UHRF2 commissions the completion of DNA demethylation through allosteric activation by 5hmC and K33-linked ubiquitination of XRCC1.

The transition of oxidized 5-methylcytosine (5mC) intermediates into the base excision repair (BER) pipeline to complete DNA demethylation remains enigmatic. We report here that UHRF2, the only paralog of UHRF1 in mammals that fails to rescue Uhrf1-/- phenotype, is physically and functionally associated with BER complex. We show that UHRF2 is allosterically activated by 5-hydroxymethylcytosine (5hmC) and acts as a ubiquitin E3 ligase to catalyze K33-linked polyubiquitination of XRCC1. This nonproteolytic action stimulates XRCC1's interaction with the ubiquitin binding domain-bearing RAD23B, leading to the incorporation of TDG into BER complex. Integrative epigenomic analysis in mouse embryonic stem cells reveals that Uhrf2-fostered TDG-RAD23B-BER complex is functionally linked to the completion of DNA demethylation at active promoters and that Uhrf2 ablation impedes DNA demethylation on latent enhancers that undergo poised-to-active transition during neuronal commitment. Together, these observations highlight an essentiality of 5hmC-switched UHRF2 E3 ligase activity in commissioning the accomplishment of active DNA demethylation.

Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction.

The type 2 ryanodine receptor/calcium release channel (RyR2), required for excitation-contraction coupling in the heart, is abundant in the brain. Chronic stress induces catecholamine biosynthesis and release, stimulating ß-adrenergic receptors and activating cAMP signaling pathways in neurons. In a murine chronic restraint stress model, neuronal RyR2 were phosphorylated by protein kinase A (PKA), oxidized, and nitrosylated, resulting in depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the channel complex and intracellular calcium leak. Stress-induced cognitive dysfunction, including deficits in learning and memory, and reduced long-term potentiation (LTP) at the hippocampal CA3-CA1 connection were rescued by oral administration of S107, a compound developed in our laboratory that stabilizes RyR2-calstabin2 interaction, or by genetic ablation of the RyR2 PKA phosphorylation site at serine 2808. Thus, neuronal RyR2 remodeling contributes to stress-induced cognitive dysfunction. Leaky RyR2 could be a therapeutic target for treatment of stress-induced cognitive dysfunction.

Detecting tipping points of complex diseases by network information entropy.

The progression of complex diseases often involves abrupt and non-linear changes characterized by sudden shifts that trigger critical transformations. Identifying these critical states or tipping points is crucial for understanding disease progression and developing effective interventions. To address this challenge, we have developed a model-free method named Network Information Entropy of Edges (NIEE). Leveraging dynamic network biomarkers, sample-specific networks, and information entropy theories, NIEE can detect critical states or tipping points in diverse data types, including bulk, single-sample expression data. By applying NIEE to real disease datasets, we successfully identified critical predisease stages and tipping points before disease onset. Our findings underscore NIEE's potential to enhance comprehension of complex disease development.

Spatially contrastive variational autoencoder for deciphering tissue heterogeneity from spatially resolved transcriptomics.

Recent advances in spatially resolved transcriptomics (SRT) have brought ever-increasing opportunities to characterize expression landscape in the context of tissue spatiality. Nevertheless, there still exist multiple challenges to accurately detect spatial functional regions in tissue. Here, we present a novel contrastive learning framework, SPAtially Contrastive variational AutoEncoder (SpaCAE), which contrasts transcriptomic signals of each spot and its spatial neighbors to achieve fine-grained tissue structures detection. By employing a graph embedding variational autoencoder and incorporating a deep contrastive strategy, SpaCAE achieves a balance between spatial local information and global information of expression, enabling effective learning of representations with spatial constraints. Particularly, SpaCAE provides a graph deconvolutional decoder to address the smoothing effect of local spatial structure on expression's self-supervised learning, an aspect often overlooked by current graph neural networks. We demonstrated that SpaCAE could achieve effective performance on SRT data generated from multiple technologies for spatial domains identification and data denoising, making it a remarkable tool to obtain novel insights from SRT studies.

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma.

