The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.

Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1+ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1+ cells arise from KRT8+ luminal cells, progressing into transcriptionally heterogeneous ASCL1+;KRT8- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.

Clinical outcomes of Asian patients with newly diagnosed atrial fibrillation and previously diagnosed atrial fibrillation: Insights from the CODE-AF registry.

BACKGROUND: Atrial fibrillation (AF) may have different clinical features in its early phase. OBJECTIVE: This study compared the characteristics and clinical outcomes of early-phase AF with later-phase AF using a large multicenter prospective registry (COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation [CODE-AF]). METHODS: Patients enrolled between June 2016 and March 2021 were divided into two groups based on AF duration: (1) newly diagnosed (AF duration ≤90 days) and (2) previously diagnosed (AF duration >90 days). The baseline characteristics and clinical outcomes were compared. RESULTS: Among the 10,001 study participants (mean age 67.0±14.5 years, and 64% men), 22% were defined as newly diagnosed and 78% as previously diagnosed. Newly diagnosed patients had fewer comorbidities and more unhealthy social behaviors. Despite lower prescription rates of oral anticoagulant, direct oral anticoagulants were more frequently used. The newly diagnosed group also had a higher composite clinical outcome risk within 90 days (adjusted HR 1.81, 95% CI 1.30-2.53, P<0.001) and revealed a higher risk of all bleeding and heart failure admission within 90 days. No significant differences remained between the groups over a 36-month follow-up. CONCLUSIONS: Patients with early-stage AF were younger and had fewer comorbidities. While there was a higher risk of heart failure admissions and minor bleeding, the risk of death, stroke, and major bleeding was not significantly increased. Structured monitoring and management during the initial months are essential to address these risks.

For Me or Against Me? Reactions to AI (vs. Human) Decisions That Are Favorable or Unfavorable to the Self and the Role of Fairness Perception.

Public reactions to algorithmic decisions often diverge. While high-profile media coverage suggests that the use of AI in organizational decision-making is viewed as unfair and received negatively, recent survey results suggest that such use of AI is perceived as fair and received positively. Drawing on fairness heuristic theory, the current research reconciles this apparent contradiction by examining the roles of decision outcome and fairness perception on individuals' attitudinal (Studies 1-3, 5) and behavioral (Study 4) reactions to algorithmic (vs. human) decisions. Results from six experiments (N = 2,794) showed that when the decision was unfavorable, AI was perceived as fairer than human, leading to a less negative reaction. This heightened fairness perception toward AI is shaped by its perceived unemotionality. Furthermore, reminders about the potential biases of AI in decision-making attenuate the differential fairness perception between AI and human. Theoretical and practical implications of the findings are discussed.

Sex Difference in 5-year Relative Survival Following Percutaneous Coronary Intervention.

Background: Survival rates following percutaneous coronary intervention (PCI) show variability across studies, particularly regarding sex-specific outcomes. Relative survival analysis, which considers survival patterns in sex-and age-matched general populations, could help explain this variability. Methods: In a 2011 nationwide South Korean PCI cohort study with 48,783 patients, all-cause death was assessed as the primary outcome over 5 years. Observed and relative survival rates at 5 years conditional on surviving 0 days, 30 days, 1 year, and 2 years were assessed. Sex-specific differences in clinical characteristics were adjusted using propensity score-matching. Results: In the unadjusted analyses, 15,710 females had more cardiovascular risk factors than 33,073 males. Both observed survival (HR 1.28; 95% CI [1.22-1.34]) and relative survival (HR 1.21; 95% CI [1.16-1.27]) were lower in females than males (all p<0.001). In the analyses of 14,454 matched pairs, females showed higher observed survival (HR 0.78; 95% CI [0.74-0.82]), but lower relative survival (HR 1.19; 95% CI [1.13-1.26]), compared to males (all p<0.001). This trend was particularly notable in females aged 60 years or older. These findings persisted in analyses conditional on surviving 30 days, 1 year and 2 years. Conclusion: The adjusted 5-year relative survival of older females was lower than that of age-matched males, highlighting the need for the excessive risk reduction in older females undergoing PCI.

