Objective Intratumoral heterogeneity refers to the presence of distinct subpopulations of cancer cells within a single tumor, which exhibits variations in phenotypic traits, such as proliferation rate, drug sensitivity, and metastatic potential. Dynamic interactions among heterogeneous cell populations have a critical role in tumor progression. Increasing evidence underscores the importance of intercellular communication among heterogeneous cancer cell subpopulations in driving malignancy. However, the molecular mechanisms governing such cancer cell-to-cancer cell interactions are poorly understood. Methods Exosomes were isolated from highly metastatic breast cancer cells (HM-BCCs) and low metastatic breast cancer cells (LM-BCCs). The role of exosome-mediated intercellular communication on metastatic behavior was assessed using wound healing and Transwell assays. Gene knockdown and overexpression strategies, small-molecule inhibitors, and xenograft mouse models were used to elucidate the role of exosomal EPHA2. Results Exosomes derived from HM-BCCs considerably enhanced the migratory and invasive capabilities of LM-BCCs in vitro and increased the metastatic potential in vivo. Mechanistically, EPHA2 was identified as a key protein enriched in exosomes from HM-BCCs and was shown to be transferred to LM-BCCs by these vesicles. Exosomal EPHA2 promoted epithelial-to-mesenchymal transition in LM-BCCs when internalized by stabilizing TGF-u03B2RI and activating the transforming growth factor-u03B2/mothers against decapentaplegic homolog 3 (TGF-u03B2/SMAD3) signaling pathway, thereby facilitating the acquisition of a metastatic phenotype. Conclusions The results underscore the pivotal function of exosomal EPHA2 in mediating the transfer of metastatic potential among heterogeneous breast cancer cell populations. Targeting the EPHA2-TGF-u03B2RI signaling axis may provide a novel therapeutic approach for preventing or limiting breast cancer metastasis.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central sensor of innate immunity that plays critical roles in recognizing cytosolic DNA and initiating antitumor immune responses. However, this pathway exhibits extensive spatiotemporal duality and context dependency in tumor regulation. In recent years, modulating this pathway to convert immunologically "cold" tumors into immunologically "hot," inflamed tumors has emerged as a cutting-edge strategy to reverse resistance to immune checkpoint inhibitors (ICIs). This review outlines the molecular mechanisms underlying the activation and regulation of the cGAS-STING pathway, with emphasis on its complex role in orchestrating the tumor immune phenotypic switch. A nuanced analysis of the pathway's duality distinguishes between acute immunostimulatory activation and chronic, pro-tumorigenic inflammation driven by chromosomal instability (CIN). Furthermore, current evidence regarding direct and indirect T-cell modulation, as well as pathway-mediated remodeling of the tumor microenvironment (TME) across diverse malignancies, is discussed in detail. Crucially, the current bottlenecks in clinical translation are described, including evaluation of the failure of first-generation agonists and the promise of next-generation delivery platforms such as antibody-drug conjugates (ADCs) and nanoparticle systems. Finally, a novel strategic framework is proposed involving mapping of specific STING-targeted modalities to distinct TME phenotypes, such as immune-desert, immune-excluded, and exhausted-inflamed states. A detailed understanding of the cGAS-STING axis has substantial value in providing theoretical guidance and supporting clinical translation in the development of next-generation combination immunotherapies, as well as broadening the patient population benefiting from clinical interventions.
Ovarian cancer was the eighth most frequently diagnosed cancer among women in 2022. The global age-standardized incidence rate of ovarian cancer decreased from 7.22/100,000 to 6.71/100,000 from 1990 to 2021. However, incidence trends varied across countries. Declining ovarian cancer incidence rates were reported in high-income countries, such as the United States, Austria, the Netherlands, and Norway, while there were increasing incidence rates in Africa and parts of Asia, including Japan and India. The global age-standardized mortality rate of ovarian cancer decreased from 4.73/100,000 to 4.06/100,000 between 1999 and 2021 with varying trends among countries. Moreover, the age-standardized 5-year net ovarian cancer survival rate in most countries remained < 50%. Several specific factors related to ovarian cancer risk have been identified, including reproductive factors, use of oral contraceptives, anti-inflammatory diets, endometriosis, pelvic inflammatory disease, obesity, diabetes, and occupational asbestos exposure. No screening or prevention strategy has been proven effective in downstaging or reducing mortality from ovarian cancer in an average-risk population without a family cancer history or pathogenic variants. Indeed, risk-reducing salpingo-oophorectomy remains the gold standard for lowering the risk of ovarian cancer in high-risk individuals with hereditary mutations. This review provides a comprehensive overview of the epidemiology, risk factors, screening, and prevention of ovarian cancer, aiming to offer a global perspective on public health strategies for addressing the disease.
