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Transcriptomic Predictors of Survival for Palbociclib + Endocrine Therapy Versus Capecitabine in Aromatase Inhibitor-Resistant Breast Cancer From the GEICAM/2013-02 PEARL Trial.
Get PDFPURPOSE: For hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC), first-line cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) is the standard of care. They are also used after progression on first-line aromatase inhibitors (AIs), but some patients may respond better to chemotherapy-based options. We examined tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET versus capecitabine in AI-resistant HR+/HER2- MBC. METHODS: For 158 and 155 patients from each arm, 878 previously published gene expression signatures were derived using RNA sequencing on pretreatment tumor specimens, both primary and metastatic. Multivariable Cox models for progression-free survival (PFS) and overall survival (OS) were constructed with 16 preselected signatures related to proliferation, loss of retinoblastoma, and immune infiltration, and via Elastic Net using all signatures. RESULTS: Significant PFS difference by PAM50 intrinsic subtype was observed with palbociclib + ET. Comparing treatment arms, luminal A subtype trended toward longer PFS with palbociclib + ET, and luminal B and nonluminal subtypes had significantly longer PFS with capecitabine. Three B-cell (B-lymphocyte)-associated signatures correlated with shorter OS with palbociclib + ET. The immune-activated Immune1 TCGA breast cancer signature had significant treatment arm interaction for OS. Elastic Net iteratively selected B-cell-associated signatures independently associated with shorter OS with palbociclib + ET. CONCLUSION: PAM50 intrinsic subtype predicted PFS differences between palbociclib + ET and capecitabine. Lower B-cell-associated gene expression predicted longer OS with palbociclib + ET versus capecitabine. These features may help identify HR+/HER2- tumors resistant to further ET-based treatment with CDK4/6i
Real-World Validation of the Purity Independent Subtyping of Tumors Classifier for Informing Therapy Selection in Pancreatic Ductal Adenocarcinoma
Get PDFPURPOSE FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) are the most commonly administered first-line (1L) regimens for advanced, nonresectable, pancreatic ductal adenocarcinoma (PDAC). In the absence of biomarkers to predict response, clinical covariates such as age and performance status are often used by clinicians to select optimal treatment regimens. Purity independent subtyping of tumors (PurIST) is a molecular subtyping algorithm that classifies tumors as classical or basal. The current study was designed to validate PurIST as a prognostic biomarker for patients receiving 1L FFX and as a predictive biomarker for patients more likely to benefit from FFX versus GnP. PATIENTS AND METHODS This is a prospectively designed, retrospective study using a real-world data set of 931 patients with advanced PDAC, treated with either 1L FFX or GnP, and designed to demonstrate associations of PurIST subtypes with clinical outcomes. The primary end point was overall survival (OS) in classical versus basal patients treated with 1L FFX, while the secondary end point was OS in classical patients—with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1—to compare 1L FFX versus GnP. RESULTS Within the cohort of patients receiving 1L FFX (n = 536), basal subtype patients had a median OS of 7 months compared with classical subtype patients with a median OS of 11.8 months (hazard ratio [HR], 1.86 [95% CI, 1.49 to 2.33]; P < .001). In an analysis restricted to patients with classical subtype and ECOG PS of 0 or 1 (n = 311), there was a 33% relative risk reduction of death in patients treated with FFX compared with GnP, adjusting for age and ECOG PS (HR, 0.67 [95% CI, 0.48 to 0.94]; P < .009), with no comparable risk reduction in basal patients (subtype-treatment interaction, P = .002). CONCLUSION Patients with PDAC of the PurIST classical subtype showed a significant OS benefit when treated with FFX as 1L versus GnP
A Threat to Evidence-Based Vaccine Policy and Public Health Security at the FDA
Get PDFTwelve former commissioners of the FDA express concern that the agency’s recent moves will undermine a regulatory model designed to ensure vaccine safety, effectiveness, and availability
Adaptability of lung and liver metastatic breast cancer cells to glucose