Predictive biomarkers for metachronous gastric cancer development after endoscopic resection of early gastric cancer.

OBJECTIVES: We aimed to identify predictive markers for metachronous gastric cancer (MGC) in early gastric cancer (EGC) patients curatively treated with endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: From EGC patients who underwent ESD, bulk RNA sequencing was performed on non-cancerous gastric mucosa samples at the time of initial EGC diagnosis. This included 23 patients who developed MGC, and 23 control patients without additional gastric neoplasms for over 3 years (1:1 matched by age, sex, and Helicobacter pylori infection state). Candidate differentially-expressed genes were identified, from which biomarkers were selected using real-time quantitative polymerase chain reaction and cell viability assays using gastric cell lines. An independent validation cohort of 55 MGC patients and 125 controls was used for marker validation. We also examined the severity of gastric intestinal metaplasia, a known premalignant condition, at initial diagnosis. RESULTS: From the discovery cohort, 86 candidate genes were identified of which KDF1 and CDK1 were selected as markers for MGC, which were confirmed in the validation cohort. CERB5 and AKT2 isoform were identified as markers related to intestinal metaplasia and were also highly expressed in MGC patients compared to controls (p < 0.01). Combining these markers with clinical data (age, sex, H. pylori and severity of intestinal metaplasia) yielded an area under the curve (AUC) of 0.91 (95% CI, 0.85-0.97) for MGC prediction. CONCLUSION: Assessing biomarkers in non-cancerous gastric mucosa may be a useful method for predicting MGC in EGC patients and identifying patients with a higher risk of developing MGC, who can benefit from rigorous surveillance.

Plasma apixaban concentrations and thrombin generation assay parameters in response to dose reduction for atrial fibrillation.

AIMS: To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban. METHODS: This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n = 166); (ii) on-label reduced dose (2.5 mg twice daily, n = 55); and (iii) off-label underdose (2.5 mg twice daily, n = 153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels. RESULTS: The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P < .001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P = .005) and standard-dose (12.7%, P < .001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations. CONCLUSION: Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria.

Transfusion and clinical outcomes after percutaneous coronary intervention.

We investigated the long-term patterns and effects of transfusion on the clinical outcome of patients undergoing percutaneous coronary intervention (PCI) using a nationwide registry. Five-year clinical outcome of all Koreans undergoing PCI using stent in year 2011 (n = 48,786) was investigated. Primary outcome was the incidence density of transfusion. The association of transfusion with major adverse clinical event (MACE) consisting all-cause death, revascularization, critically ill cardiovascular status, or stroke was assessed after adjusting the propensity of each patient for transfusion. The 5-year incidence density of transfusion was 4.74 (95% confidence interval [CI] 4.70-4.79) per 100 person-year. Patients who received transfusion were older and had higher frequency of clinical risk factors (p < 0.001, all). Transfusion was associated with MACE (hazard ratio [HR] 3.2, 95% CI 3.2-3.3, p < 0.001) and all other clinical events (HR 1.5-6.9, p < 0.001, all). The period of transfusion coincided with the period of highest MACE incidence density. Subgroup analyses showed consistent results. Within 5 years after PCI, a total of 22.9% of patients received transfusion and had a 3.2-fold higher risk of MACE compared to patients without transfusion.

Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen-targeted therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Stress resistance insights of 65 Listeria strains: Acidic, low temperature, and high salt environments.