OBJECTIVE:Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related mortality worldwide. This study was aimed at estimating regional and national variations in lifetime CRC risk worldwide. METHODS:CRC data were extracted from GLOBOCAN 2022, including 185 countries, and population and all-cause mortality data were sourced from the United Nations. The world was divided into 20 geographical regions and categorized by Human Development Index (HDI). Lifetime CRC risk was estimated with the life table method, adjusted for multiple primary cancers. RESULTS:In 2022, the lifetime risks of developing and dying from CRC were 2.69% [95% confidence interval (CI): 2.68-2.70] and 1.39% (95% CI: 1.39-1.40), respectively. Men had a higher risk of colon cancer than rectal cancer, and higher CRC risk than women. Lifetime risk varied by region and HDI: regions with very high, high, moderate, and low HDI had incidence risks of 5.17%, 2.75%, 0.72%, and 0.57%, respectively, and mortality risks of 2.48%, 1.50%, 0.44%, and 0.41%, respectively. Australia/New Zealand had the highest incidence risk (7.41%, 95% CI: 7.30-7.52), and Northern Europe the highest mortality risk (3.28%, 95% CI: 3.24-3.32). Risks were stable before 40 years of age, peaked in middle age, and declined after 70 years of age. Temporally, Thailand had the highest increasing trend in lifetime risk, whereas the United States and Austria showed a decreasing trend. CONCLUSIONS:Lifetime CRC risk differs by subtype, sex, HDI, and geography, and residual risk gradually decreases with age. Targeted primary prevention strategies should be implemented in various countries and regions to mitigate CRC burden.
Human papillomavirus(HPV)is the most prevalent sexually transmitted infection worldwide1.More than 200 HPV geno-types have been identified and are classified as high-risk HPV(HR-HPV)or low-risk HPV(LR-HPV)according to their onco-genic potential.
OBJECTIVE:Breast cancer is the most frequently diagnosed cancer among women worldwide and is a leading cause of cancer-related deaths. Comparative assessments of breast cancer lifetime risks across populations are limited. This study estimated the global, regional, and national lifetime risks, temporal trends, and socioeconomic inequalities in the burden of breast cancer. METHODS:Using incidence and mortality data from GLOBOCAN 2022 (185 countries) and United Nations population and all-cause death data, lifetime risks were calculated using the adjusted for multiple primaries (AMP) method, which could adjust for multiple primary cancers, competing risks of other causes death, and life expectancy. Longitudinal data of breast cancer incidence from 2003-2017 were retrieved from the Cancer Incidence in Five Continents (CI5) Plus database. The temporal trends for breast cancer deaths were abstracted from the WHO Mortality Database. The lifetime risk of developing and dying from breast cancer were analyzed by socioeconomic characteristics, 20 predefined geographic regions and menopausal status. RESULTS:The overall worldwide lifetime risk of developing and dying from breast cancer was 5.51% (95% CI: 5.50%-5.52%) and 1.82% (95% CI: 1.82%-1.83%) in 2022, respectively. The estimated lifetime risks of developing breast cancer had a positive relationship with Human Development Index (HDI) levels and corresponding risks of 10.37%, 4.42%, 2.96%, and 2.91% in very high, high, middle, and low HDI regions, respectively. Very high HDI regions presented the highest lifetime risk of breast cancer death (2.70%), followed by low HDI (1.70%), medium HDI (1.54%), and high (1.38%) HDI regions. A significant correlation was identified between lifetime risks and health economics capacity. The lifetime risk of developing and dying from breast cancer primarily involved individuals ≥ 55 years of age with remaining risks of 3.77% (developing) and 1.43% (dying) from 55 years to death. The proportion of lifetime risks among individuals 0-44 years of age was higher in Africa regions compared to other regions. In surveillance data from 36 countries, a significant increasing trend in the average annual percentage change (AAPC) was noted in 32 countries, which ranged from 0.17% in the United States to 5.84% in the Republic of Korea. CONCLUSIONS:Globally, an estimated 1 in 18 individuals were diagnosed with breast cancer during their lifetime and approximately 1 in 55 died from the disease in 2022. Lifetime risk of breast cancer disparities reveal the socioeconomic inequalities of breast cancer. Therefore, country-tailored intervention plans for breast cancer require prioritization within precision prevention to mitigate global breast cancer inequities and burden.
