Uncovering the power of neurofeedback: a meta-analysis of its effectiveness in treating major depressive disorders.

Neurofeedback, a non-invasive intervention, has been increasingly used as a potential treatment for major depressive disorders. However, the effectiveness of neurofeedback in alleviating depressive symptoms remains uncertain. To address this gap, we conducted a comprehensive meta-analysis to evaluate the efficacy of neurofeedback as a treatment for major depressive disorders. We conducted a comprehensive meta-analysis of 22 studies investigating the effects of neurofeedback interventions on depression symptoms, neurophysiological outcomes, and neuropsychological function. Our analysis included the calculation of Hedges' g effect sizes and explored various moderators like intervention settings, study designs, and demographics. Our findings revealed that neurofeedback intervention had a significant impact on depression symptoms (Hedges' g = -0.600) and neurophysiological outcomes (Hedges' g = -0.726). We also observed a moderate effect size for neurofeedback intervention on neuropsychological function (Hedges' g = -0.418). As expected, we observed that longer intervention length was associated with better outcomes for depressive symptoms (ß = -4.36, P < 0.001) and neuropsychological function (ß = -2.89, P = 0.003). Surprisingly, we found that shorter neurofeedback sessions were associated with improvements in neurophysiological outcomes (ß = 3.34, P < 0.001). Our meta-analysis provides compelling evidence that neurofeedback holds promising potential as a non-pharmacological intervention option for effectively improving depressive symptoms, neurophysiological outcomes, and neuropsychological function in individuals with major depressive disorders.

SUMMER: a Mendelian randomization interactive server to systematically evaluate the causal effects of risk factors and circulating biomarkers on pan-cancer survival.

Genome-wide association studies (GWASs) underlying case-control design have uncovered hundreds of genetic loci involved in tumorigenesis and provided rich resources for identifying risk factors and biomarkers associated with cancer susceptibility. However, the application of GWAS in determining the genetic architecture of cancer survival remains unestablished. Here, we systematically evaluated genetic effects at the genome-wide level on cancer survival that included overall survival (OS) and cancer-specific survival (CSS), leveraging data deposited in the UK Biobank cohort of a total of 19 628 incident patients across 17 cancer types. Furthermore, we assessed the causal effects of risk factors and circulating biomarkers on cancer prognosis via a Mendelian randomization (MR) analytic framework, which integrated cancer survival GWAS dataset, along with phenome-wide association study (PheWAS) and blood genome-wide gene expression/DNA methylation quantitative trait loci (eQTL/meQTL) datasets. On average, more than 10 traits, 700 genes, and 4,500 CpG sites were prone to cancer prognosis. Finally, we developed a user-friendly online database, SUrvival related cancer Multi-omics database via MEndelian Randomization (SUMMER; http://njmu-edu.cn:3838/SUMMER/), to help users query, browse, and download cancer survival results. In conclusion, SUMMER provides an important resource to assist the research community in understanding the genetic mechanisms of cancer survival.

Genetic variants in hypoxia-inducible factor pathway are associated with colorectal cancer risk and immune infiltration.

Hypoxia-inducible factor (HIF) pathway genes influence tumorigenesis and immune status. However, the associations between genetic variants in hypoxia-related genes and colorectal cancer risk and the immune status of hypoxia-associated genes in colorectal cancer have not been systematically characterized. The associations between genetic variants and colorectal cancer risk were evaluated in Chinese, Japanese and European populations using logistic regression analysis. The relationships between target genes and tumour immune infiltration were predicted by Tumour Immune Estimation Resource (TIMER). We found that rs34533650 in EPAS1 was associated with colorectal cancer risk (OR = 1.43, 95% CI = 1.20-1.70, P(FDR) = 8.35 × 10-4 ), and this finding was validated in two independent populations (Japanese: OR = 1.07, 95% CI = 1.01-1.15, p = 3.38 × 10-2 ; European: OR = 1.11, 95% CI = 1.03-1.19, p = 6.04 × 10-3 ). EPAS1-associated genes were enriched in immune-related pathways. In addition, we found that EPAS1 copy number variation (CNV) was associated with the degree of infiltration of immune cells and observed correlations between EPAS1 expression and immune cell infiltration levels in colorectal cancer. These results highlight that genetic variants of hypoxia-related genes play roles in colorectal cancer risk and provide new insight that EPAS1 might be a promising predictor of colorectal cancer susceptibility and immune status.

