Prevalence of placenta previa among deliveries: An update systematic review and meta-analysis after the introduction of the two-child policy in Mainland China.

Background: As birth policy can affect maternal and infant health, we sought to identify whether and how the introduction of the two-child policy might have affected the prevalence of placenta previa in pregnant women in mainland China. Methods: In this update meta-analysis and systematic review, we searched PubMed, Web of Science, the Cochrane Library, Weipu, Wanfang, and the China National Knowledge Infrastructure (CNKI) databases for studies evaluating the prevalence of placenta previa in China published between the inception of each database and March 2024, with no restrictions. Two investigators independently extracted the data from each included study. We then combined the prevalence of placenta previa using random-effects models. Results: We included 128 studies in our analysis, 48 more than in our previous review. The prevalence of placenta previa among Chinese pregnant women was 1.44% (95% confidence interval (CI) = 1.32, 1.56). After the implementation of the two-child policy, the prevalence increased significantly, from 1.25% (95% CI = 1.16, 1.34) to 4.12% (95% CI = 3.33, 4.91). Conclusions: The prevalence of placenta previa increased significantly from the one-child policy period to the two-child policy period among mainland Chinese pregnant women, with varying trends across regions. This change requires the attention of health officials and timely adjustment of resource allocation policies. Registration: PROSPERO: CRD42021262309.

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets.

Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts.

Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.

QDPR deficiency drives immune suppression in pancreatic cancer.

The relevance of biopterin metabolism in resistance to immune checkpoint blockade (ICB) therapy remains unknown. We demonstrate that the deficiency of quinoid dihydropteridine reductase (QDPR), a critical enzyme regulating biopterin metabolism, causes metabolite dihydrobiopterin (BH2) accumulation and decreases the ratio of tetrahydrobiopterin (BH4) to BH2 in pancreatic ductal adenocarcinomas (PDACs). The reduced BH4/BH2 ratio leads to an increase in reactive oxygen species (ROS) generation and a decrease in the distribution of H3K27me3 at CXCL1 promoter. Consequently, myeloid-derived suppressor cells are recruited to tumor microenvironment via CXCR2 causing resistance to ICB therapy. We discovered that BH4 supplementation is capable to restore the BH4/BH2 ratio, enhance anti-tumor immunity, and overcome ICB resistance in QDPR-deficient PDACs. Tumors with lower QDPR expression show decreased responsiveness to ICB therapy. These findings offer a novel strategy for selecting patient and combining therapies to improve the effectiveness of ICB therapy in PDAC.

Associations of maternal serum concentration of iron-related indicators with birth outcomes in Chinese: a pilot prospective cohort study.

BACKGROUND: Previous studies of maternal iron and birth outcomes have been limited to single indicators that do not reflect the comprehensive relationship with birth outcomes. We aimed to investigate the relationship between maternal iron metabolism and neonatal anthropometric indicators using comprehensive iron-related indicators. METHODS: A total of 914 Chinese mother-child dyads were enrolled in this prospective study. Subjects' blood samples were collected at ≤ 14 weeks of gestation. Serum concentrations of iron-related indicators were measured by enzyme-linked immunosorbent assay (ELISA). Femur length was measured by B-ultrasound nearest delivery. Neonatal anthropometric indicators were collected from medical records. RESULTS: After adjustment for potential covariates, higher iron (per one standard deviation, SD increase) was detrimentally associated with - 0.22 mm lower femur length, whereas higher transferrin (per one SD increase) was associated with 0.20 mm higher femur length. Compared with normal subjects (10th-90th percentiles), subjects with extremely high (> 90th percentile) iron concentration were detrimentally associated with lower femur length, birth weight, and chest circumference, and a higher risk of low birth weight, LBW (HR: 3.92, 95%CI: 1.28, 12.0). Subjects with high concentration of soluble transferrin receptor, sTFR and transferrin (> 90th percentile) were associated with higher femur length. Subjects with low concentration of iron and ferritin concentrations (< 10th percentile) were associated with a higher risk of LBW (HR: 4.10, 95%CI: 1.17, 14.3) and macrosomia (HR: 2.79, 95%CI: 1.06, 7.35), respectively. CONCLUSIONS: Maternal iron overload in early pregnancy may be detrimentally associated with neonatal anthropometric indicators and adverse birth outcomes.