Genetically, Listeria monocytogenes is closely related to non-L. monocytogenes (L. innocua, L. welshimeri, L. grayi, L. aquatica, and L. fleischimannii). This bacterium is well known for its resistance to harsh conditions including acidity, low temperatures, and high salt concentrations. This study explored the responses of 65 Listeria strains to stress conditions and characterized the prevalence of stress-related genes. The 65 Listeria strains were isolated from different environments and their viability was assessed in four different tests: independent tests for pH 3, 1 °C, and 5 % salt concentration and multiple resistance tests that combined pH 3, 1 °C, 5 % salt. From the data, the 65 strains were categorized into stress-resistant (56) or stress-sensitive groups (9), with approximately 4 log CFU/mL differences. The PCR assay analyzed the prevalence of two virulence genes prfA and inlA, and eight stress-related genes: three acid (gadB, gadC, and atpD), two low temperature (betL and opuCA) and three salt resistance genes (flaA, cysS, and fbp). Two low temperature (bet and opuCA) and salt resistance (fbp) genes were more prevalent in the stress-resistant strains than in the stress-sensitive Listeria group.

Yeast Small Ubiquitin-Like Modifier (SUMO) Protease Ulp2 is Involved in RNA Splicing.

In eukaryotes, RNA splicing, an essential biological process, is crucial for precise gene expression. Inaccurate RNA splicing can cause aberrant mRNA production, disrupting protein synthesis. To regulate splicing efficiency, some splicing factors are reported to undergo Ubiquitin-like Modifier (SUMO)ylation. Our data indicate that in Saccharomyces cerevisiae, the SUMO protease, Ulp2, is involved in splicing. In the ulp2Δ mutant, some ribosomal protein (RP) transcripts exhibited a significant increase in the levels of intron-containing pre-mRNA because of improper splicing. Moreover, we confirmed Ulp2 protein binding to the intronic regions of RP genes. These findings highlight a critical Ulp2 role in RP transcript splicing.

Association between changes in renal function and clinical outcomes in anticoagulated atrial fibrillation patients with marginal renal function. A nationwide observational cohort study.

Background: Renal function is one of the crucial components for determining the dose and type of oral anticoagulants in atrial fibrillation (AF) patients, and is also closely associated with the risks of stroke and bleeding. This study aimed to assess renal function changes and their impact on clinical outcomes in anticoagulated AF patients with marginal renal function. Methods: From a Korean claims database, patients with AF on anticoagulants and a baseline eGFR of 45 to <60 ml/min/1.73 m2 were studied. Patients were grouped by changes in renal function over two years-maintained, improved (eGFR >60 ml/min/1.73 m2), or worsened (eGFR <45 ml/min/1.73 m2)-the study analyzed outcomes including ischemic stroke, major bleeding, end-stage renal disease (ESRD), all-cause death, and a composite of clinical outcomes. Results: A total of 5,126 patients were included in the study: 2,170 (42.3%) in the maintained group, 2,276 (44.4%) in the improved group, and 680 (13.1%) in the group with worsened renal function. The worsened group was older and had more prevalent comorbidities than other groups. After multivariable adjustment, the worsened group was associated with significantly higher risks of major bleeding (adjusted hazard ratio, 95% confidence interval; 1.46, 1.03-2.07, p = 0.035), ESRD (1.49, 1.24-1.80, p < 0.001), all-cause death (9.29, 4.92-17.6, p < 0.001), and the composite outcome (1.57, 1.36-1.83, p < 0.001). Conclusions: In anticoagulated AF patients with marginal renal function, a substantial proportion of patients experienced renal function decline below eGFR 45 ml/min/1.73 m2 within 2 years. Renal function decline was associated with higher risks of major bleeding, ESRD, all-cause death, and the composite outcome compared to those who maintained their baseline renal function.

Clinical characteristics of apixaban prescription in AF patients with single dose-reduction criterion: the ASPIRE (efficAcy and safety of aPixaban in rEal-world practice in Korean frail patients with atrial fibrillation) study.

