , 4.68 , 4.56 , 4.51 , 4.00–3.92 , 3.87 , 3.80 , 3.56 , 3.19 , 3.03 , 2.95 , 2.77 , 2.45 , 2.25–2.20 , 2.11–2.07 , 1.87 , 1.76 , 1.68 , 1.51 , 0.96 . 13C-NMR , δ(ppm): 174.31, 172.10, 171.71, 161.60, 159.06, 152.82, 149.00, 147.84, 140.21, 138.72, 133.41, 131.48, 130.52, 130.36, 128.95, 128.66, 115.59, 72.86, 71.05, 70.73, 68.84, 60.82, 58.14, 58.05, 57.98, 43.71, 42.87, 38.91, 37.22, 34.27, 30.62, 30.38, 27.06, 27.00, 26.92, 21.10, 17.94, 15.86. ESI-MS m/z: calculated for C47H61F3N9O6S 936.4385, found [M + H]+ = 936.4412.; Purity = 97.2%.Yield = 31%. 1H-NMR : δ 8.30 , 8.07 , 7.74 , 7.49 , 7.10 , 6.84 , 5.18 , 4.46 , 4.11 , 4.01 , 3.59 , 3.21 , 2.99 , 2.84–2.70 , 2.32 , 2.19–2.16 , 1.93–1.87 , 1.70–1.62 . LCMS [M + H]+ = 737.0. 13C-NMR , δ(ppm): 171.03, 169.51, 168.76, 167.76, 158.76, 157.43, 145.12, 137.19, 133.74, 132.77, 131.70, 129.25, 127.65, 125.68, 121.37, 114.51, 71.58, 70.05, 67.44, 51.81, 46.18, 46.03, 41.50, 32.91, 31.44, 26.22, 26.01, 23.27, 20.60, 17.54. ESI-MS m/z: calculated for C36H40F3N8O6 737.3014, found [M + H]+ = 737.3017.; Purity = 95.9%. LCMS [M + H]+ = 737.0.Yield = 51%. 1H-NMR : δ 8.83 , 7.52 , 7.34 , 7.10–7.07 , 6.80 , 4.69 , 4.62 , 4.51–4.45 , 4.29 , 3.97–3.88 , 3.80 , 3.55 , 3.22 , 2.98 , 2.78 , 2.75–2.70 , 2.50 , 2.32 , 2.19–2.14 , 1.91 , 1.84–1.76 , 1.69–1.61 , 0.91 . 13C-NMR , δ(ppm): 172.62, 171.78, 169.88, 158.91, 157.62, 151.30, 147.10, 137.91, 136.93, 132.46, 130.27, 129.60, 128.31, 127.59, 119.23, 117.08, 114.53, 71.45, 71.06, 69.96, 67.44, 59.97, 58.60, 56.35, 46.12, 43.48, 41.58, 35.14, 35.12, 33.00, 26.29, 25.91, 20.46, 17.40, 15.27. ESI-MS m/z: calculated for C45H57F3N9O6S 908.4116, found [M + H]+ = 908.4099; Purity = 99.2%.Yield = 67%. 1H-NMR : δ 8.31 , 7.70 , 7.45 , 7.07 , 6.80 , 5.12 , 4.38 , 4.08 , 3.98 , 3.67 , 3.18 , 3.12 , 2.99–2.86 , 2.81–2.69 , 2.28–2.22 , 2.13–2.10 , 1.97–1.83 , 1.66–1.61 . 13C-NMR , δ(ppm): 171.12, 170.01, 168.81, 167.70, 158.78, 157.40, 137.15, 133.75, 132.90, 131.64, 129.20, 127.61, 125.60, 121.36, 119.30, 117.15, 114.47, 71.55, 70.03, 67.42, 52.44, 46.33, 46.00, 41.47, 32.87, 31.91, 27.08, 26.19, 25.97, 22.60, 20.52, 17.45. ESI-MS m/z: calculated for C37H42F3N8O6 751.3171, found [M + H]+ = 751.3174; Purity = 100%.Yield = 42%. Affinity selection mass spectrometer (ASMS)in vitro stability of the PROTAC compounds was performed in BALB/C (BALB/cAnNCrlBltw) mice plasma. The reactions were initiated by adding 10 μM PROTAC compounds to 0.5 mL of pre-warmed plasma solution. The assays were performed in Thermomixer at 37 °C. During the incubation, 20 μL samples were taken at 0, 30, 60, 120, and 240 min time points, and added to 120 μL of acetonitrile to deproteinize the plasma. After 10 min of centrifugation at 14,000 rpm, the supernatants were collected for subsequent HPLC-UV analysis (Waters 1525 Binary and 2707 Autosampler).The + (1.3 mM), glucose-6-phosphate (3.3 mM), glucose-6-phosphate dehydrogenase (0.4 U/mL), magnesium chloride (3.3 mM) and the test article (1 μM) with 1% (v/v) final concentration of DMSO. The reaction was incubated at 37 °C with shaking. At 0, 10, 20, and 30 min time points, 20 μL of the reaction mixture was taken and quenched immediately with 120 μL acetonitrile. The quenched sample were centrifuged, and the supernatant was then analyzed by LC-MS/MS (ABI4000Q-TRAP). 1 μM warfarin and 1 μM verapamil with same reaction conditions was used as negative and positive control, respectively.The mouse CD-1 pooled liver microsome  was used to test compound stability. The reaction was carried out in 100 mM, pH 7.4 phosphate buffer containing microsome (0.8 mg/mL), NADPR cells were generous gifts from Dr. Allen C. Gao at UC Davis. Parental C4-2B cells were cultured in the RPMI-1640 medium supplemented with 10% FBS, while C4-2B/EnzR cells were maintained in the RPMI-1640 complete medium containing 10 μM enzalutamide. All cell lines were recently validated with STR analysis, and confirmed to be mycoplasma-free by Mycoplasma PCR Detection Kit . Enzalutamide (Enz) was purchased from Selleck Chemicals .Cell lines LNCaP , CWR22Rv1 , VCaP (RRID:CVCL_2235), DU145 (RRID:CVCL_0105), PC3 (RRID:CVCL_0035) and HEK293T  were purchased from ATCC, PNT2 was purchased from Sigma–Aldrich . All cell lines were cultured under conditions as recommended. C4-2B and C4-2B/EnzThe Flag-AR(ΔLBD) plasmid (pLenti4/TO/Flag-TC-AR) was cloned from cDNA obtained from CWR22Rv1 as described in the previous study.To obtain total lysates, cells were lysed in RIPA buffer . The lysates were resolved by SDS-polyacrylamide gel electrophoresis, and the protein expression was analyzed by western blotting using primary antibodies against AR , AR-V7 , GAPDH  and Actin . pLenti4/TO/Flag-AR or pLenti4/TO/Flag-TC-AR plasmid was co-transfected with HA-ubiquitin plasmid into 293T cells. 