Citations

Endocrine therapy remains the cornerstone of treatment for estrogen receptor alpha (ERα)-positive breast cancer, yet the relationship between individual genetic background and molecular response to ERα-targeted therapy remains incompletely understood. Using a well-characterized panel of lymphoblastoid cell lines (LCLs), we performed genome-wide pharmacogenomic expression quantitative trait locus (PGx-eQTL) analysis to identify estradiol (E2)- and tamoxifen (TAM)-induced SNP-gene pairs. PGx-eQTL signals were integrated with previously published breast cancer genome-wide association study datasets to examine their association with clinically relevant breast cancer phenotypes. We identified two ER-mediated PGx-eQTL SNP-gene pairs associated with breast cancer prognosis post-treatment with E2 or TAM. Notable loci included E2-regulated MRPL15 and TAM-regulated SYCP3, which have effects in a genotype-dependent manner, with genotype-dependent survival outcomes, from worse to better relapse-free survival. Similar endocrine-therapy effects on patient survival and breast cancer risk were observed in SIK2, post TAM-treatment, and in LSM4 with E2-treatment. Moreover, qRT-PCR validation in an independent LCL panel confirmed the genotype-specificity of these signals. Overall, we identified ER-mediated PGx-eQTL SNP-gene pairs which represent potential pharmacogenomic tools for identifying patients likely to benefit from ERα-targeted endocrine therapy, offering a foundation for more genotype-informed individualized treatment decisions in breast cancer.

Abstract Background Evaluation of middle ear prostheses requires high-resolution imaging to assess position and structural integrity. Purpose To assess the diagnostic performance of photon-counting-detector (PCD)-CT for middle ear prosthesis imaging in cadaveric specimens. Materials and Methods Nine different middle ear prostheses were implanted in five fresh-frozen whole-head specimens, both in correct anatomic position and displaced to mimic malposition. Specimens were scanned on PCD-CT (NAEOTOM Alpha, Siemens) and energy-integrating-detector (EID)-CT (SOMATOM Force, Siemens), reconstructed at 0.2mm and 0.4mm, respectively. Eighteen cases (9 prostheses, 2 positions) per scanner were evaluated by two neuroradiologists (36 readings), blinded to scanner and position, who scored prosthesis position, reader confidence, and overall image quality. Agreement with the reference standard and between readers was compared. Results PCD-CT showed higher diagnostic confidence compared with EID-CT, while accuracy and inter-reader agreement did not demonstrate significant differences between scanners. Correct readings, PCD-CT versus EID-CT: lateral contact, 31/36 (86.1%; 95% CI: 58.3%-94.4%) vs. 29/36 (80.6%; 55.6%-91.7%), p = 0.500; medial contact, 30/36 (83.3%; 55.6%-94.4%) vs. 26/36 (72.2%; 50.0%-83.3%), p = 0.250. PCD-CT identified all cases of complete contact loss (score 3), while EID-CT missed one reading per contact. Inter-reader agreement may be higher with PCD-CT vs EID-CT (lateral: κw: 0.804 [0.578-0.941] vs. 0.571 [0.302-0.778], p = 0.250; medial: 0.684 [0.191-0.934] vs. 0.481 [0.024-0.835], p = 0.250). Reader confidence was significantly higher with PCD-CT; mean paired differences for Readers 1 and 2 were 9.4 (1.8-17.1; Holm-adjusted p = 0.019) and 23.1 points (13.4-32.7; p < 0.001) for lateral contact, and 16.4 (10.0-22.8; p < 0.001) and 17.8 points (6.8-28.8; p = 0.007) for medial contact. Readers preferred PCD-CT image quality in 16/18 (88.9%; 65.3%-98.6%) and 17/18 cases (94.4%; 72.7%-99.9%), respectively. Conclusion PCD-CT was associated with significantly higher reader confidence and preferred image quality, without significant differences in diagnostic accuracy or inter-reader agreement. These findings suggest PCD-CT is a promising modality for postoperative middle ear evaluations that warrants further investigations.

Abstract Background Glioblastoma (GBM) represents the most common and aggressive central nervous system malignancy where overall survival is a dismal 14.6 months despite an aggressive standard of care treatment regimen that includes maximally safe surgical resection, radiotherapy, and temozolomide. It has recently been established that GBM tumors have increased transferrin receptor expression and iron content which corresponds with worse patient prognosis. This has led to the hypothesis that iron metabolism is a viable therapeutic target. An emergent therapeutic strategy to target GBM iron metabolism is gallium maltolate (GaM), which is an orally bioavailable form of Ga3+ that functions as a redox inactive iron mimic to disrupt iron metabolism. As mitochondrial iron metabolism serves as a central connection point between iron and DNA metabolism, the goal of this study was to determine if GaM could disrupt this system. Methods The effects of GaM on GBM cells were interrogated using conventional techniques including colony formation assays to assess clonogenicity, alkaline comet assays to evaluate DNA damage induction, and MitoFerro Green analysis to evaluate mitochondrial iron content. The effects of GaM on tumor growth in vivo were evaluated using a subcutaneous flank xenograft model system to determine the induction of DNA damage and an orthtopic model system to evaluate the combinatorial effects of GaM, radiation, and temozolomide on murine survival. Results This study uncovered that maintenance of high mitochondrial iron content corresponds with increased proliferative capacity in GBM cells. This study also shows that GaM can deplete mitochondrial iron to induce DNA damage both in vitro and in a subcutaneous xenograft model. Furthermore, GaM enhances the efficacy of radiation and temozolomide when delivered concomitant and adjuvantly in an orthotopic GBM model system. Conclusion These results suggest that GaM warrants further consideration for use in combination with standard of care GBM therapy.