Biomechanical evaluation on a new type of vertebral titanium porous mini-plate and mechanical comparison between cervical open-door laminoplasty and laminectomy: a finite element analysis.

Objective: Compare the spine's stability after laminectomy (LN) and laminoplasty (LP) for two posterior surgeries. Simultaneously, design a new vertebral titanium porous mini plate (TPMP) to achieve firm fixation of the open-door vertebral LP fully. The objective is to enhance the fixation stability, effectively prevent the possibility of "re-closure," and may facilitate bone healing. Methods: TPMP was designed by incorporating a fusion body and porous structures, and a three-dimensional finite element cervical model of C2-T1 was constructed and validated. Load LN and LP finite element models, respectively, and analyze and simulate the detailed processes of the two surgeries. It was simultaneously implanting the TPMP into LP to evaluate its biomechanical properties. Results: We find that the range of motion (ROM) of C4-C5 after LN surgery was greater than that of LP implanted with different plates alone. Furthermore, flexion-extension, lateral bending, and axial rotation reflect this change. More noteworthy is that LN has a much larger ROM on C2-C3 in axial rotation. The ROM of LP implanted with two different plates is similar. There is almost no difference in facet joint stress in lateral bending. The facet joint stress of LN is smaller on C2-C3 and C4-C5, and larger more prominent on C5-C6 in the flexion-extension. Regarding intervertebral disc pressure (IDP), there is little difference between different surgeries except for the LN on C2-C3 in axial rotation. The plate displacement specificity does not significantly differ from LP with vertebral titanium mini-plate (TMP) and LP with TPMP after surgery. The stress of LP with TPMP is larger in C4-C5, C5-C6. Moreover, LP with TMP shows greater stress in the C3-C4 during flexion-extension and lateral bending. Conclusion: LP may have better postoperative stability when posterior approach surgery is used to treat CSM; at the same time, the new type of vertebral titanium mini-plate can achieve almost the same effect as the traditional titanium mini-plate after surgery for LP. In addition, it has specific potential due to the porous structure promoting bone fusion.

Factors and outcomes for placental anomalies: An umbrella review of systematic reviews and meta-analyses.

Background: Placental anomalies, including placenta previa (PP), placenta accreta spectrum disorders (PAS), and vase previa (VP), are associated with several adverse foetal-neonatal and maternal complications. However, there is still a lack of robust evidence on the pathogenesis and adverse outcomes of the diseases. Through this umbrella review, we aimed to systematically review existing meta-analyses exploring the factors and outcomes for pregnancy women with placental anomalies. Methods: We searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to February 2023. We used AMSTAR 2 to assess the quality of the reviews and estimated the pooled risk and 95% confidence intervals (CIs) for each meta-analysis. Results: We included 34 meta-analyses and extracted 55 factors (27 for PP, 22 for PAS, and 6 for VP) and 16 outcomes (12 for PP, and 4 for VP) to assess their credibility. Seven factors (maternal cocaine use (for PP), uterine leiomyoma (for PP), prior abortion (spontaneous) (PP), threatened miscarriage (PP), maternal obesity (PP), maternal smoking (PAS), male foetus (PAS)) had high epidemiological evidence. Twelve factors and six outcomes had moderate epidemiological evidence. Twenty-two factors and eight outcomes showed significant association, but with weak credibility. Conclusions: We found varying levels of evidence for placental anomalies of different factors and outcomes in this umbrella review. Registration: PROSPERO: CRD42022300160.

Single-cell transcriptomic analysis deciphers heterogenous cancer stem-like cells in colorectal cancer and their organ-specific metastasis.

OBJECTIVE: Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered. DESIGN: We performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). We also conducted immunofluorescence staining and functional experiments to examine the mechanism. RESULTS: Integrative analyses of epithelial cells reveal a stem-like cell cluster with high protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA) expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary. CONCLUSION: We uncover a mechanism for organ-specific CRC metastasis.

