Prostate cancer (PC), the second most prevalent malignancy in men worldwide, has been proven to depend on the aberrant activation of androgen receptor (AR) signaling. Long-term androgen deprivation for the treatment of PC inevitably leads to castration-resistant prostate cancer (CRPC) in which AR remains a crucial oncogenic driver. Thus, there is an urgent need to develop new strategies to address this unmet medical need. Targeting AR for degradation has recently been in a vigorous development stage, and accumulating clinical studies have highlighted the benefits of AR degraders in CRPC patients. Herein, we provide a comprehensive summary of small-molecule AR degraders with diverse mechanisms of action including proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tags (HyT), and other AR degraders with distinct mechanisms. Accordingly, their structure-activity relationships, biomedical applications, and therapeutic values are also dissected to provide insights into the future development of promising AR degradation-based therapeutics for CRPC.

A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives.

INTRODUCTION
Approximately half of the 13.4 billion COVID-19 vaccine doses administered globally were inactivated or viral vector platforms. The harmonization and optimization of vaccine regimens has become a key focus of policy makers and healthcare providers and presents an opportunity to reassess the continued use of pandemic-era vaccines.


AREAS COVERED
Immunological evidence from studies of various homologous and heterologous regimens has been rapidly published, however interpretation of these data are complicated by the many vaccine types and highly variable participant viral exposure and vaccination histories. Recent studies demonstrate that after primary series doses of inactivated (i.e. BBV152, and BBIBP-CorV), and viral vector (ChAdOx1 nCov-2019) vaccines, a heterologous boost with protein-based NVX-CoV2373 elicits more potent ancestral strain and omicron-specific antibody responses compared to homologous and heterologous inactivated and viral vector boosts.


EXPERT OPINION
While mRNA vaccines likely yield similar performance to protein-based heterologous booster doses, the later offers notable advantages to countries with high uptake of inactivated and viral vector vaccines in terms of transportation and storage logistics and can potentially appeal to vaccine hesitant individuals. Moving forward, vaccine-mediated protection in inactivated and viral vector recipients may be optimized with the use of a heterologous protein-based booster such as NVX-CoV2373.

https://www.tandfonline.com/doi/pdf/10.1080/14760584.2023.2232020?needAccess=true&role=button

Pivoting to protein: the immunogenicity and safety of protein-based NVX-CoV2373 as a heterologous booster for inactivated and viral vector COVID-19 vaccines.

(1) Background: This study aimed to explore the relationship between years of participation, subjective exercise experience, and group cohesion among gender-specific square dance practitioners. (2) Methods: The Subjective Exercise Experience Questionnaire (SEEQ) and Group Environment Questionnaire (GEQ) were used to evaluate Subjective Exercise Experience (SEE) and group cohesion (GC). An analysis was conducted on 130 Chinese (63 males and 67 females) using multiple group analysis within a structural equation model. (3) Results: (a) The positive aspects of Subjective Exercise Experience (SEE) and Positive Well-Being (PWB), had a strongly positive effect on GC in both groups. The negative aspects of SEE, Psychological Fatigue (PF), and Psychological Distress (PD), had negative effects on GC. (b) Only for the male group was there an indirect effect of participation years on the association between SEE and GC in the model (a × b = 0.062, 95% CI [0.001, 0.181]; standard error (SE) = 0.062, p = 0.048). (c) The significant differences between paths coefficients were noticed in the association of years of participation with SEE (t = −2.043) and GC (t = −1.962). (4) Conclusion: Based on these results, gender differences in terms of the partial mediating role of adherence in the relationship of SEE and GC were presented for future research, fitness popularization, and society.

https://www.mdpi.com/1660-4601/19/19/12978/pdf?version=1665465955

Subjective Exercise Experience and Group Cohesion among Chinese Participating in Square Dance: A Moderated Mediation Model of Years of Participation and Gender

Introduction Physical activity among college students since the COVID-19 pandemic was well studied; however, subjective exercise experience and the emotional response toward physical exercise received less attention. Methods The present study used latent profile analysis (LPA) to explore the latent class of subjective exercise experience among physically vulnerable college students who scored 59 points or less in tests under the National Student Physical Health Standard. Three non-duplicated samples at different stages of the COVID-19 pandemic were collected in March 2020 (N = 127), March 2021 (N = 118), and November 2021 (N = 206) respectively. Psychometrically validated scales, namely, Subjective Exercise Experiences Scale (SEES), Generalized Anxiety Disorder (GAD-7), and Patient Health Questionnaire (PHQ-9) were used to measure subjective exercise experience, anxiety symptoms, and depressive symptoms. Results and discussion LPA revealed a 3-class solution for the subjective exercise experience of physically unfit students, namely, the “negative experience group” (30.82%), the “fatigue group” (41.91%), and the “positive experience group” (27.27%). Multinomial regression showed that probable anxiety [odds ratio (OR) = 0.12] was associated with the overall negative exercise experience while probable depression (OR = 0.19) was associated with psychological fatigue. Women (OR = 0.496) were more likely to experience overall negative exercise experience, and the outbreak of the COVID- 19 (OR = 2.14) pandemic influenced the psychological distress of the subjective exercise experience compared with the other two phases in the post-COVID- 19 era. Our findings provided significant implications for physical education targeting university students that interventions should be tailored differently for three profiles of the subjective exercise experience.

