Breast cancer is the leading cancer affecting women in Singapore. Its survivors commonly experience decline in physical function and quality of life post-mastectomy, due to their upper limb morbidity and wound issues. Rehabilitation can address the aforementioned issues. When rehabilitation is accessible and easy to adhere, it can optimize recovery.Home-based tele-rehabilitation guided by healthcare professionals and self-managed by patients can potentially optimize the patients’ adherence to rehabilitation and recovery. With that in mind, a team of breast cancer specialists  in Singapore has developed one of the first tele-rehabilitation systems for local women undergoing a unilateral mastectomy. To our knowledge, no such systems have been evaluated or proven effective as a treatment option among local breast cancer patients with acute disabilities.This is a pilot quasi-experimental trial that aims to evaluate the feasibility of tele-rehabilitation and tele-drain care compared to usual care. Up to 40 patients (20 per group) will be recruited for this trial. They will be assigned to an intervention group that receives rehabilitation via a tele-rehabilitation system or a control group that receives rehabilitation in person at their clinic. The primary outcome of this trial is rehabilitation participation . The secondary outcomes are upper extremity functioning, perceived health, and quality of life.As part of this pilot trial, patients who opt in for the tele-rehabilitation will be asked to share their experience with and thoughts on the tele-rehabilitation system. With the evidence obtained from the tele-rehabilitation patients of this trial, we will be able to improve the current system for our future trial. Further, our additional data on rehabilitation participation, physical function, and quality of life will help us design a sufficiently powered future main trial.www.ClinicalTrials.gov (#NCT04269967) in February 2020.The trial was approved by the National Healthcare Group’s Domain Specific Review Board (#2019/00283) and registered with  Breast cancer is the leading cancer affecting women in Singapore. It accounts for approximately 30% of cancer diagnosis among women in the nation . The majRehabilitation  is known to maintain or improve physical function and QoL . It can When rehabilitation (services) is accessible and easy to adhere, it can optimize patients’ recovery post-surgery. However, a Singaporean mixed methods study of 70 patients discharged from inpatient rehabilitation found their common intention to discontinue their rehabilitation after their hospital discharge due to foreseeable barriers , while the majority acknowledged the benefits of rehabilitation .Telemedicine  refers to the use of telecommunications and technology to deliver health services  outside of traditional settings  . Tele-reThe first aim of this study is to gather preliminary evidence for the feasibility of a tele-rehabilitation and tele-drain care among women who undergo a unilateral mastectomy for breast cancer. The second aim is to understand the lived experience of breast cancer diagnosis, treatment, and recovery process.This is a pilot quasi-experimental trial. Patients will be placed into the intervention group (tele-rehabilitation) or control group  based on their preference. The total length of the study period will be 15 weeks; patients will undergo a 3-week drain care period (post-surgery) which will be followed by a 12-week rehabilitation period. A baseline assessment will be conducted prior to commencing rehabilitation (approximately 3 weeks from the surgery) and a follow-up (exit) assessment will be conducted at the end of their rehabilitation period (approximately 12 weeks from the baseline assessment). An additional qualitative study is embedded within the trial to gain a deeper understanding of the lived experience of women who are diagnosed with breast cancer to achieve the second aim.We plan to recruit up to 40 patients (20 per group) from the Singapore General Hospital (SGH) and National Cancer Centre Singapore (NCCS), where they will be receiving preoperative, surgical, postoperative, and rehabilitation care. Patients are recruited from multiple clinics, under a single healthcare system in Singapore, consisting of a multi-ethnic Asian population.Patients are eligible to participate in the trial when they meet the following four criteria: (i) female 21 years of age and older, (ii) undergoing or underwent a recent unilateral breast surgery (wide excision or simple mastectomy) with lymph nodes removed, (iii) speak and write English or Mandarin, and (iv) no past or active psychiatric condition as assessed by a referring clinician. Patients are ineligible to participate if they meet one of the following four criteria: (i) having breast reconstruction, (ii) having legal blindness or severe visual impairment, (iii) having life expectancy of less than 3 months, or (iv) having previous upper limb injury or conditions that limit upper limb range of motion (shoulder flexion (< 150°) or elbow extension/flexion (< 0/145°) respectively).Potential participants will be approached by a breast care nurse and/or doctor (who will be providing the patient care related to breast cancer and mastectomy) during their pre-operation counseling session. These nurses and doctors will provide their patients with our study invitation letter. The patients will be asked to contact the research team directly using the contact information provided in the study invitation letter if they are interested in the study. Alternatively, if the patients agree, the nurses and doctors will obtain patients’ contact information  which will be forwarded to the research team to initiate contact.If patients agree to participate in the trial, they will complete the informed consent process with a trained member of the research team. The informed consent process can occur anytime between the time of their surgical consultation and 5 days post-surgery. After the informed consent process is completed, patients will self-assign themselves to the intervention group (tele-rehabilitation) or the control group . The prescription and administration of drain care (education) and rehabilitation for both groups of patients are determined and managed by an assigned nurse and therapist per usual practice.All consented patients will be asked to complete two assessments with a trained member of the research team at their home (or at the university where the research is being conducted). The first (baseline) assessment will take place approximately 3-week post-surgery after completing drain-care (education) period . The second (exit) assessment will take place after completing a 12-week physical rehabilitation period   and the following 12 weeks will be for physical tele-rehabilitation . During the physical rehabilitation period, patients (in the tele-rehabilitation group) and/or an assigned occupational therapist may arrange up to five 30-min video conferences .Patients in the control group will receive the same instructions (for drain care education as well as shoulder and arm exercise and self-arm massage) by their multidisciplinary rehabilitation team but without remote support with the tele-rehabilitation and tele-drain care system. Their drain care education and physical rehabilitation sessions will instead take place in-person at their clinic with their assigned nurse and therapist . For the additional qualitative interview, patients will be asked a series of simple open-ended questions which may include the following: (1) tell us about how you navigated your diagnosis, (2) how do you describe rehabilitation that you participated in over the past 12 weeks, and (3) how has your recovery process been—as expected or unexpected? The interview data will be digitally recorded with the patient’s permission and transcribed for qualitative analysis.The secondary outcomes of this trial are upper extremity functioning, perceived health, and QoL. Upper extremity functioning will be measured by shoulder active range of motion (AROM) , arm cirPatients will have their AROM (pain-free) measured for shoulder flexion, extension, and abduction on both arms using goniometry . AROM foThe MUAC will be specifically noted by measuring the arm circumference at the mid-point between the tip of the shoulder and tip of the elbow (acromion and olecranon process) . Each meThe QuickDASH is an 11-item questionnaire designed to assess self-reported disability of the arm, shoulder, and hand among individuals with upper extremity disorders . Its totThe EQ-5D-3L is a questionnaire designed to measure self-perceived health status of individuals . It consThe EORTC QLQ-C30 is a QoL measure specifically designed for cancer patients. It consists of 30 items which form functional scales, a global health status/QoL scale, and symptoms scales  . Scores T test, chi-square test) will be performed to compare the outcome measures between the two groups. We will perform a random data (entry) check by the secondary data management personnel . Missing data will not be replaced or imputed.For quantitative data, we will report means and standard deviations for parametric data, medians and inter-quartile ranges for non-parametric data, and numbers and percentages of all categorical variables for descriptive purposes. Further, inferential statistics  .The data obtained from this pilot trial will be used to estimate a sufficient sample size for our future main trial. The existing literature suggests the minimum sample size of 10 to 15 participants per group  or 10% oOur pilot trial is designed to evaluate the feasibility of one of the first tele-rehabilitation systems for women undergoing a unilateral mastectomy developed in Singapore by a multidisciplinary team . To our knowledge, there is no published trial that assessed and proved the effectiveness of such systems as a treatment option among breast cancer patients with acute disabilities.As part of this pilot trial, patients who opt in for the tele-rehabilitation will be asked to share their experience with and thoughts on the tele-rehabilitation system. With the evidence obtained from the tele-rehabilitation patients of this trial, we will be able to improve the current system for our future trial. Further, our additional data on rehabilitation participation, physical function, and quality of life will help us design a sufficiently powered future main trial. In the long term, if successful, we could have a safe and effective tele-rehabilitation system to implement as part of our regular healthcare services and optimize patients’ recovery in the comfort and privacy of their home as well as at their own convenience.www.ClinicalTrials.gov (#NCT04269967) in February 2020. The study recruitment began in November 2020 and data collection is currently ongoing.The trial obtained the institutional review board approval (#2019/00283) and registered with


