Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

Background: Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. Methods: We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. Findings: The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Interpretations: Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.

Variation in biosynthesis and metal-binding properties of isonitrile-containing peptides produced by Mycobacteria versus Streptomyces.

A number of bacteria are known to produce isonitrile-containing peptides (INPs) that facilitate metal transport and are important for cell survival; however, considerable structural variation is observed among INPs depending on the producing organism. While non-heme iron 2-oxoglutarate dependent isonitrilases catalyze isonitrile formation, how the natural variation in INP structure is controlled and its implications for INP bioactivity remain open questions. Herein, total chemical synthesis is utilized with X-Ray crystallographic analysis of mycobacterial isonitrilases to provide a structural model of substrate specificity that explains the longer alkyl chains observed in mycobacterial versus Streptomyces INPs. Moreover, proton NMR titration experiments demonstrate that INPs regardless of alkyl chain length are specific for binding copper instead of zinc. These results suggest that isonitrilases may act as gatekeepers in modulating the observed biological distribution of INP structures and this distribution may be primarily related to differing metal transport requirements among the producing strains.

Mature neurons from iPSCs unveil neurodegeneration-related pathways in mucopolysaccharidosis type II: GSK-3ß inhibition for therapeutic potential.

Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without effective therapy, the severe form of MPS II causes progressive neurodegeneration and death. This study generated multiple clones of induced pluripotent stem cells (iPSCs) and their isogenic controls (ISO) from four patients with MPS II neurodegeneration. MPS II-iPSCs were successfully differentiated into cortical neurons with characteristic biochemical and cellular phenotypes, including axonal beadings positive for phosphorylated tau, and unique electrophysiological abnormalities, which were mostly rescued in ISO-iPSC-derived neurons. RNA sequencing analysis uncovered dysregulation in three major signaling pathways, including Wnt/ß-catenin, p38 MAP kinase, and calcium pathways, in mature MPS II neurons. Further mechanistic characterization indicated that the dysregulation in calcium signaling led to an elevated intracellular calcium level, which might be linked to compromised survival of neurons. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform and a small-molecule glycogen synthase kinase-3ß inhibitor was found to significantly rescue neuronal survival, neurite morphology, and electrophysiological abnormalities in MPS II neurons. Our results underscore that the MPS II-iPSC-based platform significantly contributes to unraveling the mechanisms underlying the degeneration and death of MPS II neurons and assessing potential drug candidates. Furthermore, the study revealed that targeting the specific dysregulation of signaling pathways downstream of GAG accumulation in MPS II neurons with a well-characterized drug could potentially ameliorate neuronal degeneration.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Repurposing Iron- and 2-Oxoglutarate-Dependent Oxygenases to Catalyze Olefin Hydration.

Mononuclear nonheme iron(II) and 2-oxoglutarate (Fe/2OG)-dependent oxygenases and halogenases are known to catalyze a diverse set of oxidative reactions, including hydroxylation, halogenation, epoxidation, and desaturation in primary metabolism and natural product maturation. However, their use in abiotic transformations has mainly been limited to C-H oxidation. Herein, we show that various enzymes of this family, when reconstituted with Fe(II) or Fe(III), can catalyze Mukaiyama hydration-a redox neutral transformation. Distinct from the native reactions of the Fe/2OG enzymes, wherein oxygen atom transfer (OAT) catalyzed by an iron-oxo species is involved, this nonnative transformation proceeds through a hydrogen atom transfer (HAT) pathway in a 2OG-independent manner. Additionally, in contrast to conventional inorganic catalysts, wherein a dinuclear iron species is responsible for HAT, the Fe/2OG enzymes exploit a mononuclear iron center to support this reaction. Collectively, our work demonstrates that Fe/2OG enzymes have utility in catalysis beyond the current scope of catalytic oxidation.

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Prevalence of comorbidities and their impact on survival among older adults with the five most common cancers in Taiwan: a population study.

Because of the cancer incidence increase and population aging in Taiwan, we aimed to assess the cancer prevalence, to summarize the comorbidities of older patients with the five most common cancers (i.e., breast, colorectal, liver, lung, and oral), and to develop a Taiwan cancer comorbidity index (TCCI) for studying their actual prognosis. The linkage of the Taiwan Cancer Registry, Cause of Death Database, and National Health Insurance Research Database was used. We followed the standard statistical learning steps to obtain a survival model with good discriminatory accuracy in predicting death due to noncancer causes, from which we obtained the TCCI and defined comorbidity levels. We reported the actual prognosis by age, stage, and comorbidity level. In Taiwan, cancer prevalence nearly doubled in 2004-2014, and comorbidities were common among older patients. Stage was the major predictor of patients' actual prognoses. For localized and regional breast, colorectal, and oral cancers, comorbidities correlated with noncancer-related deaths. Compared with the US, the chances of dying from comorbidities in Taiwan were lower and the chances of dying from cancer were higher for breast, colorectal, and male lung cancers. These actual prognoses could help clinicians and patients in treatment decision-making and help policymakers in resource planning.