Background: Data on off-label reduced dose risk among patients with atrial fibrillation (AF) who qualify for a single-dose reduction of apixaban is scarce. Objectives: We prospectively assessed apixaban dosing and clinical characteristics in AF patients meeting a dose reduction criterion. Methods: The multicentre, prospective cohort study, the efficAcy and Safety of aPixaban In REal-world practice in Korean frail patients with AF (ASPIRE), encompasses patients with AF who met the criteria for a single-dose reduction of apixaban and were given varying doses of apixaban, either the on-label standard dose or the off-label reduced dose. Results: Of 2,000 patients (mean age 74.3 ± 7.9 years, 55.8% women), 29.7% were ≥80 years, 62.6% weighed ≤60 kg, and 7.8% had serum creatinine ≥1.5 mg/dL. Of these, 51.3% were prescribed an off-label reduced dose of apixaban. The off-label group was characterized with older age, more comorbidities, and antiplatelet agents, while the on-label group had more prior strokes. Physicians preferred off-label reduced dose in the "marginal zone," defined as age 75-80 years, weight 60-65 kg, and creatinine levels 1.2-1.5 mg/dL. Conclusions: In real-world clinical setting of the Korean population, off-label reduced dose apixaban was administered to nearly half of the patients who qualified for a single dose reduction. This reduced dosage was more commonly prescribed to patients with frail characteristics, while patients with a history of stroke were more often given the standard dose as per the label. A future study is planned to contrast the safety and effectiveness of the standard dose against the reduced dose of apixaban in this population.

Prevalence and Characterization of NOTCH2NLC GGC Repeat Expansions in Koreans: From a Hospital Cohort Analysis to a Population-Wide Study.

Background and Objectives: GGC repeat expansions in the NOTCH2NLC gene are associated with a broad spectrum of progressive neurologic disorders, notably, neuronal intranuclear inclusion disease (NIID). We aimed to investigate the population-wide prevalence and clinical manifestations of NOTCH2NLC-related disorders in Koreans. Methods: We conducted a study using 2 different cohorts from the Korean population. Patients with available brain MRI scans from Seoul National University Hospital (SNUH) were thoroughly reviewed, and NIID-suspected patients presenting the zigzag edging signs underwent genetic evaluation for NOTCH2NLC repeats by Cas9-mediated nanopore sequencing. In addition, we analyzed whole-genome sequencing data from 3,887 individuals in the Korea Biobank cohort to estimate the distribution of the repeat counts in Koreans and to identify putative patients with expanded alleles and neurologic phenotypes. Results: In the SNUH cohort, among 90 adult-onset leukoencephalopathy patients with unknown etiologies, we found 20 patients with zigzag edging signs. Except for 2 diagnosed with fragile X-associated tremor/ataxia syndrome and 2 with unavailable samples, all 16 patients (17.8%) were diagnosed with NIID (repeat range: 87-217). By analyzing the Korea Biobank cohort, we estimated the distribution of repeat counts and threshold (>64) for Koreans, identifying 6 potential patients with NIID. Furthermore, long-read sequencing enabled the elucidation of transmission and epigenetic patterns of NOTCH2NLC repeats within a family affected by pediatric-onset NIID. Discussion: This study presents the population-wide distribution of NOTCH2NLC repeats and the estimated prevalence of NIID in Koreans, providing valuable insights into the association between repeat counts and disease manifestations in diverse neurologic disorders.

Perioperative Management in Patients with Atrial Fibrillation Treated with Non-Vitamin K Antagonist Oral Anticoagulants Undergoing Minor Bleeding Risk Procedure: Rationale and Protocol for the PERIXa Study.