/pdf/a-latent-profile-analysis-of-subjective-exercise-experiences-3e17qvx3.pdf

A latent profile analysis of subjective exercise experiences among physically vulnerable college students and psychiatric symptoms correlates during three phases of the COVID-19 pandemic in Wuhan, China

/pdf/little-but-intense-using-a-hiit-based-strategy-to-improve-59ojg4eh.pdf

Little but Intense: Using a HIIT-Based Strategy to Improve Mood and Cognitive Functioning in College Students

Purpose: To explore the influencing factors that restrict the exercise behavior of children and adolescents, investigate the effect of subjective exercise experience on exercise behavior, and reveal the mediating effect of exercise commitment between subjective exercise experience and exercise behavior so as to promote children and adolescents to maintain good health exercise habits and improve their physical and mental health. Methods: The Subjective Exercise Experience Scale (SEES), Exercise Commitment Scale (ECC), and Physical Exercise Rating Scale (PARS-3) were used to conduct a questionnaire survey on 600 children and adolescents in Chongqing, China, and SPSS21.0 and AMOS21.0 statistical analysis software was used to carry out statistics and analyses on the questionnaires. Results: (1) Among children and adolescents, boys’ exercise commitment and exercise behavior were significantly higher than girls’, and there was no significant gender difference in subjective exercise experience. The exercise behavior of children and adolescents aged 9–12 was significantly higher than that of children and adolescents aged 13–15, and there was no significant age difference in subjective exercise experience and exercise commitment. (2) There was a significant correlation between the subjective exercise experience, exercise commitment, and exercise behavior of children and adolescents, and subjective exercise experience could directly and positively predict exercise commitment (β = 0.63) and exercise behavior (β = 0.57)—exercise commitment could also directly and positively predict exercise behavior (β = 0.52). (3) The exercise commitment of children and adolescents has a partial mediating effect between subjective exercise experience and exercise behavior (accounting for 37.50% of the total effect), and has a mediating effect between different exercise amounts, with the strongest mediating effect being on high exercise amount (32.10% of the total effect). Conclusions: The exercise behavior of children and adolescents was not only directly affected by subjective exercise experience, but also affected by the mediating effect of exercise commitment, and maintaining a good exercise experience and commitment was an effective way to effectively improve exercise behavior and amount of exercise in children and adolescents.

/pdf/the-effect-of-subjective-exercise-experience-on-exercise-2qtgn4vp.pdf

The Effect of Subjective Exercise Experience on Exercise Behavior and Amount of Exercise in Children and Adolescents: The Mediating Effect of Exercise Commitment

https://doi.org/10.1016/j.apsb.2022.05.003

A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer


 Background
 ZF2001 is a recombinant protein subunit vaccine against SARS-CoV-2 that has been approved for use in China, Colombia, Indonesia, and Uzbekistan in adults aged 18 years or older, but not yet in children and adolescents younger than 18 years. We aimed to evaluate the safety and immunogenicity of ZF2001 in children and adolescents aged 3–17 years in China.
 
 Methods
 The randomised, double-blind, placebo-controlled, phase 1 trial and the open-label, non-randomised, non-inferiority, phase 2 trial were done at the Xiangtan Center for Disease Control and Prevention (Hunan Province, China). Healthy children and adolescents aged 3–17 years, without a history of SARS-CoV-2 vaccination, without a history of COVID-19, without COVID-19 at the time of the study, and without contact with patients with confirmed or suspected COVID-19 were included in the phase 1 and phase 2 trials. In the phase 1 trial, participants were divided into three groups according to age (3–5 years, 6–11 years, and 12–17 years). Each group was randomly assigned (4:1), using block randomisation with five blocks, each with a block size of five, to receive three 25 μg doses of the vaccine, ZF2001, or placebo intramuscularly in the arm 30 days apart. The participants and investigators were masked to treatment allocation. In the phase 2 trial, participants received three 25 μg doses of ZF2001 30 days apart and remained stratified by age group. For phase 1, the primary endpoint was safety and the secondary endpoint was immunogenicity (humoral immune response on day 30 after the third vaccine dose: geometric mean titre [GMT] of prototype SARS-CoV-2 neutralising antibodies and seroconversion rate, and geometric mean concentration [GMC] of prototype SARS-CoV-2 receptor-binding domain [RBD]-binding IgG antibodies and seroconversion rate). For phase 2, the primary endpoint was the GMT of SARS-CoV-2 neutralising antibodies with seroconversion rate on day 14 after the third vaccine dose, and the secondary endpoints included the GMT of RBD-binding antibodies and seroconversion rate on day 14 after the third vaccine dose, the GMT of neutralising antibodies against the omicron BA.2 subvariant and seroconversion rate on day 14 after the third vaccine dose, and safety. Safety was analysed in participants who received at least one dose of the vaccine or placebo. Immunogenicity was analysed in the full-analysis set (ie, participants who received at least one dose and had antibody results) by intention to treat and in the per-protocol set (ie, participants who completed the whole vaccination course and had antibody results). Non-inferiority in the phase 2 trial (neutralising antibody titre of participants from this trial aged 3–17 years vs that of participants aged 18–59 years from a separate phase 3 trial) for clinical outcome assessment was based on the geometric mean ratio (GMR) and was considered met if the lower bound of the 95% CI for the GMR was 0·67 or greater. These trials are registered with ClinicalTrials.gov, NCT04961359 (phase 1) and NCT05109598 (phase 2).
 