Elucidation of divergent desaturation pathways in the formation of vinyl isonitrile and isocyanoacrylate.

Two different types of desaturations are employed by iron- and 2-oxoglutarate-dependent (Fe/2OG) enzymes to construct vinyl isonitrile and isocyanoacrylate moieties found in isonitrile-containing natural products. A substrate-bound protein structure reveals a plausible strategy to affect desaturation and hints at substrate promiscuity of these enzymes. Analogs are synthesized and used as mechanistic probes to validate structural observations. Instead of proceeding through hydroxylated intermediate as previously proposed, a plausible carbocation species is utilized to trigger C=C bond installation. These Fe/2OG enzymes can also accommodate analogs with opposite chirality and different functional groups including isonitrile-(D)-tyrosine, N-formyl tyrosine, and phloretic acid, while maintaining the reaction selectivity.

Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan.

BACKGROUND: Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan. METHODS: Using Taiwanese multiple data sources, we formed an age-matched case-control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011-2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem. RESULTS: The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%). CONCLUSIONS: The adapted PLCOT models had high predictive performance. IMPACT: The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Deciphering the Reaction Pathway of Mononuclear Iron Enzyme-Catalyzed N≡C Triple Bond Formation in Isocyanide Lipopeptide and Polyketide Biosynthesis.

Despite the diversity of reactions catalyzed by 2-oxoglutarate-dependent nonheme iron (Fe/2OG) enzymes identified in recent years, only a limited number of these enzymes have been investigated in mechanistic detail. In particular, several Fe/2OG-dependent enzymes capable of catalyzing isocyanide formation have been reported. While the glycine moiety has been identified as a biosynthon for the isocyanide group, how the actual conversion is effected remains obscure. To elucidate the catalytic mechanism, we characterized two previously unidentified (AecA and AmcA) along with two known (ScoE and SfaA) Fe/2OG-dependent enzymes that catalyze N≡C triple bond installation using synthesized substrate analogues and potential intermediates. Our results indicate that isocyanide formation likely entails a two-step sequence involving an imine intermediate that undergoes decarboxylation-assisted desaturation to yield the isocyanide product. Results obtained from the in vitro experiments are further supported by mutagenesis, the product-bound enzyme structure, and in silico analysis.

Hypouricemic Effect of Submerged Culture of Ganoderma lucidum in Potassium Oxonate-Induced Hyperuricemic Rats.

Hyperuricemia is a disease caused by a high level of uric acid in the blood. It is an important factor for gout and may be linked to renal and hepatic failure. The objective of this study was to investigate the hypouricemic effects of submerged culture of Ganoderma lucidum. The lyophilized powder of mycelium (GM) and extracellular polysaccharides (GP) of the G. lucidum submerged culture were prepared. The contents of hypouricemic components, including phenolics and flavonoids, in GM (34.33 ± 0.41 mg/g and 0.32 ± 0.01 mg/g) were higher than that in GP (20.52 ± 1.49 mg/g and not detected). The hypouricemic effect of GM and GP was evaluated in potassium oxonate (PO)-injected rats. The average food intake (23.3 ± 1.2 g/day) and body weight (355.7 ± 28.0 g) were decreased, and the serum level of uric acid (5.56 ± 0.41 mg/dL) was increased in PO-injected rats. However, allopurinol (10 mg/kg b.w.) or GM treatment (200 or 400 mg/kg b.w) improved food intake (26.3 ± 2.7 g/day) and reduced the level of uric acid (4.45 ± 0.46 mg/dL). In parallel, the activity of hepatic xanthine oxidase (XOD) was downregulated from 841.29 ± 299.58 µU/mg protein to 540.80 ± 199.20 µU/mg protein. Moreover, GM and GP (200 or 400 mg/kg b.w) alleviated the level of blood urea nitrogen (BUN) from 30.49 ± 4.71 to 21.16 ± 4.25 mg/dL. GP treatment also diminished the level of alanine transaminase (ALT) from 52.63 ± 18.82 to 27.35 ±6.82 U/L. These results clearly demonstrated the hypouricemic effect of submerged G. lucidum culture and their potential against hyperuricemia-associated renal and hepatic damage. GM was more potent to alleviate hyperuricemia, and GP was more potent to improve renal and hepatic function.

Develop and Apply Electrocardiography-Based Risk Score to Identify Community-Based Elderly Individuals at High-Risk of Mortality.

