Articles in press have been peer-reviewed and accepted, which are not yet assigned to volumes /issues, but are citable by Digital Object Identifier (DOI).
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doi: 10.3967/bes2024.083
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doi: 10.3967/bes2024.068
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doi: 10.3967/bes2024.101
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doi: 10.3967/bes2024.100
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doi: 10.3967/bes2024.098
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doi: 10.3967/bes2024.097
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doi: 10.3967/bes2024.096
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doi: 10.3967/bes2024.095
Melanocytes derived from neural crest cells harbor the BRAFV600E mutation, which is the predominant driver of nevus formation in humans. This mutation leads to malignant cell proliferation and subsequent cell cycle arrest, culminating in oncogene-induced senescence and nevus development. Nevertheless, emerging evidence has highlighted the heterogeneity of cellular senescence markers in BRAFV600E-induced senescent melanocytes. Moreover, the capacity of melanocytes within nevi to regain their proliferative ability raises questions about the molecular mechanisms by which BRAFV600E, via the mitogen-activated protein kinase signaling pathway, triggers nevus formation. This study provides an overview and discussion of the molecular mechanisms underpinning BRAFV600E-induced melanocyte nevus formation and the relevant animal models employed for their elucidation. It also highlights the significance of elucidating dynamic changes in cytoplasmic and nuclear substrates that interact with phosphorylated extracellular signal-regulated protein kinases 1 and 2 and underscores the value of using targeted BRAFV600E animal models created through gene editing technologies.
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doi: 10.3967/bes2024.094
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doi: 10.3967/bes2024.093
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doi: 10.3967/bes2024.092
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doi: 10.3967/bes2024.090
Cerebral hemorrhage, the second most prevalent subtype of stroke, exacerbates blood-brain barrier (BBB) disruption, leading to vasogenic edema, plasma protein extravasation, and infiltration of neurotoxic substances. The brain's clearance capacity plays a crucial role in maintaining BBB homeostasis and facilitating patient recovery post-hemorrhage. This study aims to investigate the impact of circadian rhythms on BBB function, neuronal damage, and clearance capabilities. A Neurovascular Unit (NVU) model was established through a four-cell co-culture of neurons, astrocytes, microglia, and brain microvascular endothelial cells (BMECs). Circadian rhythms were found to play a pivotal role in preserving BBB integrity, reducing oxidative stress-induced neuronal damage and apoptosis, and enhancing the phagocytic capabilities of microglial cells. The study underscores the potential circadian modulation of BBB integrity through key protein expressions, including Occludin, melatonin receptor 1A (MTNR1A), Aquaporin-4 (AQP4), and Low-density lipoprotein receptor-related protein 1 (LRP1). This comprehensive exploration of the NVU under circadian influence provides valuable insights into enhancing brain clearance abilities post-cerebral hemorrhage. The study emphasizes the significance of circadian regulation in neurological disorders, proposing potential therapeutic interventions and highlighting the importance of maintaining circadian rhythms for optimal brain health. The findings lay the foundation for future research targeting circadian-influenced mechanisms within the NVU to improve outcomes for patients post-cerebral hemorrhage.
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doi: 10.3967/bes2024.088
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doi: 10.3967/bes2024.087
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doi: 10.3967/bes2024.086
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doi: 10.3967/bes2024.085
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doi: 10.3967/bes2024.084
Despite well-known limitations, mice remain useful as model animals to study tuberculosis (TB) pathogenesis, the basic immune response, the extent of lung pathology as well as efficacy of new drugs against Mycobacterium tuberculosis[1,2]. There are four routes of tuberculosis infection in mice: aerosol generation and exposition, intravenous injection, intranasal administration, and subcutaneous administration[3], and the first two are the most commonly used. The low-dose aerosol model was found to best fit the dissemination of TB cases in the community while intravenous infection is useful to study strain virulence[4]. Intra-nasal and intra-tracheal inoculation techniques have a high degree of variability in the delivery of bacilli into the alveoli and the generation of an aerosol cloud of very small droplet nuclei containing the bacilli was shown to be the most reproducible method[1]. In the case of the intravenous tail injection, the administered doses are higher compared to the aerosol route. The intravenous infection leads to the initial infection established in the lungs followed by the dissemination of the bacteria through the body of the animal. The genetic background of mice plays an important role in susceptibility to the infection and further progression to disease. Intravenous infection can lead to a rapid development of disease and an increased animal lethality after 28 days of the infection but this concerns susceptible C3H/HeJ mice lineage and not resistant C57BL/6 lineage[5]. The latter is resistant to infection and develops severe pulmonary damage after a long period since intravenous infection, around 200 days. Therefore, this design is relevant to study the virulence and is appropriate for observation of the long-term therapy of multi-drug resistant (MDR) M. tuberculosis infection.