24 h after transfection, the cells were treated with 10 μM of the PROTAC compounds for 16 h, followed by 4-h treatment of 5 μM MG132. The cells were lysed with lysis buffer  containing 1 ng/mL of N-ethylmaleimide, followed by immunoprecipitation with anti-Flag M2  antibody. The ubiquitinated AR was then detected by western blotting using anti-HA  antibody.KLK3 promoter luciferase plasmid as described previously,LNCaP and CWR22Rv1 cells were seeded in 24-well plates and cultured in RPMI1640 medium containing 10% charcoal dextran-treated-FBS for hormone deprivation 1 day prior to transfection. Cells were co-transfected with RPL13A and GAPDH cDNA levels using Bio-Rad CFX software.TRIzol™ Reagent (Thermo Fisher Scientific) was used to isolate total RNA, and iScript™ cDNA Synthesis Kit  was used for cDNA synthesis. The cDNA expression level of each gene was then quantified by the Bio-Rad CFX Real-Time PCR detection system using iTaq Universal SYBR Green Supermix (Bio-Rad) and primers listed in 50 assessment, the alamarBlue™ Cell Viability Reagent (Thermo Fisher Scientific) was added to cells 7 days after PROTAC treatment, followed by fluorescence detection as the manufacturer instructed. The IC50 was calculated by dose-inhibition regression. For proliferation monitoring, 2, 4, 6 and 8 days after PROTAC treatment (day 0), viable cells were detected by MTT Cell Proliferation Kit I (Sigma–Aldrich) according to the manufacturer's instructions. Cellular caspase activity was measured by Caspase-Glo 3/7 Assay System (Promega) 1 or 2 days after the drug treatment.Cells were seeded in triplicate in 96-well plates 1 day prior to drug treatment for all assays. For viability test and ICAll procedures were performed according to the “Guide for the Care and Use of Laboratory Animals” issued by the National Institutes of Health . The experimental protocols were prepared and approved by the IACUC of Industrial Technology Research Institute before study .In vivo PK analysis of the PROTAC compounds was performed with 2 mg/kg for intravenous injection , 10 mg/kg for intraperitoneal injection , and 10 or 30 mg/kg for oral  dosing route. Blood samples from the mice were collected using Microvette® CB 300 EDTA blood collection tubes by a lancet at 0.167 h (IV only), 0.5, 1, 2, 4, 7 and 24 h time points. The plasma was then subjected to LC-MS analysis to quantitate the drug concentration against calibration curves that were established with drug standards prepared in mice plasma.Six to eight-week-old male BALB/c (BALB/cAnNCrlBltw) mice weighing between 22 and 30 g were purchased from BioLASCO Taiwan Co., Ilan, Taiwan. Prkdcscid/NcrCrlBltw) at 4–6 weeks of age were purchased from BioLASCO Taiwan Co., Ilan, Taiwan. All mice were housed in conventional cages in the AAALAC Full Accreditation (2011) in Industrial Technology Research Institute and were allowed to acclimatize and recover from shipping-related stress for one week prior to the study. The health of the mice was monitored by daily observations. Animals were kept in rooms at temperature of 22–26 °C with 40–70% humidity, positive pressure, 60% air recirculation, ventilation rate 15–20 changes per hour, and a controlled light–dark cycle (12–12 h). The order and location of each animal cage was randomly assigned to minimize potential confounders. CWR22Rv1 cells (5 × 106) were suspended in 100 μL of PBS with 30% Matrigel and subcutaneously implanted into the right flank of male C.B-17 SCID mice. Tumors were measured with calipers, and tumor size was calculated as follows: tumor volume (V) = (L × S2)/2 . When mean tumor volume reached 150–200 mm3, the mice were randomly assigned into indicated groups (n = 5–6/group) and the day of initiating treatments was assigned as day 0. In the study using intraperitoneal (IP) injection, the mice received vehicle