Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

Integrative splicing-quantitative-trait-locus analysis reveals risk loci for non-small-cell lung cancer.

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82-0.93, p = 1.87 × 10-5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1-011. Transcript FARP1-011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk.

Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression.

Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.

Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells.

Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.

Characterization of structural, biochemical, pharmacokinetic, and pharmacodynamic properties of the LSD1 inhibitor bomedemstat in preclinical models.

INTRODUCTION: Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes. METHODS: Bomedemstat was characterized via crystallization, flavine adenine dinucleotide spectrophotometry, and enzyme kinetics. On-target effects were assessed in relevant prostate cancer cell models by measuring proliferation and H3K4 methylation using western blot analysis. In vivo, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of bomedemstat are also described. RESULTS: Structural, biochemical, and PK/PD properties of bomedemstat, an irreversible, orally-bioavailable inhibitor of LSD1 are reported. Our data demonstrate bomedemstat has >2500-fold greater specificity for LSD1 over monoamine oxidase (MAO)-A and -B. Bomedemstat also demonstrates activity against several models of advanced CRPC, including NEPC patient-derived xenografts. Significant intra-tumoral accumulation of orally-administered bomedemstat is measured with micromolar levels achieved in vivo (1.2 ± 0.45 µM at the 7.5 mg/kg dose and 3.76 ± 0.43 µM at the 15 mg/kg dose). Daily oral dosing of bomedemstat at 40 mg/kg/day is well-tolerated, with on-target thrombocytopenia observed that is rapidly reversible following treatment cessation. CONCLUSIONS: Bomedemstat provides enhanced specificity against LSD1, as revealed by structural and biochemical data. PK/PD data display an overall safety profile with manageable side effects resulting from LSD1 inhibition using bomedemstat in preclinical models. Altogether, our results support clinical testing of bomedemstat in the setting of mCRPC.

Transcriptome analysis of the Bactrian camel (Camelus bactrianus) reveals candidate genes affecting milk production traits.

BACKGROUND: Milk production traits are complex traits with vital economic importance in the camel industry. However, the genetic mechanisms regulating milk production traits in camels remain poorly understood. Therefore, we aimed to identify candidate genes and metabolic pathways that affect milk production traits in Bactrian camels. METHODS: We classified camels (fourth parity) as low- or high-yield, examined pregnant camels using B-mode ultrasonography, observed the microscopic changes in the mammary gland using hematoxylin and eosin (HE) staining, and used RNA sequencing to identify differentially expressed genes (DEGs) and pathways. RESULTS: The average standard milk yield over the 300 days during parity was recorded as 470.18 ± 9.75 and 978.34 ± 3.80 kg in low- and high-performance camels, respectively. Nine female Junggar Bactrian camels were subjected to transcriptome sequencing, and 609 and 393 DEGs were identified in the low-yield vs. high-yield (WDL vs. WGH) and pregnancy versus colostrum period (RSQ vs. CRQ) comparison groups, respectively. The DEGs were compared with genes associated with milk production traits in the Animal Quantitative Trait Loci database and in Alashan Bactrian camels, and 65 and 46 overlapping candidate genes were obtained, respectively. Functional enrichment and protein-protein interaction network analyses of the DEGs and candidate genes were conducted. After comparing our results with those of other livestock studies, we identified 16 signaling pathways and 27 core candidate genes associated with maternal parturition, estrogen regulation, initiation of lactation, and milk production traits. The pathways suggest that emerged milk production involves the regulation of multiple complex metabolic and cellular developmental processes in camels. Finally, the RNA sequencing results were validated using quantitative real-time PCR; the 15 selected genes exhibited consistent expression changes. CONCLUSIONS: This study identified DEGs and metabolic pathways affecting maternal parturition and milk production traits. The results provides a theoretical foundation for further research on the molecular mechanism of genes related to milk production traits in camels. Furthermore, these findings will help improve breeding strategies to achieve the desired milk yield in camels.

A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations.

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10-5, PLung = 2.89 × 10-5), CBL (Pcross-tissue = 5.08 × 10-7, PLung = 1.82 × 10-4), ATR (Pcross-tissue = 1.45 × 10-5, PLung = 9.68 × 10-5), GYPE (Pcross-tissue = 1.45 × 10-5, PLung = 2.17 × 10-3) and PARD3 (Pcross-tissue = 5.79 × 10-6, PLung = 4.05 × 10-3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, PGWAS = 5.54 × 10-5) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, PGWAS = 5.55 × 10-5), as well as the expression of DCAF16 (ßGTEx = 0.24, PGTEx = 9.81 × 10-15; ßNJLCC = 0.29, PNJLCC = 3.84 × 10-8) and CBL (ßGTEx = -0.17, PGTEx = 2.82 × 10-8; ßNJLCC = -0.32, PNJLCC = 2.61 × 10-7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.

