Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms

Abstract Background Acquired imatinib (IM) resistance is frequently characterized by Bcr-Abl mutations that affect IM binding and kinase inhibition in patients with chronic myelogenous leukemia (CML). Bcr-Abl-T315I mutation is the predominant mechanism of the acquired resistance to IM. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that nickel pyrithione (NiPT) potently inhibits the ubiquitin proteasome system via targeting the 19S proteasome-associated deubiquitinases (UCHL5 and USP14), without effecting on the 20S proteasome. In this present study, we investigated the effect of NiPT, a novel proteasomal deubiquitinase inhibitor, on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. Methods Cell viability was examined by MTS assay and trypan blue exclusion staining assay in KBM5, KBM5R, K562, BaF3-p210-WT, BaF3-p210-T315I cells, and CML patients’ bone marrow samples treated with NiPT. Cell apoptosis in CML cells was detected with Annexin V-FITC/PI and rhodamine-123 staining followed by fluorescence microscopy and flow cytometry and with western blot analyses for apoptosis-associated proteins. Expression levels of Bcr-Abl in CML cells were analyzed by using western blotting and real-time PCR. The 20S proteasome peptidase activity was measured using specific fluorogenic substrate. Active-site-directed labeling of proteasomal DUBs, as well as the phosphorylation of USP14 was used for evaluating the inhibition of the DUBs activity by NiPT. Mouse xenograft models of KBM5 and KBM5R cells were analyzed, and Bcr-Abl-related proteins and protein biomarkers related to proliferation, differentiation, and adhesion in tumor tissues were detected by western blots and/or immunohistological analyses. Results NiPT induced apoptosis in CML cells and inhibited the growth of IM-resistant Bcr-Abl-T315I xenografts in nude mice. Mechanistically, NiPT induced decreases in Bcr-Abl proteins, which were associated with downregulation of Bcr-Abl transcription and with the cleavage of Bcr-Abl protein by activated caspases. NiPT-induced ubiquitin proteasome system inhibition induced caspase activation in both IM-resistant and IM-sensitive CML cells, and the caspase activation was required for NiPT-induced Bcr-Abl downregulation and apoptotic cell death. Conclusions These findings support that NiPT can overcome IM resistance through both Bcr-Abl-dependent and Bcr-Abl-independent mechanisms, providing potentially a new option for CML treatment

Perception and willingness toward various immunization routes for COVID-19 vaccines: a cross-sectional survey in China

Conclusion: Needle-free vaccination is a promising technology for the next generation of vaccines, but we found that intramuscular injection was still the most acceptable immunization route in this survey. One major reason might be that most people lack knowledge about needle-free vaccination. We should strengthen the publicity of needle-free vaccination technology, and thus improve the acceptance and coverage of vaccination in different populations

Perception and willingness toward various immunization routes for COVID-19 vaccines: a cross-sectional survey in China

BackgroundTo date, most vaccines, including the COVID-19 vaccine, are mainly administered by intramuscular injection, which might lead to vaccine hesitancy in some populations due to needle fear. Alternatively, needle-free immunization technology is extensively developed to improve the efficacy and acceptance of vaccination. However, there is no study to report the perception and willingness toward various immunization routes of the COVID-19 vaccine in the general population.MethodsA cross-sectional survey was conducted nationwide using an online questionnaire. Bivariate analyses were undertaken to assess variable associations among the participants who reported a hesitancy to receive the COVID-19 booster vaccination. Multivariable logistic regression with a backward step-wise approach was used to analyze the predicted factors associated with the willingness to receive the COVID-19 booster vaccination.ResultsA total of 3,244 valid respondents were included in this survey, and 63.2% of participants thought they had a good understanding of intramuscular injection, but only 20.7, 9.2, 9.4, and 6.0% of participants had a self-perceived good understanding of inhalation vaccine, nasal spray vaccine, oral vaccine, and microneedle patch vaccine. Correspondingly, there was high acceptance for intramuscular injection (76.5%), followed by oral inhalation (64.4%) and nasal spray (43.0%). Those participants who were only willing to receive an intramuscular vaccine had less vaccine knowledge (OR = 0.78; 95% CI: 0.65–0.94) than those who were willing to receive a needle-free vaccine (OR = 1.97; 95% CI: 1.52–2.57). Some factors were found to be associated with vaccine hesitancy toward booster COVID-19 vaccination.ConclusionNeedle-free vaccination is a promising technology for the next generation of vaccines, but we found that intramuscular injection was still the most acceptable immunization route in this survey. One major reason might be that most people lack knowledge about needle-free vaccination. We should strengthen the publicity of needle-free vaccination technology, and thus improve the acceptance and coverage of vaccination in different populations