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doi: 10.3967/bes2024.081
2024, 37(5): 445-456.
doi: 10.3967/bes2024.051
Objective The leptin receptor, encoded by the LEPR gene, is involved in tumorigenesis. A potential functional variant of LEPR, rs1137101 (Gln223Arg), has been extensively investigated for its contribution to the risk of digestive system (DS) cancers, but results remain conflicting rather than conclusive. Here, we performed a case–control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk. Methods A total of 1,727 patients with cancer (gastric/liver/colorectal: 460/480/787) and 800 healthy controls were recruited. Genotyping of rs1137101 was conducted using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and confirmed using Sanger sequencing. Twenty-four eligible studies were included in the meta-analysis. Results After Bonferroni correction, the case–control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population. The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS, gastric, and liver cancer in the Chinese population. Conclusion The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers (especially liver and gastric cancer) in the Chinese population.
2024, 37(5): 457-470.
doi: 10.3967/bes2024.014
Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2 (HER2)-low early breast cancer (BC) and HER2-IHC0 BC. Methods Patients diagnosed with HER2-negative BC (N = 999) at our institution between January 2011 and December 2015 formed our study population. Clinicopathological characteristics, association between estrogen receptor (ER) expression and HER2-low, and evolution of HER2 immunohistochemical (IHC) score were assessed. Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes (5-year follow-up) between the HER2-IHC0 and HER2-low groups. Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor (PgR) positivity than HER2-IHC0 BC group (P < 0.001). The rate of HER2-low status increased with increasing ER expression levels (Mantel-Haenszel χ2 test, P < 0.001, Pearson’s R = 0.159, P < 0.001). Survival analysis revealed a significantly longer overall survival (OS) in HER2-low BC group than in HER2-IHC0 group (P = 0.007) in the whole cohort and the hormone receptor (HR)-negative group. There were no significant differences between the two groups in terms of disease-free survival (DFS). The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%. Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.
2024, 37(5): 471-478.
doi: 10.3967/bes2024.052
Objective Little is known about the association between whole-blood nicotinamide adenine dinucleotide (NAD+) levels and nabothian cysts. This study aimed to assess the association between NAD+ levels and nabothian cysts in healthy Chinese women. Methods Multivariate logistic regression analysis was performed to analyze the association between NAD+ levels and nabothian cysts. Results The mean age was 43.0 ± 11.5 years, and the mean level of NAD+ was 31.3 ± 5.3 μmol/L. Nabothian cysts occurred in 184 (27.7%) participants, with single and multiple cysts in 100 (15.0%) and 84 (12.6%) participants, respectively. The total nabothian cyst prevalence gradually decreased from 37.4% to 21.6% from Q1 to Q4 of NAD+ and the prevalence of single and multiple nabothian cysts also decreased across the NAD+ quartiles. As compared with the highest NAD+ quartile (≥ 34.4 μmol/L), the adjusted odds ratios with 95% confidence interval of the NAD+ Q1 was 1.89 (1.14–3.14) for total nabothian cysts. The risk of total and single nabothian cysts linearly decreased with increasing NAD+ levels, while the risk of multiple nabothian cysts decreased more rapidly at NAD+ levels of 28.0 to 35.0 μmol/L. Conclusion: Low NAD+ levels were associated with an increased risk of total and multiple nabothian cysts.
2024, 37(5): 479-493.
doi: 10.3967/bes2024.053
Objective To investigate changes in the urinary metabolite profiles of children exposed to polycyclic aromatic hydrocarbons (PAHs) during critical brain development and explore their potential link with the intestinal microbiota. Methods Liquid chromatography-tandem mass spectrometry was used to determine ten hydroxyl metabolites of PAHs (OH-PAHs) in 36-month-old children. Subsequently, 37 children were categorized into low- and high-exposure groups based on the sum of the ten OH-PAHs. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to identify non-targeted metabolites in the urine samples. Furthermore, fecal flora abundance was assessed by 16S rRNA gene sequencing using Illumina MiSeq. Results The concentrations of 21 metabolites were significantly higher in the high exposure group than in the low exposure group (variable importance for projection > 1, P < 0.05). Most of these metabolites were positively correlated with the hydroxyl metabolites of naphthalene, fluorine, and phenanthrene (r = 0.336–0.531). The identified differential metabolites primarily belonged to pathways associated with inflammation or proinflammatory states, including amino acid, lipid, and nucleotide metabolism. Additionally, these distinct metabolites were significantly associated with specific intestinal flora abundances (r = 0.34–0.55), which were mainly involved in neurodevelopment. Conclusion Higher PAH exposure in young children affected metabolic homeostasis, particularly that of certain gut microbiota-derived metabolites. Further investigation is needed to explore the potential influence of PAHs on the gut microbiota and their possible association with neurodevelopmental outcomes.