An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study.

BACKGROUND: Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. METHODS: We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes. RESULTS: The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99-2.78] than LOPC (HR = 1.95, 95% CI 1.89-2.01; I2 = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98-5.54) but not to LOPC (HR = 0.98, 95% CI 0.96-1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancer Age-based PheWAS; https://mulongdu.shinyapps.io/proap ), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures. CONCLUSIONS: This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.

Minimally invasive versus open ileal ureter with ileocystoplasty: comparative outcomes and 5-year experience.

PURPOSE: To present the experience of ileal ureter with ileocystoplasty (IUC), and compare the outcomes of IUC in minimally invasive procedures to open procedures. PATIENTS AND METHODS: From December 2017 to April 2023, twenty patients underwent IUC in open or minimally invasive (including laparoscopic and robotic) procedures. The baseline characteristics, perioperative data and follow-up outcomes were collected. Success was defined as relief of clinical symptoms, stable postoperative serum creatine and absence of radiographic obstruction. The perioperative and follow-up outcomes of open procedures and minimally invasive procedures were compared. RESULTS: The etiology included pelvic irradiation (14/20), urinary tuberculosis (3/20) and surgical injury (3/20). Bilateral ureter strictures were repaired in 15 cases. The surgeries conducted consisted of open procedures in 9 patients and minimally invasive procedures in 11 patients. Compared to open procedures, minimally invasive surgeries had less median estimated blood loss (EBL) (100 ml vs. 300 min, p = 0.010) and shorter postoperative hospitalization (27 d vs. 13 d, p = 0.004). Two patients in the open group experienced grade 3 complications (sigmoid fistula and acute cholecystitis in one patient, and pulmonary embolism in another patient). Over a median follow-up period of 20.1 months, the median bladder functional capacity was 300 ml, with a 100% success rate of IUC. CONCLUSION: IUC is feasible in both open and minimally invasive procedures, with acceptable complications and a high success rate. Minimally invasive procedures can have less EBL and shorter postoperative hospitalization than open procedure. However, prospective studies with larger groups and longer follow-up are needed.

Insights into urinary incontinence after robot-assisted radical prostatectomy: urgent urinary incontinence or stress urinary incontinence.

PURPOSE: Urinary incontinence is a common complication following robot-assisted radical prostatectomy (RARP). Few studies have explored the relationships and differences between stress urinary incontinence (SUI) and urgent urinary incontinence (UUI) after RARP. This study aimed to investigate the occurrence rates and risk factors of UUI and SUI in short term after RARP. METHODS: We prospectively included prostate cancer patients who underwent RARP by a single surgeon. Demographics, lower urinary tract function, oncology, and follow-ups were recorded. Occurrence rates and risk factors of UUI and SUI within 3 months after catheter withdrawal were calculated. RESULTS: The study cohort included 363 subjects with a mean age of 66.05 years. The median preoperative International Prostate Symptom Score (IPSS) was 14 (range 0-35), and the median Overactive Bladder Symptom Score (OABSS) was 3 (range 0-14). The occurrence rate of UUI and SUI at 3 months after catheter withdrawal was 8.5% (31/363) and 15.2% (55/363). Nearly all patients with UUI also had SUI. Diabetes history and high OABSS before RARP were independent risk factors for UUI, especially within 1 month after catheter withdrawal. The Gleason Score was an independent risk factor for SUI at 3 months after catheter withdrawal. Additionally, UUI but not SUI might be an influencing factor for decision-making regarding postoperative radiotherapy. CONCLUSION: The occurrence rate of SUI after RARP was persistently higher than that of UUI. Nearly all of the patients with UUI simultaneously had SUI. The risk factors of UUI and SUI after RARP were absolutely different.