RPB10 mRNA and the Rpb10 protein, which correlated with suppression of Pol III assembly defects. Rbs1 is a poly(A)mRNA-binding protein and mutational analysis identified R3H domain to be required for mRNA interactions and genetic enhancement of Pol III biogenesis. Rbs1 also binds to Upf1 protein, a key component in nonsense-mediated mRNA decay (NMD) and levels of RPB10 mRNA were increased in a upf1Δ strain. Genome-wide RNA binding by Rbs1 was characterized by UV cross-linking based approach. We demonstrated that Rbs1 directly binds to the 3′ untranslated regions (3′UTRs) of many mRNAs including transcripts encoding Pol III subunits, Rpb10 and Rpc19. We propose that Rbs1 functions by opposing mRNA degradation, at least in part mediated by NMD pathway. Orthologues of Rbs1 protein are present in other eukaryotes, including humans, suggesting that this is a conserved regulatory mechanism.The biogenesis of eukaryotic RNA polymerases is poorly understood. The present study used a combination of genetic and molecular approaches to explore the assembly of RNA polymerase III (Pol III) in yeast. We identified a regulatory link between Rbs1, a Pol III assembly factor, and Rpb10, a small subunit that is common to three RNA polymerases. Overexpression of Rbs1 increased the abundance of both  Saccharomyces cerevisiae . The yePol III is the largest of the three polymerases. It has additional distinctive subunits at the periphery of the core of the enzyme. They form Pol III-specific subcomplexes, Rpc82–Rpc34–Rpc31 and Rpc53–Rpc37, that function in the initiation and termination of transcription  have lerpc128-1007, in which Rpb10 was also selected . However, Rbs1 also binds to the 3′UTRs of other mRNAs in vivo. Moreover, Rbs1 forms a complex with the helicase Upf1, which is similarly involved in controlling RPB10 mRNA levels. RNA binding requires the R3H domain present in the N-terminal part of Rbs1 protein. We identified Rbs1 homologs in other eukaryotes, including human R3H domain protein 2 (R3HDM2), which is known to interact with mRNA  and isogenic wild type strain MB159-4D, described previously . The following media were used for growing yeast: YPD  and SC . SC-ura, SC-leu or SC-ura-leu contained 20 μg/ml of the amino acids required for growth, except for uracil, leucine or both, respectively. The start liquid cultures were grown overnight in SC-ura SC-leu or SC-ura-leu, transferred to YPD and grown to log phase (OD600 = 0.6). For experiments presented on Figures The t Figure . rbs1Δ aRBS1  and pRS316-RPB10  called here [RBS1] and [RPB10], respectively were described previously  were washed according to the manufacturer's instructions and mixed with the 1.5 mg of lysate. The mixture was incubated at room temperature for 40 min with gentle stirring. Then oligo(dT)25 beads were washed two times with buffer A  and two times with buffer B . Elution was performed by adding 30 μl of 10 mM Tris–HCl, pH 7.5 at 80°C for 2 min with shaking (1000 rpm) in a mixer. 15 μl of sample was separated by 10% SDS-PAGE and analyzed by western blotting.Cells were resuspended with 25 ml of phosphate buffered saline (PBS) containing 0,005% NP40 and transferred to a 10 cm Petri dish and placed on ice. Dishes were exposed to 254 nm UV in a UV crosslinker with 400 mJ/cm2 . Then ce2 . Cells wThe CRAC  analysis was performed as previously described . In brieCells were resuspended in lysis buffer  and lysed by shaking with glass beads for 30 min at 4°C. The lysate was cleared by centrifugation (20 min at 4°C and 14 000 rpm). Protein concentration of extracts were determined with Bradford assay (Bio-Rad). Extracts were divided into two equal parts, one part was treated with RNase A and RNase T1 and the other part was not. Immunoprecipitations were done in parallel. Extract was treated first with 25 units of RNase A (Thermo scientific) and 500 units/ml of RNase T1 (Thermo scientific) and 20 min on ice, before immunoprecipitation. The sample was also treated a second time with RNase A and RNase T1, after adsorption of proteins on beads and washing . DynabeaRNA isolation and northern hybridization; cDNA synthesis and reverse transcription-quantitative PCR (RT-qPCR); protein extraction and western blot analysis were described in the supplementary data. The primer sequences used for northern hybridization and RT-qPCR are listed in the Apteryx mantelli, XP_013815153.1). For further analysis we used R3H domain-containing protein 2 from human and arbitrarily chosen sequences from Xenopus leavis (Xl) and Danio rerio (Dr). Next, we performed a PSI-BLAST search with Rbs1 as a query against the non-redundant database of nucleotide sequences from animals excluding vertebrates, which retrieved multiple sequences from invertebrates, including Drosophila encore. Searches with Rbs1 and DIP1 sequences as queries found 500 homologues form various fungal and plant species, respectively. The sequences from each search were aligned and their redundancy was reduced using Expasy Decrease Redundancy server with similarity threshold set to 60%. The regions corresponding to R3H-SUZ domains were extracted and sequences from all PSI-BLAST searches combined. The final alignment was performed using Promals3D  as queries. Four rounds of PSI-BLAST was performed with the sequence number limit for each round set to 500. In the search with human protein sequence query, all 500 sequences hits were from vertebrates. They were essentially identical (similarity of 95% or higher), with the exception of a sequence from North Island brown kiwi  and Rbs1 ΔC2 of 230 aa (deletion of 231–457 aa fragment). All of mutated RBS1 alleles retained the original reading frame and the modified versions of Rbs1 protein were efficiently expressed  was low. The low SUP11 dosage and resulting red colony color were presumed to indicate that the global low tRNA levels were a consequence of the Pol III assembly defect in rpc128-1007 cells ; their length is estimated for 143 and 365 nucleotides, respectively  mRNA–protein complexes were affinity-purified using oligo(dT)25 beads. Proteins that were associated with mRNA were detected by western blot using Myc-specific antibody. Rbs1 bound with polyadenylated mRNA, whereas only a weak signal of mRNA-bound mutated Rbs1 R3H protein was observed, despite the fact that mutated protein was abundant in the whole cell extract  or SCR1 (lower panel) commonly used as a loading controls in studying NMD-dependent mRNA decay . To allow CRAC Rbs1 was expressed as a fusion with a tripartite tag (His6–TEV protease cleavage site–protein A [HTP]) from the chromosomal locus, which was the only source of Rbs1 in the cell. Wild type, BY4741 strain, expressing untagged Rbs1 served as a negative control. Strains expressing Rbs1-HTP showed wild type growth rates, demonstrating that the fusion protein is functional. The CRAC analysis was performed as previously described (RSpearman = 0.82) and Pearson (RPearson = 0.97) correlation co-efficients.To confirm binding sites of Rbs1 in escribed . The seqescribed . Analysiescribed  as shownRSpearman = 0.7) and Ribo-seq (RSpearman = 0.74) data (To test the correlation level of Rbs1 CRAC data with mRNA abundance and translation level we compared the Rbs1 CRAC data with RNA-seq data  and ribo74) data  reveal dn = 1989). To normalize gene length, we divided each transcript into 120 bins: 10 for the 5′ UTR, 100 for CDS and 10 for the 3′ UTR. All reads mapping to a given transcript were normalized to 1, to construct an unbiased binding profile across all the analyzed transcripts. This analysis revealed that Rbs1 binding has a strong 3′ bias  (n = 1989). The analysis showed that nearly 75% of Rbs1 binding occurs within the 3′ UTR on mRNAs  in CRAC data and constructed metagene profile  . To confs Figure .P value <0.01. To increase number of samples, and therefore statistical robustness of our analysis, we used two technical replicates of Rbs1 CRAC for each biological replicate. Application of filtering criteria allowed us to define high confidence targets of Rbs1 (n = 160)  and the mRNA encoding another Pol III subunit RPC19 .Finally, we focused on mRNAs enriched in Rbs1 binding over RNAseq data. To do this, we applied three filtering criteria: (i) more than 128 RPM in Rbs1 CRAC data, (ii) 1.5-fold enrichment in Rbs1 CRAC data over RNA-seq and ) Figure . Rbs1 pr) Figure  as showeMET13, RPC19, NAM8 and RPB10 mRNAs are presented . No sequence conservation is found in the C-terminal portion of the proteins, outside the RH3-SUZ region, and no easily identified domains are found there. Therefore, the R3H-SUZ portion is likely the main functional module of these proteins.One interesting issue is whether equivalents of Rbs1 play similar roles in other organisms, particularly animals. In order to address this issue, we performed a preliminary search for metazoan Rbs1 homologues using BLAST. Interestingly, this initial analysis revealed not only the conservation of the R3H domain (aa 5–90 in Rbs1) but also in a region located downstream to the R3H domain (aa 124–195 in Rbs1). Further analysis of this region revealed the presence of motifs that are characteristic of the SUZ domain Figure  and C. Tproteins . S. cereNext, we searched the literature for other proteins that would contain an R3H-SUZ domains combination. Alike yeast Rbs1, ARPP21 protein from mouse possess adjacent N-proximal R3H and SUZ domains and a large, unstructured C terminus. ARPP21 is mRNA binding protein which recognizes uridine-rich sequences with high specificity for 3′UTRs. Furthermore, ARPP21 physically interacts with the components of the translation initiation factor eIF4F suggesting a role of ARPP21 in translation .Drosophila melanogaster, both of which were partially characterized. DIP1 interacts with DBF1 protein, which is involved in the response to abiotic stress  mRNA. Importantly, spatiotemporal control of gurken mRNA translation is required for establishing the embryonic body axes. Encore was also implicated in the RNA turnover of bam, another gene that controls differentiation in Drosophila  mRNA-binding protein that interacts with Upf1 helicase and controls Rpb10 expression at the level of mRNA. Both mRNA binding by Rbs1 and the participation of this protein in Pol III assembly depend on the functional R3H domain. Rbs1 is involved in a more general regulatory mechanism that controls mRNA that might be conserved in not only in fungi but also in plants and metazoans, which was suggested by the identification of Rbs1 orthologues in other organisms, including humans.rpc128-1007 mutant that is defective in assembly of the Pol III complex was a successful genetic tool in the present study. A clear growth phenotype of this mutant previously allowed the selection of Rpb10 and Rbs1 as overdose suppressors, and both proteins have been shown to play a role in Pol III biogenesis  has been postulated as a general principle in yeast and mammalian cells . Our novAccording to the current model Figure , Rbs1, bA functional link of Rbs1 with Upf1, the main player in the NMD surveillance mechanism has been provided here by several lines of evidence. The physical interaction between Rbs1 and Upf1 that was identified in previous studies ,23 was cRPB10 mRNA and corrected the Pol III assembly defect in the rpc128-1007 mutant  mRNA is mediated by the R3H domain. One example of a poly(A)-binding protein that contains the R3H domain is the human poly(A)-specific RNase PARN. Remarkably, deletion of the R3H domain prevented PARN from binding to the poly(A) substrate and dramatically reduced cleavage activity .In the light of the above, a natural question is, whether mechanisms of the global control of RNA metabolism similar to the one described in this work operate in other organisms, in particular in metazoans. Our analysis of Rbs1 homologs revealed a presence of proteins with the combination of R3H and SUZ domains in many species of fungi, plants and animals. In these sequences, the only conserved regions are the R3H domain and the SUZ domain with latter containing highly conserved sequence motifs. This implies that the R3H-SUZ region is the main functional module of these proteins. Both R3H and SUZ domains in isolation have been implicated in RNA binding and regulation ,47. Potegkaa1069_Supplemental_FileClick here for additional data file.