Get PDFBackground Breast cancer is the most common cancer among women, and metastasis is the leading cause of mortality. It is still unknown how breast cancer cells metabolically adapt to successfully metastasize to different organs to survive adverse conditions, including varying nutrient availability. The purpose of this study is to elucidate the metabolic characteristics and glucose adaptation mechanisms of breast cancer cells that preferentially metastasize to the lungs or the liver. Methods Using a Wnt-driven breast cancer model with preferential metastasis to lung (metM-WntLung) or liver (metM-WntLiver), we measured 14C-glucose uptake, 13C6-glucose metabolic flux, metabolic enzyme levels, and cell viability under normal (5 mM), high (25 mM), and low (1 or 0 mM) glucose conditions. Results Under normal glucose conditions, metM-WntLung cells were more glycolytic, exhibiting greater flux of 13C6-glucose-derived carbons into glycolytic intermediates, such as pyruvate and lactate. In contrast, metM-WntLiver cells favored oxidative phosphorylation, with higher levels of 13C6-glucose-derived carbons in tricarboxylic acid (TCA) cycle metabolites such as oxaloacetate indicative of higher pyruvate carboxylase (PC) activity. Exposure to high glucose reduced metM-WntLiver cell viability, with no effect on metM-WntLung cells, suggesting better adaptability of metM-WntLung cells to glucose excess. This was accompanied by increased PC activity and oxidative phosphorylation in metM-WntLung cells, whereas metM-WntLiver cells shifted to a more glycolytic phenotype. Under glucose deprivation, metM-WntLung cells were more viable than metM-WntLiver cells, suggesting that metM-WntLung cells have better adaptability to glucose deprivation. Inhibiting phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis, reduced metM-WntLung cell viability compared to metM-WntLiver cells. Similarly, inhibiting catabolism of glutamine, a gluconeogenic substrate, decreased metM-WntLung cell viability compared to metM-WntLiver cells, indicating that metM-WntLung cells rely on more on gluconeogenesis and glutamine metabolism under glucose deprivation. Conclusion Our findings reveal that metM-WntLung cells exhibit greater metabolic flexibility to glucose than metM-WntLiver cells by shifting from glycolysis to oxidative phosphorylation under high glucose conditions while utilizing gluconeogenesis and glutamine under glucose deprivation conditions
A gene-based model of fitness and its implications for genetic variation: Genetic and inbreeding loads
Get PDFIn the companion paper to this, we examined the consequences for patterns of linkage disequilibrium of the “gene” model of fitness, which postulates that the effects of recessive or partially recessive deleterious mutations located at different sites within a gene fail to complement each other. Here, we examine the consequences of the gene model for the genetic and inbreeding loads, using both analytical and simulation methods, and contrast it with the frequently used “sites” model that allows allelic complementation. We show that the gene model results in a slightly lower genetic load, but a much smaller inbreeding load, than the sites model, implying that standard predictions of mutational contributions to inbreeding depression may be overestimates. Synergistic epistasis between pairs of mutations was also modeled, and shown to considerably reduce the inbreeding load for both the gene and sites models. The theoretical results are discussed in relation to data on inbreeding load in Drosophila melanogaster. The widespread assumption that inbreeding depression is largely due to deleterious mutations should be re-examined in the light of our findings
Selective targeting of coagulation factor X Gla domain by negatively charged gold nanoparticles: a novel method for controlled antithrombotic therapy
Get PDFVenous thromboembolism (VTE) presents a significant global health burden due to its high incidence and potentially life-threatening complications. Although anticoagulants targeting vitamin K-dependent (VKD) factors, particularly factor X (FX), are widely employed, their efficacy is often limited by bleeding risks arising from off-target effects. Nanoparticle-based strategies, by contrast, enable precise and tunable modulation of protein activity through controlled adjustments in particle size, charge, and functionalization. In this work, we engineered negatively charged gold nanoparticles (GNPs) of defined sizes to selectively interact with the γ-carboxyglutamic acid (Gla) domain of VKD coagulation proteins. Using computational simulations, we systematically compared their binding conformations and affinities between GNPs and diverse VKD coagulation proteins, uncovering a size-dependent binding mechanism. This finding was subsequently validated through biochemical assays at both the molecular and cellular levels. Notably, GNPs with diameters of 2 ∼ 3 nm demonstrated significantly higher affinity for FX compared to other VKD proteins, such as factor IX and