Effect of polycyclic aromatic hydrocarbons on cancer risk causally mediated via vitamin D levels.

Polycyclic aromatic hydrocarbons (PAHs) widely exist in environmental substrates and are closely related to individual circulating vitamin D levels and tumorigenesis. Therefore, we proposed to evaluate the relationship between PAH exposure, vitamin D, and the risks for 14 cancer types via a causal inference framework underlying the mediation analysis. We evaluated seven urine monohydroxylated PAH (OH-PAH) and serum vitamin D concentrations of 3306 participants from the National Health and Nutrition Examination Survey between the 2013 and 2016 survey cycles and measured PAH concentrations in 150 subjects from the Nanjing cohort. We observed a significant negative dose-response relationship between increased OH-PAH levels and vitamin D deficiency. Each unit increase in ∑OH-PAHs could lead to a decrease in vitamin D levels (ßadj = -0.98, Padj = 2.05 × 10-4 ). Body mass index could have interaction effects with ∑OH-PAHs and affect vitamin D levels. Coexposure to naphthalene and fluorene metabolites mutually affected vitamin D levels. Notably, vitamin D could causally mediate the relationship between OH-PAHs and nine types of cancer (e.g., colorectal cancer, liver cancers, etc.). This study first emphasizes the causal cascade of individual OH-PAHs, vitamin D, and cancer risk, providing insights into prevention via the environment.

Robot-assisted modified bilateral dismembered V-shaped flap pyeloplasty for ureteropelvic junction obstruction in horseshoe kidney using KangDuo-Surgical-Robot-01 system.

PURPOSE: Horseshoe kidney (HSK) is the most common renal fusion anomaly, occurring in 0.25% of the population (1). It presents technical obstacles to pyeloplasty for ureteropelvic junction obstruction (UPJO) despite robotic assistance (2, 3). KangDuo-Surgical-Robot-01 (KD-SR-01), an emerging robotic platform in China, has yielded satisfactory outcomes in pyeloplasty (4, 5). We first describe our modified technique of robotic bilateral pyeloplasty for UPJO in HSK using KD-SR-01 system in the Lithotomy Trendelenburg position. MATERIALS AND METHODS: A 36-year-old man with HSK and bilateral UPJO suffered right flank pain due to renal calculi (Figure-1). Repeated double-J stent insertion and ureteroscopy lithotripsy did not relieve his symptoms. A robot-assisted modified bilateral dismembered V-shaped flap pyeloplasty was performed using KD-SR-01 system in the Lithotomy Trendelenburg position. RESULTS: Total operative time was 298 minutes with 50 ml estimated blood loss. There was no conversion to laparoscopic or open surgery. A follow-up of 14 months showed relieving symptoms and stable renal function. Cine magnetic resonance urography and computed tomography urography revealed improved hydronephrosis and good drainage. No intraoperative or postoperative complications occurred. CONCLUSIONS: It is technically feasible to perform a KD-SR-01-assisted modified bilateral dismembered V-shaped flap pyeloplasty in the Lithotomy Trendelenburg position for HSK. This procedure achieves managing UPJO on both sides without redocking the system and provides a wider operative field. In addition, it may be associated with better ergonomics, better cosmetic outcomes, and less possibility of postoperative bowel adhesion. However, further investigation is still warranted to confirm its safety, efficacy, and advantages over traditional procedures.

Noninvasive evaluation of tumor immune microenvironment in patients with clear cell renal cell carcinoma using metabolic parameter from preoperative 2-[18F]FDG PET/CT.