The high AR expression group showed superior systemic recurrence-free survival when compared with the low AR expression group (p = 0.027). AR was an independent prognostic factor for both overall survival  and disease-free survival . A high AR expression was a significant favorable prognostic factor only in the subgroups with positive hormone receptors (HRc) and negative human epidermal growth factor receptor 2 (HER2) when considering disease-free survival (p = 0.026). The high AR expression group was significantly associated with superior overall survival and disease-free survival when compared with the low AR expression group with breast cancer patients. AR was a significant independent prognostic factor for both overall survival and disease-free survival. The prognostic impact of AR was valid in the HRc(+)/HER2(−) subtype when considering disease-free survival. These findings suggest the clinical usefulness of AR as a prognostic marker of breast cancer in clinical settings.We investigated the prognostic influence of androgen receptor (AR) on breast cancer. AR status was assessed using immunohistochemistry with tissue microarrays from 395 operable primary breast cancer patients who received curative surgery. The Kaplan–Meier estimator was used to analyze the survival rates and a log-rank test was used to determine the significance of the differences in survival. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI) of survival. There were 203 (51.4%) subjects with a low expression of AR, and 192 patients (48.6%) with a high expression rate. The high AR expression group showed superior overall survival ( The androgen receptor (AR) and its related pathways are emerging as a therapeutic target in breast cancer, and the possibility of AR-targeted therapy in breast cancer is under active investigation . AR exprAR expression is reported to be closely related to clinicopathologic parameters of breast cancer and also related to the prognosis of patients to breast cancer. Efforts have been made to reveal the prognostic role of AR in breast cancer, but the results have been controversial to date. Some studies have reported a favorable prognostic effect of AR ,14,15,16These inconsistencies in the literature regarding the prognostic role of AR in breast cancer precipitated this study. In this study, we investigated the prognostic role of AR in breast cancer patients and looked at both overall survival and disease-free survival. We also investigated the association of AR status with various clinicopathologic features including breast cancer subtypes.Patients with primary invasive breast cancer were prospectively registered in the Boramae Hospital Breast Cancer Registry. In 2012, we made tissue microarrays using cancer tissues from 420 registered patients and designed this study to analyze the data. Three patients were excluded because of duplication. Eleven patients, who were initially diagnosed as having stage IV breast cancer, were excluded. An additional 11 patients were excluded because there was an insufficient amount of remnant tumor tissues for AR staining. Finally, 395 patients were enrolled in this study. Data acquisition and analysis were performed in compliance with protocols approved by the institutional review boards of the Seoul Metropolitan Government Seoul National University Boramae Medical Center . Written informed consent was obtained from all participants prior to the study.The tissue microarrays were constructed with 2 mm diameter cores of formalin-fixed paraffin-embedded tissue blocks from representative tumor areas. Immunohistochemical staining was performed on the tissue microarrays with the DAKO Omnis autostainer  using a rabbit anti-AR (SP107) monoclonal antibody . The results of the staining were evaluated based on the proportion of stained tumor cells and the average intensity of the nuclear staining in the tumor cells. The proportion scores were dichotomously classified as follows: ≤10% of tumor cells vs. >10% of tumor cells. The intensity scores were scored on the following scale: 0, negative; 1, weak; 2, moderate; 3, strong . An AllrAR status was classified as low vs. high using the intensity score with a cut-off value of 10% with immunohistochemistry. The stage was described according to the 8th edition of the American Joint Committee on Cancer. The status of the ER or the PR was interpreted as positive if there were at least 1% positive tumor nuclei in the sample. A sample is considered negative if <1% or 0% of tumor cell nuclei are immunoreactive ,23. The t-test was used to determine the statistical difference of the mean ages, and a Pearson’s χ2 test was used to determine the statistical difference of all of the other baseline characteristics. Recurrence was defined as any first event of local, regional, systemic, and contralateral breast cancer recurrence. The time duration of overall survival was calculated as the time from the initial diagnosis until death from any cause. The time duration for disease-free survival was defined as the time difference from the operation until any recurrence. The Kaplan–Meier estimator was used to analyze the survival rates and a log-rank test was used to determine the significance of the difference between the survival curves. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI). Two models were used for the multivariable analysis. In Model 1, the AR was adjusted for all of the clinicopathologic factors. In Model 2, the AR was adjusted for factors that were significant in the univariable analysis. All of the statistical analyses were carried out using IBM SPSS Statistics, version 20.0 . All of the tests were two-sided and statistical significance was considered when the p-value was less than 0.05.A two-sample The total number of subjects was 395 and their mean age was 53.3 ± 12.3 years . The study was conducted between July 1999 and April 2012. The mean follow-up duration for overall survival and disease-free survival was 120.8 ± 51.0 months  and 87.5 ± 50.5 months , respectively. The event numbers for death and any type of recurrence were 107 and 104, respectively. The subjects with low and high AR expression were 203 (51.4%) and 192 (48.6%), respectively . The higp = 0.004; cut-off value of 10%), the intensity score , another intensity score , and the Allred score , but no significant differences were observed between intensity score 3 and 2, and between intensity score 1 and 0  and disease-free survival (p = 0.004) when compared with the low AR expression group  and Model 2 . The AR was a strong significant prognostic factor for disease-free survival in the univariable analysis  and Model 2 .The AR was a significant prognostic factor for overall survival in the univariable analysis /HER2(−) breast cancer subgroup only  [p = 0.007) [p  =  0.60) [p = 0.002) [p = 0.014) [Previous studies have reported inconsistent results regarding the prognostic role of AR expression in breast cancer. The majority of the previous studies have reported a favorable prognostic effect for AR positivity ,14,15,16= 0.025) . Aleskan= 0.007) ,4. Howev= 0.007) ,17. Agra= 0.007) . Kensler=  0.60) . Zhang e= 0.002) . Jiang eThe proportion of tumors with positive AR expression in breast cancer patients varies widely, and mainly depends on the study population and the definition of AR positivity. The definition of AR status particularly has been highly inconsistent. A study that conducted a systemic review reported that AR-positive tumors accounted for 60.5% of all breast cancers, with a wide range of 28% to 84% . Anotherp < 0.001) and the PR (p = 0.035), but not with the other conventional parameters such as T, N, stage, histologic grade, age, and HER2 [AR status is closely associated with certain clinicopathologic parameters. In this study, a high AR status was significantly associated with favorable clinicopathologic features such as small tumor size and low histologic grade. In particular, the AR status was most significantly associated with the ER/PR status. A significant association between AR and ER/PR has been reported in previous studies. Yu et al. reported that the AR expression was closely associated with the ER , but was associated with worse disease-free survival in the triple-negative subtype (p = 0.014) [p = 0.002) and disease-free survival (p = 0.006) in triple-negative breast cancer patients who received neoadjuvant chemotherapy, but had no association in non-triple-negative breast cancers [AR expression varies across the breast cancer subtypes. Yu et al. reported that AR-positive cases accounted for 83.8%, 75.6%. 55.8%, and 39.0% in luminal A, luminal B, HER2 overexpressing, and basal breast cancer subtypes, respectively [ cancers . In the Among breast cancer subtypes, the triple-negative subtype is of major concern for researchers. Since Lehmann et al. reported that the luminal AR subtype, which was characterized by high expression of AR, accounted for a part of the triple-negative breast cancers , the AR The biological mechanism of AR in breast cancer varies according to its ER status. In ER-positive breast cancers, the AR and the ERα are thought to inhibit each other’s activity via multiple mechanisms for crosstalk between the two receptors . A studyThis study analyzed the detailed information of 395 primary breast cancer patients. The survival analyses and the long-term follow-up are significant strong points of this study. However, this study does have several limitations. First, this study analyzed a relatively small number of subjects, which probably weakened the statistical power. This is especially true for the subgroup analyses, which might have lost statistical significance due to the relatively small number of subjects. Second, this study adopted a cut-off value of 10% of the proportion score using immunohistochemistry to define the AR status. Because the definition of the AR status is crucial for AR studies, we hope that a standardized definition of AR status could be determined in the near future.The high AR expression group was significantly associated with superior overall survival and disease-free survival when compared with the low AR expression group in breast cancer patients. The AR was a significant independent prognostic factor for both overall survival and disease-free survival. The high AR expression group was associated with favorable clinicopathologic features; especially with positive ER and PR. The prognostic impact of the AR was valid in the HRc(+)/HER2(−) subtype when considering disease-free survival. These findings as a whole suggest the clinical usefulness of AR as a prognostic marker of breast cancer in clinical settings.


Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant free survival time for patients with castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved by the US Food and Drug Administration (FDA) for the treatment of both metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019). This is an inspiring drug discovery story created by an amazing interdisciplinary collaboration. Equally important, the successful clinical use of enzalutamide proves the notion that the second-generation AR antagonists can serve as hormonal therapeutics for three forms of advanced prostate cancer. This has been further verified by the recent FDA approval of the other two second-generation AR antagonists, apalutamide and darolutamide, for the treatment of prostate cancer. This review focuses on the rational design and discovery of these three second-generation AR antagonists, and then highlights their syntheses, clinical studies, and use. Strategies to overcome the resistance to the second-generation AR antagonists are also reviewed. Prostate cancer continues to be a main health concern due to the highest incidence and the second highest cancer-related death rate in American men. In 2020, estimates indicate about 21% of all new cancer cases will be attributed to prostate cancer, while over 33,000 deaths caused by prostate cancer are projected to occur in the United States ;,40;36 an step b,  41]. Al. Al36 an42 was subjected to a Strecker reaction with cyclobutanone and the resulting amino nitrile 43 was reacted with isothiocyanate 13 formed in-situ from aniline 17 and 1,1′-thiocarbonylbis(pyridine-2(1H)-one (vide infra). Appending the methyl amide functional group can then be accomplished in several ways  affords amino amide 49, which undergoes the cyclization reaction with thiophosgene in the presence of 8-fold excess of DMAP to provide ester 49 in 28% overall yield [The second strategy focuses on the late stage formation of thiohydantoin core through cyclization of the amino amide otection . Copper-ll yield .12, use of Boc as protecting group for the amino acid 50, and use of 1,1′-thiocarbonylbis(pyridine-2(1H)-one (or phenylthionochloroformate) as thiophosgene alternative for the formation of thiohydantoin core [15  with thiourea in the presence of triethylamine to give thiohydantoin 54. Compound 54 then undergoes two SNAr reactions. Deprotonation with NaH in DMF followed by addition of 4-bromo-3-(trifluoromethyl)benzonitrile (55) furnished compound 56, which is deprotonated again and reacted with aryl bromide 28 to provide enzalutamide  w57 was first reacted with potassium isothiocyanate to give thiohydantoin 58, which was then coupled with aryl bromide 59 to give apalutamide. Both 57 and 58 can be purified by crystallization, which is a significant advantage for process development  acetate-catalyzed Suzuki cross-coupling of 61 with aryl bromide 62 delivers intermediate 63. The nitrogen was deprotected with aqueous acid and reacted with N-protected (S)-(+)-2-amino-1-propanol (64) under Mitsunobu conditions followed by deprotection at low pH to give intermediate 65. The synthesis of darolutamide diastereomers was completed by amide coupling of 65 with carboxylic acid 66 followed by reduction of the methyl ketone with NaBH4 in ethanol.The development of synthesis of darolutamide was mostly focused on process improvements, such as isolation via crystallization, elimination of expensive and hazardous reagents, and the general strategy remained unchanged since the original disclosure  48,49,5,51. The Only those clinical studies directly associated with the US FDA approval of enzalutamide, apalutamide, and darolutamide were highlighted in this review.Enzalutamide  has been approved by the FDA in 2012, 2018, and 2019, respectively, for the treatment of mCRPC, nmCRPC, and mCSPC. Enzalutamide possesses a generally good safety profile and is now widely used as a standard-of-care for the treatment of three forms of prostate cancer. The clinical use of enzalutamide not only helps to better manage prostate cancer but also verifies that androgen receptor signaling continues to be one of critical driving forces for CRPC. Enzalutamide can be sequentially used with other therapeutic methods.The earlier clinical trials of enzalutamide were initiated by its promising efficacy and drug-like properties collected from the preclinical CRPC models. The competitive AR binding capability and clinically effective antitumor activity, together with tolerable safety profile of enzalutamide, were verified in human by a phase I/II study that enrolled 140 patients with CRPC in both pre- and post-chemotherapy settings . The maxWith overall survival as its primary end point, AFFIRM aimed to assess whether enzalutamide can prolong the survival time of patients with mCRPC in a post-chemotherapy setting . The cliInspired by the positive results from AFFIRM and the greater benefit observed in chemotherapy-naïve patients in the phase I-II clinical trial , anotherThe patients with nmCRPC are refractory to ADT treatment and at the onset of metastasis. It has therefore been recognized that new treatment strategies are urgently needed to reduce the risk for metastasis in men with nmCRPC in accompany with a short PSA doubling time. PROSPER phase III trial was designed to investigate whether enzalutamide can meet this need . This stPatients with mCSPC is defined as those who have metastatic prostate cancer that still responds to ADT. Up to 5% of annual prostate cancer incidences belong to mCSPC in the United States . With ADThe promising preclinical data of apalutamide were well-mirrored by its phase I clinical trial ,58. ThirThe SPARTAN trial is a randomized, double blind and multicenter phase III study that evaluated the efficacy of apalutamide in nmCRPC. There were 1207 enrolled men with nmCRPC on ADT with a PSA doubling time of over 10 months randomized to 2:1 to receive apalutamide with ADT or placebo with ADT .The first interim analysis, which concluded in May 2017, determined that there was statistical significance in metastasis free survival (MFS), progression free survival (PFS), time to metastasis and time to symptomatic progression . Due to Disease progression was the most frequent indicator for treatment discontinuation. Only 28% of the treatment group compared to 37% of control experienced cancer progression for discontinuation. Apalutamide treatment led to the extension of the second PFS rate by approximately 11.8 months versus placebo. The four-year second PFS rate for the treatment had a 19% difference when compared to the control . AdverseOverall, apalutamide showed a quarter reduction for risk of death when compared to placebo as well as a higher subsequent life-prolongation, despite crossover. The resulting data for SPARTAN included statistical significance in improving MFS and time to symptomatic progression compared to placebo. The observations that apalutamide delays progression and death when combined with ongoing ADT suggests that the drug may be advantageous to high-risk nmCRPC patients. FDA immediately approved apalutamide for high-risk nmCRPC patients on 14 February 2018 .Apalutamide was approved by the US FDA, after a priority review, on 17 September 2019, to extend its treatment from patients with nmCRPC to those with mCSPC based on the efficacy demonstrated by its TITAN (NCT02489318) phase III trial. This clinical trial was designed as a randomized, double blind and multicenter phase III study and aimed to assess the clinical efficacy of apalutamide in combination with ADT  in patients with mCSPC. A study of 1052 men with mCSPC were randomized 1:1 to treatment and control groups. This involved patients regardless of disease volume and with a history of docetaxel treatment and treatment for localized prostate cancer. At the conclusion of the first interim analysis in November 2018, it was found that 68.2% of patients in the apalutamide and ADT group had a 24-month radiographic progression-free survival compared to 47.5% of the placebo group . The oveIn the lack of direct comparative studies, Chowdhury et al. conducted a matching-adjusted indirect comparison (MAIC) of the efficacy and quality of life of apalutamide to that of enzalutamide in nmCRPC using data collected from SPARTAN and PROSPER trials . A totalIt has recently been recognized that early and effective suppression of AR signaling may serve as a good strategy to manage nmCRPC , which hThe AR is a nuclear receptor and a ligand-dependent transcription factor that regulates the expression of certain specific genes, including PSA. Its most potent native ligand is 5α-dihydrotestosterone (DHT) that is generated by intracellular metabolism of testosterone, an endogenous androgen synthesized primarily in the testes. The DHT-AR binding drives the AR translocation from cytoplasm to cell nucleus where the AR forms dimer and binds to the androgen response elements in DNA. Co-activators (coregulatory proteins) are then recruited to boost transcription, leading to prostate cancer cell proliferation and survival ,3. As shIn spite of the above-mentioned therapeutic benefits of three second-generation AR antagonists in patients with mCRPC, nmCRPC, or mCSPC, a considerable portion of patients are primarily resistant to the treatment. As summarized in The accurate mechanisms of the resistance to the second-generation AR antagonists are still not very clear. Several proposed mechanisms underlying the resistance to the second-generation AR antagonists are summarized in β inhibitor, NCT02452008), AZD5363 (protein kinase B (AKT) inhibitor, NCT0331054), pembrolizumab , and AZD5069  are currently in clinical studies in combination with enzalutamide.Combination therapy through targeting multiple complementary mechanisms of action has been recognized in recent years to be a promising strategy to overcome drug resistance . Taking C-terminal end), the DNA-binding domain , and the transactivation domain  [AR is a nuclear steroid receptor that comprises three functional domains including the ligand-binding domain  . EnzalutNew AR antagonists that still bind to the LBD but with distinct chemical structures can overcome the resistance due to the point mutations, which has been exemplified by the successful story of darolutamide . As abovSeveral compounds that target the TAD or DBD of the AR have been demonstrated to possess potential in treating CRPC, which have been comprehensively summarized in an excellent review article . The EPIHairpin polyamide was developed as an AR antagonist that directly inhibits AR binding to DNA and blocks the transcription processes mediated by AR . HairpinA new strategy to combat the resistance of the second-generation AR antagonists is to target AR protein for degradation, which is a completely different mechanism compared with those for AR antagonists. Additionally, AR degradation has been reported to be a likely prerequisite for prostate cancer tumor shrinkage based on an in vivo experiment . AR degrAdditionally, the association between metformin (an antidiabetic drug) and reduced prostate cancer risk in patients with type 2 diabetics prompted a plethora of investigations on the therapeutic effects of metformin. Metformin is undergoing several clinical trials for prostate cancer, which has been summarized in the literature . The mecIn conclusion, an interdisciplinary collaboration led the discovery of enzalutamide as the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Enzalutamide can significantly prolong not only overall survival time and metastatic free survival time for patients with lethal CRPC, but also castration resistant free survival time for patients with CSPC. Enzalutamide has thus been approved by the US Food and Drug Administration (FDA) for the treatment of both metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019) on the basis of the therapeutic benefits observed from AFFIRM, PREVAIL, PROSPER, and ARCHES Phase III clinical trials. Encouraged by the positive clinical results of enzalutamide, two other second-generation AR antagonists, apalutamide, and darolutamide have recently been approved by the FDA for the treatment of prostate cancer. These three second-generation AR antagonists not only offer patients with different stages of prostate cancer with alternative therapeutics, but also verified that AR signaling pathway plays a pivotal role in the progression of both CSPC and CRPC. Several approaches have been developed for the syntheses of these three second-generation AR antagonists, with three main strategies for the syntheses of the core structure of enzalutamide and apalutamide. The drawback of these AR antagonists as therapeutics for prostate cancer is the drug resistance, which can be developed by reactivating or bypassing androgen receptor signaling pathway. Combination therapies taking advantage of multiple complementary mechanisms of action and targeting AR with other mechanisms may serve as good strategies to overcome the resistance.


