Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma.

The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib achieves a remarkable clinical response in mantle cell lymphoma (MCL). Acquired drug resistance, however, is significant and affects long-term survival of MCL patients. Here, we demonstrate that DNA methyltransferase 3A (DNMT3A) is involved in ibrutinib resistance. We find that DNMT3A expression is upregulated upon ibrutinib treatment in ibrutinib-resistant MCL cells. Genetic and pharmacological analyses reveal that DNMT3A mediates ibrutinib resistance independent of its DNA-methylation function. Mechanistically, DNMT3A induces the expression of MYC target genes through interaction with the transcription factors MEF2B and MYC, thus mediating metabolic reprogramming to oxidative phosphorylation (OXPHOS). Targeting DNMT3A with low-dose decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-mediated metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL.

Electromagnetic exposure analysis of the subway passenger under the civil communication system radiation.

In order to assess the electromagnetic exposure safety of passengers under the civil communication system of the subway, the radio-frequency (RF) electromagnetic environment of subway carriage is established by using COMSOL Multiphysics software, it includes a 1-1/4 " leaky coaxial cable (LCX1) and a 1-5/8" leaky coaxial cable (LCX2), which are designed to be the exposure sources, and twelve passengers at different position. The electromagnetic environment model has been verified through field measurement. The exposure dose distribution of twelve passengers is compared and analyzed, when LCX1 and LCX2 works respectively. The simulated results show that, to compare with LCX2, the electromagnetic dose absorbed by the passengers is reduced by 9.19% and 22.50% at 2100 MHz and 2600 MHz respectively. The specific absorption rate (SAR) of passengers obtains the maximum value of 1.91×10-4 W/Kg and the temperature rise to 0.214 K when the LCX1 works at 3400 MHz. By comparing with the public exposure limitation of the International Commission of Non-Ionizing Radiation Protection (ICNIRP), it demonstrates the electromagnetic exposure safety of the passengers under the civil communication system. More importantly, the proposed LCX1 not only could add the 5G signal cover but also lower the SAR absorbed by the passengers, which indicates that the public electromagnetic exposure dose could be reduced by adjusting the radiation performances of exposure source, which provide a new way for electromagnetic protecting.

Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment.

BACKGROUND AIMS: RAD51 is a highly conserved DNA repair protein and is indispensable for embryonic viability. As a result, the role of RAD51 in liver development and function is unknown. Our aim was to characterize the function of RAD51 in postnatal liver development. APPROACH RESULTS: RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in chronic liver diseases. We generated hepatocyte-specific Rad51 deletion mouse model using Alb-Cre (Rad51-CKO) and AAV8-TBG-Cre to evaluate the function of RAD51 in liver development and regeneration. The phenotype in Rad51-CKO mice is dependent on Cre recombinase dosage, with Rad51fl/fl; Alb-Cre+/+ manifesting a more severe phenotype than the Rad51fl/fl; Alb-Cre+/- mice. RAD51 deletion in postnatal hepatocytes results in aborted mitosis and early onset of pathological polyploidization that is associated with oxidative stress and cellular senescence. Remarkable liver fibrosis occurs spontaneously as early as in 3-month-old Rad51fl/fl; Alb-Cre+/+ mice. While liver regeneration is compromised in Rad51-CKO mice, they are more tolerant of carbon tetrachloride (CCl4)-induced hepatic injury and resistant to DEN/CCl4-induced hepatocellular carcinoma (HCC). A chronic inflammatory microenvironment created by the senescent hepatocytes appears to activate ductular reaction and consequently a transdifferentiation of cholangiocytes to hepatocytes. The newly-derived RAD51 functional immature hepatocytes proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. CONCLUSIONS: Our results demonstrate a novel function of RAD51 in liver development, homeostasis and tumorigenesis. The Rad51-CKO mice represent a unique genetic model for premature liver senescence, fibrosis and hepatocellular carcinogenesis.

Generation of Functional and Mature Sympathetic Neurons from Human Pluripotent Stem Cells via a Neuroepithelial Route.