PURPOSE: Nowadays, it is necessary to explore effective biomarkers associated with tumor immune microenvironment (TIME) noninvasively. Here, we investigated whether the metabolic parameter from preoperative 2-[18F]FDG PET/CT could provide information related to TIME in patients with clear cell renal cell carcinoma (ccRCC). METHODS: Ninety patients with newly diagnosed ccRCC who underwent 2-[18F]FDG PET/CT prior to surgery were retrospectively reviewed. The immunological features included tumor-infiltrating lymphocytes (TILs) density, programmed death-ligand 1 (PD-L1) expression, and tumor immune microenvironment types (TIMTs). TIMTs were classified as TIMT I (positive PD-L1 and high TILs), TIMT II (negative PD-L1 and low TILs), TIMT III (positive PD-L1 and low TILs), and TIMT IV (negative PD-L1 and high TILs). The relationship between maximum standardized uptake value (SUVmax) in the primary lesion from 2-[18F]FDG PET/CT and immunological features was analyzed. Cox proportional hazards analyses were performed to identify the prognostic factors for disease-free survival (DFS) after nephrectomy. RESULTS: Tumors with high TILs infiltration showed remarkable correlation with elevated SUVmax and aggressive clinicopathological characteristics, such as high World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade. PD-L1 expression on tumor cells was positively associated with WHO/ISUP grade and negatively correlated with body mass index (BMI). However, no correlation was observed between SUVmax and PD-L1 expression, regardless of its spatial tissue distribution. SUVmax of TIMT I and IV was higher than that of TIMT II, but there was remarkable difference merely between TIMT II and IV. In multivariate analysis, SUVmax (P = 0.022, HR 3.120, 95% CI 1.175-8.284) and WHO/ISUP grade (P = 0.046, HR 2.613, 95% CI 1.017-6.710) were the significant prognostic factors for DFS. Six cases (16.2%) with normal SUVmax showed disease progression, while 25 cases (71.4%) with elevated SUVmax experienced disease progression. Conversely, the immunological features held no prognostic value. CONCLUSIONS: Our findings demonstrated that 2-[18F]FDG PET/CT could provide metabolic information of TIME for ccRCC patients and develop image-guided therapeutic strategies accordingly. Patients with elevated preoperative SUVmax should be seriously considered, and perioperative immunotherapy might be beneficial for them.

Genetic variations in the CTLA-4 immune checkpoint pathway are associated with colon cancer risk, prognosis, and immune infiltration via regulation of IQCB1 expression.

The programmed cell death-1 (PD-1)/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint pathways serve as targets of immunotherapy for colorectal cancer. However, the associations between genetic variations in these pathways and colorectal cancer risk, prognosis, and immune status remain unclear. The associations between single-nucleotide polymorphisms (SNPs) and colorectal cancer risk and survival were evaluated in a case-control study comprising 1150 cases and 1342 controls along with 287 cases with overall survival information. We found that individuals with the A allele of B7-2 rs2681416 in CTLA-4 immune checkpoint pathway had a significantly increased risk of colorectal cancer [odds ratio (OR) = 1.37, P = 3.17 × 10-4] than those with G allele under the dominant model, which had a predominant site-specific effect in colon cancer (OR = 1.55, P = 3.11 × 10-5). In addition, rs2681416 significantly decreased the overall survival time of patients with colon cancer [hazard ratio (HR) = 1.96, P = 1.10 × 10-2], but not of patients with rectal cancer (P = 0.271). Moreover, rs2681416 had an expression quantitative trait locus effect on the B7-2 flanking gene IQCB1 in colon tissues, which contributed to colon cancer risk by regulating genome organization and influenced the expression of IQCB1 in an allele-specific manner. IQCB1 expression was upregulated in colorectal cancer tissues compared with normal tissues, accounting for various critical carcinogenic states in colon cancer and promoting immune infiltration of Th17 cells in the tumor microenvironment. Our study highlights the important roles of genetic variations in immune checkpoint pathways and provides new insight into potential site-specific independent biomarkers for colorectal cancer susceptibility, prognosis, and tumor immune status.