Nomogram for Predicting Bone Development State of Female Children and Adolescents–A Fast Screening Approach Based on Pubes Stages for Growth and Development

Objective: To develop a nomogram for predicting bone development state (BDS) of female children and adolescents in a large scale.Methods: Four hundred forty-seven female students were designated as the training cohort to develop the predictive model, whereas 196 female students were used as the validation cohort to verify the established model. Bone age, height, body mass, body fat percentage, and secondary sexual characteristics were recorded, and BDS was determined with the chronological age and bone age. Multivariate logistic regression was conducted to determine the factors, and nomogram was developed and validated with the training and validation cohorts, respectively.Results: One hundred forty-seven female students were identified as BDS abnormal in the training cohort (32.9%), and 104 were determined in the validation cohort (53.1%). Age, height, weight, and pubes stage were selected for the predictive model. A nomogram was developed and showed a good estimation, with a C-index of 0.78 and a good calibration in the training cohort. Application of the nomogram to the validation cohort showed a similar C-index of 0.75 and a good calibration.Conclusion: A nomogram for predicting bone development was developed, which can provide a relatively good estimation of BDS for female children and adolescents in Chinese metropolis

High-rise buildings: A risk factor in the COVID-19 Omicron epidemic period

Objectives: This study aimed to investigate possible viral transmission scenarios inside a high-rise building during the Omicron phase of the COVID-19 pandemic. Study design: Cross-sectional study design. Methods: In order to determine the pathogenicity of the Omicron variant of SARS-CoV-2, demographic, vaccination and clinical data were collected from COVID-19 positive cases during an outbreak in a high-rise residential building in Shenzhen, China, in early 2022. The pattern of viral transmission inside the building was determined through field investigation and engineering analysis. The results highlight the risk of Omicron infection in high-rise residential buildings. Results: Symptoms of infection with the Omicron variant are predominantly mild. Younger age has a greater impact on the severity of disease than vaccination status. Each floor of the high-rise building investigated contained 7 apartments, numbered 01 to 07, positioned in the same layout on each floor. The drainage system included vertical pipes from the ground to the roof of the building. There were statistically significant differences in infection rates at different time points and incidence ratios between apartment numbers ending in 07 (type 07) and other apartments (P < 0.001). Households with early disease onset were concentrated in apartment type 07 and the severity of their disease was more severe. The incubation period of the outbreak was 5.21–5.31 days and the time-dependent reproduction number (Rt) was 12.08 (95% confidence interval [CI] 7.66, 18.29). Results suggest both non-contact and contact viral transmission may have contributed to the outbreak. The drainage system in the building allows aerosol regurgitation, thus indicating that the structure of the building may have led to spread of the virus from the sewage pipes. Infections in other apartments may have been as result of viral transmission in the elevators and intimate family contact. Conclusions: Results from this study suggest that Omicron transmission was likely to be via the sewage system, supplemented by contact transmission in the stairs and elevators. The environmental spread of Omicron needs to be highlighted and prevented

Dietary Interventions of Salmon and Silver Carp Phospholipids on Mice with Metabolic Syndrome Based on Lipidomics