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential.

SNP rs4971059 predisposes to breast carcinogenesis and chemoresistance via TRIM46-mediated HDAC1 degradation.

Identification of the driving force behind malignant transformation holds the promise to combat the relapse and therapeutic resistance of cancer. We report here that the single nucleotide polymorphism (SNP) rs4971059, one of 65 new breast cancer risk loci identified in a recent genome-wide association study (GWAS), functions as an active enhancer of TRIM46 expression. Recreating the G-to-A polymorphic switch caused by the SNP via CRISPR/Cas9-mediated homologous recombination leads to an overt upregulation of TRIM46. We find that TRIM46 is a ubiquitin ligase that targets histone deacetylase HDAC1 for ubiquitination and degradation and that the TRIM46-HDAC1 axis regulates a panel of genes, including ones critically involved in DNA replication and repair. Consequently, TRIM46 promotes breast cancer cell proliferation and chemoresistance in vitro and accelerates tumor growth in vivo. Moreover, TRIM46 is frequently overexpressed in breast carcinomas, and its expression is correlated with lower HDAC1 expression, higher histological grades, and worse prognosis of the patients. Together, our study links SNP rs4971059 to replication and to breast carcinogenesis and chemoresistance and support the pursuit of TRIM46 as a potential target for breast cancer intervention.

Distinct neuronal types contribute to hybrid temporal encoding strategies in primate auditory cortex.

Studies of the encoding of sensory stimuli by the brain often consider recorded neurons as a pool of identical units. Here, we report divergence in stimulus-encoding properties between subpopulations of cortical neurons that are classified based on spike timing and waveform features. Neurons in auditory cortex of the awake marmoset (Callithrix jacchus) encode temporal information with either stimulus-synchronized or nonsynchronized responses. When we classified single-unit recordings using either a criteria-based or an unsupervised classification method into regular-spiking, fast-spiking, and bursting units, a subset of intrinsically bursting neurons formed the most highly synchronized group, with strong phase-locking to sinusoidal amplitude modulation (SAM) that extended well above 20 Hz. In contrast with other unit types, these bursting neurons fired primarily on the rising phase of SAM or the onset of unmodulated stimuli, and preferred rapid stimulus onset rates. Such differentiating behavior has been previously reported in bursting neuron models and may reflect specializations for detection of acoustic edges. These units responded to natural stimuli (vocalizations) with brief and precise spiking at particular time points that could be decoded with high temporal stringency. Regular-spiking units better reflected the shape of slow modulations and responded more selectively to vocalizations with overall firing rate increases. Population decoding using time-binned neural activity found that decoding behavior differed substantially between regular-spiking and bursting units. A relatively small pool of bursting units was sufficient to identify the stimulus with high accuracy in a manner that relied on the temporal pattern of responses. These unit type differences may contribute to parallel and complementary neural codes.

IKZF3 polymorphisms contribute to the increased risk of acute lymphoblastic leukemia in children.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. IKZF3 (IKAROS family zinc finger 3) is a hematopoietic-specific transcription factor, and it has been validated that it is involved in leukemia. However, the role of IKZF3 single-nucleotide polymorphisms (SNPs) remains unclear. In this case-control study, the authors investigated the association of IKZF3 SNPs with ALL in children. METHODS: Six IKZF3 reference SNPs (rs9635726, rs2060941, rs907092, rs12946510, rs1453559, and rs62066988) were genotyped in 692 patients who had ALL (cases) and in 926 controls. The associations between IKZF3 polymorphisms and ALL risk were determined using odds ratios (ORs) and 95% confidence intervals (CIs). The associations of rs9635726 and rs2060941 with the risk of ALL were further estimated by using false-positive report probability (FPRP) analysis. Functional analysis in silico was performed to evaluate the probability that rs9635726 and rs2060941 might influence the regulation of IKZF3. RESULTS: The authors observed that rs9635726C>T (adjusted OR, 1.49; 95% CI, 1.06-2.11; p = .023) and rs2060941G>T (adjusted OR, 1.51; 95% CI, 1.24-1.84; p = .001) were related to and increased risk of ALL in the recessive and dominant models, respectively. Furthermore, the associations of both rs9635726 (FPRP = .177) and rs2060941 (FPRP < .001) with ALL were noteworthy in the FPRP analysis. Functional analysis indicated that rs9635726 and rs2060941 might repress the transcription of IKZF3 by disrupting its binding to MLLT1, TAF1, POLR2A, and/or RAD21. CONCLUSIONS: This study revealed that IKZF3 polymorphisms were associated with increased ALL susceptibility in children and might influence the expression of IKZF3 by disrupting its binding to MLLT1, TAF1, POLR2A, and/or RAD21. IKZF3 polymorphisms were suggested as a biomarker for childhood ALL.