The sympathetic nervous system (SNS) is a crucial branch of the autonomic nervous system (ANS) that is responsible for regulating visceral function and various physiological processes. Dysfunction of the SNS can lead to various diseases, such as hypertension and metabolic disorders. However, obtaining sympathetic neurons from human tissues for research is challenging. The current research aimed at recapitulating the process of human sympathetic neuron development and achieved the successful establishment of a stepwise, highly efficient in vitro differentiation protocol. This protocol facilitated the generation of functional and mature sympathetic neurons from human pluripotent stem cells (hPSCs) using a chemical-defined induction medium. Initially, each differentiation stage was refined to derive sympathoadrenal progenitors (SAPs) from hPSCs through neural epithelial cells (NECs) and trunk neural crest stem cells (NCSCs). hPSC-derived SAPs could be expanded in vitro for at least 12 passages while maintaining the expression of SAP-specific transcription factors and neuronal differentiation potency. SAPs readily generated functional sympathetic neurons (SymNs) when cultured in the neuronal maturation medium for 3-4 weeks. These SymNs expressed sympathetic markers, exhibited electrophysiological properties, and secreted sympathetic neurotransmitters. More importantly, we further demonstrated that hPSC-derived SymNs can efficiently regulate the adipogenesis of human adipose-derived stem cells (ADSCs) and lipid metabolism in vitro. In conclusion, our study provided a simple and robust protocol for generating functional sympathetic neurons from hPSCs, which may be an invaluable tool in unraveling the mechanisms of SNS-related diseases.

Metal-catalyzed asymmetric reactions enabled by organic peroxides.

As a class of multifunctional reagents, organic peroxides play vital roles in the chemical industry, pharmaceutical synthesis and polymerization reactions. Metal-catalyzed asymmetric catalysis has emerged as one of the most straightforward and efficient strategies to construct enantioenriched molecules, and an increasing number of metal-catalyzed asymmetric reactions enabled by organic peroxides have been disclosed by researchers in recent years. Despite remarkable progress, the types of asymmetric reactions facilitated by organic peroxides remain limited and the catalysis systems need to be further broadened. To the best of our knowledge, there is still no review devoted to summarizing the reactions from this perspective. In this review, we will endeavor to highlight the advances in metal-catalyzed asymmetric reactions enabled by organic peroxides. We hope that this survey will summarize the functions of organic peroxides in catalytic reactions, improve the understanding of these compounds and inspire future developments in this area.

Photocatalytic selective synthesis of (E)-ß-aminovinyl sulfones and (E)-ß-amidovinyl sulfones using Ru(bpy)3Cl2 as the catalyst.

Selectively producing a variety of valuable compounds using controlled chemical reactions starting from a common material is an appealing yet complex concept. Herein, a photocatalytic approach for the selective synthesis of (E)-ß-aminovinyl sulfones and (E)-ß-amidovinyl sulfones from allenamides and sodium sulfinates was established. This reaction exhibits the traits of an eco-friendly solvent and adjustable amide cleavage, and can accommodate a diverse range of substrates with exceptional functional group tolerance. Based on control experiments and deuterium labeling experiments, a plausible radical reaction pathway is proposed.

What Works for Controlling Meningitis Outbreaks: A Case Study from China.

The meningococcal meningitis (MM) vaccine reduces the incidence of MM significantly; however, outbreaks still occur in communities with high vaccine coverage. We aimed to analyze the driving factors of infection from a community outbreak. A total of 266 children aged 9 to 15 years old from the three junior high schools of Tongzi county were identified. We documented infection cases using laboratory tests and analyzed attack rates, infection rates and risk factors for transmission. The index case in School A was identified, and the attack rate in School A was 0.03%. Children showed a significantly low infection rate of MenC in School A (13.2% vs. 19.5% in total children, p = 0.002), while exhibiting significantly high infection rates of MenA in School B (44.1% vs. 24.8% in total children, p < 0.001) and MenB in School C (11.1% vs. 4.1% in total children, p = 0.015). The infection rate of MenA for females (30.0%) was higher (p = 0.055) than for males (19.9%). In School A, 63.19% of children were vaccinated against MenC, while in School B the rate was 42.65% and in School C, it was 59.26%. Three male MenC infection cases were detected as breakthrough infection cases in addition to the index case. The findings suggest that the current full-course immunization has limited long-term effectiveness and is inefficient in preventing the transmission of MM among older children.

Establishing an Ion-Sieving Separator by Depositing Oxygen-Deficient SiOx Layer for Stabilized Zinc Metal Anode.

Stable plating/stripping of Zn metal anode remains a great challenge owing to uncontrollable dendrite growth and side reactions. Ion-sieving separators is a unique and promising solution, that possess Zn2+ permeability and promote Zn2+ transport, can effectively alleviate the abovementioned problems. Ion-sieving on glass fiber separator by deposition of oxygen-deficient SiOx layer via active screen plasma technology is achieved. While having chemical composition similar to the glass fiber, the SiOx nanoparticles contain oxygen-rich vacancies that promoted dissociation of the adsorbed water and generation of the hydroxyl groups. The negatively-charged hydroxylated SiOx layer can repel SO4 2- and attract Zn2+ , which can alleviate the side reactions. The strong interplay between hydroxyl groups and Zn2+ can boost Zn affinity and yield fast Zn2+ transport. Consequently, the SiOx -deposited GF separator enabled dendrite-free Zn deposition morphology, which displays lower overpotential of 18 mV and longer cycling life over 2000 h for Zn symmetric cell. Such a separator can also be easily scaled up to prepare the high-performance large-area (4 × 6 cm2 ) pouch Zn-based devices, showing remarkable flexibility and practicality.

Spliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy.

Regulation of alternative splicing (AS) enables a single transcript to yield multiple isoforms that increase transcriptome and proteome diversity. Here, we report that spliceosome component Usp39 plays a role in the regulation of hepatocyte lipid homeostasis. We demonstrate that Usp39 expression is downregulated in hepatic tissues of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) subjects. Hepatocyte-specific Usp39 deletion in mice leads to increased lipid accumulation, spontaneous steatosis and impaired autophagy. Combined analysis of RNA immunoprecipitation (RIP-seq) and bulk RNA sequencing (RNA-seq) data reveals that Usp39 regulates AS of several autophagy-related genes. In particular, deletion of Usp39 results in alternative 5' splice site selection of exon 6 in Heat shock transcription factor 1 (Hsf1) and consequently its reduced expression. Importantly, overexpression of Hsf1 could attenuate lipid accumulation caused by Usp39 deficiency. Taken together, our findings indicate that Usp39-mediated AS is required for sustaining autophagy and lipid homeostasis in the liver.

Polo-like kinase 1 promotes sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is the main cause of mortality in sepsis. In this study, we identified Polo-like kinase 1 (Plk-1) is a promoter of SIMD. Plk-1 expression was increased in lipopolysaccharide (LPS)-treated mouse hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of Plk-1 either by heterozygous deletion of Plk-1 or Plk-1 inhibitor BI 6727 alleviated LPS-induced myocardial injury, inflammation, cardiac dysfunction, and thereby improved the survival of LPS-treated mice. Plk-1 was identified as a kinase of inhibitor of kappa B kinase alpha (IKKα). Plk-1 inhibition impeded NF-κB signal pathway activation in LPS-treated mouse hearts and NRCMs. Augmented Plk-1 is thus essential for the development of SIMD and is a druggable target for SIMD.

Effects of excitation power density on the Stern-Volmer constant measurement.

The Stern-Volmer constant (KSV) is an important parameter to describe the capability of energy transfer to oxygen for porphyrin and its derivatives. By fitting Stern-Volmer equation, IP0/IP = 1 + KSV[O2], the KSV is generally determined through phosphorescence intensities (IP) under aerobic and oxygen-free conditions. In this work, the effect of excitation power density on the KSV measurement is theoretically analyzed and experimentally studied, using palladium octaethylporphyrin (PdOEP) as an example. The IP of PdOEP increased nonlinearly with excitation power density, and the power dependent slope of IP0/IP could be obtained. By way of the functional relationship between the slope of IP0/IP and power density, the real KSV of PdOEP was fitted to be 58 ± 2 kPa-1. The oxygen-dependent phosphorescence lifetimes (τP) and IP under a weak excitation power are also measured to calculate the real KSV, which verifies our analysis.

EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma.

The use of Bruton tyrosine kinase inhibitors, such as ibrutinib, to block B-cell receptor signaling has achieved a remarkable clinical response in several B-cell malignancies, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and affects the long-term survival of these patients. Here, we demonstrate that the transcription factor early growth response gene 1 (EGR1) is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through the transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular adenosine triphosphate production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL.

Establishment and functional characterization of immortalized rabbit dermal papilla cell lines.

Hair follicle (HF) undergo periodic growth and development in mammals, which regulated by dermal papilla cells (DPCs) are reported to play an important role in HF morphogenesis and development. However, primary DPCs have low proliferative activity, age quickly, and fresh cell isolation is both time-consuming and laborious. In this study, we introduced the SV40 large T antigen (SV40T) into dissociated early passage rabbit vibrissae DPCs with lentiviral vectors and established seven immortalized DPC lines (R-1, R-2, R-3, R-4, R-5, R-6 and R-7). These cell lines displayed early passage morphology and high alkaline phosphatase activity. RT-PCR and immunofluorescence staining showed that all the immortalized cell lines expressed the DPC markers (α-SMA, IGF1, ALPL, FGF2, BMP2 and TGFß2), but α-SMA was only expressed well in R-3, R-4, and R-7. Furthermore, it was found that R-7 was the only line to survive beyond 50 passages. Compared to melanoma cells, R-7 did not undergo malignant transformation. Karyotyping and cell growth viability analysis illustrated that the R-7 cell line preserved the basic characteristics of primary DPCs. The R-7 DPCs established have potential application for future hair research. The study provides the theoretical basis in the cell research of HF growth and development.

