A potential strategy for bladder cancer treatment: inhibiting autophagy to enhance antitumor effects of Nectin-4-MMAE.

Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer. During the course of this study, we identified that autophagy serves as a cytoprotective mechanism during Nectin-4-MMAE treatment and proposed a strategy to enhance the antitumor effects of Nectin-4-MMAE in bladder cancer. Nectin-4-MMAE rapidly internalized into bladder cancer cells in 30 minutes and released MMAE, inducing the onset of caspase-mediated apoptosis and leading to the inhibition of tumor cell growth. Transcriptomics showed significant alterations in autophagy-associated genes in bladder cancer cells treated with Nectin-4-MMAE, which suggested autophagy was activated by Nectin-4-MMAE. Furthermore, autophagy activation was characterized by ultrastructural analysis of autophagosome accumulation, immunofluorescence of autophagic flux, and immunoblotting autophagy marker proteins SQSTM1 and LC3 I/II. Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells. Additionally, we detected the participation of the AKT/mTOR signaling cascade in the induction of autophagy by Nectin-4-MMAE. The combination of Nectin-4-MMAE and an autophagy inhibitor demonstrated enhanced antitumor effects in the HT1376 xenograft tumor model. After receiving a single dose of Nectin-4-MMAE, the group that received the combination treatment showed a significant decrease in tumor size compared to the group that received only one type of treatment. Notably, one mouse in the combination treatment group achieved complete remission of the tumor. The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.

Embodied Conversational Agents for Chronic Diseases: Scoping Review.

BACKGROUND: Embodied conversational agents (ECAs) are computer-generated animated humanlike characters that interact with users through verbal and nonverbal behavioral cues. They are increasingly used in a range of fields, including health care. OBJECTIVE: This scoping review aims to identify the current practice in the development and evaluation of ECAs for chronic diseases. METHODS: We applied a methodological framework in this review. A total of 6 databases (ie, PubMed, Embase, CINAHL, ACM Digital Library, IEEE Xplore Digital Library, and Web of Science) were searched using a combination of terms related to ECAs and health in October 2023. Two independent reviewers selected the studies and extracted the data. This review followed the PRISMA-ScR (Preferred Reporting Items of Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) statement. RESULTS: The literature search found 6332 papers, of which 36 (0.57%) met the inclusion criteria. Among the 36 studies, 27 (75%) originated from the United States, and 28 (78%) were published from 2020 onward. The reported ECAs covered a wide range of chronic diseases, with a focus on cancers, atrial fibrillation, and type 2 diabetes, primarily to promote screening and self-management. Most ECAs were depicted as middle-aged women based on screenshots and communicated with users through voice and nonverbal behavior. The most frequently reported evaluation outcomes were acceptability and effectiveness. CONCLUSIONS: This scoping review provides valuable insights for technology developers and health care professionals regarding the development and implementation of ECAs. It emphasizes the importance of technological advances in the embodiment, personalized strategy, and communication modality and requires in-depth knowledge of user preferences regarding appearance, animation, and intervention content. Future studies should incorporate measures of cost, efficiency, and productivity to provide a comprehensive evaluation of the benefits of using ECAs in health care.

The Use of Gamification in the Self-Management of Patients With Chronic Diseases: Scoping Review.

BACKGROUND: Chronic disease self-management is a public health issue of worldwide concern, and gamification is an emerging strategy to improve patients' participation in chronic disease self-management. Some studies have summarized designs for the gamification of chronic disease self-management from the perspective of eHealth technology, but they have not mentioned differences in design methods, functions, and evaluation methods of gamified designs for self-management in different chronic diseases. OBJECTIVE: This scoping review aims to synthesize the characteristics of realization forms, functions, and evaluation methods in chronic disease self-management gamification to improve self-management among the chronic disease population. METHODS: We applied a methodological framework for scoping reviews and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist. As of January 7, 2023, we systematically searched 9 databases for relevant studies from January 2012 to December 2022. Related data were extracted based on the research questions. We calculated the frequencies, charted the quantitative data, and coded the extracted material for qualitative content analysis. RESULTS: We retrieved 16,221 records, of which 70 (0.43%) met the eligibility criteria. In the included research, the target populations for gamified designs for self-management of chronic diseases included patients with stroke, cancer, diabetes, chronic obstructive pulmonary disease, coronary heart disease, obesity, and hypertension. Almost all studies mentioned technical support for gamification (68/70, 97%), mainly in the form of active video games (58/70, 83%); however, less than half of the studies mentioned the theoretical basis for gamification (31/70, 44%). There were 37 concepts or theories relevant to gamification design, most of which were in the field of psychology or were cross-disciplinary (n=33, 89%). Gamification for the self-management of chronic diseases has been widely recognized, including for promoting physical exercise and rehabilitation training (48/99, 48%), increasing initiative for symptom management (18/99, 18%), providing psychological support (14/99, 14%), improving cognitive function (12/99, 12%), and improving medication adherence (7/99, 7%). A total of 39 studies mentioned the gamification effect; however, we did not find a unified evaluation standard. CONCLUSIONS: This scoping review focuses on gamification designs for chronic disease self-management and summarizes the realization forms and functions of gamification in self-management for different patient populations. With practice in a gamified internet-based environment, patients can not only master the knowledge and skills of self-management in fascinating scenarios but also benefit from gaming experience and make better health-related decisions in real life. It is worth noting that a comprehensive evaluation of the users as well as a personalized and targeted intervention should be developed before gamification.

TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface antigen overexpressed in the tumors of more than half of pancreatic cancer patients, has been identified as a potential target for antibody-drug conjugates (ADCs). Almost all reported TROP2-targeted ADCs are of the IgG type and have been poorly studied in pancreatic cancer. Here, we aimed to develop a novel nanobody-drug conjugate (NDC) targeting TROP2 for the treatment of pancreatic cancer. RESULTS: In this study, we developed a novel TROP2-targeted NDC, HuNbTROP2-HSA-MMAE, for the treatment of TROP2-positive pancreatic cancer. HuNbTROP2-HSA-MMAE is characterized by the use of nanobodies against TROP2 and human serum albumin (HSA) and has a drug-antibody ratio of 1. HuNbTROP2-HSA-MMAE exhibited specific binding to TROP2 and was internalized into tumor cells with high endocytosis efficiency within 5 h, followed by intracellular translocation to lysosomes and release of MMAE to induce cell apoptosis in TROP2-positive pancreatic cancer cells through the caspase-3/9 pathway. In a xenograft model of pancreatic cancer, doses of 0.2 mg/kg and 1 mg/kg HuNbTROP2-HSA-MMAE demonstrated significant antitumor effects, and a dose of 5 mg/kg even eradicated the tumor. CONCLUSION: HuNbTROP2-HSA-MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer.

A collagen-binding SIRPαFc fusion protein for targeted cancer immunotherapy.

Collagen is abundant but exposed in tumor due to the abnormal tumor blood vessels, thus is considered as a tumor-specific target. The A3 domain of von Willebrand factor (vWF A3) is a kind of collagen-binding domain (CBD) which could bind collagen specifically. Previously we reported a chemosynthetic CBD-SIRPαFc conjugate, which could block CD47 and derived tumor-targeting ability by CBD. CBD-SIRPαFc conjugate represented improved anti-tumor efficacy with increased MHC II+ M1 macrophages, but the uncertain coupling ratio remained a problem. Herein, we produced a vWF A3-SIRPαFc fusion protein through eukaryotic expression system. It was examined at both molecular and cellular levels with its collagen affinity, uninfluenced original affinity to targets and phagocytosis-promoting function compared to unmodified SIRPαFc. Living imaging showed that vWF A3-SIRPαFc fusion protein derived the improved accumulation and retention in tumor than SIRPαFc. In the MC38 allograft model, vWF A3-SIRPαFc demonstrated a superior tumor-suppressing effect, characterized by increased MHC II+ M1 macrophages and T cells (particularly CD4+ T cells). These results revealed that vWF A3-SIRPαFc fusion protein derived tumor-targeting ability, leading to improved anti-tumor immunotherapeutic efficacy compared to SIRPαFc. Altogether, vWF A3 improved the anti-tumor efficacy and immune-activating function of SIRPαFc, supporting targeting tumor collagen as a possible targeted strategy.

The development of a glossary of contemporary Chinese values and its initial application.

A value is an outward or inward view of what is "worthwhile" and is a belief system that people uses to distinguish between good and bad and to guide their behavior. Values vary from culture to culture and from time to time. In order to develop a vocabulary for measuring the values of contemporary Chinese, an open-ended survey was conducted in Study 1 to collect the value vocabulary of the Chinese public, and a text analysis was conducted in Study 2 to acquire the value vocabulary of the Chinese society. In Study 3, a word list of contemporary Chinese values was developed by integrating the words obtained from the above two studies and combining words from previous studies, and a preliminary application of the word list was conducted. The results revealed that Chinese values include four dimensions: self-fulfillment, self-cultivation, social development, and interpersonal ethics. Chinese values are characterized by diversity, and some of the socially advocated values have been internalized into the value system of individuals.