control (NMP: Cremophor: PBS = 1:2:7 (v:v:v)), ITRI-90  or ITRI-126  for the indicated days. In the study using oral (PO) gavage, the mice received vehicle control or ITRI-90  for 21 days. Tumor size and body weight of the animals were monitored and recorded two to three times per week. Mice were sacrificed when one of the tumor reached over 1000 mm3 in size. Tumors were collected and immediately subjected to liquid nitrogen freezing and homogenization. The homogenized tumor samples were stored at −80 °C for subsequent western blotting analysis. The drug antitumor efficacy was presented as percentages of TGI of each tested animal, calculated as follows: [1 − /average of ] × 100. Body weight of each mouse was also compared to that on the first day of treatment (day 0) and expressed as a percentage of day 0 value. All data points were included for calculation and the values are presented as mean ± SEM. Statistical analysis of the differences between two drug and vehicle treated groups was determined by two-tailed Student's t test. For negative control, same procedures as described above were followed. PC3 cells (5 × 106) mixing with 50% matrigel were subcutaneously implanted into both flanks of 8 male C.B-17 SCID mice, followed by random assignment for oral administration of vehicle control or ITRI-90 drug  treatment (n = 4/group).Immunodifficient male C.B-17 SCID mice  using AR NTD (221–320) purified protein. A series of EPI compounds, Niclosamide, and AZD3514 were selected as candidates for structure modification and the subsequent warhead screen. The EPI compounds are AR NTD binders proven to inhibit AR signaling by interfering AR-coactivator interaction.rization , Fig. 1ain vitro profiles displayed in ITRI-90 and ITRI-125, ITRI-126, which utilizes the same AR binding moiety but CRBN ligand pomalidomide as E3 ligase-binding moiety was synthesizedin vitro models (CWR22Rv1 and VCaP cells),,50 of these PROTACs for AR degradation is similar across three cell lines within low micromolar range, with the Dmax reaching over 60% and up to 100%. Of note, all three compounds showed higher potency for AR-V7 degradation over AR-FL in CWR22Rv1 and VCaP cells, possibly reflecting a difference of protein stability regulation between full-length and alternatively spliced AR. Conversely, ITRI-126 achieved the lowest DC50 for both AR-FL and AR-V7, suggesting that in agreement with the consensus of PROTAC development, CRBN ligand-based compound with lower molecular weight in nature, may significantly increase the potency compared to VHL ligand-based compounds.Given the promising To understand the temporal kinetics and duration of AR degradation, cells treated with the ITRI compounds were analyzed at different timepoint post-drug removal. As shown in ,Following the evidence showing the dependence of E3-ligase recruitment for AR down-regulation a and b, KLK3. In both LNCaP and CWR22Rv1 cells, DHT treatment after hormone depletion induced the KLK3 promoter activity, whereas the degraders significantly impaired such activation in a dose-dependent manner  gene t manner a. The exreatment b. Genes reatment c. These reatment . These r50 of ITRI-90 and ITRI-125 ranging from 3 to 6 μM, while that of ITRI-126 ranges from 0.07 to 0.4 μM in all three cell lines  profiles. Via intravenous administration, all compounds showed low plasma clearance rate , while ITRI-90 and ITRI-125 achieved a better actual body exposure compared to ITRI-126 with the AUC/Dose being 2502.4 ± 49.2, 2839.9 ± 36.7 and 441.0 ± 37.8 h·ng/mL for 90, 125, and 126, respectively. Given that ITRI-125 showed shorter sustainability towards AR degradation compared to ITRI-90 and ITRI-126 in vitro   . These dy (4.6%) g and h. y (4.6%) i. The any (4.6%) . These d,,AR NTD containing the transactivation domain is the hub for interaction between AR and many proteins including basic transcriptional machinery and co-activators, and governs the transcriptional activities of all AR species. Sadar et al.We presented PROTAC compounds targeting the AR NTD for degradation of both full length and LBD-truncated AR. ITRI-90, ITRI-125 and ITRI-126 which utilizes VHL and CRBN binding ligand, respectively, are valid PROTAC degraders that displayed strong degradation potencies on AR-FL and AR-V(ΔLBD) proteins via a