2024, 37(5): 494-502.
doi: 10.3967/bes2024.054
Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury (DILI) caused by different drugs and their correlation with clinical indicators. Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests (RUCAM) scoring criteria and clinically diagnosed with DILI. Based on Chinese herbal medicine, cardiovascular drugs, non-steroidal anti-inflammatory drugs (NSAIDs), anti-infective drugs, and other drugs, patients were divided into five groups. Cytokines were measured by Luminex technology. Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed. Results 73 patients were enrolled. Age among five groups was statistically different (P = 0.032). Alanine aminotransferase (ALT) (P = 0.033) and aspartate aminotransferase (AST) (P = 0.007) in NSAIDs group were higher than those in chinese herbal medicine group. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in patients with Chinese herbal medicine (IL-6: P < 0.001; TNF-α: P < 0.001) and cardiovascular medicine (IL-6: P = 0.020; TNF-α: P = 0.001) were lower than those in NSAIDs group. There was a positive correlation between ALT (r = 0.697, P = 0.025), AST (r = 0.721, P = 0.019), and IL-6 in NSAIDs group. Conclusion Older age may be more prone to DILI. Patients with NSAIDs have more severe liver damage in early stages of DILI, TNF-α and IL-6 may partake the inflammatory process of DILI.
2024, 37(5): 503-510.
doi: 10.3967/bes2024.055
Objective VATER/VACTERL-like association is associated with adverse pregnancy outcomes. Genetic evidence of this disorder is sporadic. In this study, we aimed to provide genetic insights to improve the diagnosis of VACTERL. Methods We have described a Chinese family in which four members were affected by renal defects or agenesis, anal atresia, and anovaginal fistula, which is consistent with the diagnosis of a VACTERL-like association. Pedigree and genetic analyses were conducted using genome and exome sequencing. Results Segregation analysis revealed the presence of a recessive X-linked microdeletion in two living affected individuals, harboring a 196–380 kb microdeletion on Xq27.1, which was identified by familial exome sequencing. Genome sequencing was performed on the affected male, confirming a -196 kb microdeletion in Xq27.1, which included a 28% loss of the CDR-1 gene. Four family members were included in the co-segregation analysis, and only VACTERL-like cases with microdeletions were reported in X27.1. Conclusion These results suggest that the 196–380 kb microdeletion in Xq27.1 could be a possible cause of the VATER/VACTERL-like association. However, further genetic and functional analyses are required to confirm or rule out genetic background as the definitive cause of the VACTERL association.
2024, 37(5): 511-520.
doi: 10.3967/bes2024.056
Objective This study employs the Geographically and Temporally Weighted Regression (GTWR) model to assess the impact of meteorological elements and imported cases on dengue fever outbreaks, emphasizing the spatial-temporal variability of these factors in border regions. Methods We conducted a descriptive analysis of dengue fever’s temporal-spatial distribution in Yunnan border areas. Utilizing annual data from 2013 to 2019, with each county in the Yunnan border serving as a spatial unit, we constructed a GTWR model to investigate the determinants of dengue fever and their spatio-temporal heterogeneity in this region. Results The GTWR model, proving more effective than Ordinary Least Squares (OLS) analysis, identified significant spatial and temporal heterogeneity in factors influencing dengue fever’s spread along the Yunnan border. Notably, the GTWR model revealed a substantial variation in the relationship between indigenous dengue fever incidence, meteorological variables, and imported cases across different counties. Conclusion In the Yunnan border areas, local dengue incidence is affected by temperature, humidity, precipitation, wind speed, and imported cases, with these factors’ influence exhibiting notable spatial and temporal variation.
2024, 37(5): 557-557.
doi: 10.3967/bes2024.089
2015, 28(1): 57-71.
doi: 10.3967/bes2015.006
2022, 35(7): 573-603.
doi: 10.3967/bes2022.079
2018, 31(2): 87-96.
doi: 10.3967/bes2018.011
2012, 25(3): 317-324.
doi: 10.3967/0895-3988.2012.03.010
2019, 32(8): 559-570.
doi: 10.3967/bes2019.074
2003, 16(3): 246-255.
2014, 27(8): 606-613.
doi: 10.3967/bes2014.093
2019, 32(9): 659-672.
doi: 10.3967/bes2019.085
2018, 31(9): 637-644.
doi: 10.3967/bes2018.088
2018, 31(3): 208-214.
doi: 10.3967/bes2018.026
2023, 36(8): 669-701.
doi: 10.3967/bes2023.106
2019, 32(8): 578-591.
doi: 10.3967/bes2019.076
2016, 29(3): 212-218.
doi: 10.3967/bes2016.026
2022, 35(5): 381-392.
doi: 10.3967/bes2022.054
2019, 32(6): 419-426.
doi: 10.3967/bes2019.057
2019, 32(10): 769-778.
doi: 10.3967/bes2019.096
2017, 30(5): 384-389.
doi: 10.3967/bes2017.051
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