protein C. This specific binding triggered substantial conformational changes in FX, diminishing its membrane-binding affinity. These structural alterations also reduced its enzymatic activity and impaired its activation efficiency within the coagulation cascade, thereby effectively attenuating the cascade by selectively modulating FX activity. Comprehensive in vitro coagulation assays and in vivo murine thrombosis models further validated that GNP treatment effectively prolonged coagulation time, demonstrating robust antithrombotic efficacy. Collectively, our results establish a novel nanoparticle-based therapeutic paradigm for targeting FX, offering an innovative and promising approach for enhancing the safety and efficacy of VTE prevention and management
Association of Epigenetic Age Acceleration and Mitochondrial DNA‐Based Aging Metrics Provides Insights Into Mechanisms of Aging‐Related Diseases
Get PDFInvestigating the interplay between mitochondrial DNA (mtDNA) variations and epigenetic aging metrics may elucidate biological mechanisms associated with age-related diseases. We estimated epigenetic age acceleration (EAA) metrics from DNA methylation data and derived mtDNA metrics, including heteroplasmic variants and mtDNA copy number (mtDNA CN) from whole genome sequencing. Linear regressions and meta-analyses were conducted to assess associations between EAA and mtDNA metrics, adjusting for chronological age, self-identified sex, and other covariates in 6,316 participants (58% female, 41% non-White Americans). Mediation analysis was conducted to examine whether EAA mediated the relationship between mtDNA CN and metabolic traits. A higher burden of rare heteroplasmic variants was associated with accelerations of first-generation EAA metrics, while a lower level mtDNA CN was associated with accelerations of second- and third-generation EAA metrics. For example, one standard deviation (SD) higher MSS, a score based on the predicted functions of rare heteroplasmic variants, was associated with a 0.22-year higher EAA by the Hannum method (p = 1.3E-6) among all participants, while one SD lower mtDNA CN was associated with higher DunedinPACE (β = -0.005, p = 6.0E-4). No significant association was observed between the heteroplasmy burden of common variants and EAAs. Furthermore, we observed DunedinPACE mediated 11.1% and 10.8% of the associations of mtDNA CN with obesity and T2DM in older FHS participants, respectively. Our analysis indicated that higher levels of heteroplasmy burden of rare variants and lower mtDNA CN were associated with accelerated epigenetic aging, and these associations showed stronger magnitudes among older participants
Antibiotics accumulate in Klebsiella pneumoniae liver abscesses but fail to eliminate antibiotic-tolerant populations.
Get PDFLiver abscesses caused by hypervirulent Klebsiella pneumoniae (hvKp) can lead to severe metastatic complications, with mortality rates ranging from 5 to 40%. Even in the absence of antibiotic resistance, hvKp liver abscesses often respond poorly to treatment, sometimes requiring surgical resection. The reason for these poor outcomes remains unknown. Here, we established an hvKp wound model in outbred immunocompetent mice, which progresses to systemic infection and hepatic abscesses that were intractable to antibiotic therapy. Using a combination of quantitative and infrared matrix-assisted laser desorption electrospray ionization imaging mass spectrometry, we found that antibiotics fail to kill K. pneumoniae in liver abscesses, independently of resistance or spatial distribution of antibiotics. Our results show that antibiotic concentrations detected in the liver are sufficient to eradicate hvKp under standard in vitro conditions, but the continued presence of viable bacteria in vivo indicates that hvKp adopts an antibiotic-tolerant state within the liver. Notably, the inadequate antibiotic efficacy observed in our mouse studies mirrors clinical outcomes. These findings underscore the urgent need to elucidate the mechanism underlying hvKp tolerance, which could inform the development of novel therapeutic approaches
Risk of Late-Onset Depression in Long-Term Survivors of Breast, Prostate, and Colorectal Cancer