Inositol 1,4,5-trisphosphate receptor gene variants are related to the risk of breast cancer in a Chinese population.

BACKGROUND: Mammalian inositol 1,4,5-trisphosphate receptor (ITPR) genes encode ubiquitously expressed endoplasmic reticulum Ca2+ channels that have recently been shown to be closely linked to the pathogenesis of several cancers. However, few studies to date have explored associations between ITPR gene family single nucleotide polymorphisms (SNPs) and breast cancer risk. METHODS: In the present case-control study, 12 SNPs in the potential functional regions of the ITPR1, ITPR2, and ITPR3 genes were genotyped using an Illumina Infinium® Beadchip in 2095 Chinese women (1032 cases and 1063 controls). RESULTS: Multivariate logistic regression analyses indicated that a missense SNP in the ITPR3 coding region (rs2229642) was significantly related to breast cancer risk when using an additive model in this study (rs2229642-adjusted odds ratio = 1.40, 95% confidence interval = 1.12-1.74, p = 2.97 × 10-3 ). Expression quantitative trait loci analyses indicated that the SNP rs2229642 was associated with reduced ITPR3 expression levels (p = 3.2 × 10-7 ) and with marked reductions in the expressions of several proximal genes, including BAK1, GRM4, HLA-DOB, and UQCC2 (p = 0.013, 0.018, 3.4 × 10-3 , 3.8 × 10-5 ), suggesting that it may further regulate other genes associated with oncogenic susceptibility. Kaplan-Meier analyses indicated that the patients with higher ITPR3 expression exhibited significantly poorer outcomes compared to the patients with lower expression of this gene (hazard ratio = 1.11, 95% confidence interval = 1-1.23, p = 0.046). CONCLUSIONS: The results indicated that genetic variant in the coding region of ITPR3 gene may regulate the expressions of its host and some other cancer-related genes, as well as act as potential predictive biomarker for susceptibility to breast cancer in the Chinese population.

Feasibility of caffeic acid as a crosslinking agent in modifying acellular extracellular matrices.

Acellular extracellular matrices (aECM) are commonly utilized, both experimentally and clinically, in the regenerative medicine field. However, some disadvantages such as rapid degradation, poor mechanical properties, chronic inflammatory reactions and low antioxidant activity have limited their further application. In this study the feasibility of caffeic acid as a crosslinking agent in fixing small intestinal submucosa (SIS) was evaluated. The ninhydrin assay, swelling ratio and FTIR spectra indicated that caffeic acid can efficiently react with free amino groups to crosslink SIS and the highest crosslinking index reached 21.60 ± 1.37%. Moreover, the shrinkage temperature of SIS remarkably increased from 59 °C to about 80 °C and the degradation rate of CA-SIS was all lower than 6%, demonstrating their improved biostability and hydrothermal stability. Importantly, the antioxidant activity of CA-SIS ranged from 55% to 90%, statistically higher than that of native SIS (37.33 ± 2.94%). Additionally the cytotoxicity test presented that the cytotoxicity grade of CA-SIS was 1 or 0, whilst large numbers of living HUVECs were attached to the surface of the material and exhibited high cell viability. These results indicated their excellent cytocompatibility. The data of subcutaneous implant displayed that the number of inflammatory cells in 2%- and 2.5%CA-SIS groups remained at a low level (below 100 cells/field) while that of the native SIS group continued increasing, finally reaching 142.33 ± 30.92 cells/field. In conclusion, caffeic acid is a promising candidate for modifying aECM and may play a vital role in the design and fabrication of tissue engineering scaffolds.

Spectroscopic atomic sample plane localization for precise digital holography.