Lung cancer is a fatal and the most common malignancy globally. Despite the significant therapeutic benefits of immune checkpoint inhibitors (ICIs), 60%–80% of patients respond poorly to immunotherapy. The identification of reliable predictive biomarkers is essential for implementing precision medicine strategies. In recent years the microbiome has emerged as a promising predictor of immunotherapy outcomes. The influence of the microbiome on lung cancer immunotherapy was systematically and comprehensively reviewed. Moreover, the distinctive microbiome profiles among patients with lung cancer and the correlation with treatment effectiveness are discussed. We investigated the core mechanisms of the interactions between the microbiome and the tumor microenvironment, assessed the usefulness of microbial metabolites as predictive biomarkers, and discussed strategies for microbiome-targeted interventions. Furthermore, we evaluated the current limitations in research methodology and highlighted future research directions, offering novel insights, including multi-site integrated biomarker approaches, site-specific intervention strategies, metabolite-based functional biomarkers, and lung cancer-specific microbiome considerations for developing personalized immunotherapy.
OBJECTIVE:We aimed to evaluate chemotherapy-free apatinib-based immunotherapy regimens for patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) who were chemotherapy-intolerant or declined chemotherapy. METHODS:Enriched KEGG/GO pathway analyses were used to identify pathways modulated by apatinib treatment and those associated with trastuzumab sensitivity. RNA-seq data from TCGA were used to evaluate interleukin-6 (IL-6)'s role in HER2-positive GC. The efficacy of combination therapy was validated in HER2-positive GC cell lines, humanized hematopoietic stem cells, tumor cell line-derived xenografts (hHSC-CDXs), and 3 patients with stage IV GC. Mechanistic studies involved co-immunoprecipitation, western blotting, immunohistochemistry, and immunofluorescence assays. RESULTS:Apatinib enhanced the trastuzumab-induced inhibition of HER2-positive GC by blocking the IL-6/glycoprotein 130 (gp130)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in vitro, as validated through bioinformatics analysis. We confirmed the synergistic effects of apatinib with the targeted immunotherapy combination in inhibiting HER2-positive GC in both hHSC-CDXs and patients with HER2-positive GC. Given that apatinib suppressed HER2-positive GC via IL-6, we also confirmed that tocilizumab (a monoclonal antibody targeting IL-6R) significantly potentiated apatinib's efficacy with targeted immunotherapy in hHSC-CDXs. Potential mechanisms of immunotherapy enhancement with apatinib and tocilizumab included decreased angiogenesis, M2-like tumor-associated macrophages (M2-TAMs), and regulatory T cells (Tregs), as well as increased cytotoxic CD8+ T cell infiltration in the tumor microenvironment. CONCLUSIONS:Our data support the potential application value of tocilizumab and apatinib for targeted immunotherapy in patients with HER2-positive GC, particularly in older patients who cannot tolerate chemotherapy.
Neuroblastoma (NB) is a pediatric cancer that develops from immature nerve cells in the peripheral sympathetic nervous system. NB is remarkably heterogeneous, ranging from spontaneous regression to aggressive progression, and is characterized by widespread dissemination and relapse. Approximately half of all NB patients present with widespread metastasis at diagnosis and are classified as high-risk with a substantial likelihood of treatment failure, despite receiving aggressive multimodal therapies, including surgery, chemotherapy, radiotherapy, autologous hematopoietic stem cell transplantation, and monoclonal antibody treatment. Beyond conventional multimodal approaches, immunotherapy has emerged as an essential part of cancer treatment, by boosting the immune system to recognize and eliminate tumor cells. In this review, we provide an overview of current therapeutic strategies for NB patients and summarize recent advances in the development of next-generation NB immunotherapies, highlighting their potential to improve NB management. We further discuss future directions for therapeutic improvement, and the potential limitations and challenges associated with translating these approaches into long-term benefits for NB patients.