Background: While treatment interruption of non-vitamin K antagonist oral anticoagulants (NOACs) for elective surgery or procedures among patients with atrial fibrillation (AF) is becoming more prevalent, there remains insufficient evidence regarding the optimal perioperative management of NOACs, particularly procedures with minor bleeding risks. Objective: This study aims to evaluate the safety and effectiveness of a simplified, standardized protocol for perioperative management of direct factor Xa inhibitors in patients, with AF undergoing procedures associated with minor bleeding risk. Methods: This multicenter, prospective single-arm registry study plans to enroll patients undergoing procedures with minor bleeding risk who were prescribed direct factor Xa inhibitors for AF. The procedures with minor bleeding risk will include gastrointestinal endoscopy for diagnostic purposes, selected dental procedures, and ocular surgery for cataracts or glaucoma. For apixaban, patients will withhold the last evening dose and resume either from the evening dose of the procedure day or the following morning, depending on the bleeding risk of the patient. For edoxaban or rivaroxaban, patients will withhold only a single dose on the procedure day. The primary outcome is the occurrence of major bleeding events within 30 days. Secondary outcomes include systemic thromboembolism, all-cause mortality, and a composite of major and clinically relevant non-major bleeding events. Conclusion: This study has the potential to generate evidence regarding the safety of perioperative management for patients, with AF undergoing procedures associated with minor bleeding risk. Trial Registration: Clinicaltrials.gov: NCT05801068.

Alcohol is neither a risk factor nor a protective factor for sudden cardiac death and/or fatal ventricular arrhythmia: A population-based study with genetic traits and alcohol consumption in the UK Biobank.

BACKGROUND: The association between alcohol consumption and the risk of sudden cardiac death and/or fatal ventricular arrhythmia remains controversial. OBJECTIVE: We analyzed the association between alcohol consumption, genetic traits for alcohol metabolism, and the risk of sudden cardiac death and/or fatal ventricular arrhythmia. METHODS: We identified 397,164 individuals enrolled between 2006 and 2010 from the UK Biobank database and followed them until 2021. Alcohol consumption was categorized as current nondrinkers (nondrinkers and ex-drinkers), mild drinkers, moderate drinkers, or heavy drinkers. Genetic traits of alcohol metabolism were stratified according to the polygenic risk score tertiles. The primary and secondary outcomes were a composite of sudden cardiac death and fatal ventricular arrhythmia as well as their individual components. RESULTS: During follow-up (median 12.5 years), 3543 cases (0.89%) of clinical outcomes occurred. Although mild, moderate, and heavy drinkers showed deceased risks of outcomes compared with current nondrinkers, there was no prognostic difference among nondrinkers, mild drinkers, moderate drinkers, and heavy drinkers. Ex-drinkers showed an increased risk in univariate analysis, but the significance was attenuated after adjusting covariates (hazard ratio 1.19; 95% confidence interval 0.94-1.50). As a continuous variable, alcohol consumption was not associated with clinical outcomes (hazard ratio 1.01; 95% confidence interval 0.99-1.02). Consistent with these findings, there was no association between genetic traits for alcohol metabolism and the risk of clinical outcomes. CONCLUSION: Alcohol consumption was neither a protective factor nor a risk factor for sudden cardiac death or fatal ventricular arrhythmia. Genetic traits of alcohol metabolism were not associated with the clinical prognosis.

GnRH peripherally modulates nociceptor functions, exacerbating mechanical pain.

The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment in vitro, which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.

Association between types of antihypertensive medication and the risk of atrial fibrillation: a nationwide population study.

Background: Patients with hypertension are at a high risk of atrial fibrillation (AF). Recent research has indicated the varying effects of antihypertensive medications on developing AF. Objectives: We investigated the relationship between different types of antihypertensive medications and the risk of AF occurrence. Methods: We analyzed data from 113,582 subjects with national health screening examinations between 2009 and 2014. The study population was categorized according to antihypertensive medication type. The primary outcome was the incidence of AF. Results: Among 113,582 subjects (mean age 59.4 ± 12.0 years, 46.7% men), 93,557 received monotherapy [angiotensin receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEi), beta-blockers, calcium channel blockers (CCB), or diuretics], while 34,590 received combination therapy (ARB/beta-blockers, ARB/CCB, ARB/diuretics, or ARB/CCB/diuretics). During a mean follow-up duration of 7.6 ± 2.1 years, 3.9% of patients were newly diagnosed with AF. In monotherapy, ACEi and CCB had similar AF risks as ARB, while beta-blockers and diuretics showed higher AF risks than ARB. In combination therapy, ARBs/CCBs and ARBs/diuretics had the lowest AF risk, whereas ARBs/beta-blockers had the highest compared to ARB/CCB. Among the specific ARBs, the AF risk varied insignificantly, except for telmisartan and candesartan. Conclusions: In hypertensive patients receiving monotherapy, ACEi and CCB showed a similar AF risk as ARBs, while beta-blockers and diuretics were associated with a higher risk. Among those receiving combination therapy, ARBs/CCBs and ARBs/diuretics had the lowest AF risk, whereas ARBs/beta-blockers showed the highest risk. Various types of ARBs have different associations with AF risk.