Transcriptome analysis method based on differential distribution evaluation.

Identifying differential genes over conditions provides insights into the mechanisms of biological processes and disease progression. Here we present an approach, the Kullback-Leibler divergence-based differential distribution (klDD), which provides a flexible framework for quantifying changes in higher-order statistical information of genes including mean and variance/covariation. The method can well detect subtle differences in gene expression distributions in contrast to mean or variance shifts of the existing methods. In addition to effectively identifying informational genes in terms of differential distribution, klDD can be directly applied to cancer subtyping, single-cell clustering and disease early-warning detection, which were all validated by various benchmark datasets.

Improved fluorescence-based assay for rapid screening and evaluation of SARS-CoV-2 main protease inhibitors.

The outbreak of coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global threat to human health. In parallel with vaccines, efficacious antivirals are urgently needed. SARS-CoV-2 main protease (Mpro) is an attractive drug target for antiviral development owing to its key roles in virus replication and host immune evasion. Due to the limitations of currently available methods, the development of novel high-throughput screening assays is of the highest importance for the discovery of Mpro inhibitors. In this study, we first developed an improved fluorescence-based assay for rapid screening of Mpro inhibitors from an anti-infection compound library using a versatile dimerization-dependent red fluorescent protein (ddRFP) biosensor. Utilizing this assay, we identified MG-101 as a competitive Mpro inhibitor in vitro. Moreover, our results revealed that ensitrelvir is a potent Mpro inhibitor, but baicalein, chloroquine, ebselen, echinatin, and silibinin are not. Therefore, this robust ddRFP assay provides a faithful avenue for rapid screening and evaluation of Mpro inhibitors to fight against COVID-19.

Male vitellogenin regulates gametogenesis through a testis-enriched big protein in Chrysopa pallens.

In insects, vitellogenin (Vg) is generally viewed as a female-specific protein. Its primary function is to supply nutrition to developing embryos. Here, we reported Vg from the male adults of a natural predator, Chrysopa pallens. The male Vg was depleted by RNAi. Mating with Vg-deficient male downregulated female Vg expression, suppressed ovarian development and decreased reproductive output. Whole-organism transcriptome analysis after male Vg knockdown showed no differential expression of the known spermatogenesis-related regulators and seminal fluid protein genes, but a sharp downregulation of an unknown gene, which encodes a testis-enriched big protein (Vcsoo). Separate knockdown of male Vg and Vcsoo disturbed the assembly of spermatid cytoplasmic organelles in males and suppressed the expansion of ovary germarium in mated females. These results demonstrated that C. pallens male Vg signals through the downstream Vcsoo and regulates male and female reproduction.

Bacterial isolation and genome analysis of a novel Klebsiella quasipneumoniae phage in southwest China's karst area.