With an aging world population, risk stratification of community-based, elderly population is required for primary prevention. This study proposes a combined score developed using electrocardiographic (ECG) parameters and determines its long-term prognostic value for predicting risk of cardiovascular mortality. A cohort-study, conducted from December 2008 to April 2019, enrolled 5,380 subjects in Taiwan, who were examined, using three-serial-12-lead ECGs, and their health/demographic information were recorded. To understand the predictive effects of ECG parameters on overall-survival, Cox hazard regression analysis were performed. The mean age at enrollment was 69.04 ± 8.14 years, and 47.4% were males. ECG abnormalities, LVH [hazard ratio (HR) = 1.39, 95% confidence intervals (CI) = (1.16-1.67), P = 0.0003], QTc [HR = 1.31, CI = (1.07-1.61), P = 0.007] and PR interval [HR = 1.40, CI = (1.01-1.95), P = 0.04], were significantly associated with primary outcome all-cause death. Furthermore, LVH [HR = 2.37, CI = (1.48-3.79), P = 0.0003] was significantly associated with cardiovascular death, while PR interval [HR = 2.63, CI = (1.24- 5.57), P = 0.01] with unexplained death. ECG abnormality (EA) score was defined based on the number of abnormal ECG parameters for each patient, which was used to divide all patients into sub-groups. Competing risk survival analysis using EA score were performed by using the Gray's test, which reported that high-risk EA groups showed significantly higher cumulative incidence for all three outcomes. Prognostic models using the EA score as predictor were developed and a 10-fold cross validation design was adopted to conduct calibration and discrimination analysis, to establish the efficacy of the proposed models. Overall, ECG model could successfully predict people, susceptible to all three death outcomes (P < 0.05), with high efficacy. Statistically significant (P < 0.001) improvement of the c-indices further demonstrated the robustness of the prediction model with ECG parameters, as opposed to a traditional model with no EA predictor. The EA score is highly associated with increased risk of mortality in elderly population and may be successfully used in clinical practice.

Current Understanding toward Isonitrile Group Biosynthesis and Mechanism.

Isonitrile group has been identified in many natural products. Due to the broad reactivity of N≡C triple bond, these natural products have valuable pharmaceutical potentials. This review summarizes the current biosynthetic pathways and the corresponding enzymes that are responsible for isonitrile-containing natural product generation. Based on the strategies utilized, two fundamentally distinctive approaches are discussed. In addition, recent progress in elucidating isonitrile group formation mechanisms is also presented.

Association between Alzheimer's disease genes and trajectories of cognitive function decline in Han Chinese in Taiwan.

Genetic background has been considered one of the important contributors to the rate of cognitive decline among patients with Alzheimer's disease (AD). We conducted a 4-year longitudinal follow-up study, recruited 255 AD and 44 mild cognitive impairment (MCI) patients, and used a data-driven trajectory analysis to examine the influence of selected AD risk genes on the age for and the rate of cognitive decline in Han Chinese population. Genotyping of selected single-nucleotide polymorphisms in the APOE, ABCA7, SORL1, BIN1, GAB2, and CD33 genes was conducted, and a Bayesian hierarchical model was fitted to analyze the trajectories of cognitive decline among different genotypes. After adjusting for sex and education years, the APOE ε4 allele was associated with an earlier mean change of -2.39 years in the age at midpoint of cognitive decline, the G allele in ABCA7 rs3764650 was associated with an earlier mean change of -1.75 years, and the T allele in SORL1 rs3737529 was associated with a later mean change of 2.6 years. Additionally, the rate of cognitive decline was associated with the APOE ε4 allele and SORL1 rs3737529. In summary, APOE and SORL1 might be the most important genetic factors related to cognitive decline in Han Chinese population.

Disruption on right temporoparietal junction with transcranial magnetic stimulation affects moral judgment: No difference between first- and third-personal narration with TMS.

Brain imaging studies have observed that the right temporoparietal junction (rTPJ) was involved in the information processing of moral judgments and in the understanding of the beliefs/intentions of other people. However, most of these studies used moral stories in the third-person point of view. This study aimed to investigate to what extent the disruption of rTPJ affected moral judgments with stories in first-person narration by non-invasive transcranial magnetic stimulation (TMS). The study hypothesized that, first, TMS would disrupt moral judgment, causing one to neglect the beliefs of perpetrators and to make judgments based on eventual harmful outcomes. Thus, the experimental group would be more tolerant towards "intentional harm" and more prohibitive towards "accidental harm" in comparison to sham. Secondly, TMS might disrupt the mechanism to change perspectives - TMS would influence the moral judgment of the stories narrated in third person (perspective of others), but not those narrated in first person (perspective of oneself). The results demonstrated that (1) TMS accelerated moral judgment (Experiment 1), which might be due to the practice effect from the order of TMS application (Experiment 2); (2) TMS affected moral judgment in several conditions. Participants adopted a more prohibitive attitude towards conditions of "intentional harm", as well as "accidental harm" with TMS disruption; (3) The effect of personal perspective was marginally significant, revealing a tendency "to be stringent with oneself and tolerant towards others". However, the interaction between personal perspectives and TMS was insignificant. No difference between the first- and third-person perspectives was found with TMS disruption.