ubiquitin-proteasome system. The degradation of AR attenuated DHT-induced AR transactivation, suppressed gene expression including AR-V7 specific targets, and resulted in efficient growth inhibition specific to cancer cells. The ability of degrade both AR-FL and AR-Vs in cells harboring AR mutation, alternative splicing, and amplification, as represented by the three cell lines used in this study, suggests that targeting the common N-terminal part of these variants for degradation is an efficient strategy to inhibit AR signaling-dependent CRPC cell growth. It should also be noted that targeting AR through DBD-binder-induced degradation such as the case of MTX-23,in vitro, as well as different PK profiles in animal. ITRI-90 and ITRI-126, sharing the same linker, appeared to display longer duration of intracellular efficacy in AR degradation compared to ITRI-125, which contains two more atoms in the linker. Different from a traditional occupancy-based mechanism, PROTAC functions by catalytically recruiting enzyme cascade for POI degradation, hence has the ability to undergo multiple rounds of actions. The duration of PROTAC efficacy in cells may indicate the intracellular drug stability before clearance, thereby affecting target engagement. Strategies to improve intracellular PROTAC stability are inadequately addressed in this field thus far. We speculate that while linker length is crucial for degradation activity,in vitro potencies of protein degradation (DC50) and growth inhibition (IC50) for ITRI-126, presumably due to its lower molecular weight, the overall in vivo PK profile of this compound is inferior to ITRI-90 that utilizes VHL binding ligand. Although ITRI-90 showed higher DC50 compared to other reported PROTAC agents that are in nanomolar range, the therapeutic regimen for ITRI-90 required to suppress tumor growth in the xenograft model is in a reasonable range.The three PROTAC compounds presented here share an identical AR binding moiety, and differ only in their linker length or the E3 ligase binding ligand. Interestingly, these compounds displayed different kinetics and potency for AR degradation in vivo potencies. Moreover, unlike AR antagonist agents whose efficacy can be attenuated by high androgen levels, ITRI-90 by degrading the AR proteins, is sufficient to inhibit tumor growth even in high androgen environment, which is present in CRPC tumors resulting from intracrine steroidogenesis.Despite widely recognized advantages of PROTAC degraders as a therapeutic modality, one aspect that remains challenging is the achievement of oral availability.In summary, this preclinical study presented orally available ITRI-90 PROTAC that targets the AR N-terminal transactivation domain for induced degradation of all active, NTD-containing AR proteins including the clinical relevant AR-V7. ITRI-PROTAC compounds effectively impaired the tumor growth in a castration- and enzalutamide-resistant xenograft animal model. Given that sustained AR signaling attributed to the truncated AR variants or AR overexpression is the major mechanism underlying the therapy resistance in advanced prostate cancer, we anticipate that simultaneously degrading both AR-FL and constitutively active AR-Vs is an efficient alternative approach to intervene CRPC and overcome anti-androgen drug resistance.C.-L.H. and L.-Y.W. designed the research, performed data analysis and interpretation; C.-L.H., H.-J.K. and L.-Y.W. wrote the paper; C.-L.H., H.-H.L., and C.-W.F. performed chemical design and synthesis; H.-H.Y. performed qPCR, ubiquitination, caspase and MTT analysis; L.-Y.W. performed luciferase assay; T.-L.H. and Y.-C.L. performed pharmacokinetics studies; Z.-K.K., and M.-R.J. performed animal studies and Western blot analysis; C.-L.H., C.-S.H. and L.-Y.W. acquired funding; C.-S.H. and H.-C.H. provided critical consultations. C.-L.H. and L.-Y.W. verified the underlying data. All authors read and approved the final manuscript.All data supporting the findings of this study are available from the corresponding author upon reasonable request.All authors have declared that no competing interest exists.