Abstract Biallelic colony‐stimulating factor 1 receptor ( CSF1R ) variants are a major cause of early‐onset CSF1R ‐related disorder (CSF1R‐RD), although fewer than 30 cases have been reported and genotype–phenotype correlations remain unclear. The aim of this study was to characterize the clinical, radiological, and genetic features of patients with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). Six patients with biallelic CSF1R variants underwent detailed clinical, neurological, and magnetic resonance imaging evaluation. Three siblings with a homozygous p.Gly585Val variant showed marked phenotypic variability, ranging from severe childhood‐onset neurodegeneration to an asymptomatic presentation, all with white matter abnormalities. Three unrelated patients carried different biallelic CSF1R variants and presented with congenital skeletal abnormalities or early‐onset neurological disease of variable severity. These cases broaden the phenotypic spectrum of biallelic CSF1R‐RD and demonstrate that disease severity cannot be predicted solely by genotype, suggesting an important role for genetic or environmental modifiers.

Abstract Therapeutic resistance in ovarian cancer is frequently driven by persistent replication stress, yet the molecular mechanisms that convert replication stress into a therapeutically exploitable vulnerability remain incompletely understood. Here, we identify drug-induced nuclear cathepsin L (nCTSL) as a previously unrecognized regulator of replication stress and DNA repair. Clofarabine (CLF) combined with the ATR inhibitor AZD6738, or the CHK1 inhibitor prexasertib promoted nuclear accumulation of CTSL, where it remodeled the replication machinery through degradation of CCNE1, MCM3, MCM6, and geminin, accompanied by loss of RAD51 and 53BP1 and increased γH2AX and phospho-RPA2. DNA fiber analysis demonstrated marked inhibition of replication fork progression following CLF-based combinations, whereas CTSL depletion accelerated fork progression and abolished therapy-induced replication stress. Reconstitution with the nuclear M1F CTSL isoform restored replication restraint, confirming a direct role for nuclear CTSL in regulating replication dynamics. GFP-based DNA repair reporter assays further revealed that CLF-based combinations suppress DNA repair competence in a CTSL-dependent manner, indicating that nuclear CTSL couples replication stress amplification with functional inhibition of repair pathways. Functionally, CLF-based combinations selectively targeted transformed fallopian tube secretory epithelial cells while sparing non-transformed counterparts, demonstrated broad activity in patient-derived ovarian cancer ascites spheroids, and significantly inhibited tumor growth and prolonged survival in vivo . Collectively, our findings identify nuclear CTSL as a mechanistic driver of replication stress that remodels the replication machinery, impairs DNA repair, and creates a therapeutically exploitable vulnerability in ovarian cancer. We propose that nuclear CTSL promotes a transition from replication competence to replication catastrophe, thereby establishing a conceptual framework for biomarker-guided therapeutic strategies targeting CTSL-dependent replication stress.

Background & Aims: Multi-target stool DNA (mt-sDNA) is an established stool-based colorectal cancer screening test, yet long-term performance is not well-described. We evaluated follow-up colonoscopy rates & quality, neoplasia yield, and repeat-testing adherence over 10 years with an integrated screening program. Methods: We assembled a retrospective cohort of mt-sDNA tests (September 2014–July 2025) within a multi-site health system. A validated large-language-model pipeline extracted colonoscopy, pathology, and quality endpoints from free-text reports. Detection outcomes (adenoma detection rate, advanced neoplasia, modified advanced adenoma, sessile serrated lesion (SSL), and negative exams) were calculated among high-quality exams; adenocarcinoma, bowel preparation adequacy, and cecal intubation rate (CIR) used all screening exams. We assessed colonoscopy completion ≤1 year after positive mt-sDNA, follow-up colonoscopy findings, findings by time-to-colonoscopy, and adherence to repeat mt-sDNA after negative result. Results: Among 148,624 tests in 110,410 individuals, positivity was 13.6%. Of 19,506 positives, 65.1% completed colonoscopy within 12 months (median 82 days). Colonoscopy after a positive mt-sDNA had high yield: advanced adenoma diagnosis was 30.7%; adenocarcinoma was 1.3%. Of patients who had colonoscopy within 3 years of a negative mt-sDNA test, 45.2% had adenoma/serrated lesion, 9.3% had advanced adenoma and 0.5% had colon cancer. Adenoma detection rate after positive mt-sDNA (>50%) exceeded specialty society quality benchmarks and increased over time; Longer intervals (>6 months) to colonoscopy after a positive test were associated with higher advanced adenoma (trend P=0.001).After an initial negative mt-sDNA, only 35.3% were screened again by mt-sDNA testing within 3 years. Conclusions: Over a decade,mt-sDNA screening achieved high colonoscopy qualitybut revealed critical gaps in the care cascade. One-third of positive tests lacked timely follow-up and nearly two-thirds of negative tests were not repeated on schedule, suggesting opportunities for system-level interventions.