BACKGROUND: Southwest China is one of the largest karst regions in the world. Karst environment is relatively fragile and vulnerable to human activities. Due to the discharge of sewage and domestic garbage, the karst system may be polluted by pathogenic bacteria. The detection of bacterial distribution and identification of phage capable of infecting them is an important approach for environmental assessment and resource acquisition. METHODS: Bacteria and phages were isolated from karst water in southwest China using the plate scribing and double plate method, respectively. Isolated phage was defined by transmission electron microscopy, one-step growth curve and optimal multiplicity of infection (MOI). Genomic sequencing, phylogenetic analysis, comparative genomic and proteomic analysis were performed. RESULTS: A Klebsiella quasipneumoniae phage was isolated from 32 isolates and named KL01. KL01 is morphologically identified as Caudoviricetes with an optimal MOI of 0.1, an incubation period of 10 min, and a lysis period of 60 min. The genome length of KL01 is about 45 kb, the GC content is 42.5%, and it contains 59 open reading frames. The highest average nucleotide similarity between KL01 and a known Klebsiella phage 6939 was 83.04%. CONCLUSIONS: KL01 is a novel phage, belonging to the Autophagoviridae, which has strong lytic ability. This study indicates that there were not only some potential potentially pathogenic bacteria in the karst environment, but also phage resources for exploration and application.

Discovery of novel thiophene-3-carboxamide derivatives as potential VEGFR-2 inhibitors with anti-angiogenic properties.

VEGFR-2 is an attractive target for the development of anti-tumor drugs and plays a crucial role in tumor angiogenesis. This study reports a series of novel thiophene-3-carboxamide derivatives based on PAN-90806 as VEGFR-2 inhibitors, among which compound 14d exhibits excellent anti-proliferative activity against HCT116, MCF7, PC3, and A549 cell lines, and has effective VEGFR-2 inhibitory activity with an IC50 value of 191.1 nM. Additionally, CETSA results indicated that VEGFR-2 was a relevant target of compound 14d in the cell lines, and compound 14d could also inhibit VEGFR-2 protein phosphorylation in A549 cell line. Furthermore, compound 14d inhibited colony formation, cell migration, and HUVECs tube formation in a dose-dependent manner. The mechanism by which 14d induced cancer cell death involves blocking the cell cycle, increasing ROS production, inducing apoptosis, and dose-dependently reducing the levels of phosphorylated ERK and MEK. Molecular docking and molecular dynamics simulations had shown that compound 14d could stably bind to the active site of VEGFR-2. These results confirmed that compound 14d might be a promising lead compound for anti-angiogenesis.

Hemorrhagic cystitis induced by JC polyomavirus infection following COVID-19: a case report.

JC polyomavirus (JCPyV) is a human polyomavirus that can establish lifelong persistent infection in the majority of adults. It is typically asymptomatic in immunocompetent individuals. However, there is a risk of developing progressive multifocal leukoencephalopathy (PML) in immunocompromised or immunosuppressed patients. Though JCPyV commonly resides in the kidney-urinary tract, its involvement in urinary system diseases is extremely rare. Here, we reported a case of a 60-year-old male patient with coronavirus disease 2019 (COVID-19) infection who developed hemorrhagic cystitis after receiving treatment with nirmatrelvir 300 mg/ritonavir 100 mg quaque die (QD). Subsequent metagenomic next-generation sequencing (mNGS) confirmed the infection to be caused by JCPyV type 2. Then, human immunoglobulin (PH4) for intravenous injection at a dose of 25 g QD was administered to the patient. Three days later, the hematuria resolved. This case illustrates that in the setting of compromised host immune function, JCPyV is not limited to causing central nervous system diseases but can also exhibit pathogenicity in the urinary system. Moreover, mNGS technology facilitates rapid diagnosis of infectious etiology by clinical practitioners, contributing to precise treatment for patients.

Efficacy of balloon Eustachian tuboplasty plus tympanostomy tube insertion in postirradiation otitis media with effusion.

OBJECTIVE: This study aimed to compare the efficacy of balloon Eustachian tuboplasty (BET) plus tympanostomy tube insertion (TTI) and simple TTI for postirradiation otitis media with effusion (OME) in patients with nasopharyngeal carcinoma. METHOD: This study included 36 patients (51 ears) with OME after the first radiotherapy course for nasopharyngeal carcinoma and categorized them into the BET + TTI and simple TTI groups. Effective rates, pure tone hearing threshold, Eustachian tube function score, and complication incidences were compared. RESULTS: The effective rates of the BET+TTI and TTI groups were 93.75 % and 75 %, respectively, with no statistically significant difference (P = 0.29). The pure tone hearing threshold examination at 9 months postoperatively revealed significantly lower mean air-pure tone and air-bone gap in both the BET + TTI and TTI groups than preoperatively. Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) scores at every postoperative visit were significantly higher than preoperative scores in the two groups (all P < 0.05); ETDQ-7 score reduction in the BET + TTI group at 3, 9, and 12 months postoperatively was significantly higher than that in the TTI group. Otorrhea and recurrence both occurred in the BET+TTI and TTI groups, but the BET+TTI group demonstrated a lower incidence. CONCLUSION: BET + TTI is an effective treatment method for postirradiation OME.