Polo-like kinase 1 promotes pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well understood. The aim of this study was to investigate the role of mitotic regulator Polo-like kinase 1 (PLK1) in PH development. METHODS: Mouse lungs along with human pulmonary arterial smooth muscle cells and endothelial cells were used to investigate the effects of hypoxia on PLK1. Hypoxia- or Sugen5416/hypoxia was applied to induce PH in mice. Plk1 heterozygous knockout mice and PLK1 inhibitors (BI 2536 and BI 6727)-treated mice were checked for the significance of PLK1 in the development of PH. RESULTS: Hypoxia stimulated PLK1 expression through induction of HIF1α and RELA. Mice with heterozygous deletion of Plk1 were partially resistant to hypoxia-induced PH. PLK1 inhibitors ameliorated PH in mice. CONCLUSIONS: Augmented PLK1 is essential for the development of PH and is a druggable target for PH.

BIDL: a brain-inspired deep learning framework for spatiotemporal processing.

Brain-inspired deep spiking neural network (DSNN) which emulates the function of the biological brain provides an effective approach for event-stream spatiotemporal perception (STP), especially for dynamic vision sensor (DVS) signals. However, there is a lack of generalized learning frameworks that can handle various spatiotemporal modalities beyond event-stream, such as video clips and 3D imaging data. To provide a unified design flow for generalized spatiotemporal processing (STP) and to investigate the capability of lightweight STP processing via brain-inspired neural dynamics, this study introduces a training platform called brain-inspired deep learning (BIDL). This framework constructs deep neural networks, which leverage neural dynamics for processing temporal information and ensures high-accuracy spatial processing via artificial neural network layers. We conducted experiments involving various types of data, including video information processing, DVS information processing, 3D medical imaging classification, and natural language processing. These experiments demonstrate the efficiency of the proposed method. Moreover, as a research framework for researchers in the fields of neuroscience and machine learning, BIDL facilitates the exploration of different neural models and enables global-local co-learning. For easily fitting to neuromorphic chips and GPUs, the framework incorporates several optimizations, including iteration representation, state-aware computational graph, and built-in neural functions. This study presents a user-friendly and efficient DSNN builder for lightweight STP applications and has the potential to drive future advancements in bio-inspired research.

Sparser spiking activity can be better: Feature Refine-and-Mask spiking neural network for event-based visual recognition.

Event-based visual, a new visual paradigm with bio-inspired dynamic perception and µs level temporal resolution, has prominent advantages in many specific visual scenarios and gained much research interest. Spiking neural network (SNN) is naturally suitable for dealing with event streams due to its temporal information processing capability and event-driven nature. However, existing works SNN neglect the fact that the input event streams are spatially sparse and temporally non-uniform, and just treat these variant inputs equally. This situation interferes with the effectiveness and efficiency of existing SNNs. In this paper, we propose the feature Refine-and-Mask SNN (RM-SNN), which has the ability of self-adaption to regulate the spiking response in a data-dependent way. We use the Refine-and-Mask (RM) module to refine all features and mask the unimportant features to optimize the membrane potential of spiking neurons, which in turn drops the spiking activity. Inspired by the fact that not all events in spatio-temporal streams are task-relevant, we execute the RM module in both temporal and channel dimensions. Extensive experiments on seven event-based benchmarks, DVS128 Gesture, DVS128 Gait, CIFAR10-DVS, N-Caltech101, DailyAction-DVS, UCF101-DVS, and HMDB51-DVS demonstrate that under the multi-scale constraints of input time window, RM-SNN can significantly reduce the network average spiking activity rate while improving the task performance. In addition, by visualizing spiking responses, we analyze why sparser spiking activity can be better. Code.

Accurate Determination of the Photosensitizer Stern-Volmer Constant by the Oxygen-Dependent Consumption of 1,3-Diphenylisobenzofuran.

Because of the absence of phosphorescence, the Stern-Volmer constant (KSV) of the photosensitizer is hard to determine accurately. Although the delayed fluorescence and correlated fluorescence methods have been proposed to determine KSV, the weak signal detection and non-uniform excitation enlarged the measurement error. In this work, a method was proposed to accurately determine KSV by oxygen-dependent consumption of 1,3-diphenylisobenzofuran. The consumption time (δ), as a measurable quantity, is introduced and could be obtained by the absorption spectrum with a high signal-to-noise ratio. Analytically, δ is linearly related to the inverse of oxygen content, and the ratio of the intercept to the slope equals KSV. Experimentally, rose Bengal was selected to perform this determination; the KSV is measured to be 43(1) kPa-1, and the error is reduced by 1 order of magnitude. In addition, metalloporphyrin was used to verify this method.