Genomic alterations driving precancerous to cancerous lesions in esophageal cancer development.

Esophageal squamous cell carcinoma (ESCC) develops through a series of increasingly abnormal precancerous lesions. Previous studies have revealed the striking differences between normal esophageal epithelium and ESCC in copy number alterations (CNAs) and mutations in genes driving clonal expansion. However, due to limited data on early precancerous lesions, the timing of these transitions and which among them are prerequisites for malignant transformation remained unclear. Here, we analyze 1,275 micro-biopsies from normal esophagus, early and late precancerous lesions, and esophageal cancers to decipher the genomic alterations at each stage. We show that the frequency of TP53 biallelic inactivation increases dramatically in early precancerous lesion stage while CNAs and APOBEC mutagenesis substantially increase at late stages. TP53 biallelic loss is the prerequisite for the development of CNAs of genes in cell cycle, DNA repair, and apoptosis pathways, suggesting it might be one of the earliest steps initiating malignant transformation.

Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression.

Epithelial-mesenchymal transition (EMT) and proliferation play important roles in epithelial cancer formation and progression, but what molecules and how they trigger EMT is largely unknown. Here we performed spatial transcriptomic and functional analyses on samples of multistage esophageal squamous-cell carcinoma (ESCC) from mice and humans to decipher these critical issues. By investigating spatiotemporal gene expression patterns and cell-cell interactions, we demonstrated that the aberrant epithelial cell interaction via EFNB1-EPHB4 triggers EMT and cell cycle mediated by downstream SRC/ERK/AKT signaling. The aberrant epithelial cell interaction occurs within the basal layer at early precancerous lesions, which expands to the whole epithelial layer and strengthens along the cancer development and progression. Functional analysis revealed that the aberrant EFNB1-EPHB4 interaction is caused by overexpressed ΔNP63 due to TP53 mutation, the culprit in human ESCC tumorigenesis. Our results shed new light on the role of TP53-TP63/ΔNP63-EFNB1-EPHB4 axis in EMT and cell proliferation in epithelial cancer formation.

Super-enhancer RNA m6A promotes local chromatin accessibility and oncogene transcription in pancreatic ductal adenocarcinoma.

The biological functions of noncoding RNA N6-methyladenosine (m6A) modification remain poorly understood. In the present study, we depict the landscape of super-enhancer RNA (seRNA) m6A modification in pancreatic ductal adenocarcinoma (PDAC) and reveal a regulatory axis of m6A seRNA, H3K4me3 modification, chromatin accessibility and oncogene transcription. We demonstrate the cofilin family protein CFL1, overexpressed in PDAC, as a METTL3 cofactor that helps seRNA m6A methylation formation. The increased seRNA m6As are recognized by the reader YTHDC2, which recruits H3K4 methyltransferase MLL1 to promote H3K4me3 modification cotranscriptionally. Super-enhancers with a high level of H3K4me3 augment chromatin accessibility and facilitate oncogene transcription. Collectively, these results shed light on a CFL1-METTL3-seRNA m6A-YTHDC2/MLL1 axis that plays a role in the epigenetic regulation of local chromatin state and gene expression, which strengthens our knowledge about the functions of super-enhancers and their transcripts.

CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes.

N6-methyladenosine (m6A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m6A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m6A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m6A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m6A regulator CSTF2 that co-transcriptionally regulates m6A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m6As have positive effects on the RNA level of host genes, and CSTF2-regulated m6As are mainly recognized by IGF2BP2, an m6A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC.

Collagen 1-mediated CXCL1 secretion in tumor cells activates fibroblasts to promote radioresistance of esophageal cancer.