In digital holography, the coherent scattered light fields can be reconstructed volumetrically. By refocusing the fields to the sample planes, absorption and phase-shift profiles of sparsely distributed samples can be simultaneously inferred in 3D. This holographic advantage is highly useful for spectroscopic imaging of cold atomic samples. However, unlike e.g. biological samples or solid particles, the quasi-thermal atomic gases under laser-cooling are typically featureless without sharp boundaries, invalidating a class of standard numerical refocusing methods. Here, we extend the refocusing protocol based on the Gouy phase anomaly for small phase objects to free atomic samples. With a prior knowledge on a coherent spectral phase angle relation for cold atoms that is robust against probe condition variations, an "out-of-phase" response of the atomic sample can be reliably identified, which flips the sign during the numeric back-propagation across the sample plane to serve as the refocus criterion. Experimentally, we determine the sample plane of a laser-cooled 39K gas released from a microscopic dipole trap, with a δz ≈ 1 µm ≪ 2λp/NA2 axial resolution, with a NA=0.3 holographic microscope at λp = 770 nm probe wavelength.

Superradiant Detection of Microscopic Optical Dipolar Interactions.

The interaction between light and cold atoms is a complex phenomenon potentially featuring many-body resonant dipole interactions. A major obstacle toward exploring these quantum resources of the system is macroscopic light propagation effects, which not only limit the available time for the microscopic correlations to locally build up, but also create a directional, superradiant emission background whose variations can overwhelm the microscopic effects. In this Letter, we demonstrate a method to perform "background-free" detection of the microscopic optical dynamics in a laser-cooled atomic ensemble. This is made possible by transiently suppressing the macroscopic optical propagation over a substantial time, before a recall of superradiance that imprints the effect of the accumulated microscopic dynamics onto an efficiently detectable outgoing field. We apply this technique to unveil and precisely characterize a density-dependent, microscopic dipolar dephasing effect that generally limits the lifetime of optical spin-wave order in ensemble-based atom-light interfaces.

Analysis of the expression and prognostic significance of DDK complex in Hepatocarcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common and lethal malignancies worldwide. Although DBF4-dependent kinase (DDK) complex composed of CDC7 kinase and its regulatory subunit DBF4 has been shown to be overexpressed in primary tumors and promotes tumor development, while its role and prognostic value in HCC remain largely unknown. In the present study, the expression of DBF4 and CDC7 and their relationship with clinical characteristics were comprehensively analyzed. METHODS: The mRNA expression profiles of HCC and the corresponding clinical data of HCC patients were downloaded from TCGA and GEO databases, respectively. The differences in DBF4 and CDC7 expression in tumor tissues and adjacent normal tissues were analyzed. HCC-derived tissue microarray (TMA) was used to evaluate and score the expression of CDC7 by immunohistochemistry (IHC) staining. The Kaplan-Meier method and the Cox regression method were used to analyze the relationship between overall survival and clinical characteristics of the patients. Gene set enrichment analysis (GSEA) was used to analyze the pathway enrichment of DBF4 and CDC7. RESULTS: DBF4 and CDC7 had similar expression patterns in HCC patients. Detailly, compared with adjacent tissues, both mRNA and protein of DBF4 and CDC7 were significantly higher in HCC, and their expression was positively correlated with AJCC_T stage, clinical stage and G stage (grade) of liver cancer patients, and higher DBF4 or CDC7 expression predicted a worse prognosis in HCC patients with shorter overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS) and progress-free survival (PFS). Cox regression analysis suggested that both DBF4 and CDC7 were independent risk factors for the prognosis of HCC patients in TCGA dataset. GSEA suggested that both DBF4 and CDC7 were positively correlated with cell cycle and DNA replication. Finally, the prognostic value of CDC7 was furtherly confirmed by TMA-based IHC staining results. CONCLUSIONS: Our study showed that DDK complex was significantly increased in HCC. Both DBF4 and CDC7 may be potential diagnostic and prognostic markers for HCC, and high expression of DDK members predicts a worse prognosis in patients with HCC, which may be associated with high tumor cell proliferation rate.

Establishment and validation of preclinical models of SMARCA4-inactivated and ARID1A/ARID1B co-inactivated dedifferentiated endometrial carcinoma.