The mitochondria in schizophrenia with 22q11.2 deletion syndrome: From pathogenesis to therapeutic promise of targeted natural drugs.

Schizophrenia is a complex multi-factor neurological disorder that caused an array of severe indelible consequences to the individuals and society. Additionally, anti-schizophrenic drugs are unsuitable for treating negative symptoms and have more significant side effects and drug resistance. For better treatment and prevention, we consider exploring the pathogenesis of schizophrenia from other perspectives. A growing body of evidence of 22q11.2 deletion syndrome (22q11DS) suggested that the occurrence and progression of schizophrenia are related to mitochondrial dysfunction. So combing through the literature of 22q11DS published from 2000 to 2023, this paper reviews the mechanism of schizophrenia based on mitochondrial dysfunction, and it focuses on the natural drugs targeting mitochondria to enhance mitochondrial function, which are potential to improve the current treatment of schizophrenia.

Multimorbidity and polypharmacy in hospitalized older patients: a cross-sectional study.

BACKGROUND: The growing trend of ageing population has become a worldwide concern. In comparison with the youth, older people are more likely to suffer from multimorbidity and polypharmacy, both of which are associated with adverse outcomes and increased healthcare costs. This study aimed to investigate the status of multimorbidity and polypharmacy in a large sample of hospitalized older patients aged 60 years and over. METHODS: A retrospective cross-sectional study was conducted among 46,799 eligible patients aged 60 years and over, who were hospitalized from January 1, 2021 to December 31, 2021. Multimorbidity was defined as the presence of 2 or more morbidities in one patient during the stay in hospital, and polypharmacy as prescription of 5 or more different oral medications. Spearman rank correlation analysis was used to assess the relationship of factors with the number of morbidities or oral medications. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated from logistic regression models to determine the predictors for polypharmacy and all-cause death. RESULTS: The prevalence of multimorbidity was 91.07% and increased with age. The prevalence of polypharmacy was 56.32%. Older age, polypharmacy, prolonged length of stay (LOS), higher cost on medications were significantly associated with an increased number of morbidities (all P < 0.01). The number of morbidities (OR = 1.29, 95% CI: 1.208-1.229) and LOS (OR = 1.171, 95% CI: 1.166-1.177) were potential risk factors for polypharmacy. As for all-cause death, age (OR = 1.107, 95% CI: 1.092-1.122), number of morbidities (OR = 1.495, 95% CI: 1.435-1.558) and LOS (OR = 1.020, 95% CI: 1.013-1.027) were the potential risk factors, but the number of medications (OR = 0.930, 95% CI: 0.907-0.952) and polypharmacy (OR = 0.764, 95% CI: 0.608-0.960) were associated with a reduction of mortality. CONCLUSION: Morbidities and LOS might be predictors for polypharmacy and all-cause death. The number of oral medications was inversely associated with the risk of all-cause mortality. Appropriate polypharmacy was beneficial for the clinical outcomes of older patients during hospitalization.

Temporal trends of breast cancer burden in the Western Pacific Region from 1990 to 2044: Implications from the Global Burden of Disease Study 2019.

INTRODUCTION: Breast cancer (BC) is a malignant disease that occurs worldwide and poses serious health burden. OBJECTIVES: To assess the prevalence of BC burden in the Western Pacific region (WPR) from 1990 to 2019, and to predict trends from 2020 to 2044. To analyze the driving factors and put forward the region-oriented improvement. METHODS: Based on the Global Burden of Disease Study 2019, BC cases, deaths, disability-adjusted life years (DALYs) cases, age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALYs rate in WPR from 1990 to 2019 was obtained and analysed. Age-period-cohort (APC) model was used to analyze age, period, and cohort effects in BC, and Bayesian APC (BAPC) was used to predict trends over the next 25 years. RESULTS: In conclusion, BC incidence and deaths in the WPR have increased rapidly over the past 30 years and are expected to continue to increase between 2020 and 2044. Among behavioral and metabolic factors, high body-mass index was the main risk factor for BC mortality in middle-income countries, whereas alcohol use was the main risk factor in Japan. Age is a key factor in the development of BC, with 40 years being the critical point. Incidence trends coincide with the course of economic development. CONCLUSIONS: The BC burden remains an essential public health issue in the WPR and will increase substantially in the future. More efforts should be made in middle-income countries to prompt the health behavior and minimize the burden of BC because these nations accounts for the majority of BC burden in the WPR.