MRI-based Bosniak Classification of Cystic Renal Masses, Version 2019: Interobserver Agreement, Impact of Readers' Experience, and Diagnostic Performance.

Background The 2019 Bosniak classification (version 2019) of cystic renal masses (CRMs) provides a systematic update to the currently used 2005 Bosniak classification (version 2005). Further validation is required before widespread application. Purpose To evaluate the interobserver agreement of MRI criteria, the impact of readers' experience, and the diagnostic performance between version 2019 and version 2005. Materials and Methods From January 2009 to December 2018, consecutive patients with CRM who had undergone renal MRI and surgical-pathologic examination were included in this retrospective study. On the basis of version 2019 and version 2005, all CRMs were independently classified by eight radiologists with different levels of experience. By using multirater κ statistics, interobserver agreement was evaluated with comparisons between classifications and between senior and junior radiologists. Diagnostic performance between classifications by dichotomizing classes I-IV into lower (I-IIF) and higher (III-IV) classes was compared by using the McNemar test. P < .05 was considered to indicate a statistically significant difference. Results A total of 207 patients (mean age ± standard deviation, 49 years ± 12; 139 male and 68 female patients) with CRMs were included. Overall, interobserver agreement was higher with version 2019 than version 2005 (weighted κ = 0.64 vs 0.50, respectively; P < .001). Interobserver agreement between senior and junior radiologists did not differ between version 2019 (weighted κ = 0.65 vs 0.64, respectively; P = .71) and version 2005 (weighted κ = 0.54 vs 0.46; P < .001). Diagnostic specificity for malignancy was higher with version 2019 than with version 2005 (83% [92 of 111] vs 68% [75 of 111], respectively; P < .001), without any difference in sensitivity (89% [85 of 96] vs 84% [81 of 96]; P = .34). Conclusion In the updated Bosniak classification, interobserver agreement improved and was unaffected by observers' experience. The diagnostic performance with version 2019 was superior to that with version 2005, with higher specificity. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Choyke in this issue.

Association of Catechol-O-methyltransferase val/met polymorphism with cognitive function in Gilles de la Tourette syndrome patients.

Gilles de la Tourette syndrome (GTS) is a kind of neuropsychiatric disorder with childhood onset. The cognitive dysfunction caused by GTS could affect the growth and learning of children and adolescents. The mechanism of cognitive functions was associated with dopaminergic system, thus we access the associations between polymorphism of some dopaminergic system-related genes including Catechol-O-methyltransferase (COMT) met/val, Dopamine receptor D4 (DRD4) exon III 48 bp VNTR (variable number of tandem repeats), Interleukin 1 (IL-1) Ra 86 bp and IL-1ß exon 5, and cognitive functions in GTS patients. Genotyping analysis was performed through polymerase chain reaction (PCR). Test for cognitive functions of GTS patients included modified wisconsin card sorting test (WCST), trail making test, visual reproduction test, stroop test and verbal fluency test. The patients with COMT met/met genotype showed less perseverative errors in modified WCST test compared with patients with COMT val/val genotype (P < 0.05). Meanwhile, patients without allele val had better delayed memory in visual reproduction test, less errors in the stroop test and less perseverative errors in modified WCST test compared with patients with allele val (P < 0.05). However, no significant difference was found in cognitive functions among patients with different genotypes or alleles of polymorphisms of DRD4 exon III 48 bp VNTR, IL-1 Ra 86 bp and IL-1ß exon 5 (P > 0.05). Polymorphism of COMT met/val was correlated with cognitive functions in GTS patients. This study provided basis for the analysis of molecular genetic pathology of cognitive dysfunctions in GTS.

Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing.