The Influence of Personal Harmony Value on Temporal Order Perception.

Empirical studies have demonstrated that self-relevant information affects temporal order perception. Therefore, the question arises of whether personal values-which are the core components of the self-influence temporal order perception. To explore this problem, we chose harmony, one of the most common values in Chinese culture, as the starting point. First, the harmony scale was used to measure the harmony values of the participants, and the participants were divided into high- and low-harmony groups. The validity of the grouping was then verified using an implicit-association test. Furthermore, two temporal order judgment (TOJ) tasks were used to explore the impact of harmony values on temporal order perception. The results revealed that in both TOJ tasks, participants in the high-harmony group tended to perceive harmonious stimuli before non-harmonious stimuli, while the effect was not found in the low-harmony group. We conclude that harmony values affect temporal order perception, and only if the values are important to the individual.

Research progress of interleukin-15 in cancer immunotherapy.

Interleukin-15 (IL-15) is a cytokine that belongs to the interleukin-2 (IL-2) family and is essential for the development, proliferation, and activation of immune cells, including natural killer (NK) cells, T cells and B cells. Recent studies have revealed that interleukin-15 also plays a critical role in cancer immunotherapy. Interleukin-15 agonist molecules have shown that interleukin-15 agonists are effective in inhibiting tumor growth and preventing metastasis, and some are undergoing clinical trials. In this review, we will summarize the recent progress in interleukin-15 research over the past 5 years, highlighting its potential applications in cancer immunotherapy and the progress of interleukin-15 agonist development.

The impact of stereotype threat on endogenous poverty-elimination dynamics in generationally poor individuals.

Introduction: The study examines the impact of stereotype threat on generationally poor individuals and its effect on achievement motivation. It also explores the extent to which self-affirmation has an intervention effect on the negative impact of stereotype threat. Methods and results: In Study 1, statements that contained negative stereotypes were used to elicit stereotype threat in generationally poor individuals; the results show that stereotype threat reduced the performance of generationally poor individuals in a mental-rotation task. Study 2 used a questionnaire to measure the endogenous dynamics of generationally poor individuals attempting to escape poverty after experiencing stereotype threat; participants in the stereotype-threat group showed lower-level endogenous poverty-elimination dynamics than those in the control group. In Study 3, a self-affirmation intervention was administered to the stereotype-threat group after the stereotype threat was induced. Participants in the self-affirmation group were shown to have higher-level endogenous poverty-elimination dynamics than those in the control group. Discussion: These findings confirm the negative effect of stereotype threat on endogenous poverty-elimination dynamics and verify the effectiveness of self-affirmation in mitigating the negative effects of stereotype threat.

Neural correlates of aftereffects induced by adaptations to single and average durations.

Duration perception can be heavily distorted owing to repetitive exposure to a relatively long or short sensory event, often causing a duration aftereffect. Here, we used a novel procedure to show that adaptations to both single and average durations produced the duration aftereffect. Participants completed a duration reproduction task (Experiment 1) or a duration category rating task (Experiment 2) after long-term adaptations to a stimulus of medium duration and to stimuli of averagely medium duration. We found that adaptations to both single and average durations resulted in duration aftereffects. The simultaneously recorded functional magnetic resonance imaging (fMRI) data revealed that the reduction in neural activity due to long-term adaptation to single duration was observed in the right supramarginal gyrus (SMG) of the parietal lobe, while adaptation to average duration resulted in fMRI adaptations in the left postcentral gyrus (PCG) and middle cingulate gyrus (MCG). At the individual level, the magnitude of the behavioral aftereffect was positively correlated with the magnitude of fMRI adaptation in the right SMG after adaptation to single duration, while there were no significantly positive correlations between the behavioral aftereffect and fMRI adaptations in the left PCG and MCG. These results suggest that there are different neural mechanisms for aftereffects caused by adaptations to single and average durations.

Spatial selectivity of the visual duration aftereffect in the sub-second range: An event-related potentials study.

Prolonged adaptation to one duration biases the perception of subsequent durations in a phenomenon known as duration adaptation. There is controversy regarding the neural substrates of the visual duration aftereffect: some researchers have argued that duration adaptation occurs in early visual cortical areas, whereas others have argued for high-level visual areas. Investigation of spatial selectivity of the duration aftereffect could help reveal the neural mechanisms underlying duration adaptation. In the present study, we used event-related potentials (ERPs) to demonstrate spatial selectivity of the visual duration aftereffect in the sub-second range. We measured the duration aftereffect at a 20° adapt-test distance that spanned 10° on either side of fixation. Our results revealed that duration adaptation first affected the N1 ERP component and then influenced the contingent negative variation (CNV) component. Moreover, the CNV component showed position effects in the temporal encoding stage, and the post-stimulus positive component was subject to a duration effect but not a position effect. These findings indicate that sub-second duration coding is closely linked to the early processing of the visual cortex. Moreover, the adaptation not only affects the earlier temporal coding stage, but also the later temporal processing stage.