Another major resistance mechanism involves a lineage alteration into AR-indifferent carcinoma such a neuroendocrine which is diagnostically characterized by robust 18F-FDG uptake and loss of AR signaling. PCa is also characterized by metabolic alterations such as fatty acid and polyamine metabolism depending on AR signaling. In some cases, AR targeting induces rather than suppresses these alterations in cellular metabolism and energetics, which can be explored as therapeutic targets in lethal CRPC.Metabolic reprogramming is associated with re/activation and antagonism of androgen receptor (AR) signaling that drives prostate cancer (PCa) progression to castration resistance, respectively. In particular, AR signaling influences the fates of citrate that uniquely characterizes normal and malignant prostatic metabolism . The emergence of castration-resistant PCa (CRPC) involves reactivation of AR signaling, which is then further targeted by androgen synthesis inhibitors (abiraterone) and AR-ligand inhibitors . However, based on AR dependency, two distinct metabolic and cellular adaptations contribute to development of resistance to these agents and progression to aggressive and lethal disease, with the tumor ultimately becoming highly glycolytic and with imaging by a tracer of tumor energetics,  Normal cells gain distinctive capabilities to overcome the restrictions in the tissue of origin to initiate primary tumor formation –3. The p“The Warburg effect (aerobic glycolysis)” observed by Otto Warburg nearly a century ago is the phenomenon that cancer cells preferentially convert most glucose to lactate even in the presence of oxygen by which mitochondrial oxidative phosphorylation can proceed to generate ATP more efficiently, 10. HisProstate cancer (PCa) is unique from a metabolic perspective. Ironically, the normal prostatic epithelial cell is one of the best cell types that fit to the original Warburg’s theory: mitochondria must be dysfunctional to get higher rate of glycolysis. Instead, primary PCa does not exhibit the Warburg effect. Contrary to other cancer cells, malignant transformation involves the conversion from energy-inefficient (“glycolytic”) secretory epithelial cells to energy-efficient (“oxidative”) PCa cells –20  plays pivotal roles in both normal and malignant prostate cells. Indeed, AR transcriptional program supports PCa viability during the course from primary tumor formation to progression to metastasis. AR has the capabilities of regulating virtually all aspects of cellular metabolism  –24. ConvUnderstanding of the relationship between these distinctive metabolic features and AR signaling in PCa will lead to identification of metabolic vulnerabilities that offer the opportunity for diagnosis and therapy. In this review, we will characterize metabolic phenotypes of PCa in relation to AR signaling and review the current knowledge of metabolism-based imaging tools and therapeutic interventions to target cancer metabolism.Androgens are hormones required for development and maintenance of the male reproductive system. The functions of prostatic cells in both normal and malignant condition have been characterized by the relationship to the status and availability of androgen and its cognate receptor AR. Upon binding to androgen, AR which is otherwise sequestered in the cytoplasm translocates to nucleus and acts as sequence-specific dimerized transcription factors .The unique metabolic processes in the prostate are well adapted to fulfill the major function as a secretory tissue to generate prostatic fluid comprised of high concentration of citrate along with zinc, lipids, and kallikrein enzymes including prostate-specific antigen (PSA) , 38 Fi.The normal human prostate retains the capability of accumulating the highest levels of zinc in any soft tissue of the human body through expression of specific zinc transporters (ZIP1–4 for uptake and ZnT1–10 for release) . High le18F-FDG in primary PCa  define the AR as a master regulator that orchestrates cellular metabolism to fuel proliferation and growth of PCa cells , 48, 49.13C magnetic resonance spectroscopic imaging (MRSI) demonstrates that in vivo conversion [1-13C] lactate into [1-13C] pyruvate occurred more efficiently in PDX models of AR-driven CRPC than those of AR-negative PCa  and pyruvate flux into mitochondria  , 42, 50.tive PCa . Monocartive PCa . OverallAR regulates FA metabolism by controlling expression of more than 20 enzymes involved in many aspects of lipid metabolism, including uptake, trafficking, synthesis, and degradation , 49.de novo lipogenesis and permits incorporation of dietary FA enriched in polyunsaturated FA which are prone to lipid peroxidation when subjected to oxidizers such as arsenic trioxide (AR and the master regulator of lipid homeostasis sterol regulatory-element binding protein (SREBP) regulate each other in a positive feedback system , 56, 57.trioxide , 61.de novo or exogenous FA  is the dominant energy producing pathway through decomposition of enous FA –65. Bothenous FA , 63. Thienous FA . Neverthenous FA . Moreoveenous FA . More exenous FA .On the other hand, there is growing body of evidence that PCa utilizes exogenous FA derived from diet or adipocytes –72. Blocvia glutamate production as an alternative energy source, providing pharmacological glutamine starvation as a therapeutic strategy  , 73–76. strategy , 77–80.S-adenosyl-methionine (SAM), the universal methyl donor for protein and DNA methyltransferase reactions, and methionine cycle  which interact with trans-sulfuration pathway  and polyamine synthesis  –83. The reactions. Thus, treactions. As discreactions.Dependence of AR on reprogrammed metabolic characteristics occurs in FA and ornithine metabolism. AR signaling is blunted when genetic or pharmacological inhibition of the rate-limiting enzymes in the pathways, such as ODC1, FASN, and CPT1 , 68, 82.Since 1950s, inhibition of AR activity has remained a mainstay in the treatment of advanced PCa –89. Althde novo steroidogenesis, which involves upregulation of enzymes required for stepwise synthesis from cholesterol to T and DHT (4-androstenedione (AD) by 3β-hydroxysteroid dehydrogenase/isomerase (HSD3B1) in PCa (5α-Reduction of testosterone (T) in prostate results in the formation of the more potent ligand dihydroxytestosterone (DHT) to activate AR. Thus, ADT is the frontline treatment and directed toward disruption of T-DHT-AR axis by suppression of gonadal T by medical or surgical castration . Resista and DHT , 111. An) in PCa , 26. AD ) in PCa , 113. Th) in PCa . The resvia reductive carboxylation  radiotracers in the PCa field  used as indicator of AR(-FL) expression  whose uptake is driven by mitochondrial membrane potential (ΔΨm)  . Thus, cAs discussed above, PCa develops adaptive resistance to AR-targeting therapy through two distinct groups of mechanism based on AR dependency. In addition to alterations in AR structure of function, AR-dependent mechanism involves aberrant pre-receptor metabolism of steroids which is arguably unique to CRPC. AR-independent paths include transdifferentiation into NEPC and DNPC. Nevertheless, advanced CRPC, NEPC, and DNPC are ultimately addicted to aerobic glycolysis which is associated with high avidity of FDG in PET scan , 35. IroTwo biological events are emerging as hallmarks of cancer: reprogramming of energy metabolism and evading immune destruction . The latTherapeutic targets in cancer metabolism in many cases exist even in the normal cells, which adds potential toxicity and non-specificity to drugs targeting metabolic pathways . It is nWe have described how PCa is unique from other cancers from the metabolic point of view. In addition, AR signaling persists in normal and malignant prostatic cells except for when AR antagonism triggers the transition to highly glycolytic AR-indifferent carcinoma. AR determines virtually all aspects of cellular metabolism while a selected phenotype is dominant depending on the stage of disease progression. Accordingly, the question remains as to what directs AR toward specified metabolic preference. The underlying mechanisms may include the presence of AR-Vs, differential actions of AR co-regulators, epigenetics, and tumor microenvironment. Understanding and targeting the selective AR-metabolome axis may provide the unique therapeutic opportunity for AR-driven CRPC which is resistant to current anti-AR therapy.11C acetate uptake suggests tumors are lipogenic. High avidity to 18F-FDG is supported by expression of glycolytic gene signature in NEPC, providing a rationale to target glucose metabolism for therapy. Tumor plasticity adds another layer of complexity to PCa as it develops and spreads. Altered metabolic pathways may be dispensable or indispensable depending on the stage of tumor progression. This is true for de novo FA synthesis whose pharmacological inhibition is detrimental in some cases (antitumorigenic regardless of availability of exogenous lipids) but tolerable in others   , 163. Netissues) , 70.To develop effective metabolism-based target therapy , it is cTU and SRP conceived and wrote the manuscript. All authors contributed to the article and approved the submitted version.VA merit review award (I01BX003324) and DoD award  to SRP. NCI P50 CA097186, and the Institute for Prostate Cancer Research at the University of Washington and Fred Hutchinson Cancer Research Center.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Neurorehabilitation for stroke is important for upper limb motor recovery. Conventional rehabilitation such as occupational therapy has been used, but novel technologies are expected to open new opportunities for better recovery. Virtual reality (VR) is a technology with a set of informatics that provides interactive environments to patients. VR can enhance neuroplasticity and recovery after a stroke by providing more intensive, repetitive, and engaging training due to several advantages, including: (1) tasks with various difficulty levels for rehabilitation, (2) augmented real-time feedback, (3) more immersive and engaging experiences, (4) more standardized rehabilitation, and (5) safe simulation of real-world activities of daily living. In this comprehensive narrative review of the application of VR in motor rehabilitation after stroke, mainly for the upper limbs, we cover: (1) the technologies used in VR rehabilitation, including sensors; (2) the clinical application of and evidence for VR in stroke rehabilitation; and (3) considerations for VR application in stroke rehabilitation. Meta-analyses for upper limb VR rehabilitation after stroke were identified by an online search of Ovid-MEDLINE, Ovid-EMBASE, the Cochrane Library, and KoreaMed. We expect that this review will provide insights into successful clinical applications or trials of VR for motor rehabilitation after stroke. Stroke is one of the leading causes of disability and socioeconomic burden worldwide . AlthougUpper limb hemiparesis is one of the most common impairments after stroke  and is aVirtual rehabilitation using virtual reality (VR) technology is a novel promising modality for motor rehabilitation after stroke  that canIn this comprehensive narrative review of the application of VR in motor rehabilitation after stroke, we will cover (1) the technologies used in VR rehabilitation including sensors, haptic devices, and VR displays; (2) the clinical application and evidence for VR in motor rehabilitation in stroke; and (3) considerations for VR application in stroke rehabilitation. We