The current study aimed to investigate associations of circRNAs and related genetic variants with risk of prostate cancer (PCa) as well as to elucidate biological mechanisms underlying the associations. By using the MiOncoCirc database, we first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify risk-associated circRNAs. We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls, and identified circHIBADH rs11973492 as a significant risk-associated variant (odds ratio = 1.20, 95% confidence interval: 1.08-1.34, P = 7.06 × 10 -4) in a dominant genetic model, which altered the secondary structure of the corresponding RNA chain. In the in silico analysis, we found circHIBADH to sponge and silence 21 RNA-binding proteins (RPBs) enriched in the RNA splicing pathway, among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house (four tissue samples) and publicly available single-cell transcriptomes. Additionally, we demonstrated that HNRNPA1 might influence hallmarks including MYC, DNA repair, and E2F target signaling pathways, thereby promoting carcinogenesis. In conclusion, genetic variants in circHIBADH may act as a sponge and inhibitor of RNA splicing-associated RBPs including HNRNPA1, playing an oncogenic role in PCa.

HCMMD: systematic evaluation of metabolites in body fluids as liquid biopsy biomarker for human cancers.

Metabolomics is a rapidly expanding field in systems biology used to measure alterations of metabolites and identify metabolic biomarkers in response to disease processes. The discovery of metabolic biomarkers can improve early diagnosis, prognostic prediction, and therapeutic intervention for cancers. However, there are currently no databases that provide a comprehensive evaluation of the relationship between metabolites and cancer processes. In this review, we summarize reported metabolites in body fluids across pan-cancers and characterize their clinical applications in liquid biopsy. We conducted a search for metabolic biomarkers using the keywords ("metabolomics" OR "metabolite") AND "cancer" in PubMed. Of the 22,254 articles retrieved, 792 were deemed potentially relevant for further review. Ultimately, we included data from 573,300 samples and 17,083 metabolic biomarkers. We collected information on cancer types, sample size, the human metabolome database (HMDB) ID, metabolic pathway, area under the curve (AUC), sensitivity and specificity of metabolites, sample source, detection method, and clinical features were collected. Finally, we developed a user-friendly online database, the Human Cancer Metabolic Markers Database (HCMMD), which allows users to query, browse, and download metabolite information. In conclusion, HCMMD provides an important resource to assist researchers in reviewing metabolic biomarkers for diagnosis and progression of cancers.

Laparoscopic continent cutaneous urinary diversion using a modified Yang-Monti technique in an adult: A case report including 5-year follow-up.

Continuous cutaneous urinary diversion is challenging when the appendix is physically unavailable. The Yang-Monti channel is an alternative to the tunneled appendix for urinary diversion. We present a case involving a 49-year-old man who underwent total urethrectomy and cystostomy 10 months previously. No tumor recurrence was observed; however, the patient experienced severe catheter-related bladder irritation after the procedure. The patient was readmitted to the authors' hospital and underwent laparoscopic continent cutaneous urinary diversion using extracorporeal construction of a modified Yang-Monti channel. The operation lasted 232 minutes, with an estimated blood loss of 10 mL. The patient was discharged from hospital 6 days after surgery and removal of the cystostomy tube. After this, clean intermittent catheterization was performed every 3 hours for 4 weeks. Five years after the procedure, the modified Yang-Monti channel was still used for clean intermittent catheterization without any stomal stenosis being observed. The patient was satisfied with his postoperative quality of life.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression.

Genetic variants in super-enhancers (SEs) are increasingly implicated as a disease risk-driving mechanism. Previous studies have reported an associations between benzo[a]pyrene (BaP) exposure and some malignant tumor risk. Currently, it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk, nor the associated intrinsic molecular mechanisms. In the current study, by using logistic regression analysis, we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk (odds ratio = 1.26, P = 7.61 × 10 -5). We also have found that the rs6001092T>G, in a high linkage disequilibrium with rs5750581T>C ( r 2 = 0.98), is located in a regulatory aryl hydrocarbon receptor (AhR) motif and may interact with the FAM227A promoter in further bioinformatics analysis. We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene. Biologically, the rs6001092-G allele strengthened the transcription factor binding affinity to AhR, thereby upregulating FAM227A, especially upon exposure to BaP, which induced the malignant phenotypes of prostate cancer. The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk, which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

Benzo[a]pyrene exposure affects colorectal cancer susceptibility by regulating ERß-mediated LINC02977 transcription.

Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been investigated as genotoxicants, they can also operate through nongenotoxic pathways in estrogen-dependent malignancies, such as breast, cervical and ovarian cancer. However, whether PAHs induce colorectal cancer (CRC) risk through estrogenic effects is still illusive. Here, we systematically investigated the abnormal expression and activation of estrogen receptor beta (ERß) regulated by PAHs in CRC as well as the underlying mechanisms of ERß-mediated CRC risk. Based on the 300 plasma samples from CRC patients and healthy controls detected by GC-MS/MS, we found that the plasma concentrations of benzo[a]pyrene (BaP) were significantly higher in CRC cases than in healthy controls, with significant estrogenic effects. Moreover, histone deacetylase 2 (HDAC2)-induced deacetylation of the promoter decreases ERß expression, which is associated with poor overall survival and advanced tumor stage. The study also revealed that BaP and estradiol (E2) had different carcinogenic effects, with BaP promoting cell proliferation and inhibiting apoptosis, while E2 had the opposite effects. Additionally, this study mapped ERß genomic binding regions by performing ChIP-seq and ATAC-seq and identified genetic variants of rs1411680 and its high linkage disequilibrium SNP rs6477937, which were significantly associated with CRC risk through meta-analysis of two independent Chinese population genome-wide association studies comprising 2,248 cases and 3,173 controls and then validation in a large-scale European population. By integrating data from functional genomics, we validated the regulatory effect of rs6477937 as an ERß binding-disrupting SNP that mediated allele-specific expression of LINC02977 in a long-range chromosomal interaction manner, which was found to be highly expressed in CRC tissues. Overall, this study suggests that the different active effects on ERß by PAHs and endogenous E2 may play a crucial role in the development and progression of CRC and highlights the potential of targeting ERß and its downstream targets for CRC prevention and treatment.

Genetic variants in primary cilia-related genes associated with the prognosis of first-line chemotherapy in colorectal cancer.

BACKGROUND: Primary cilia are antenna-like organelles that conduct physical and chemical signals, which affect cell proliferation, migration, and differentiation. Some researchers have reported the correlation between primary cilia-related genes and prognosis of colorectal cancer (CRC). METHODS: The association between single nucleotide polymorphisms (SNPs) of primary cilia-related genes and outcome after the first-line chemotherapy was explored by the Cox regression model. Expression qualitative trait locus (eQTL) analysis was performed to explore the impact of SNPs on gene expression. Tumor Immune Estimation Resource and TISIDB databases were used for investigating the relevance between ODF2L and tumor infiltration immune cells and immunomodulators. RESULTS: We identified that rs4288473 C allele of ODF2L had poor progression-free survival (PFS) and overall survival (OS) of CRC patients in the additive model (adjusted HRPFS = 1.39, 95% CI = 1.14-1.70, p = 1.36 × 10-3 , and adjusted HROS = 1.31, 95% CI = 1.03-1.65, p = 2.62 × 10-2 ). The stratified analysis indicated that rs4288573 CC/CT genotype was involved with poor prognosis in the irinotecan-treated subgroup (PPFS = 1.03 × 10-2 , POS = 3.29 × 10-3 ). Besides, ODF2L mRNA expression level was notably up-regrated in CRC tissues. The C allele of rs4288573 was notably related to higher ODF2L mRNA expression levels based on eQTL analysis. Functionally, knockdown of ODF2L inhibited cell proliferation and decrease the chemoresistance of HCT-116 and DLD-1 cells to irinotecan. CONCLUSION: Our study indicates that rs4288573 in ODF2L is a potential predictor of the chemotherapy prognosis of CRC.