In vitro Inhibition of Clinical Isolates of Otitis Media Pathogens by the Probiotic Streptococcus salivarius BLIS K12.

Otitis media is a common childhood infection, frequently requiring antibiotics. With high rates of antibiotic prescribing and increasing antibiotic resistance, new strategies in otitis media prevention and treatment are needed. The aim of this study was to assess the in vitro inhibitory activity Streptococcus salivarius BLIS K12 against otitis media pathogens. Efficacy of the bacteriocin activity of S. salivarius BLIS K12 against the otitis media isolates was assessed using the deferred antagonism test. Overall, 48% of pathogenic isolates exhibited some growth inhibition by S. salivarius BLIS K12. S. salivarius BLIS K12 can inhibit the in vitro growth of the most common pathogens.

Prognostic value and prevalence of complete right bundle branch block in an elderly population: a community-based 10-year prospective study.

Complete right bundle branch block (CRBBB) occurs in 0.2% to 1.3% of the general population, but its prognostic significance in the geriatric population is unknown. We prospectively investigated the prevalence and prognostic value of CRBBB in individuals aged ≥65 years in a community-based population in Taiwan. A total of 5,830 community-dwelling individuals were prospectively recruited from 7 regions across Taiwan starting in December 2008 through March 2013. Those aged ≥65 years were included in the analysis (N=3,383). All subjects underwent a home visit and standardized medical exams and were followed up annually until the end of April 2019; cause of death was documented by citizen death records. The mean age of the study cohort was 73.5±5.9 years (65-104), and 47.21% were men. Among these individuals, 171 (5.05%) had CRBBB; the prevalence was higher in men (7.08%) than in women (3.25%). Subjects with CRBBB were older than those without CRBBB (75.4±6.5 vs. 73.4±5.9), and the frequency of CRBBB increased with age. Survival analysis revealed that all-cause mortality and cardiac mortality were similar in individuals with and without CRBBB during a mean follow-up of 92.6±23.6 months. CRBBB is not associated with increased risk of mortality in the geriatric population.

A Polarization-Actuated Plasmonic Circulator.

A circulator for surface plasmon polaritons (SPPs) based on a plasmonic two-wire transmission-line (TWTL) structure is experimentally realized. A TWTL offers two distinct plasmon modes that can be independently excited, solely determined by the polarization of the laser field. Through controlled superposition of the two modes, TWTLs are exploited to enable polarization-actuated plasmonic circulators. In the first demonstration, the coupling antennas to the plasmonic circulator are designed to circulate SPPs sensitive to linearly polarized excitation. In the second design, the circulator reacts to the spin angular momenta carried by circularly polarized laser excitations. In both cases, the SPP circulation directions are directly controlled by the laser polarization, and the number of ports is easily expandable. Experimentally, a wide optical operational bandwidth of ∼100 nm is achieved. The results show a major step toward the realization of multifunctioning photonic nanocircuitry.

BCAS2, a protein enriched in advanced prostate cancer, interacts with NBS1 to enhance DNA double-strand break repair.

BACKGROUND: Breast cancer amplified sequence 2 (BCAS2) plays crucial roles in pre-mRNA splicing and androgen receptor transcription. Previous studies suggested that BCAS2 is involved in double-strand breaks (DSB); therefore, we aimed to characterise its mechanism and role in prostate cancer (PCa). METHODS: Western blotting and immunofluorescence microscopy were used to assay the roles of BCAS2 in the DSBs of PCa cells and apoptosis in Drosophila, respectively. The effect of BCAS2 dosage on non-homologous end joining (NHEJ) and homologous recombination (HR) were assayed by precise end-joining assay and flow cytometry, respectively. Glutathione-S-transferase pulldown and co-immunoprecipitation assays were used to determine whether and how BCAS2 interacts with NBS1. The expression of BCAS2 and other proteins in human PCa was determined by immunohistochemistry. RESULTS: BCAS2 helped repair radiation-induced DSBs efficiently in both human PCa cells and Drosophila. BCAS2 enhanced both NHEJ and HR, possibly by interacting with NBS1, which involved the BCAS2 N-terminus as well as both the NBS1 N- and C-termini. The overexpression of BCAS2 was significantly associated with higher Gleason and pathology grades and shorter survival in patients with PCa. CONCLUSION: BCAS2 promotes two DSB repair pathways by interacting with NBS1, and it may affect PCa progression.