BCMA/CD47-directed universal CAR-T cells exhibit excellent antitumor activity in multiple myeloma.

BACKGROUND: BCMA-directed autologous chimeric antigen receptor T (CAR-T) cells have shown excellent clinical efficacy in relapsed or refractory multiple myeloma (RRMM), however, the current preparation process for autologous CAR-T cells is complicated and costly. Moreover, the upregulation of CD47 expression has been observed in multiple myeloma, and anti-CD47 antibodies have shown remarkable results in clinical trials. Therefore, we focus on the development of BCMA/CD47-directed universal CAR-T (UCAR-T) cells to improve these limitations. METHODS: In this study, we employed phage display technology to screen nanobodies against BCMA and CD47 protein, and determined the characterization of nanobodies. Furthermore, we simultaneously disrupted the endogenous TRAC and B2M genes of T cells using CRISPR/Cas9 system to generate TCR and HLA double knock-out T cells, and developed BCMA/CD47-directed UCAR-T cells and detected the antitumor activity in vitro and in vivo. RESULTS: We obtained fourteen and one specific nanobodies against BCMA and CD47 protein from the immunized VHH library, respectively. BCMA/CD47-directed UCAR-T cells exhibited superior CAR expression (89.13-98.03%), and effectively killing primary human MM cells and MM cell lines. BCMA/CD47-directed UCAR-T cells demonstrated excellent antitumor activity against MM and prolonged the survival of tumor-engrafted NCG mice in vivo. CONCLUSIONS: This work demonstrated that BCMA/CD47-directed UCAR-T cells exhibited potent antitumor activity against MM in vitro and in vivo, which provides a potential strategy for the development of a novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.

Improved antitumor effects elicited by an oncolytic HSV-1 expressing a novel B7H3nb/CD3 BsAb.

Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and redirect cytotoxic T lymphocytes, enhancing the antitumor response. To take advantage of the specific infection capacity and carrying ability of exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-1dko-B7H3nb/CD3 or HSV-1dko-B7H3nb/mCD3, carrying a B7H3nb/CD3 or B7H3nb/mCD3 BsAb that replicates and expresses BsAb in tumor cells in vitro and in vivo. The new generation of oncolytic viruses has been genetically modified using CRISPR/Cas9 technology and the cre-loxp system to increase the efficiency of HSV genome editing. Additionally, we used two fully immunocompetent models (GL261 and MC38) to assess the antitumor effect of HSV-1dko-B7H3nb/mCD3. Compared with the HSV-1dko control virus, HSV-1dko-B7H3nb/mCD3 induced enhanced anti-tumor immune responses and T-cell infiltration in both GL261 and MC38 models, resulting in improved treatment efficacy in the latter. Furthermore, flow cytometry analysis of the tumor microenvironment confirmed an increase in NK cells and effector CD8+ T cells, and a decrease in immunosuppressive cells, including FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and CD206+ macrophages (M2). Overall, our study identified a novel camel B7H3 nanobody and described the genetic modification of the HSV-1 genome using CRISPR/Cas9 technology and the cre-loxp system. Our findings indicate that expressing B7H3nb/CD3 BsAb could improve the antitumor effects of HSV-1 based oncolytic virus.

Association between social integration and loneliness among the female migrant older adults with children: the mediating effect of social support.

BACKGROUND: The number of migrant older adults with children (MOAC) in China has been increasing in recent years, and most of them are women. This study aimed to explore the mediating effect of social support between social integration and loneliness among the female MOAC in Jinan, China. METHODS: In this study, 418 female MOAC were selected using multi-stage cluster random sampling in Jinan, Shandong Province, China. Loneliness was measured by the eight-item version of the University of California Los Angeles Loneliness Scale (ULS-8), and social support was measured by The Social Support Rating Scale (SSRS). Descriptive analyses, t-tests, ANOVA, and structural equation modeling (SEM) were used to illustrate the relationship between social integration, social support, and loneliness. RESULTS: The average scores of ULS-8 and SSRS were 12.9 ± 4.0 and 39.4 ± 5.9 among female MOAC in this study. Social integration and social support were found to be negatively related to loneliness, and the standardized direct effect was -0.20 [95% CI: -0.343 to -0.068] and -0.39 [95% CI: -0.230 to -0.033], respectively. Social support mediated the relationship between social integration and loneliness, and the indirect effect was -0.16 [95% CI: -0.252 to -0.100]. CONCLUSION: The female MOAC's loneliness was at a relatively lower level in this study. It was found that social integration was negatively associated with loneliness, and social support mediated the relationship between them. Helping female MOAC integrate into the inflow city and improving their social support could be beneficial for alleviating their loneliness.

Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma.

Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.

Delivery of CD47-SIRPα checkpoint blocker by BCMA-directed UCAR-T cells enhances antitumor efficacy in multiple myeloma.

In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple myeloma cells highly expressed CD47 molecule and interact with the SIRPα ligand on the surface of macrophages, in which evade the clearance of macrophages through the activation of "don't eat me" signal. In this study, a BCMA-directed universal CAR-T cells, BC404-UCART, secreting a CD47-SIRPα blocker was developed using CRISPR/Cas9 gene-editing system. BC404-UCART cells significantly inhibited tumor growth and prolonged the survival of mice in the xenograft model. The anti-tumor activity of BC404-UCART cells was achieved via two mechanisms, on the one hand, the UCAR-T cells directly killed tumor cells, on the other hand, the BC404-UCART cells enhanced the phagocytosis of macrophages by secreting anti-CD47 nanobody hu404-hfc fusion that blocked the "don't eat me" signal between macrophages and tumor cells, which provides a potential strategy for the development of novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.

The chain mediation model of social support and life satisfaction among migrant older adults with children: The role of mental health and sleep quality.

INTRODUCTION: Few studies have examined the life satisfaction of migrant older adults with children (MOAC), who emerged due to rapid urbanization and population aging in China. This study aimed to explore the chain mediating effect of mental health and sleep quality on the association between social support and life satisfaction among MOAC in Weifang, China. METHODS: A cross-sectional study was conducted using multi-stage cluster random sampling, and 613 participants were included. The Social Support Rating Scale, Depression Anxiety Stress Scale, Pittsburgh Sleep Quality Index, and Scale with Life Satisfaction were used to measure the social support, mental health, sleep quality, and life satisfaction of MOAC, respectively. Descriptive statistics, t-tests, and ANOVA were used to explore the relationship between sociodemographic variables and life satisfaction. Pearson's correlation analysis and structural equation modeling (SEM) were conducted to investigate the association between social support, mental health, sleep quality, and life satisfaction. RESULTS: The mean total SWLS score was 27.87±5.58. SEM analysis demonstrated that social support had a positive effect on life satisfaction (ß= 0.197). Mental health and sleep quality partially mediated the association between social support and life satisfaction (95% CI: 0.083-0.193), and the mediating effect accounted for 39.198% of the total effect. CONCLUSION: Life satisfaction was relatively high, and mental health and sleep quality partially mediated the association between social support and life satisfaction. Policy suggestions were provided based on these results.

The relationships of preventive behaviors and psychological resilience with depression, anxiety, and stress among university students during the COVID-19 pandemic: A two-wave longitudinal study in Shandong Province, China.