A SIRPαFc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung Cancer.

The SIRPαFc fusion protein can block the immunosuppressive CD47-SIRPα signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide "TKKTLRT" is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRPαFc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT-SIRPαFc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT-SIRPαFc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. In vivo distribution experiments showed that CBD-SIRPαFc accumulated in tumor tissue more effectively compared to unmodified SIRPαFc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD-SIRPαFc presented more stable and effective antitumor efficacy than SIRPαFc, along with significantly increased CD11b+F4/80+ macrophages especially MHC II+ M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRPαFc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD-SIRPαFc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.

Color Sensitivity of the Duration Aftereffect Depends on Sub- and Supra-second Durations.

The perception of duration becomes biased after repetitive duration adaptation; this is known as the duration aftereffect. The duration aftereffect exists in both the sub-second and supra-second ranges. However, it is unknown whether the properties and mechanisms of the adaptation aftereffect differ between sub-second and supra-second durations. In the present study, we addressed this question by investigating the color sensitivity of the duration aftereffect in the sub-second (Experiment 1) and supra-second (Experiment 2) ranges separately. We found that the duration aftereffect in the sub-second range could only partly transfer across different visual colors, whereas the duration aftereffect in the supra-second range could completely transfer across different visual colors. That is, the color-sensitivity of the duration aftereffect in the sub-second duration was stronger than that in the supra-second duration. These results imply that the mechanisms underlying the adaptation aftereffects of the sub-second and supra-second ranges are distinct.

Near infrared light-responsive and drug-loaded black phosphorus nanosheets for antibacterial applications.

The management of wound infection remain a major global challenge, effectively ablation of bacteria is of significant in fighting wound infectious diseases. Herein, black phosphorus nanosheets (BPNSs) were successfully prepared by liquid phase exfoliation technology, and composite nanosheets (BPNSs@phy) were formed by loading antimicrobial physcion（Phy）via hydrophobic interaction. Studies have shown that BPNSs@phy has good stability and low cytotoxicity under physiological conditions. In addition, BPNSs@phy has excellent photothermal conversion ability. After the irradiation of 808 nm near-infrared light, the light energy is converted into heat to promote the release of physcion. Under the synergistic effect of photothermal therapy (PTT) and antibacterial agents, BPNSs@phy has an excellent bactericidal effect against S.aureus (99.7%) and P.aeruginosa (99.9%). This study is expected to provide a new strategy for the development of BPNSs based antibacterial materials.

The Association of Sense of Power with Well-Being Outcomes: The Mediating Role of Hope-Agency.

Studies have shown that sense of power is positively associated with subjective well-being, but this relationship has proved inconsistent in collectivist contexts. The present study aimed to investigate the relationship between sense of power, well-being outcomes, and psychological maladjustment in Chinese early adults, and further investigated the potential mediating role of hope. Sense of power, dispositional hope, life satisfaction, and positive and negative affect were measured in Study 1 (n = 522). Sense of power was found to be positively related to hope and to emotional and cognitive well-being. Furthermore, mediating analysis indicated that hope-agency (but not hope-pathway) was a significant mediator of the relationship between perceived power and subjective well-being. Study 2 (n = 391) additionally measured loneliness and perceived stress as components of psychological maladjustment. The results showed that sense of power was negatively associated with stress and loneliness, and that hope-agency partially mediated the link of perceived power to psychological maladjustment. Overall, our findings contribute to a deeper understanding of the relationship between sense of power and well-being outcomes, and suggest that a sense of power might foster people's well-being and mental health by activating their motivation to achieve desired goals.

The functional connectome predicts feeling of stress on regular days and during the COVID-19 pandemic.

Although many studies have explored the neural mechanism of the feeling of stress, to date, no effort has been made to establish a model capable of predicting the feeling of stress at the individual level using the resting-state functional connectome. Although individuals may be confronted with multidimensional stressors during the coronavirus disease 2019 (COVID-19) pandemic, their appraisal of the impact and severity of these events might vary. In this study, connectome-based predictive modeling (CPM) with leave-one-out cross-validation was conducted to predict individual perceived stress (PS) from whole-brain functional connectivity data from 817 participants. The results showed that the feeling of stress could be predicted by the interaction between the default model network and salience network, which are involved in emotion regulation and salience attribution, respectively. Key nodes that contributed to the prediction model comprised regions mainly located in the limbic systems and temporal lobe. Critically, the CPM model of PS based on regular days can be generalized to predict individual PS levels during the COVID-19 pandemic, which is a multidimensional, uncontrollable stressful situation. The stability of the results was demonstrated by two independent datasets. The present work not only expands existing knowledge regarding the neural mechanism of PS but also may help identify high-risk individuals in healthy populations.