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Association between body mass index and results of cryoballoon ablation in Korean patients with atrial fibrillation: an analysis from the Korean Heart Rhythm Society Cryoablation registry.

AIMS: Pulmonary vein isolation using cryoablation is effective and safe in patients with atrial fibrillation (AF). Although both obesity and underweight are associated with a higher risk for incident AF, there is limited data on the efficacy and safety following cryoablation according to body mass index (BMI) especially in Asians. METHODS AND RESULTS: Using the Korean Heart Rhythm Society Cryoablation registry, a multicentre registry of 12 tertiary hospitals, we analysed AF recurrence and procedure-related complications after cryoablation by BMI (kg/m2) groups (BMI < 18.5, underweight, UW; 18.5-23, normal, NW; 23-25, overweight, OW; 25-30, obese Ⅰ, OⅠ; ≥30, obese Ⅱ, OⅡ). A total of 2648 patients were included (median age 62.0 years; 76.7% men; 55.6% non-paroxysmal AF). Patients were categorized by BMI groups: 0.9% UW, 18.7% NW, 24.8% OW, 46.1% OI, and 9.4% OII. Underweight patients were the oldest and had least percentage of non-paroxysmal AF (33.3%). During a median follow-up of 1.7 years, atrial arrhythmia recurred in 874 (33.0%) patients (incidence rate, 18.9 per 100 person-years). After multivariable adjustment, the risk of AF recurrence was higher in UW group compared with NW group (adjusted hazard ratio, 95% confidence interval; 2.55, 1.18-5.50, P = 0.02). Procedure-related complications occurred in 123 (4.7%) patients, and the risk was higher for UW patients (odds ratio, 95% confidence interval; 2.90, 0.94-8.99, P = 0.07), mainly due to transient phrenic nerve palsy. CONCLUSION: Underweight patients showed a higher risk of AF recurrence after cryoablation compared with NW patients. Also, careful attention is needed on the occurrence of phrenic nerve palsy in UW patients.

The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.

Lineage plasticity is a recognized hallmark of cancer progression that can shape therapy outcomes. The underlying cellular and molecular mechanisms mediating lineage plasticity remain poorly understood. Here, we describe a versatile in vivo platform to identify and interrogate the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression. Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e.g., Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+), but only those with Rb1 deletion progress to ASCL1+ neuroendocrine prostate cancer (NEPC), a highly aggressive, androgen receptor signaling inhibitor (ARSI)-resistant tumor. Importantly, we show this lineage transition requires a native in vivo microenvironment not replicated by conventional organoid culture. By integrating multiplexed immunofluorescence, spatial transcriptomics and PrismSpot to identify cell type-specific spatial gene modules, we reveal that ASCL1+ cells arise from KRT8+ luminal epithelial cells that progressively acquire transcriptional heterogeneity, producing large ASCL1+;KRT8- NEPC clusters. Ascl1 loss in established NEPC results in transient tumor regression followed by recurrence; however, Ascl1 deletion prior to transplantation completely abrogates lineage plasticity, yielding adenocarcinomas with elevated AR expression and marked sensitivity to castration. The dynamic feature of this model reveals the importance of timing of therapies focused on lineage plasticity and offers a platform for identification of additional lineage plasticity drivers.