Introduction: Studies have shown that the psychological impact of the COVID-19 pandemic may lead to long-term health problems; therefore, more attention should be paid to the mental health of university students. This study aimed to explore the longitudinal effects of preventive behaviors and psychological resilience on the mental health of Chinese college students during COVID-19. Methods: We recruited 2,948 university students from five universities in Shandong Province. We used a generalized estimating equation (GEE) model to estimate the impact of preventive behaviors and psychological resilience on mental health. Results: In the follow-up survey, the prevalence of anxiety (44.8% at T1 vs 41.2% at T2) and stress (23.0% at T1 vs 19.6% at T2) decreased over time, whereas the prevalence of depression (35.2% at T1 vs 36.9% at T2) increased significantly (P < 0.001). Senior students were more likely to report depression (OR = 1.710, P < 0.001), anxiety (OR = 0.815, P = 0.019), and stress (OR = 1.385, P = 0.011). Among all majors, medical students were most likely to report depression (OR = 1.373, P = 0.021), anxiety (OR = 1.310, P = 0.040), and stress (OR = 1.775, P < 0.001). Students who wore a mask outside were less likely to report depression (OR = 0.761, P = 0.027) and anxiety (OR = 0.686, P = 0.002) compared to those who did not wear masks. Students who complied with the standard hand-washing technique were less likely to report depression (OR = 0.628, P < 0.001), anxiety (OR = 0.701, P < 0.001), and stress (OR = 0.638, P < 0.001). Students who maintained a distance of one meter in queues were less likely to report depression (OR = 0.668, P < 0.001), anxiety (OR = 0.634, P < 0.001), and stress (OR = 0.638, P < 0.001). Psychological resilience was a protective factor against depression (OR = 0.973, P < 0.001), anxiety (OR = 0.980, P < 0.001), and stress (OR = 0.976, P < 0.001). Discussion: The prevalence of depression among university students increased at follow-up, while the prevalence of anxiety and stress decreased. Senior students and medical students are vulnerable groups. University students should continue to follow relevant preventive behaviors to protect their mental health. Improving psychological resilience may help maintain and promote university students' mental health.

A drug screening to identify novel combinatorial strategies for boosting cancer immunotherapy efficacy.

BACKGROUND: Chimeric antigen receptor (CAR) T cells and immune checkpoint blockades (ICBs) have made remarkable breakthroughs in cancer treatment, but the efficacy is still limited for solid tumors due to tumor antigen heterogeneity and the tumor immune microenvironment. The restrained treatment efficacy prompted us to seek new potential therapeutic methods. METHODS: In this study, we conducted a small molecule compound library screen in a human BC cell line to identify whether certain drugs contribute to CAR T cell killing. Signaling pathways of tumor cells and T cells affected by the screened drugs were predicted via RNA sequencing. Among them, the antitumor activities of JK184 in combination with CAR T cells or ICBs were evaluated in vitro and in vivo. RESULTS: We selected three small molecule drugs from a compound library, among which JK184 directly induces tumor cell apoptosis by inhibiting the Hedgehog signaling pathway, modulates B7-H3 CAR T cells to an effector memory phenotype, and promotes B7-H3 CAR T cells cytokine secretion in vitro. In addition, our data suggested that JK184 exerts antitumor activities and strongly synergizes with B7-H3 CAR T cells or ICBs in vivo. Mechanistically, JK184 enhances B7-H3 CAR T cells infiltrating in xenograft mouse models. Moreover, JK184 combined with ICB markedly reshaped the tumor immune microenvironment by increasing effector T cells infiltration and inflammation cytokine secretion, inhibiting the recruitment of MDSCs and the transition of M2-type macrophages in an immunocompetent mouse model. CONCLUSION: These data show that JK184 may be a potential adjutant in combination with CAR T cells or ICB therapy.

Loss of furin site enhances SARS-CoV-2 spike protein pseudovirus infection.

BACKGROUND: SARS-CoV-2 has a significant impact on healthcare systems all around the world. Due to its high pathogenicity, live SARS-CoV-2 must be handled under biosafety level 3 conditions. Pseudoviruses are useful virological tools because of their safety and versatility, but the low titer of these viruses remains a limitation for their more comprehensive applications. METHOD: Here, we constructed a Luc/eGFP based on a pseudotyped lentiviral HIV-1 system to transduce SARS-CoV-2 S glycoprotein to detect cell entry properties and cellular tropism. RESULTS: The furin cleavage site deletion of the S protein removed (SFko) can help SARS-CoV-2 S to be cleaved during viral packaging to improve infection efficiency. The furin cleavage site in SARS-CoV-2-S mediates membrane fusion and SFko leads to an increased level of S protein and limits S1/S2 cleavage to enhance pseudovirus infection in cells. Full-length S (SFL) pseudotyped with N, M, and E helper packaging can effectively help SFL infect cells. Finally, pseudotyped SFko particles were successfully used to detect neutralizing antibodies in RBD protein-immunized mouse serum. CONCLUSION: Overall, our study indicates a series of modifications that result in the production of relatively high-titer SARS-COV-2 pseudo-particles that may be suitable for the detection of neutralizing antibodies from COVID-19 patients.

CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM.

Evaluation of B7-H3 Targeted Immunotherapy in a 3D Organoid Model of Craniopharyngioma.

A craniopharyngioma (CP) is a rare epithelial tumor of the sellar and parasellar region. CPs are difficult to treat due to their anatomical proximity to critical nervous structures, which limits the ability of the surgeon to completely resect the lesion, exposing patients to a high risk of recurrence. The treatment of craniopharyngiomas is primarily surgery and radiotherapy. So far, neither a cell line nor an animal model has been established, and thus data on other treatment options, such as chemotherapy and immunotherapy, are limited. Here, the expression profile of the pan-cancer antigen B7-H3 in various cancer types including CP was examined by immunohistochemistry. An in vitro organoid model was established by using fresh tissue biospecimens of CP. Based on the organoid model, we evaluated the antitumor efficacy of B7-H3-targeted immunotherapy on CP. As a result, the highest expression of B7-H3 was observed in CP tissues across various cancer types. Although B7-H3-targeted chimeric antigen-receptor T cells show obvious tumor-killing effects in the traditional 2D cell culture model, limited antitumor effects were observed in the 3D organoid model. The B7-H3-targeted antibody-DM1 conjugate exhibited a potent tumor suppression function both in 2D and 3D models. In conclusion, for the first time, we established an organoid model for CP and our results support that B7-H3 might serve as a promising target for antibody-drug conjugate therapy against craniopharyngioma.

The mediating effect of social support on the association between socioeconomic status and self-reported oral health status among the migrant elderly following children in Weifang, China: a cross-sectional study.

BACKGROUND: Driven by population aging and the rapid urbanization in China, many migrant elderly following children (MEFC) moved to big cities to care for their grandchildren. The purpose of this study is to clarify the mediating effect of social support on the relationship between socioeconomic status (SES) and self-reported oral health status among the MEFC in Weifang, China. METHODS: Multistage cluster random sampling was used to select the participants and finally 613 MEFC were included in the survey. The Social Support Rating Scale (SSRS) and the Chinese version of the Geriatric Oral Health Assessment Index (GOHAI) scale were used for data collection. Descriptive analysis, Rao-Scott test, t-test and structural equation modeling (SEM) were conducted in this study. RESULTS: Mean score of GOHAI of the MEFC was 54.95 ± 6.47. The SES of MEFC exerted positive direct effect both on social support (standardized coefficient = 0.15) and self-reported oral health status (standardized coefficient = 0.22); social support exerted positive direct effect on self-reported oral health status (standardized coefficient = 0.17). Social support partially mediated the association between SES and self-reported oral health status [95% confidence interval (CI) 0.003-0.064, P < 0.05], and the mediating effect of social support accounted for 12.0% of the total effect. CONCLUSIONS: Higher GOHAI score of MEFC indicated their better self-reported oral health status. MEFCs' SES could exert positive effect both on social support and self-reported oral health status, while the mediating effect of social support between SES and self-reported oral health status of MEFC was established.

Effects of Health Service Utilization and Informal Social Support on Depression, Anxiety, and Stress among the Internal Migrant Elderly following Children in Weifang, China.