Esophageal squamous-cell carcinoma (ESCC) is commonly treated with radiotherapy; however, radioresistance hinders its clinical effectiveness, and the underlying mechanism remains elusive. Here, we develop patient-derived xenografts (PDXs) from 19 patients with ESCC to investigate the mechanisms driving radioresistance. Using RNA sequencing, cytokine arrays, and single-cell RNA sequencing, we reveal an enrichment of cancer-associated fibroblast (CAF)-derived collagen type 1 (Col1) and tumor-cell-derived CXCL1 in non-responsive PDXs. Col1 not only promotes radioresistance by augmenting DNA repair capacity but also induces CXCL1 secretion in tumor cells. Additionally, CXCL1 further activates CAFs via the CXCR2-STAT3 pathway, establishing a positive feedback loop. Directly interfering with tumor-cell-derived CXCL1 or inhibiting the CXCL1-CXCR2 pathway effectively restores the radiosensitivity of radioresistant xenografts in vivo. Collectively, our study provides a comprehensive understanding of the molecular mechanisms underlying radioresistance and identifies potential targets to improve the efficacy of radiotherapy for ESCC.

LncRNA BCAN-AS1 stabilizes c-Myc via N6-methyladenosine-mediated binding with SNIP1 to promote pancreatic cancer.

C-Myc overexpression contributes to multiple hallmarks of human cancer but directly targeting c-Myc is challenging. Identification of key factors involved in c-Myc dysregulation is of great significance to develop potential indirect targets for c-Myc. Herein, a collection of long non-coding RNAs (lncRNAs) interacted with c-Myc is detected in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, lncRNA BCAN-AS1 is identified as the one with highest c-Myc binding enrichment. BCAN-AS1 was abnormally elevated in PDAC tumors and high BCAN-AS1 level was significantly associated with poor prognosis. Mechanistically, Smad nuclear-interacting protein 1 (SNIP1) was characterized as a new N6-methyladenosine (m6A) mediator binding to BCAN-AS1 via recognizing its m6A modification. m6A-modified BCAN-AS1 acts as a scaffold to facilitate the formation of a ternary complex together with c-Myc and SNIP1, thereby blocking S phase kinase-associated protein 2 (SKP2)-mediated c-Myc ubiquitination and degradation. Biologically, BCAN-AS1 promotes malignant phenotypes of PDAC in vitro and in vivo. Treatment of metastasis xenograft and patient-derived xenograft mouse models with in vivo-optimized antisense oligonucleotide of BCAN-AS1 effectively represses tumor growth and metastasis. These findings shed light on the pro-tumorigenic role of BCAN-AS1 and provide an innovant insight into c-Myc-interacted lncRNA in PDAC.

Exploring the potential use of Chinese herbs in regulating the inflammatory microenvironment of tumours based on the concept of 'state-target identification and treatment': a scooping review.

Tumours do not exist in isolation from the organism; their growth, proliferation, motility, and immunosuppressive response are intricately connected to the tumour's microenvironment. As tumour cells and the microenvironment coevolve, an inflammatory microenvironment ensues, propelling the phenomenon of inflammation-cancer transformation-an idea proposed by modern medicine. This review aims to encapsulate the array of representative factors within the tumour's inflammatory microenvironment, such as interleukins (IL-6, IL-10, IL-17, IL-1ß), transforming growth factor-beta (TGF-ß), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Moreover, drawing upon research in traditional Chinese medicine (TCM) and pharmacology, we explore the delicate interplay between these factors and tumour-associated inflammatory cells: tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (TANs) and dendritic cells (DCs). By analyzing the tumour-promoting effects of these entities, we delve into the connotations of Academician Tong Xiao-lin's novel model of "state-target differentiation" and its application in the diagnosis and treatment of tumours. Our aim is to enhance the precision and targeting of tumour treatment in clinical practice. Delving deeper into our understanding of tumour pathogenesis through the lens of modern medicine, we discern the key etiology and pathogenesis throughout the entire developmental stage of tumours, unveiling the evolutionary patterns of Chinese Medicine (CM) states: heat state → phlegm state → stagnation state → deficiency state. Building upon this foundation, we devised a state-regulating formula. Simultaneously, drawing on pharmacological research in traditional Chinese medicine (TCM), we meticulously identified a range of targeted drugs that effectively modulate the aforementioned tumour-related mediators. This comprehensive strategy-a harmonious integration of state identification, target recognition, and simultaneous regulation-aims to elevate clinical efficacy. The fusion of TCM with Western medicine in tumour treatment introduces novel dimensions to the precise and refined application of TCM in clinical practice.