OBJECTIVE: Dedifferentiated endometrial cancer (DDEC) is an uncommon and clinically highly aggressive subtype of endometrial cancer characterized by genomic inactivation of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex protein. It responds poorly to conventional systemic treatment and its rapidly progressive clinical course limits the therapeutic windows to trial additional lines of therapies. This underscores a pressing need for biologically accurate preclinical tumor models to accelerate therapeutic development. METHODS: DDEC tumor from surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and cell line development. The histologic, immunophenotypic, genetic and epigenetic features of the patient tumors and the established PDX models were characterized. The SMARCA4-deficienct DDEC model was evaluated for its sensitivity toward a KDM6A/B inhibitor (GSK-J4) that was previously reported to be effective therapy for other SMARCA4-deficient cancer types. RESULTS: All three DDEC models exhibited rapid growth in vitro and in vivo, with two PDX models showing spontaneous development of metastases in vivo. The PDX tumors maintained the same undifferentiated histology and immunophenotype, and exhibited identical genomic and methylation profiles as seen in the respective parental tumors, including a mismatch repair (MMR)-deficient DDEC with genomic inactivation of SMARCA4, and two MMR-deficient DDECs with genomic inactivation of both ARID1A and ARID1B. Although the SMARCA4-deficient cell line showed low micromolecular sensitivity to GSK-J4, no significant tumor growth inhibition was observed in the corresponding PDX model. CONCLUSIONS: These established patient tumor-derived models accurately depict DDEC and represent valuable preclinical tools to gain therapeutic insights into this aggressive tumor type.

Malignant function of nuclear factor-kappaB axis in prostate cancer: Molecular interactions and regulation by non-coding RNAs.

Prostate carcinoma is a malignant situation that arises from genomic alterations in the prostate, leading to changes in tumorigenesis. The NF-κB pathway modulates various biological mechanisms, including inflammation and immune responses. Dysregulation of NF-κB promotes carcinogenesis, including increased proliferation, invasion, and therapy resistance. As an incurable disease globally, prostate cancer is a significant health concern, and research into genetic mutations and NF-κB function has the efficacy to facilitate the introduction of novel therapies. NF-κB upregulation is observed during prostate cancer progression, resulting in increased cell cycle progression and proliferation rates. Additionally, NF-κB endorses resistance to cell death and enhances the capacity for metastasis, particularly bone metastasis. Overexpression of NF-κB triggers chemoresistance and radio-resistance, and inhibition of NF-κB by anti-tumor compounds can reduce cancer progression. Interestingly, non-coding RNA transcripts can regulate NF-κB level and its nuclear transfer, offering a potential avenue for modulating prostate cancer progression.

Pigment epithelium-derived factor maintains tight junction stability after myocardial infarction in rats through inhibition of the Wnt/ß-catenin signaling pathway.

PURPOSE: The impairment of the coronary microcirculatory barrier caused by acute myocardial infarction (AMI) is closely related to poor prognosis. Recently, pigment epithelial-derived factor (PEDF) has been proven to be a promising cardiovascular protective drug. In this study, we demonstrated the protective role of PEDF in endothelial tight junctions (TJs) and the vascular barrier in AMI. MATERIALS AND METHODS: 2, 3, 5-triphenyltetrazolium chloride (TTC), echocardiography and immunofluorescence staining were used to observe the size of infarcted myocardium area and cardiac function in myocardial tissue, and the distribution of TJ proteins in human coronary endothelial cells (HCAEC). Dextran leakage assay and Transwell were used to assess the extent of vascular and HCAEC leakage. Polymerase chain reaction (PCR) and Western blot were used to detect TJ-related mRNA and protein, and signaling pathway protein expression. RESULTS: PEDF effectively reduced the infarction area and improved cardiac function in AMI rats, and lowered the leakage in AMI rats' angiocarpy and oxygen-glucose deprivation (OGD)-treated HCAEC. Furthermore, PEDF upregulated the expression of TJ mRNA and proteins in vivo and vitro. Mechanistically, PEDF inhibited the expression of phosphorylated low-density lipoprotein receptor-related protein 6 (p-LRP6) and active ß-catenin under OGD, thus suppressing the activation of the classical Wnt pathway. CONCLUSIONS: These novel findings demonstrated that PEDF maintained the expression of TJ proteins and endothelial barrier integrity by inhibiting the classical Wnt pathway during AMI.

Efficacy of antibacterial agents combined with erbium laser and photodynamic therapy in reducing titanium biofilm vitality: an in vitro study.