 Findings
 Between July 10 and Sept 4, 2021, 75 children and adolescents were randomly assigned to receive ZF2001 (n=60) or placebo (n=15) in the phase 1 trial and were included in safety and immunogenicity analyses. Between Nov 5, 2021, and Feb 14, 2022, 400 participants (130 aged 3–7 years, 210 aged 6–11 years, and 60 aged 12–17 years) were included in the phase 2 trial and were included in the safety analysis; six participants were excluded from the immunogenicity analyses. 25 (42%) of 60 participants in the ZF2001 group and seven (47%) of 15 participants in the placebo group in phase 1, and 179 (45%) of 400 participants in phase 2, had adverse events within 30 days after the third vaccination, without a significant difference between groups in phase 1. Most adverse events were grade 1 or 2 (73 [97%] of 75 in the phase 1 trial, and 391 [98%] of 400 in the phase 2 trial). One participant in the phase 1 trial and three in the phase 2 trial who received ZF2001 had serious adverse events. One serious adverse event (acute allergic dermatitis) in the phase 2 trial was possibly related to the vaccine. In the phase 1 trial, on day 30 after the third dose, in the ZF2001 group, seroconversion of neutralising antibodies against SARS-CoV-2 was observed in 56 (93%; 95% CI 84–98) of 60 participants, with a GMT of 176·5 (95% CI 118·6–262·8), and seroconversion of RBD-binding antibodies was observed in all 60 (100%; 95% CI 94–100) participants, with a GMC of 47·7 IU/mL (95% CI 40·1–56·6). In the phase 2 trial, on day 14 after the third dose, seroconversion of neutralising antibodies against SARS-CoV-2 was seen in 392 (99%; 95% CI 98–100) participants, with a GMT of 245·4 (95% CI 220·0–273·7), and seroconversion of RBD-binding antibodies was observed in all 394 (100%; 99–100) participants, with a GMT of 8021 (7366–8734). On day 14 after the third dose, seroconversion of neutralising antibodies against the omicron subvariant BA.2 was observed in 375 (95%; 95% CI 93–97) of 394 participants, with a GMT of 42·9 (95% CI 37·9–48·5). For the non-inferiority comparison of participants aged 3–17 years with those aged 18–59 years for SARS-CoV-2 neutralising antibodies, the adjusted GMR was 8·6 (95% CI 7·0–10·4), with the lower bound of the GMR greater than 0·67.
 
 Interpretation
 ZF2001 is safe, well tolerated, and immunogenic in children and adolescents aged 3–17 years. Vaccine-elicited sera can neutralise the omicron BA.2 subvariant, but with reduced activity. The results support further studies of ZF2001 in children and adolescents.
 
 Funding
 Anhui Zhifei Longcom Biopharmaceutical and the Excellent Young Scientist Program from National Natural Science Foundation of China.
 
 Translation
 For the Chinese translation of the abstract see Supplementary Materials section.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9937662

Safety and immunogenicity of a protein subunit COVID-19 vaccine (ZF2001) in healthy children and adolescents aged 3–17 years in China: a randomised, double-blind, placebo-controlled, phase 1 trial and an open-label, non-randomised, non-inferiority, phase 2 trial

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The Effect of Subjective Exercise Experience on Exercise Behavior and Amount of Exercise in Children and Adolescents: The Mediating Effect of Exercise Commitment

A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer

Safety and immunogenicity of a protein subunit COVID-19 vaccine (ZF2001) in healthy children and adolescents aged 3–17 years in China: a randomised, double-blind, placebo-controlled, phase 1 trial and an open-label, non-randomised, non-inferiority, phase 2 trial