Oxytocin weakens self-other distinction in males during empathic responses to sadness: an event-related potentials study.

By making use of event-related potential (ERP) technology, a randomized, double-blind, between-subject design study was performed in order to investigate whether OXT can weaken men's self-other distinction during empathic responses to sad expressions. In the two experimental tasks, 39 male subjects were asked to either evaluate the emotional state shown in a facial stimulus (other-task) or to evaluate their own emotional responses (self-task). The results revealed that OXT reduced the differences in P2 (150-200 ms) amplitudes between sad and neutral expressions in the self-task but enhanced P2 to sad expressions in the other-task, indicating OXT's role in integrating the self with others instead of separating them. In addition, OXT also reduced the LPC (400-600 ms) amplitudes between sad-neutral expressions in the self-task, implying that OXT's weakening effects on the self-other distinction could occur at both the early and late cognitive control stages of the empathic response.

Neural Oscillations Associated With Auditory Duration Maintenance in Working Memory in Tasks With Controlled Difficulty.

The neural representation of the external events duration in working memory (WM) remains to be understood. It has been reported that there were different neural representations below and above 3 s/2 s for visual/auditory duration, respectively. However, these studies had limitations in experimental design, i.e., the interference of task difficulty was not assessed. Consequently, the results of these studies require verification. In the present study, we eliminated these limitations using an exploratory experiment in which the probe stimulus conditions were reset, while the other settings remained similar to those used in previous studies. In the exploratory experiment, we found that accuracy and reaction times were comparable among all the four duration conditions, suggesting that task difficulty was accurately matched. In the formal experiment, theta and alpha oscillations were examined using electroencephalogram recordings during the maintenance of the auditory duration in working memory, after removing the interference of task difficulty. Electroencephalogram results indicated that there were no significant differences in theta band power among different length of durations retained in working memory, whereas the alpha band power was significantly lower in the 3-s and 4-s duration conditions than in the 1-s and 2-s conditions. The findings suggest that different internal representations of auditory durations above and below the 2-s threshold are maintained in working memory. Also, our study provides evidence that the duration representation segmentation is associated with the length of the auditory duration retained in working memory, but not with task difficulty.

The influence of self-referential stimuli on duration perception.

Previous studies have shown that stimuli with subjective salience could affect duration estimation. Although self-referential stimuli possess high biological and social importance, no prior study has examined whether and how self-referential information affects duration perception. Experiment 1 used the temporal bisection task to investigate participants' duration estimation of the presentation of their own name versus familiar and unfamiliar names. The results showed that participants overestimated the duration of their own name and became more sensitive to duration perception in such trials when compared with stranger's names. Given the specificity of personal name, Experiment 2 used two types of personality-trait words in self-referential and friend-referential manner as the targets of duration perception. The duration of self-referential negative trait words was perceived to be longer relative to friend-referential negative trait words. The mechanism underlying the subjective time dilation effect of self-referential information possibly involves the engagement of increased attentional resources, which could allow the individual to preserve a certain level of stability and positivity of self-knowledge.

Emotional bias varies with stimulus type, arousal and task setting: Meta-analytic evidences.

Emotional bias, which describes human's asymmetric processing of emotional stimuli, consists of negativity bias (Increased response to negative over positive stimuli) and positivity offset (the reversed phenomenon). Previous studies suggest that stimulus arousal (high/low), stimulus type (scenic/verbal), cultural background (Eastern/Western), and task setting (explicit/implicit) may modulate emotional bias, but with inconclusive findings. To address how the profile of emotional bias varies with these factors, a meta-analysis of emotional P3 event-related potential amplitudes was performed. Forty-nine effect sizes from 38 studies involving 1263 subjects were calculated using Hedges'g. The results highlight significant moderators of arousal, stimulus type, and task setting. Specifically, high-arousal stimuli enhance negativity bias relative to low-arousal stimuli; scenic stimulus leads to a negativity bias while verbal stimulus is linked with a positivity offset; explicit emotion tasks lead to negativity bias, whereas implicit emotion tasks do not exhibit emotional bias. These results indicate that emotional bias is labile depending on stimulus arousal, stimulus type and task setting. The implication of these findings for emotion regulation is discussed.