This study explored the relationship between health service utilization, informal social support and depression, anxiety and stress among the internal migrant elderly following children (IMEFC) in Weifang, China. A total of 613 IMEFC were selected using multistage cluster random sampling. The Depression Anxiety and Stress Scale 21 (DASS-21) was used to assess the depression, anxiety and stress of the IMEFC. Descriptive analysis and univariate and binary logistic regression analyses were used to clarify the correlation between health service utilization and social support and depression, anxiety and stress of the IMEFC. The prevalence of depression, anxiety and stress of the IMEFC was 6.9%, 7.7% and 3.4%, respectively. Logistic regression analysis showed that the IMEFC who having financial stress on medical costs were more likely to feel depressed than those haven't financial stress on medical costs (OR = 6.557), while those unemployed and having no income were less likely to feel depressed than those employed (OR = 0.262), having children support were less likely to feel depressed than those haven't children support (OR = 0.257) and having comfort support were less likely to feel depressed than haven't comfort support (OR = 0.018). Trans-city migration were more likely to feel anxious than trans-county migration (OR = 3.198), having outpatient service were more likely to feel anxious than haven't experienced inpatient service (OR = 3.818), having financial stress on medical costs were more likely to feel anxious than haven't financial stress on medical costs (OR = 3.726), while having children support were less likely to feel anxious than haven't children support (OR = 0.198). Those who migrate to cure disease or rehabilitation were more likely to feel stressed than those migrated to taking care of grandchildren (OR = 12.702) and having financial stress on medical costs were more likely to feel stressed than haven't financial stress on medical costs (OR = 32.155), while having children support were less likely to feel stressed than haven't children support (OR = 0.055) and having economic support in troubles were less likely to feel stressed than haven't economic support in troubles (OR = 0.012). More effective measures should be taken to improve the accessibility and efficiency of cross-regional health insurance reimbursement, and family members should spend more time with the IMEFC to lower their psychological tension in a new environment.

The Effects of Living Environment, Health Status of Family Members, and Migrant Elderly following Children's Attitude about Care on Grandchildren's Health Status in Weifang, China.

As urbanization is growing quickly in China, many migrant elderly following children (MEFC) migrate to big cities to care for their grandchildren (grandchildren of MEFC=GMEFC). This study aimed to explore the effects of the living environment, health statuses of family members, and MEFC's attitude regarding the care of their children (children of MEFC=CMEFC) for their GMEFC on GMEFC's health statuses in Weifang, China. Multistage cluster random sampling was used to select the participants, and 613 MEFC were included in total. Descriptive analysis, univariate analysis and binary logistic regression were used to investigate the association between the related variables and GMEFC's health statuses. It was found that 74.9% of the GMEFC had excellent health statuses. The GMEFC who had siblings, the CMEFC with excellent health statuses, and the MEFC with excellent health statuses were more likely to have excellent health statuses. Moreover, the GMEFC who were female, elevators occasionally malfunctioned, the MEFC who were dissatisfied with the CMEFC's time spent on caring, and the MEFC who did not understand or forgive the CMEFC's limited time on caring were less likely to have GMEFC with excellent health statuses. The results indicated that a better living environment, better health statuses of family members, and a positive attitude of the MEFC regarding the care of CMEFC for GMEFC would result in a better health status of GMEFC.

The effects of oral health and social support on health-related quality of life of migrant older with children in Weifang, China.

BACKGROUND: With the accelerated urbanization and aging population in China, more and more migrant older with children (MOC) moved to new cities. Previous studies mainly explored the acculturation of MOC, yet few focused on the health conditions of this vulnerable group. This study aimed to investigate the effects of oral health and social support on health-related quality of life (HRQOL) of MOC in Weifang, China. METHOD: This study was a cross-sectional study and participants were selected by multi-stage cluster random sampling in Weifang, China. The HRQOL was assessed via the 12-item Short-Form Health Survey (SF-12) which included the mental component summary (MCS) and the physical component summary (PCS). The oral health was evaluated by the Geriatric Oral Health Assessment Index (GOHAI). The social support was administered using the Social Support Rating Scale (SSRS). Descriptive analysis was used to describe participants' sociodemographic variables, oral health and social support. Univariate analysis and binary logistic regression analysis was used to investigate the association between the social support, oral health and HRQOL. RESULTS AND DISCUSSION: It was found that 25.0% of MOC were defined as MCS poor and PCS poor, respectively. Those participants with average and low monthly household income compared to those around them, average and poor oral health, and low levels of social support were more likely to have poor PCS. Those with temporary residence permits, fair and poor oral health, and medium and low levels of social support were more likely to report poor MCS. CONCLUSION: Results indicated that better social support and oral health led to higher HRQOL of MOC. Implications for the government, communities and families of MOC were given to improve their HRQOL.

Genome-scale CRISPR-Cas9 screen reveals novel regulators of B7-H3 in tumor cells.