The number of metabolic syndromes (MetS) is increasing, and a fish phospholipid diet can reduce the risk of MetS. In this study, the changes in lipid metabolism of colon contents were analyzed by extensive lipidomics in mice with metabolic syndrome by fish phospholipid diet, and mice were randomly divided into experimental groups with different diet types by establishing a MetS model. After 14 weeks, the mice were sacrificed and the serum and colon contents were collected. Ultra-high liquid phase tandem mass spectrometry was used for broadly targeted lipidomic analysis, and the qualitative and quantitative detection of lipid metabolism changes in the colonic contents of mice. Under the intervention of fish phospholipids, MetS mice were significantly inhibited, serum total cholesterol (TC) and triglycerides (TG) decreased, serum high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) levels were improved, fasting blood glucose and insulin levels decreased, and inflammatory factors decreased. Through screening, it was found that thirty-three lipid metabolites may be key metabolites and five have significantly changed metabolic pathways. Modularizing lipid metabolites, it is possible to understand the extent to which different types and concentrations of fish phospholipids affect metabolic syndrome. Therefore, our study may provide new therapeutic clues for improving MetS

Structural Correlates of CA2 and CA3 Pyramidal Cell Activity in Freely-Moving Mice

Plasticity within hippocampal circuits is essential for memory functions. The hippocampal CA2/CA3 region is thought to be able to rapidly store incoming information by plastic modifications of synaptic weights within its recurrent network. High-frequency spike-bursts are believed to be essential for this process, by serving as triggers for synaptic plasticity. Given the diversity of CA2/CA3 pyramidal neurons, it is currently unknown whether and how burst activity, assessed in vivo during natural behavior, relates to principal cell heterogeneity. To explore this issue, we juxtacellularly recorded the activity of single CA2/CA3 neurons from freely-moving male mice, exploring a familiar environment. In line with previous work, we found that spatial and temporal activity patterns of pyramidal neurons correlated with their topographical position. Morphometric analysis revealed that neurons with a higher proportion of distal dendritic length displayed a higher tendency to fire spike-bursts. We propose that the dendritic architecture of pyramidal neurons might determine burst-firing by setting the relative amount of distal excitatory inputs from the entorhinal cortex

Heightened Willingness toward Pneumococcal Vaccination in the Elderly Population in Shenzhen, China: A Cross-Sectional Study during the COVID-19 Pandemic

Background: Elderly population is considered at high risk for pneumococcal diseases. The pneumococcal vaccine coverage presents extremely low among elderly people in China. However, the serious event of COVID-19 drives interest in the pneumococcal vaccine, prompting us investigating the willingness to accept the 23-valent pneumococcal polysaccharide vaccine (PPSV23) and influencing factors among people aged over 60 years during the COVID-19 pandemic. Methods: A cross-sectional study was employed using a self-administered questionnaire in Shenzhen City of China, elaborating the willingness toward PPSV23 in the elderly persons. Binomial logistic analyses were performed to estimate the influencing factors using odds ratios (ORs) and 95% confidence interval (CI). Results: Among 15,066 respondents, 91.5% presented a positive attitude toward PPSV23. Logistic analyses suggested the influencing factors included knowledge about pneumonia (adjusted OR [aOR] 1.391, 95%CI 1.214–1.593), perception of the seriousness of pneumonia (aOR 1.437, 95%CI 1.230–1.680) and preventing way for pneumonia (aOR 1.639, 95%CI 1.440–1.865), worried about getting pneumonia (aOR 2.751, 95%CI 2.444–3.096), understanding vaccine policy (aOR 1.774, 95%CI 1.514–2.079), and influenza vaccine (aOR 3.516 and 95%CI 2.261–5.468) and PPSV23 histories (aOR 3.199, 95%CI 1.492–6.860). Conclusions: The interest surge in pneumococcal vaccine coincided with the COVID-19 outbreak, foreshadowing higher demand for pneumococcal vaccine in the near future