Gastric cancer(GC)remains a leading cause of cancer mor-tality worldwide1.Helicobacter pylori(H.pylori)infection is the dominant etiologic factor2,yet GC also arises in indi-viduals without infection or after eradication,suggesting alternative carcinogenic pathways3.
Small-scale auroral spots (SsAS) are frequently observed, particularly on the nightside, yet their formation mechanisms remain unclear. Utilizing all-sky imager data from the Chinese Arctic Yellow River Station and radar measurements from the European Incoherent Scatter Scientific Association (EISCAT), we identified 65 SsAS events occurring near magnetic local noon from 2003 to 2009. We found that they are observed only in the 557.7 nm emission band. They can be classified into two types based on their morphology: sporadic SsAS and fence-like SsAS. The occurrence of these events shows clear dependence on the southward interplanetary magnetic field (IMF) Bz, with the fence-like SsAS exhibiting an even more pronounced dependence. Their occurrence also depends on the westward IMF By. Additionally, we found that most events (88%) are located on the poleward side of the auroral oval, and the drift motion of these SsAS is consistent with the motion direction of adjacent auroral structures, whose motion is strictly governed by the IMF By polarity. These observations indicate that generation of these dayside SsAS may be directly linked to the solar wind energy input through magnetopause reconnection. The EISCAT observations further show that SsAS are accompanied by pronounced electron density gradients. On the basis of these characteristics, we propose that the generation of SsAS may be related to phase mixing of Alfvén waves arising from the density gradients. This study helps elucidate the coupling chain by which solar wind energy is injected into the polar region and subsequently drives ionospheric responses.
Characterizing hourly wind variability in the mesosphere and lower thermosphere(MLT)remains challenging because direct observations are sparse and observational constraints on gridded products weaken rapidly toward the mesopause.Here we present an initial evaluation of January-March 2019 winds from a whole-atmosphere analysis produced by coupling the Whole Atmosphere Community Climate Model version 6(WACCM6)with the Next-generation Ensemble Data Assimilation System(NEDAS)using a two-stage framework.Below～80 km,we perform cross-product consistency checks against the European Centre for Medium-Range Weather Forecasts fifth-generation atmospheric reanalysis(ERA5),the Modern-Era Retrospective analysis for Research and Applications,version 2(MERRA-2),the specified-dynamics WACCM(SD-WACCM),and the Horizontal Wind Model 2014(HWM14)on a common grid.Above 76 km,hourly winds are independently evaluated against nonassimilated meteor radar observations over Wuhan(30.6°N,114.4°E).In the upper stratosphere and lower mesosphere,WACCM-NEDAS reproduces the dominant large-scale zonal-mean circulation and remains broadly consistent with ERA5 and MERRA-2,with the most coherent agreement against MERRA-2 through much of the 60-to 80-km layer.In the MLT,WACCM-NEDAS is closer to the meteor radar winds than is SD-WACCM,with full-sample correlations of 0.55 for the zonal wind and 0.67 for the meridional wind and height-resolved correlations reaching 0.7-0.8 in favorable layers.At a representative 90-km level,wavelet analysis further indicates that WACCM-NEDAS retains a broader short-period variability spectrum than does SD-WACCM and avoids the overly smoothed near-diurnal response of HWM14.A supplementary 2-to 6-d wavelet analysis during the 2018-2019 sudden stratospheric warming interval further shows that WACCM-NEDAS captures a 4-to 5-d enhancement consistent with the meteor radar spectra.These results indicate meaningful added value of WACCM-NEDAS for hourly MLT wind studies,although broader validation across additional stations,seasons,and dynamical conditions is still required.