Comparison of biomechanical parameters of two Chinese cervical spine rotation manipulations based on motion capture and finite element analysis.

Objective: The purpose of this study was to obtain the stress-strain of the cervical spine structure during the simulated manipulation of the oblique pulling manipulation and the cervical rotation-traction manipulation in order to compare the mechanical mechanism of the two manipulations. Methods: A motion capture system was used to record the key kinematic parameters of operating the two manipulations. At the same time, a three-dimensional finite element model of the C0-T1 full healthy cervical spine was established, and the key kinematic parameters were loaded onto the finite element model in steps to analyze and simulate the detailed process of the operation of the two manipulations. Results: A detailed finite element model of the whole cervical spine including spinal nerve roots was established, and the validity of this 3D finite element model was verified. During the stepwise simulation of the two cervical spine rotation manipulations to the right, the disc (including the annulus fibrosus and nucleus pulposus) and facet joints stresses and displacements were greater in the oblique pulling manipulation group than in the cervical rotation-traction manipulation group, while the spinal cord and nerve root stresses were greater in the cervical rotation-traction manipulation group than in the oblique pulling manipulation group. The spinal cord and nerve root stresses in the cervical rotation-traction manipulation group were mainly concentrated in the C4/5 and C5/6 segments. Conclusion: The oblique pulling manipulation may be more appropriate for the treatment of cervical spondylotic radiculopathy, while cervical rotation-traction manipulation is more appropriate for the treatment of cervical spondylosis of cervical type. Clinicians should select cervical rotation manipulations for different types of cervical spondylosis according to the patient's symptoms and needs.

N 6-methyladenosine Modification of FZR1 mRNA Promotes Gemcitabine Resistance in Pancreatic Cancer.

The therapeutic options for treating pancreatic ductal adenocarcinoma (PDAC) are limited, and resistance to gemcitabine, a cornerstone of PDAC chemotherapy regimens, remains a major challenge. N6-methyladenosine (m6A) is a prevalent modification in mRNA that has been linked to diverse biological processes in human diseases. Herein, by characterizing the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified a key role for elevated m6A modification of the master G0-G1 regulator FZR1 in regulating gemcitabine sensitivity. Targeting FZR1 m6A modification augmented the response to gemcitabine treatment in gemcitabine-resistant PDAC cells both in vitro and in vivo. Mechanistically, GEMIN5 was identified as a novel m6A mediator that specifically bound to m6A-modified FZR1 and recruited the eIF3 translation initiation complex to accelerate FZR1 translation. FZR1 upregulation maintained the G0-G1 quiescent state and suppressed gemcitabine sensitivity in PDAC cells. Clinical analysis further demonstrated that both high levels of FZR1 m6A modification and FZR1 protein corresponded to poor response to gemcitabine. These findings reveal the critical function of m6A modification in regulating gemcitabine sensitivity in PDAC and identify the FZR1-GEMIN5 axis as a potential target to enhance gemcitabine response. SIGNIFICANCE: Increased FZR1 translation induced by m6A modification engenders a gemcitabine-resistant phenotype by inducing a quiescent state and confers a targetable vulnerability to improve treatment response in PDAC.

Refined expression quantitative trait locus analysis on adenocarcinoma at the gastroesophageal junction reveals susceptibility and prognostic markers.