BACKGROUND: Despite advances in B7 homolog 3 protein (B7-H3) based immunotherapy, the development of drug resistance remains a major clinical concern. The heterogeneity and emerging loss of B7-H3 expression are the main causes of drug resistance and treatment failure in targeted therapies, which reveals an urgent need to elucidate the mechanism underlying the regulation of B7-H3 expression. In this study, we identified and explored the crucial role of the transcription factor SPT20 homolog (SP20H) in B7-H3 expression and tumor progression. METHODS: Here, we performed CRISPR/Cas9-based genome scale loss-of-function screening to identify regulators of B7-H3 in human ovarian cancer cells. Signaling pathways altered by SP20H knockout were revealed by RNA sequencing. The regulatory role and mechanism of SP20H in B7-H3 expression were validated using loss-of-function and gain-of-function assays in vitro. The effects of inhibiting SP20H on tumor growth and efficacy of anti-B7-H3 treatment were evaluated in tumor-bearing mice. RESULTS: We identified SUPT20H (SP20H) as negative and eIF4E as positive regulators of B7-H3 expression in various cancer cells. Furthermore, we provided evidence that either SP20H loss or TNF-α stimulation in tumor cells constitutively activates p38 MAPK-eIF4E signaling, thereby upregulating B7-H3 expression. Loss of SP20H upregulated B7-H3 expression both in vitro and in vivo. Additionally, deletion of SP20H significantly suppressed tumor growth and increased immune cells infiltration in tumor microenvironment. More importantly, antibody-drug conjugates targeting B7-H3 exhibited superior antitumor performance against SP20H-deficient tumors relative to control groups. CONCLUSIONS: Activation of p38 MAPK-eIF4E signaling serves as a key event in the transcription initiation and B7-H3 protein expression in tumor cells. Genetically targeting SP20H upregulates target antigen expression and sensitizes tumors to anti-B7-H3 treatment. Collectively, our findings provide new insight into the mechanisms underlying B7-H3 expression and introduce a potential synergistic target for existing antibody-based targeted therapy against B7-H3.

Effect of Morbidities, Depression, Anxiety, and Stress on Oral Health-Related Quality of Life among Migrant Elderly Following Children in Weifang, China.

This study explored the relationship between depression, anxiety, stress, morbidity, and oral health-related quality of life (OHRQoL) in the migrant elderly following children (MEFC) in Weifang, China. A total of 613 MEFC were selected using multistage cluster random sampling. The GOHAI scale was used to evaluate oral health-related quality of life. The DASS-21 scale was used to assess levels of depression, anxiety, and stress. Univariate analysis and binary logistic regression were used to analyze the correlation between these indicators and oral health-related quality of life, of which 43.9% were classified as having poor oral health. Logistic regression analysis showed that the MEFC who were of older age (OR = 0.965, p = 0.039), with hypertension (OR = 0.567, p = 0.004), with gastroenteropathy (OR = 0.263, p = 0.007), had received an outpatient service in the past year (OR = 0.669, p = 0.048), were depressed (OR = 0.338, p = 0.012), and anxious (OR = 0.414, p = 0.026) were less likely to report good oral health status. On the other hand, the MEFC with a high school education or above (OR = 1.872, p = 0.020) were more likely to report good oral health than those with primary school education and below. In conclusion, with regard to depression, anxiety, and stress: the results indicated that the fewer morbidities, the lower the level of depression and anxiety and the better the OHRQoL of MEFC. Targeted measures for government, communities, and family members were given to improve the OHRQoL of MEFC.

The relationship between oral health status, loneliness, and sleep quality among the migrant elderly following children in Weifang, Shandong Province, China: A comparative analysis on different migration types.