Get PDFImportance: The prevalence of depression is higher in cancer survivors than in the general population. As the long-term cancer survivor population increases, it is increasingly important to understand risk factors for late-onset depression. Objective: To identify risk factors associated with late-onset depression in long-term (5-year) survivors of breast, prostate, or colorectal cancer. Design, Setting, and Participants: This retrospective cohort study used 2022 linkage of Surveillance, Epidemiology, and End Results (SEER) and Medicare data to identify 5-year survivors of breast, prostate, or colorectal cancer 66 years or older who were enrolled in fee-for-service Medicare and had no previous depression diagnosis. Long-term survivors were diagnosed with cancer between January 1, 2007, and December 31, 2012, and followed up between January 1, 2008, and December 31, 2020. Data analysis was performed from August 2024 to July 2025. Exposures: Sociodemographic and cancer-specific characteristics, treatment within 1 year after diagnosis, comorbidities within 1 year before cancer diagnosis, and previous diagnosis of anxiety. Main Outcomes and Measures: The primary outcome was late-onset depression 5 to 10 years after cancer diagnosis, identified using a validated claims-based algorithm. Analyses were conducted separately for each survivor cohort. Fine-Gray subdistribution hazard regression, accounting for the competing risk of mortality, was used to identify factors associated with late-onset depression. Results: A total of 53 769 survivors were identified, including 13 265 breast, 26 979 prostate, and 13 525 colorectal cancer survivors (mean [SD] age, 74.1 [5.8] years; 31 279 [61.9%] male; 2375 [4.4%] Asian or Pacific Islander, 2691 [5.0%] Hispanic, 3906 [7.3%] non-Hispanic Black, 43 986 [81.8%] non-Hispanic White, and 811 [1.5%] other or unknown) were identified. The 5-year risk of late-onset depression was highest in breast cancer survivors (13.3% [1768 of 13 265]), compared with prostate (8.7% [2360 of 26 979]) and colorectal (11.8% [1591 of 13 525]) cancer survivors. Older age was associated with greater hazard of depression among some categories (eg, prostate cancer survivors aged ≥90 years vs 71-74 years: HR, 1.57; 95% CI, 1.10-2.24) but not among others (eg, colorectal cancer survivors aged ≥90 years vs 71-74 years: HR, 1.02; 95% CI, 0.84-1.24). Variables that were consistently associated with greater hazard of depression included Medicare-Medicaid dual eligibility (eg, dual eligible breast cancer survivors vs non-dual eligible: HR, 1.38; 95% CI, 1.22-1.57), anxiety (eg, prostate cancer survivors: HR, 2.82; 95% CI, 2.47-3.22), and comorbidity burden (eg, breast cancer survivors: HR, 1.33; 95% CI, 1.12-1.57). In prostate cancer survivors, receipt of radiotherapy with or without androgen deprivation therapy was also associated with higher risk (HR, 1.22; 95% CI, 1.10-1.36). The risk of depression among survivors in the high-risk tertile was twice as high compared with the low-risk tertile. Conclusions and Relevance: In this cohort study of long-term cancer survivors, Medicare and Medicaid dual eligibility, higher comorbidity burden, and preexisting anxiety were independently associated with greater risk of late-onset depression. These findings suggest that these risk factors may be used to proactively inform survivorship care during the transition from cancer surveillance to preventive care, which could reduce the risk of inconsistent follow-up care for survivors that may drive socioeconomic and racial and ethnic disparities in depression screening and treatment
Identifying HPV vaccination research priorities for the US
Get PDFTo guide researchers and funders, we sought to identify top priorities for research on increasing HPV vaccine coverage among US children ages 9-12 years. In Survey 1, 60 participants (researchers, health care professionals, and other stakeholders engaged in HPV vaccination research) viewed 57 research topics about increasing HPV vaccination coverage and provided additional topics. We integrated their suggestions into the list and condensed similar items to reach a list of 38 topics. In Survey 2, 230 participants identified their top ten research priorities. The top HPV vaccination research priorities and their corresponding themes were misinformation (chosen by 50% of respondents, from the theme of vaccine confidence), starting at age 9 years (48%, primary care), and single dose (48%, other). The top ten research priorities also included vaccine communication (40%, primary care), system-wide approach (39%, health system and payers), community settings (39%, alternative settings), immunization registries (38%, policy), geography and rurality (37%, populations), school mandates (37%, policy), and near elimination of HPV cancers (37%, other). The proportion of participants selecting topics within each theme varied between 15% for health system and payers to 32% for alternative settings. These research priorities highlight research areas likely to yield impactful strategies for increasing HPV vaccination. Focusing US HPV vaccine research on these topics can optimize resource allocation, inform evidence-based interventions, and support policymaking to enhance vaccine uptake