Objectives: This study aimed to explore cell type level expression quantitative trait loci (eQTL) in adenocarcinoma at the gastroesophageal junction (ACGEJ) and identify susceptibility and prognosis markers. Methods: Whole-genome sequencing (WGS) was performed on 120 paired samples from Chinese ACGEJ patients. Germline mutations were detected by GATK tools. RNA sequencing (RNA-seq) data on ACGEJ samples were taken from our previous studies. Public single-cell RNA sequencing (scRNA-seq) data were used to produce the proportion of epithelial cells. Matrix eQTL and a linear mixed model were used to identify condition-specific cis-eQTLs. The R package coloc was used to perform co-localization analysis with the public data of genome-wide association studies (GWASs). Log-rank and Cox regression tests were used to identify survival-associated eQTL and genes. Functions of candidate risk loci were explored by experimental validation. Results: Refined eQTL analyses of paired ACGEJ samples were performed and 2,036 potential ACGEJ-specific eQTLs with East Asian specificity were identified in total. ACGEJ-gain eQTLs were enriched at promoter regions more than ACGEJ-loss eQTLs. rs658524 was identified as the top eQTL close to the transcription start site of its paired gene (CTSW). rs2240191-RASAL1, rs4236599-FOXP2, rs4947311-PSORS1C1, rs13134812-LOC391674, and rs17508585-CDK13-DT were identified as ACGEJ-specific susceptibility eQTLs. rs309483-LINC01355 was associated with the overall survival of ACGEJ patients. We explored functions of candidate eQTLs such as rs658524, rs309483, rs2240191, and rs4947311 by experimental validation. Conclusion: This study provides new risk loci for ACGEJ susceptibility and effective disease prognosis biomarkers.

Role of breastfeeding on maternal and childhood cancers: An umbrella review of meta-analyses.

Background: Multiple studies and meta-analyses have claimed that breastfeeding is inversely correlated with maternal and childhood cancers. These results could either be causal or confounded by shared risk factors. By conducting an umbrella review, we aimed to consolidate the relationship between breastfeeding and maternal and childhood cancers. Methods: We searched PubMed, Embase, Web of Science, Elsevier ScienceDirect, and Cochrane Library databases from inception to December 2022. Two reviewers independently extracted the data and assessed the quality of the studies using standardised forms. We considered two types of breastfeeding comparisons ("ever" vs "never" breastfeeding; and "longest" vs "shortest" duration). We estimated the pooled risk and 95% confidence interval (CI) for each meta-analysis. Results: We included seventeen meta-analyses with 55 comparisons. There was an inverse correlation between breastfeeding and childhood leukaemia (pooled risk = 0.90, 95% CI = 0.81-0.99), neuroblastoma (pooled risk = 0.81, 95% CI = 0.71-0.93), maternal ovarian cancer (pooled risk = 0.76, CI = 0.71-0.81), breast cancer (pooled risk = 0.85, 95% CI = 0.82-0.88), and oesophageal cancer (pooled risk = 0.67, 95% CI = 0.54-0.81) for "ever" vs "never" breastfeeding; and with childhood leukaemia (pooled risk = 0.94, 95% CI = 0.89-0.98), and maternal ovarian cancer (pooled risk = 0.84, 95% CI = 0.78-0.90) and breast cancer (pooled risk = 0.92, 95% CI = 0.89-0.96) for "longest" vs "shortest" breastfeeding duration. Conclusions: We found evidence that breastfeeding may reduce the risk of maternal breast cancer, ovarian cancers, and childhood leukaemia, suggesting positive implications for influencing women's decision in breastfeeding. Registration: PROSPERO (CRD42021255608).

Roles and implications of mRNA N6 -methyladenosine in cancer.

RNA N6 -methyladenosine modification is the most prevalent internal modification of eukaryotic RNAs and has emerged as a novel field of RNA epigenetics, garnering increased attention. To date, m6 A modification has been shown to impact multiple RNA metabolic processes and play a vital role in numerous biological processes. Recent evidence suggests that aberrant m6 A modification is a hallmark of cancer, and it plays a critical role in cancer development and progression through multiple mechanisms. Here, we review the biological functions of mRNA m6 A modification in various types of cancers, with a particular focus on metabolic reprogramming, programmed cell death and tumor metastasis. Furthermore, we discuss the potential of targeting m6 A modification or its regulatory proteins as a novel approach of cancer therapy and the progress of research on m6 A modification in tumor immunity and immunotherapy. Finally, we summarize the development of different m6 A detection methods and their advantages and disadvantages.