expect that this review will provide insights into successful clinical applications or trials of VR for motor rehabilitation after stroke.VR technology can give users the experience of being surrounded by a computer-generated world. With VR, users experience inclusive and extensive surroundings, with vivid illusions of a virtual computer generated environment in which both realistic and unrealistic events can occur. So, users can interact as though they are in a real environment and may not even recognize that they are existing in a virtual environment . TherefoNon-immersive VR allows users to experience a virtual environment as observers and interact with the virtual environment by using devices that cannot fully overwhelm sensory perceptions , which rImmersive VR, on the other hand, improves the feeling of presence, enabling people to feel more like they are actually in the virtual environment, which means that users are more likely to interact with the stimuli given by the computer and related devices providing visual, auditory, and haptic sensations. The main goal of immersive VR is to make it possible for users to experience the illusion of being in the computer-generated environment rather than the real-world environment. By wearing a head-mounted display (HMD), tracking devices, haptic devices, and data gloves and by using wireless controllers, users can be placed in virtual environments and interact with a computer-generated world. However, the real world has a greater variety of senses including smell, taste, the feeling of warm and cold, etc., which may increase the gap between the virtual and real worlds. These could be further covered by complete immersive VR, but the need for a sophisticated artificial stimulator to provide variable sensations may require more space and have a higher cost. HMD-based immersive VR could also be enriched using physical objects or devices placed in the physical space by tracking their positions precisely in relation to where the user stands. By using this paradigm, the user could perceive the texture or temperature of objects without any awkwardness when touching it because the physical object is tracked to be placed at the same position as that in the virtual space; thus, the user touches the physical object when they touch the virtual object. Another issue to overcome is that the user must be placed in a limited space; therefore, their walking area is constrained. Using a VR treadmill allows users to physically walk or run toward any place in a virtual environment by solving two problems: realistic synchronized simulation of the user’s walk and no requirement for a large space. The Cave Automatic Virtual Environment (CAVE) has been introduced as another way to provide visual information for immersive VR, instead of using an HMD . CAVE usImmersive and non-immersive environments can be better differentiated by their level of immersion. Immersive VR strengthens the level of immersion because less mental effort is required to be immersed in the virtual environment since the hardware systems cover most sensory perceptions. In contrast, non-immersive VR requires more mental effort to be immersed in the virtual environment. Therefore, non-immersive VR may reduce the level of spatial presence, which is defined as “the sense of being in an environment” ,26.Virtual rehabilitation is a method of rehabilitation via gamification through synchronization with software content or by providing a motion guide. Various studies have been conducted to investigate the application of VR for upper limb rehabilitation .For motor rehabilitation of limbs, the patient’s body part must be captured by motion tracking sensors and synchronously transferred to an object in VR. Sensors to track the patient’s motion are mandatory for movement visualization and can be selected from a mouse and joystick, depth-sensing cameras, electromagnetic sensors, inertial sensors, bending sensors, data gloves, and so on. The sensor performance is important to precisely track the motion, but the subjective perception and preferences are also important factors to be considered, in addition to cost .A sensor technology that recognizes motion is essential for virtual rehabilitation. Such technologies are divided into wearable and nonwearable devices that recognize upper limb rehabilitation motions. Nonwearable devices are further divided into those using a vision sensor and those using a robot-based controller or a controller with three degrees of freedom (DOF) either alone or in combination. Wearable devices are usually divided into those using data gloves and those using an exoskeleton. Some studies have used both types together. Sensing using cameras in nonwearable devices has recently changed from tracking markers or color patches using webcams to tracking body or hand signals through depth sensing methods. In this way, the users’ movements are sensed within a limited space without obstacles. With wearable devices, the sensor is attached to collect high frequency data and force or torque can be tracked as well as position and movement.Most studies have primarily used visual and auditory feedback through content and some studies have applied tactile and force feedback (which are haptic feedback). We divided the studies into visuomotor and visuohaptic feedback. Visuomotor feedback provides visual information by applying measured movements through sensors to content in real time. Visuohaptic feedback refers to providing haptic feedback with visual information. Haptic feedback could be divided into tactile or force feedback, depending on whether resistance is present. Tactile feedback provides feedback to users through the sense of touch using vibration, skin deformation, or small forces. Force feedback, or kinesthetic force feedback, simulates real-world physical touch using motorized motion or resistance rather than by fine touch . ResearcCommercialized virtual rehabilitation devices that can provide gamification through content or rehabilitation guides are similar to those used in VR rehabilitation research, but they are simplified and more focused on ease of use. Sensing methods are divided into wearable and nonwearable methods using cameras, joysticks, and robots .Studies for upper limb VR rehabilitation after stroke were identified by an online search of Ovid-MEDLINE, Ovid-EMBASE, the Cochrane Library, and KoreaMed on 18 June 2020. The search queries are presented in The general characteristics of the included meta-analyses are presented in The interventions were VR rehabilitation and the controls were either conventional therapy (dose-matched or not) or no intervention . VR rehaIn one high-quality meta-analysis from 2014, VR rehabilitation showed better improvements in body function (standardized mean difference (SMD) = 0.43, 95% confidence interval (CI) = 0.22 to 0.64) and activities  when compared to conventional therapy . When VRHMDs give users a more immersive experience in a 3D artificial world and allow interaction with virtual objects using motion tracking sensors. Considering the therapy time and active motion during the rehabilitation, the HMD must be light, comfortable to wear, positioned stably on the head, and cool enough during operation . The HMD may also benefit from being wireless (with enough battery life). Although VR rehabilitation can induce eye strain or physical fatigue during extended therapy, the most common issue to overcome is motion sickness. Motion sickness can be elicited when there is a lag in processing the visual response to user input interactions, resulting in conflicting signals to the brain from the eyes, vestibular systems in the inner ear, and proprioceptive sensory receptors (sensory conflict theory) . Motion The movement kinematics of the upper limb in patients with stroke differ between VR and real environments. Viau et al. reported that patients with hemiparesis used less wrist extension and more elbow extension at the end of the placing phase during reaching, grasping, and performing tasks in VR than in a real environment . SimilarThe transfer of improved function after rehabilitation to the performance of activities of daily living is important in upper limb rehabilitation after stroke. Constraint-induced movement therapy (CIMT) comprises repetitive tasks/shaping practice with constraint of the hemiparetic upper limb, emphasizing the transfer package to foster compliance and use of the hemiparetic upper limb in the real world as a key component to improve function following CIMT . TherefoThe transfer of learning effects in VR to real environments is inconclusive. Rose et al. showed that the effect of simple sensorimotor task training is comparable between VR and real environments . HoweverGamification has been broadly and clearly defined as the “use of game design principles in non-game contexts” by Deterding et al. . GamificIn addition to the barriers caused by patients , it has been suggested that there are also barriers at the therapist level, which can lead to underuse of VR rehabilitation . Glegg eNeuroplasticity is the ability of the human brain to adapt to certain experiences, environments, and extreme changes, including brain damage ,99,100. The brain-computer interface (BCI) is one method used to improve neuroplasticity after stroke; it is based on motor imagery, which is defined as the mental simulation of a kinesthetic movement. The BCI provides sensory feedback of ongoing sensorimotor brain activities, thereby enabling stroke survivors to self-modulate their sensorimotor brain activities . BCI forAnother novel strategy to increase neuroplasticity using noninvasive brain stimulation, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), has also been suggested by various researchers ,106,107.Together with BCI and noninvasive brain stimulation, a telerehabilitation approach may also be important for motor rehabilitation after stroke in terms of better accessibility and prolonged usage at home. Telerehabilitation, by definition, can provide the inputs of multidisciplinary skilled personnel for rehabilitation, including physiatrists, physiotherapists, and occupational therapists, which are often unavailable at home or challenged by transportation restrictions for disabled patients . A recenVR-based rehabilitation is a promising tool to actively engage patients in the rehabilitation program and can lead to better motor recovery. Although current clinical evidence shows that VR-based rehabilitation is beneficial as an adjunct therapy to convenient rehabilitation therapy, the interventions in the studies included in the meta analyses were heterogeneous and it is unclear who benefits more from VR rehabilitation  and what type of VR  and feedback is more effective. Further research including large well-designed RCTs to find the factors influencing the effects of VR rehabilitation are required.To improve the efficacy of VR-based rehabilitation, VR rehabilitation is designed to improve the transfer of VR training to real environments, gamification, and feedback to promote active patient participation and neuroplasticity is necessary. The user interface and user experience must be designed to be more user-friendly to patients and therapists, considering both the patient’s physical and cognitive impairments and therapists’ needs. VR can be integrated into novel therapeutic modalities that can enhance neuroplasticity  and is expected to induce better recovery by combinational approaches, which warrant further investigation.