Androgen and androgen deprivation (castration) therapies, including androgen receptor antagonists, are clinically used to treat patients with prostate cancer. However, most hormone-dependent prostate cancer patients progress into a malignant state with loss of hormone-dependency, known as castration (drug)-resistant prostate cancer (CRPC), after prolong androgen-based treatments. Even in the CRPC state with irreversible malignancy, androgen receptor (AR) expression is detectable. An epigenetic transition to CRPC induced by the action of AR-mediated androgen could be speculated in the patients with prostate cancer. Androgen receptors belongs to the nuclear receptor superfamily with 48 members in humans, and acts as a ligand-dependent transcriptional factor, leading to local chromatin reorganization for ligand-dependent gene regulation. In this review, we discussed the transcriptional/epigenetic regulatory functions of AR, with emphasis on the clinical applications of AR ligands, AR protein co-regulators, and AR RNA coregulator (enhancer RNA), especially in chromatin reorganization, in patients with prostate cancer. Prostate cancer is a disease with several symptoms suffering over a million of men worldwide with death of over 0.3 million patients. However, the disease is curable if diagnosed early, with improved overall long-term survival in patients. The early developmental stage of prostate cancer is dependent on androgen. Therefore, hormone deprivation therapy is effective to attenuate cancer development, while adverse effects including hot flashes, anorexia and osteopenia are often seen. As standard treatments, pharmacological and surgical methods are used. Although hormone deprivation therapy is effective at the early stages, later most prostate cancer cases are transited into a hormone-independent prostate cancer state known as castration (drug)-resistant prostate cancer (CRPC) . ChemothAndrogen deprivation drugs, such as androgen antagonists and enzyme inhibitors of androgen biosynthesis, are effective against prostate cancer in the early stages . For exaDespite the clinical application of new-generation drugs, some patients with hormone (androgens) sensitive prostate cancer (HSPC) become insensitive to androgen deprivation drugs after prolonged treatment. The transition from HSPC to CRPC is irreversible and is accompanied by alterations in gene expression profile, which may affect the chromatin landscape or follow the altered chromatin landscape . Over thSOSTDC1 and FLT4, and was associated with prostate cancer development  and EZH1/2 (the sole H3K27 methytransferasess), may play a role , and the other forms serve as endogenous AR ligands with weak biological activities  and other approaches have shown that AR binds with chromatic DNA sequences that often encompass half of the core motif (5′-AGAACA-3′) of ARE (Androgen receptors belong to the nuclear receptor (NR) superfamily consisting of 48 members in humans and act as DNA-binding transcription regulatory factors  Mangels. Similar) of ARE . AR bind) of ARE  (Lupien ) of ARE . The chr) of ARE ; hence, ) of ARE .KLK3 (coding PSA), SGK, and TIPARP ] gene expression in human prostate cancer cell lines (via a liquid-liquid phase separation (LLPS) state  harboring AR binding sites in the target gene loci are important in initiating efficient transcription in response to androgens. Consistently, AR bindings have been identified in the multiple sites over the enhancers of the and KLK4 . Recent and KLK4 . Notablyll lines . MoreoveS) state  (TakayamS) state . The traS) state .CYP17) converting precursors into steroids, leading to the deprivation of locally produced androgen in prostatic tumors (Since prostate cancer is androgen-dependent at early stages, androgen-deprivation therapy is currently used in patients. The most common therapy is based on enzyme inhibitor treatments and AR antagonists , one of c tumors . These eAR antagonists can be classified into two classes, with both classes exhibiting antagonistic actions against endogenous androgens in terms of activation of AR function. However, a recently developed AR antagonist called enzalutamide acts by blocking AR translocation from the cytosol to the nucleus, irrespective of AR binding, in a manner different from the mode of action of the canonical AR antagonists flutamide and bicalutamide . Thus, eCRPC often develops after androgen deprivation therapy, and the acquired hormone resistance is irreversible . Based o