BACKGROUND AND OBJECTIVE: The emergence of peri-implant diseases has prompted various methods for decontaminating the implant surface. This study compared the effectiveness of three different approaches, chlorhexidine digluconate (CHX) combined with erbium-doped yttrium-aluminum-garnet (Er:YAG) laser, photodynamic therapy (PDT), and CHX only, for reducing biofilm vitality from implant-like titanium surfaces. STUDY DESIGN/MATERIALS AND METHODS: The study involved eight volunteers, each receiving a custom mouth device containing eight titanium discs. The volunteers were requested to wear the device for 72 h for biofilm development. Fluorescence microscopy was used to evaluate the remaining biofilm with a two-component nucleic acid dye kit. The vital residual biofilm was quantified as a percentage of the surface area using image analysis software. Sixty-four titanium discs were assigned randomly to one of four treatment groups. RESULTS: The percentage of titanium disc area covered by vital residual biofilm was 43.9% (7.7%), 32.2% (7.0%), 56.6% (3.6%), and 73.2% (7.8%) in the PDT, Er:YAG, CHX, and control groups, respectively (mean (SD)). Compared to the control group, the treatment groups showed significant differences in the area covered by residual biofilm (P < 0.001). CHX combined with Er:YAG laser treatment was superior to CHX combined with PDT, and CHX only was better than the control. CONCLUSION: Within the current in vitro model's limitations, CHX combined with Er:YAG laser treatment is a valid method to reduce biofilm vitality on titanium discs.

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR = 1.22, 95% confidence interval [CI] = 1.18-1.26). Positive associations were observed in small cell lung cancer (HR = 1.21, 95% CI = 1.10-1.33), lung adenocarcinoma (HR = 1.17, 95% CI = 1.11-1.23) and lung squamous cell carcinoma (HR = 1.22, 95% CI = 1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic = 0.78 [95% CI = 0.75-0.80]; CRP model: C-statistic = 0.79 [95% CI = 0.76-0.81]; Pnonadjusted  = .003, Padjusted  = .014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.

Air Pollution, Genetic Factors, and the Risk of Lung Cancer: A Prospective Study in the UK Biobank.

Rationale: Both genetic and environmental factors contribute to lung cancer, but the degree to which air pollution modifies the impact of genetic susceptibility on lung cancer remains unknown. Objectives: To investigate whether air pollution and genetic factors jointly contribute to incident lung cancer. Methods: We analyzed data from 455,974 participants (53% women) without previous cancer at baseline in the UK Biobank. The concentrations of particulate matter (PM) (PM ⩽2.5 µm in aerodynamic diameter [PM2.5], coarse PM between 2.5 µm and 10 µm in aerodynamic diameter [PMcoarse], and PM ⩽10 µm in aerodynamic diameter [PM10]), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated by using land-use regression models, and the association between air pollutants and incident lung cancer was investigated by using a Cox proportional hazard model. Furthermore, we constructed a polygenic risk score and evaluated whether air pollutants modified the effect of genetic susceptibility on the development of lung cancer. Measurements and Main Results: The results showed significant associations between the risk of lung cancer and PM2.5 (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.33-2.01; per 5 µg/m3), PM10 (HR, 1.53; 95% CI, 1.20-1.96; per 10 µg/m3), NO2 (HR, 1.10; 95% CI, 1.05-1.15; per 10 µg/m3), and NOx (HR, 1.13; 95% CI, 1.07-1.18; per 20 µg/m3). There were additive interactions between air pollutants and the genetic risk. Compared with participants with low genetic risk and low air pollution exposure, those with high air pollution exposure and high genetic risk had the highest risk of lung cancer (PM2.5: HR, 1.71; 95% CI, 1.45-2.02; PM10: HR, 1.77; 95% CI, 1.50-2.10; NO2: HR, 1.77; 95% CI, 1.42-2.22; NOx: HR, 1.67; 95% CI, 1.43-1.95). Conclusions: Long-term exposure to air pollution may increase the risk of lung cancer, especially in those with high genetic risk.

Mirror Clock: A Strategy for Identifying Atomic Clock Frequency Jumps.

Atomic clock frequency jumps directly influence the accuracy and reliability of timekeeping systems. The necessary corrections are typically implemented by postprocessing mutual comparison data between multiple atomic clocks based on the overly strict assumption that these atomic clocks are independent of each other. This paper describes the concept of a mirror clock, which enables atomic clock frequency jumps to be identified in real time without any assumptions. By comparing whether the real measured data and a corresponding mirror clock prediction fall within a confidence interval determined by the uncertainty of past physical clock data, atomic clock frequency jumps can be effectively identified and corrected. The results of several experiments using three hydrogen masers verify that the precision and recall of simultaneous jump identification reach 96.41% and 73.49%, respectively.