Testis (T) and epididymis (E) are waste from the abattoir that is rarely used. In fact, both organs contain important chemicals needed for spermatogenesis . Therefore, administration of a combination of testis and epididymis (CTE) extracts may activate androgen receptors (AR) and protein kinase A (PKA) molecules that play a prominent role in spermatogenesis. We, therefore, aimed at investigating the influence of the CTE extracts on the concentration of AR and PKA in male chicken.th day; we collected and processed blood samples as serum to measure the AR and PKA concentrations using commercial chicken AR and PKA enzyme-linked immunosorbent assay kits, respectively. We performed analyses by analysis of variance using SPSS 20.0.This study used a completely randomized design with four treatment groups  and five replications per group. K0 is a control group that received 1 mL normal saline, whereas K1, K2, and K3 are the test groups that received 1, 2, and 3 mL of CET extracts, respectively. Twenty male chickens (strain: broiler Mb 89), 3 weeks of age, weighing 500-700 g were used. We administered the injections in a 13-day period and on the 14The AR concentrations in K1, K2, and K3 groups increased by 4.26%, 10.97%, and 28.04%, respectively, compared to the K0 (control group). However, this increase was not significantly different between the groups (p>0.05). Moreover, the PKA concentrations increased by 2.97%, 2.60%, and 4.08% in K1, K2, and K3 groups, respectively, compared to the control group. However, this increase was not significantly different between the groups as well (p>0.05).The CTE extracts tended to increase the AR and PKA concentrations even though it is not significant. Therefore, it needs further study when using the CTE extracts for spermatogenesis in male chicken. Nowadays, the number of slaughtered animals, including goats at abattoirs, is on the rise to meet up with meat demands from communities. This has an impact on the increase of by-products, such as testes (T) and epididymis (E). However, the use of T and E is still very limited. Unknowing to many, both organs contain hormones  ,2 and ot2+) pathways, which, in turn, induce a cAMP response element-binding (CREB) protein [2+ can stimulate protein kinase C (PKC) pathways, guanine nucleotide exchange factors (GEFs), or PKA that stimulates Ras (or Ras-like GTP binding protein) resulting in MAPK pathway activation [2+ during capacitation and spermatozoa-acrosome reaction [2+, bicarbonate, and hydrogen peroxide. These collectively activate adenylyl cyclase to generate a cAMP. It then drives PKA to phosphorylate specific molecules [Androgen action is mediated by receptors called androgen receptors (AR) ,16. Sign protein . MAPK is protein . On the tivation . PKA inftivation . It alsotivation , and in reaction . The capolecules . Thus, colecules .et al. [et al. [The previous studies reported that the administration of E-extract enhances estrogen , and teset al.  found th [et al. , which s [et al. .In the current study, we aimed at investigating the effect of the administration CET extracts on the increase of AR and PKA concentrations in order to support the spermatogenesis in male chickens.All animals used in this experiment were approved by the Animal Ethics Committee of the Faculty of Veterinary Medicine, Universitas Syiah Kuala (Ref: 17/KEPH/IX/2018).This study was conducted from May to October 2019. Chickens were reared in a cage at teaching farm (UPT Hewan Coba), Faculty of Veterinary Medicine, Universitas Syiah Kuala.et al. [The extraction procedure of E and T was performed as described by Akmal et al. . In brieth day, the chickens were euthanized, and necropsied to gather serum for AR and PKA measurements. During the study, the chickens were given feed and water ad libitum.Twenty male chickens (strain: broiler Mb 89) were included, aged 3 weeks, weighing 500-700 g, and divided into four groups. We adopted a randomized sampling method to obtain four intervention groups  with five replications per group. K0 is a control group that received 1 mL normal saline, while K1, K2, and K3 are intervention groups that received 1, 2, and 3 mL of the CET extracts, respectively. Before interventions, chickens were acclimatized for 7 days for environmental adaptation. Then, they received intramuscular injections of 1 mL of normal saline for K0 (control group), whereas K1, K2, and K3 received intramuscular injections of 1, 2, and 3 mL of the CET extract, respectively. The administrations occurred for 13 days and on the 14We measured chicken AR concentrations using a commercial chicken AR enzyme-linked immunosorbent assay (ELISA) kit  following the instruction of the manufacturer. We assayed the duplicate 50 μL AR standard into a standard well (dose range 1.25-40 ng/mL). Then, we filled the duplicate 40 μL sample (serum) into sample wells, and added 10 μL anti-AR antibody. Hereafter, we added a 50 μL streptavidin-horseradish peroxidase (HRP) to the standard and sample wells, and then thoroughly mixed. Then, we covered the microplate tightly with a microplate sealer and incubated for 60 min at 37°C. After incubation, we removed the microplate sealer before been washed 5 times with 350 μL washing buffer. Thereafter, we blotted towel paper or other absorbent material. Then, we added 50 μL of substrate A and 50 μL substrate B into each well in the microplate. The microplate was covered with a new sealer and reincubated for 15 min at 37°C in the dark. We stopped the enzyme reaction using a 50 μL stop solution. Finally, we performed absorbance measurement using a microplate reader at 450 nm. Therefore, we calculated chicken AR concentrations using the Microplate Manager-6 (MPM-6) Software .Chicken PKA concentrations were measured using a commercial Chicken PKA ELISA kit  following the instruction of the manufacturer. We assayed duplicate 50 μL PKA standard into the standard well (dose range 2.5-80 ng/mL). Afterward, a 40 μL duplicate sample (serum) was filled into the sample wells and then received a 10 μL anti-PKA antibody. Thereafter, we added a 50 μL streptavidin-HRP to the sample and standard wells, and mixed thoroughly. We covered the microplate with a sealer and incubated it in 60 min at 37°C. After incubation, we removed the sealer and washed it 5 times with 350 μL washing buffer. The microplate was then blotted by a towel paper or another absorbent material. We then added with 50 μL substrate A and 50 μL substrate B to each well in the microplate. Hereafter, we covered the microplate with a new sealer and reincubated it for 15 min at 37°C in the dark. After this, we stopped the enzyme reaction using a 50 μL stop solution. Finally, we determined the absorbance using a microplate reader at 450 nm. Therefore, we calculated chicken PKA concentrations using the Microplate Manager-6 .We performed data analysis by a one-way analysis of variance (ANOVA) using Statistical Package for the Social Sciences (SPSS) version 20.0 . Statistical significance was set at α<0.05.The serum AR concentrations of K0, K1, K2, and K3 were 0.32 ± 0.03 ng/mL, 0.34 ± 0.05 ng/mL, 0.36 ± 0.10 ng/mL, and 0.42 ± 0.09 ng/mL, respectively . The serThe serum PKA concentrations of K0, K1, K2, and K3 were 0.53±0.01 ng/mL, 0.55±0.04 ng/mL, 0.55±0.02 ng/mL, and 0.56±0.01 ng/mL, respectively . Serum PThe current study demonstrates the effect of CET extracts (obtained from the abattoir) on the serum concentrations of AR and PKA in male chicken. Serum concentrations of AR and PKA showed no significant differences between the test and control groups. However, serum AR and PKA concentrations in test groups experienced an increase of 4.26-28.04%, and 2.97-4.08% compared to the control group.The results of this study are closely related to the previous studies in that we can use CET extracts to support the spermatogenesis in male chickens revealed by a significant increase in the serum testosterone concentration after given CET-extracts . We beli2+. Testosterone activates Ca2+ influx into the Sertoli cells causing calmodulin to translocate to the nucleus and slowly phosphorylate CREB in about 60 s. Slowly, Ca2+ also triggers the PKC, GEFs, or PKA, to stimulate Ras or Ras-like GTP binding protein needed to begin the MAP kinase pathway. The MAP kinase and Ca2+ pathways can induce phosphorylation of CREB and CREB-mediated gene expression in the Sertoli cells [The previous studies revealed that the testosterone-AR complex affects two molecular pathways; the MAP kinase and Cali cells . Other sli cells . Therefoli cells , which fli cells . Our preli cells , testostli cells ; meanwhi2+ channels on the outside of the acrosomal membrane thereby leading to a slight increase in intracellular Ca2+ [2+ pathway and cAMP-dependent PKA pathway are responsible for spermatozoa motility [The testosterone-AR complex in the cytoplasm of Sertoli cells influences adenylate cyclase to stimulate cAMP, which, in turn, drives PKA to open Calar Ca2+ . This inlar Ca2+ . The PKAlar Ca2+ . CREB anlar Ca2+ . Converslar Ca2+ . Furthermotility  and malemotility .A possible limitation of our study was its small sample size. The serum concentrations of PKA and AR increased in the test groups. However, this increase was not significant. Therefore, we recommend studies with larger sample sizes, to obtain a reliable effect of the CET administration on serum PKA and AR concentrations.Finally, the molecular signaling pathway mechanisms in spermatogenesis are very complex and require more explorations in future studies. Moreover, recent evidences depict that the administration of CET extracts supports the process of spermatogenesis in the male chicken.The CET extracts tended to increase the AR and PKA concentrations even though it is not significant. Therefore, it needs further study when using CET extracts for spermatogenesis in male chickens.MA and GG designed the experiments. MA, MKN, and SW performed the experiments. GG measured the AR and PKA concentration. DM and MAY provided logistical support for the experiments. MA and RR analyzed the data. MA and GG wrote the manuscript. All authors read and approved the final manuscript.The authors declare that they have no competing interests.Veterinary World remains neutral with regard to jurisdictional claims in published institutional affiliation.