Deep eutectic solvents pretreatment enhances methane production from anaerobic digestion of waste activated sludge: Effectiveness evaluation and mechanism elucidation.

Anaerobic digestion (AD) is a prevalent waste activated sludge (WAS) treatment, and optimizing methane production is a core focus of AD. Two DESs were developed in this study and significantly increased methane production, including choline chloride-urea (ChCl-Urea) 390% and chloride-ethylene glycol (ChCl-EG) 540%. Results showed that ChCl-Urea mainly disrupted extracellular polymeric substances (EPS) structures, aiding in initial sludge solubilization during pretreatment. ChCl-EG, instead, induced sludge self-driven organic solubilization and enhanced hydrolysis and acidification processes during AD process. Based on the extent to which the two DESs promoted AD for methane production, the AD process can be divided into stage Ⅰ and stage Ⅱ. In stage Ⅰ, ChCl-EG promoted methanogenesis more significantly, microbiological analysis showed both DESs enriched aceticlastic methanogens-Methanosarcina. Notably, ChCl-Urea particularly influenced polysaccharide-related metabolism, whereas ChCl-EG targeted protein-related metabolism. In stage Ⅱ, ChCl-Urea was more dominant than ChCl-EG, ChCl-Urea bolstered metabolism and ChCl-EG promoted genetic information processing in this stage. In essence, this study investigated the microbial mechanism of DES-enhanced sludge methanogenesis and provided a reference for future research.

NF1 mutation and TUBB3 amplification in gastric histiocytic sarcoma: a case report and literature review.

Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course and poor response to treatment. Primary gastric histiocytic sarcoma is rarer and just reported sporadically.Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course and poor response to treatment. Primary gastric histiocytic sarcoma is rarer and just reported sporadically. A case of a 71-year-old female admitted with a one-year history of upper abdominal pain exacerbated after meals. After CT scans revealed a bulged mass at the lesser curvature of the gastric body, the patient underwent endoscopic submucosal dissection. Microscopically, non-cohesive neoplastic cells diffusely infiltrated lamina propria and submucosa, and diffusely expressed LCA, CD4, CD163, CD68 (KP1), Cyclin D1, Lysozyme, and Vimentin. PD-L1 (22CS) expression evaluated as CPS 60. The final pathological diagnosis was gastric histiocytic sarcoma. Subsequently, next-generation sequencing identified a nonsense mutation in exon 21 of NF1 gene [c.2446C > T (p.R816*)] and the TUBB3 gene amplification (copy number: 4.55). The patient refused further treatment and died of the tumor half a year later. This case broadens the spectrum of differential diagnosis of gastric cancer and emphasizes the value of immunohistochemical and molecular tests in the accurate diagnosis of histiocytic sarcoma. Furthermore, we performed literature review of 11 cases of gastric histiocytic sarcoma so as to strengthen the understanding of the clinicopathologic features, treatment, and prognosis.

NS encodes an auxin transporter that regulates the 'numerous spines' trait in cucumber (Cucumis sativus) fruit.