Background: The migrant elderly following children (MEFC) are a vulnerable group that emerged during fast urbanization in China. The MEFC faced physical and psychological discomfort upon their arrival in the inflow city, particularly those who came from rural areas. Objective: This study aimed to explore the relationship between oral health status, loneliness, and sleep quality among the MEFC in China and to clarify the disparities in the above mentioned relationship by migration type. Methods: In 2021, a cross-sectional survey was conducted in Weifang, Shandong Province, using multistage cluster random sampling to collect data from the MEFC aged 60 years and over. In total, 613 respondents [525 rural-to-urban (RTU) and 88 urban-to-urban (UTU)] were included in the final database. The chi-square test, t-test, and structural equation modeling (SEM) were used to investigate the relationship between oral health status, loneliness, and sleep quality among the RTU and UTU MEFC. Results: Total scores [mean ± standard deviation (SD)] for oral health status, loneliness, and sleep quality were 54.95 ± 6.47, 8.58 ± 3.03, and 4.47 ± 3.60, respectively. SEM revealed that, among the RTU and UTU MEFC, oral health status was positively and significantly related to sleep quality; however, the correlation was slightly stronger in the UTU MEFC. In both groups, there was a significant negative correlation between oral health status and loneliness, which was stronger in the UTU MEFC. In the RTU MEFC, a significant negative correlation between loneliness and sleep quality was observed, and in the UTU MEFC, no significant association between loneliness and sleep quality was observed. Conclusion: The sleep quality among the MEFC in this study was higher compared to previous studies. Oral health status was negatively correlated with loneliness and positively associated with sleep quality, whereas loneliness was negatively correlated with sleep quality. These three associations differed significantly between the UTU and RTU MEFC. The government, society, and families should take measures to improve oral health and reduce loneliness among the MEFC to improve their sleep quality.

AP-64, Encoded by C5orf46, Exhibits Antimicrobial Activity against Gram-Negative Bacteria.

Antimicrobial peptides (AMPs), which are evolutionarily conserved components of the innate immune response, contribute to the first line of defense against microbes in the skin and at mucosal surfaces. Here, we report the identification of a human peptide, encoded by the chromosome 5 open reading frame 46 (C5orf46) gene, as a type of AMP, which we termed antimicrobial peptide with 64 amino acid residues (AP-64). AP-64 is an anionic amphiphilic peptide lacking cysteines (MW = 7.2, PI = 4.54). AP-64 exhibited significant antibacterial activity against Gram-negative bacteria, including Escherichia coli DH5α, Escherichia coli O157:H7, Vibrio cholerae, and Pseudomonas aeruginosa. Moreover, AP-64 was efficient in combating Escherichia coli O157:H7 infections in a mouse model and exhibited cytotoxic effects against human T-cell lymphoma Jurkat and B-cell lymphoma Raji cells. We also observed that Gm94, encoded by mouse C5orf46 homologous gene, closely resembles AP-64 in its antibacterial properties. Compared with other human AMPs, AP-64 has distinct characteristics, including a longer sequence length, absence of cysteine residues, a highly anionic character, and cell toxicity. Together, this study identified that AP-64 is an AMP worthy of further investigation.

Development of multivalent nanobodies blocking SARS-CoV-2 infection by targeting RBD of spike protein.

BACKGROUND: The outbreak and pandemic of coronavirus SARS-CoV-2 caused significant threaten to global public health and economic consequences. It is extremely urgent that global people must take actions to develop safe and effective preventions and therapeutics. Nanobodies, which are derived from single­chain camelid antibodies, had shown antiviral properties in various challenge viruses. In this study, multivalent nanobodies with high affinity blocking SARS-CoV-2 spike interaction with ACE2 protein were developed. RESULTS: Totally, four specific nanobodies against spike protein and its RBD domain were screened from a naïve VHH library. Among them, Nb91-hFc and Nb3-hFc demonstrated antiviral activity by neutralizing spike pseudotyped viruses in vitro. Subsequently, multivalent nanobodies were constructed to improve the neutralizing capacity. As a result, heterodimer nanobody Nb91-Nb3-hFc exhibited the strongest RBD-binding affinity and neutralizing ability against SARS-CoV-2 pseudoviruses with an IC50 value at approximately 1.54 nM. CONCLUSIONS: The present study indicated that naïve VHH library could be used as a potential resource for rapid acquisition and exploitation of antiviral nanobodies. Heterodimer nanobody Nb91-Nb3-hFc may serve as a potential therapeutic agent for the treatment of COVID-19.