This paper presents a detailed review of the applications of augmented reality (AR) in three important fields where AR use is currently increasing. The objective of this study is to highlight how AR improves and enhances the user experience in entertainment, medicine, and retail. The authors briefly introduce the topic of AR and discuss its differences from virtual reality. They also explain the software and hardware technologies required for implementing an AR system and the different types of displays required for enhancing the user experience. The growth of AR in markets is also briefly discussed. In the three sections of the paper, the applications of AR are discussed. The use of AR in multiplayer gaming, computer games, broadcasting, and multimedia videos, as an aspect of entertainment and gaming is highlighted. AR in medicine involves the use of AR in medical healing, medical training, medical teaching, surgery, and post-medical treatment. AR in retail was discussed in terms of its uses in advertisement, marketing, fashion retail, and online shopping. The authors concluded the paper by detailing the future use of AR and its advantages and disadvantages in the current scenario. Significant advances in technology in contemporary times have made many things possible such as creating virtual worlds or enhancing existing real-world objects and scenarios through multiple sensory modes . AugmentAR, which was commercialized long ago, has played a major role in reshaping the existing manners of performing activities. However, owing to certain challenges, the technology did not achieve the expected results in the early days . InvestoAR technologies are broadly classified into hardware, mainly consisting of varied displays and sensors, and the software algorithms required for integrating the augmentations with the real world. These technologies are used in several fields such as tourism and hospitality , educatiThis paper presents a review of the use of AR in three applications: gaming, medicine, and retail. Gaming has been the leading sector in the use of AR, as a result of which gamers have experienced immense creativity, innovation, and unforgettable experiences. Gamers find AR-enhanced games better and more thrilling because of the engaging experience provided by the technology.The use of AR in the medical industry has grown over the years. It has proven to be helpful to both doctors and patients. Patients can be educated about their diseases through AR, and the technology can also be used for complex surgeries, helping doctors to perform them with high accuracy. AR has also been used in the retail industry, and several companies have started investing in AR to create apps and amazing experiences to promote and sell their products. In-store technology, as well as online AR technology, has changed the way people shop. Different sectors of fashion that have been affected by AR and experienced retail change are discussed in this paper. AR has impacted our lives in previously unimaginable ways. Thus, it could be said that AR is the future of gaming, retail, and medicine. The expansion of the AR technology in these three sectors and its acceptance by the public was analyzed in this study. Surveys were performed and feedback from various customers was scrutinized to understand their perception of the new technology.The future of entertainment is likely to be influenced by advanced technologies such as AR , 25. MobIn addition to redefining traditional gaming, AR is also already being used to increase the effectiveness of multimedia presentations and videos. However, it can be extended to a considerably greater array of entertainment fields, such as the way we listen to music and the way that we travel. Interface and visualization technology, along with some basic enabling technologies, are being incorporated to achieve heterogeneous and tangible interfaces . AR may Ivan Sutherland was the creator of the first complete AR system with simple graphics  and a veMost AR entertainment systems have software components that run on the device such as local game control and user tracking; server connection, which is often necessary in cases where there are shared resources, location-driven games, and where constant synchronization is required, is also used . AlthougThere are mainly two types of AR systems used for the purpose of entertainment. The first is marker-based applications, which are based on image recognition. This technology uses black and white markers that are used to detect the augmented object. To illustrate, the camera in a phone is first pointed at any marker’s position; after the marker has been identified, the required or embedded digital content is superimposed on the marker on top of the real object. Here, the images are to be coded into the system beforehand, making them easier to detect. Most AR apps seen in the market are marker-based. One of the most popular marker-based applications is Snapchat, which has attracted almost all of the population, and is very popular among the youth.The second is location-based applications, which work without markers. The technology makes use of global positioning system (GPS) or some digital compass that helps in detecting the user’s position, following which the real-world physical objects are replaced with or incorporated with the augmented objects. Such applications enable users to find the best restaurants nearby or locate their cars in parking lots. They can also be used in games that require the player’s location Fig. .Fig. 3aSome popular software used to create AR applications are Unity, Vuforia, ARToolKit, Google ARCore, Android studio, and AR Spark studio. Unity is the most popular game engine used for developing games and AR apps. The aforementioned softwares are generally used by professionals and regular programmers. Figure The biggest application in entertainment is gaming. Although AR games may be limited in physical aspects and face-to-face communication, there is increased collaborative gaming and relationship building through remote multiplayer games . There iDespite the popularity of computer games, pervasive gaming, defined as gaming which increases physical movement and social interactions, enhances gamer experience . This tyA local collaborative environment study, as shown in Fig. Further, an emerging trend of serious games, which are computer games meant for non-leisure and educational purposes, has also been observed. They are different and better than traditional games because they may be used for simulations in areas, such as medicine, military operations, and education, thereby linking entertainment and work . As caseAR games are also gaining momentum as learning guides, considering the younger generations’ immense use of media. They impact motivation and knowledge acquisition. As mentioned in ref. , real-woAR broadcasting is divided into two crucial elements: AR tracking and AR display. Although AR display techniques for broadcasting purposes are still nascent, they are used to project content into three-dimensional space. They are of three forms: head-mounted, monitor-based, and projection-based. Current AR tracking approaches are classified into three types: model-based, marker-based, and tracking without prior knowledge. Technologies, such as cameras, infrared sensors, hybrid sensors, and 2D and 3D markers, can all be implemented to identify a pattern and track its position in the real world. Robotic cameraman systems have been proposed to increase the quality of broadcasting systems and replace human operators . It has An enhanced AR system displays statistical players’ information on captured images of a sports game . It is aA haptically enhanced broadcasting system that uses AR techniques to synthesize videos in real time, a multimedia streaming technology, and haptics were also implemented. The system operation sequence has four different stages: scene capture, haptic editing, data transmission, and display with haptic interaction. It can be used for creating haptic effects for cartoons and in the context of live sports broadcasts. The most noticeable feature of haptics is the sense of being social presence at the location displayed remotely. In live broadcasting, haptic interaction can enable an audience to take part in communication and discussions with those viewing the same program. Haptic interaction refers to the technology that creates an experience of touch through vibrations, motions, and the application of forces .AR makes spectator sports more entertaining because of the additional information provided to the viewers. An AR-based sports system involves two major steps: homography estimation and automatic player detection, as described in ref. . A markeAs mentioned previously, the use of AR to enhance natural environments and alter the perceptions of reality is being exploited in various fields such as entertainment, education, retail, and marketing –54. It iRef.  discusseOn the other hand, ref.  conducteMedical displays and accurate medical imaging technology are significant because they enable physicians to fully exploit rich sources of heterogeneous intraoperative and preoperative data 7) presenA rehabilitation system for hand and arm movement was implemented through a spatial AR system, as described in ref. . The sysApart from medical teaching and anatomy, medical surgery is an essential use case of AR in medicine as well. Table AR significantly impacts how companies compete with one other in the technologically advancing environment. AR, as a result of its growing acceptance rate over the years, has heavily influenced brand awareness and expansion. The concept of AR in retail is anything but new. According to ref. , some ofThe best way to compete healthily in the market is to build strong relations with customers and gain their loyalty by enhancing their engagement with the products. Ref.  talks abAs mentioned in ref. , AR has It has been demonstrated that AR can help build customer relations and boost sales by reducing the risks that customers face while purchasing a product. Ref.  discusseAccording to ref. , retaileUsing an app launched by a Swedish eye retailer, Synsam, as shown in Fig. The introduction of virtual fitting rooms (VFRs) has taken AR to new heights . These VRef.  presenteRef.  discusseThe effects of AR on customer behavior in purchasing a fashion product have been mentioned in ref. . An expeRef.  discusseTable The COVID-19 virus has spread to the entire world. It has caused a significant number of deaths and significantly changed the lives of the people who have been affected by it. Many countries have gone into lockdown to prevent the spread of the virus, thereby resulting in economic collapse within them. Many businesses have shut down, and schools have been closed. A lot of measures have been taken to reduce the effects of the virus and, expectedly, the scientific community is developing various technological methods that can benefit the society, amidst these trying times. For example, a framework for change was proposed for medical education , and refCase Western Reserve University, in collaboration with Cleveland Clinic, developed an AR app called HoloAnatomy, which helps medical students to learn about the human body in 3D. HoloAnatomy teaches students anatomy using Microsoft Hololens Fig. . The stuAR can also be used to develop long-distance healthcare systems for managing the pain and wellbeing of patients suffering from chronic pain and health care issues due to the COVID-19 outbreak. Telemedicine and web-based systems are some existing prevalent approaches. Telemedicine refers to the short message services, video conferencing, and telephone consultation. Web-based systems, such as PAIN OUT in Europe and CHOIR in the United States , make itAR can also be beneficial in the surgical field, as well. Virtual technology is responsible for saving lives and safeguarding surgical practices during the pandemic; the Proxemie platform is one such example . The ProHowever, a more significant challenge awaits the society at the end of the pandemic. The road to recovery from the pandemic will be extremely difficult. AR software and hardware shall be used to mitigate such effects even after the pandemic is long over. AR can be used to impact practical knowledge because the processes of learning and implementation. Using an AR headset, a skilled technician can seamlessly guide fellow workers and teach students. Companies can also train their workforce using AR, thereby improving their workflow and the economy. For example, Microsoft Hololens 2 AR headset can be used by companies to guide their employees Fig. . It provAnother important area where AR can prove necessary is in retail, from the customer’s perspective. Whether online or in-store, people will never buy products without being sure if a particular product fits them. AR-based technologies, such as VFRs and mobile apps, can enable the customers to try out clothes, jewelry, makeup, sunglasses, or shoes, without actually trying any of these products in reality. Such AR-based solutions will help people practice social distancing. Digital and safe shopping experiences are among the current needs of customers. As explained previously regarding various AR systems used in retail, such applications can prove to be really useful in the coming days, thus boosting the AR market.Before AR can be accepted by everyone on a large scale, it is important to note that AR faces a large number of challenges that must be overcome for it to thrive. Every technology consists of a well-defined business model based on which investments are generated. However, for AR, there is no particularly defined business model that can work long-term. It is also very early to evaluate the profitability of an AR-based business because the technology is still in its development stages. Further, because of the lack of AR development and application design standards, AR technology faces a problem relating to compatibility with the overall scenario. Security and privacy are also major concerns in the AR industry. Poor content quality, in addition to some technical software and hardware limitations in each game design, is an ongoing challenge in AR gaming. For specific surgeries and in the medical field, accuracy is of prime importance because it is essential for surgeons to have tangible information on how and when the technology is used . For fasDespite the numerous challenges, AR has an enormous scope in the near future to transform many industries. On overcoming the above mentioned obstacles, AR could have the power to revolutionize the entire market in every aspect. It has tremendous potential in areas, such as education, medicine, military, construction, automobile, travel, retail, art, and architecture . AR is aAR provides unique entertainment options that are not available with common types of digital media. With new research, future AR systems are bound to be significantly more advanced, compared to the currently available ones. Owing to AR, interactivity and content quality are noticeably different, and personalization is possible. The technology is new, and despite having been around for a considerable amount of time, it has not been fully and functionally incorporated in day-to-day activities such as retail and medicine owing to concerns such as technology, social acceptance, and usability. However, upon overcoming these challenges, AR has the ability to redefine gaming through enhanced content in real time. The use of AR in medicine may change the way surgeries are performed. Medical training and post-surgical treatments can be performed with ease using AR displays. As consumers desire new innovations that may simplify shopping experiences and make them more comfortable, they are most likely to welcome AR with excitement. We have also studied the existing AR solutions that are being implemented and have discussed its importance to recovery from the pandemic. Hence, AR is playing a very important role in providing users with technology experience like never before in almost all areas.The most recent inventions are proofs of the growing improvements in AR. AR in gaming can be seen in Pokémon Go, which also makes use of GPS, and is therefore a location-based application. Snapchat, on the other hand, is an example of a marker-based application, which uses image recognition in addition to AR. There are many AR-based software development kits and the factors determining the choice of an appropriate SDK include the cost, platforms, image recognition technology and the possibility of 3D tracking and recognition. Unity and AR toolkit are a few of the engines that can be used to create AR apps. Google and Android have also provided their respective kits, Google AR Core and AR Spark studio. The instances that have been discussed show the growing market base of AR systems and their importance in the market. Hence, the importance of a review that provides insight into three major fields where AR systems are being used cannot be overemphasized.