Fruit spine is an important agronomic trait in cucumber and the "numerous spines (ns)" cucumber varieties are popular in Europe and West Asia. Although the classical genetic locus of ns was reported more than two decades ago, the NS gene has not been cloned yet. In this study, nine genetic loci for the different densities of fruit spines were identified by a genome-wide association study. Among the nine loci, fsdG2.1 was closely associated with the classical genetic locus ns, which harbors a candidate gene Csa2G264590. Overexpression of Csa2G264590 resulted in lower fruit spine density, and the knockout mutant generated by CRISPR/Cas9 displayed an increased spine density, demonstrating that the Csa2G264590 gene is NS. NS is specifically expressed in the fruit peel and spine. Genetic analysis showed that NS regulates fruit spine development independently of the tuberculate gene, Tu, which regulates spine development on tubercules; the cucumber glabrous mutants csgl1 and csgl3 are epistatic to ns. Furthermore, we found that auxin levels in the fruit peel and spine were significantly lower in the knockout mutant ns-cr. Moreover, RNA-sequencing showed that the plant hormone signal transduction pathway was enriched. Notably, most of the auxin responsive Aux/IAA family genes were downregulated in ns-cr. Haplotype analysis showed that the non-functional haplotype of NS exists exclusively in the Eurasian cucumber backgrounds. Taken together, the cloning of NS gene provides new insights into the regulatory network of fruit spine development.

TeCD: The eccDNA Collection Database for extrachromosomal circular DNA.

BACKGROUND: Extrachromosomal circular DNA (eccDNA) is a kind of DNA that widely exists in eukaryotic cells. Studies in recent years have shown that eccDNA is often enriched during tumors and aging, and participates in the development of cell physiological activities in a special way, so people have paid more and more attention to the eccDNA, and it has also become a critical new topic in modern biological research. DESCRIPTION: We built a database to collect eccDNA, including animals, plants and fungi, and provide researchers with an eccDNA retrieval platform. The collected eccDNAs were processed in a uniform format and classified according to the species to which it belongs and the chromosome of the source. Each eccDNA record contained sequence length, start and end sites on the corresponding chromosome, order of the bases, genomic elements such as genes and transposons, and other information in the respective sequencing experiment. All the data were stored into the TeCD (The eccDNA Collection Database) and the BLAST (Basic Local Alignment Search Tool) sequence alignment function was also added into the database for analyzing the potential eccDNA sequences. CONCLUSION: We built TeCD, a platform for users to search and obtain eccDNA data, and analyzed the possible potential functions of eccDNA. These findings may provide a basis and direction for researchers to further explore the biological significance of eccDNA in the future.

New association between splicing factor-coding gene polymorphisms and the risk of acute lymphoblastic leukemia in southern Chinese children: A five-center case-control study.

BACKGROUND: The role of splicing factor-coding gene polymorphisms in pediatric acute lymphoblastic leukemia (ALL) susceptibility is still unclear. METHODS: A case-control designed model was used to estimate the overall risk of pediatric ALL and five single nucleotide polymorphisms (SNPs) of splicing factor-coding genes in 808 cases and 1,340 controls, which were genotyped using a TaqMan assay. Stratified analysis was performed to explore the association of rs2233911 genotype and pediatric ALL susceptibility. The influence of splicing factor arginine/serine-rich 1 (SFRS1) polymorphisms on the sensitivity to different chemotherapeutic regimens based on minimal residual disease (MRD) levels was analyzed. The haplotype analysis was adopted to evaluate the association between inferred haplotypes of the splicing factor-coding genes and pediatric ALL risk. RESULTS: Among the five analyzed SNPs, SFRS1 rs2233911 AG/GG exhibited a significant association with increased pediatric ALL risk. The stratified analysis further identified the harmful effect of SFRS1 rs2233911 AG/GG in specific subgroups. Moreover, rs2233911 AG/GG had a protective effect on MRD in marrow of ≥0.01%  12 weeks of Chinese Children Cancer Group chemotherapeutics, but provided a harmful effect on MRD in the marrow of ≥0.01% at days 15-19 of the South China Children Leukemia Group chemotherapeutics. Haplotype analysis of these five SNPs yielded haplotypes ACGCC and ACGTC significantly correlating with increased pediatric ALL susceptibility. On the contrary, haplotypes GCATG and GTACC were linked with remarkably decreased pediatric ALL risk. CONCLUSION: SFRS1 gene polymorphism was associated with increased pediatric ALL risk and indicated that rs2233911 AG/GG might be a potential biomarker for choosing chemotherapeutics.