The equatorial electrojet (EEJ) is a narrow eastward current that flows in the daytime equatorial E region. It is an important part of low-latitude ionospheric electrodynamics. This review presents a synthesis of recent advances in EEJ research. The main topics include historical observations, observation and inversion methods, local time and longitudinal variations, mid- and high-latitude forcing, solar activity forcing, and EEJ models. Ground-based and satellite observations show clear local time and longitudinal variations of the EEJ. These variations are mainly controlled by E-region conductivity, atmospheric tides, and geomagnetic field geometry. Among these factors, nonmigrating tides play a dominant role in the longitudinal pattern. Under disturbed conditions, mid- and high-latitude processes, such as geomagnetic storms, substorms, sudden changes in solar wind dynamic pressure, sudden stratospheric warming events, and subauroral polarization streams, can substantially modify the EEJ intensity and even reverse its direction through coupling processes. In addition, solar activity, including solar flares and solar eclipses, can modulate the EEJ primarily through rapid changes in ionospheric conductivity and associated electrodynamic adjustments. Although physics-based electrodynamic models, data-driven empirical models, and global numerical simulations have provided valuable insights across different scales, their quantitative consistency and capability of reproducing EEJ disturbances remain limited. This review points out several open issues. These include the combined effects of different driving factors, the nonlinear response of the EEJ, and the lack of reliable EEJ models during disturbed conditions. Finally, future studies should focus on combined observations, improved coupling models, and prediction of EEJ variability.
The medium-energy electron detector on board China’s second earthquake-monitoring satellite can measure the energy, flux, and direction of medium- and high-energy electrons within the satellite’s orbit. These data may provide the technical means for exploring new technologies and methods for earthquake monitoring and prediction. This work presents a description of the scientific objectives, key technical specifications, payload design, and results of ground calibration and verification for the payload.
The Earth's outer radiation belt contains a large number of relativistic(>500 keV)electrons,which can exhibit different pitch angle distributions(PADs).Whistler-mode chorus waves are considered an important factor governing the evolution of electron PADs,but their long-term and global effects remain insufficiently studied.This paper presents a statistical analysis using observations from the Van Allen Probes during 2013-2018.A pitch angle anisotropy index A is employed to characterize electron PADs,and its correlation with chorus waves is investigated.Statistical results show that when chorus waves intensify,the index A increases,implying that electrons tend to exhibit pancake PADs.In addition,the index A is found to be positively correlated with enhanced solar wind dynamic pressure or substorm activity.Our results demonstrate that chorus waves play an important role in accelerating relativistic electrons and reshaping their PADs,which contributes to a deeper insight into the physical mechanisms underlying the dynamic evolution of the outer radiation belt.
Jupiter's rotating magnetic field,together with its satellites and rings,generate a composite flow that we term the Jupiter wind in this paper:a multi-source mixture of particles originating from Io's volcanism,Jupiter's other moons,its rings,and its atmosphere,subsequently reprocessed by ionization,acceleration,corotation,and outward and tailward transport.Inspired by the unifying role of the solar wind in heliophysics,we argue that a Jupiter wind perspective can similarly integrate disparate domains of Jovian science—interior structure,Io's volcanic activity and neutral cloud,plasma dynamics,radiation belts,and distant magnetotail evolution—into a coupled evolutionary framework.We highlight three systematically interconnected knowledge gaps that form a coherent investigative chain:(1)What are the electromagnetic processes inside Io,influencing the fundamental source characteristics of Jupiter wind?(2)What quantitative role do neutral particles play in processes such as supplying the inner radiation belt,representing the intermediate processing stage of Jupiter wind evolution?(3)How do magnetic field and charged particles evolve across the distant(～100 RJ to>9000 RJ)magnetotail,concerning the ultimate fate and control mechanisms of Jupiter wind?The forthcoming Tianwen-4 mission—potentially synergistic with JUICE and Europa Clipper,if their operations overlap—offers a unique opportunity to deliver instruments to investigate magnetic field and charged and neutral particles,enabling testable predictions regarding the source and evolution of Jupiter wind.Framing Jupiter wind within a generalized"planet wind"paradigm may ultimately clarify how internal driving competes with solar forcing to shape planetary systems across the solar system and beyond.
