Citations

Abstract Pancreatic adenocarcinoma remains one of the most lethal malignancies, primarily due to its robust resistance to genotoxic therapies, such as chemotherapy and radiotherapy. Understanding the mechanisms underlying this resistance is essential to improve clinical outcomes. In this study, we identified trimethylguanosine synthase 1 (TGS1), previously known for its role in RNA modification, as a critical mediator of homologous recombination (HR) repair that specifically contributes to resistance in pancreatic adenocarcinoma. TGS1 was significantly overexpressed in pancreatic adenocarcinoma tissues, correlating strongly with advanced disease stages, therapy resistance, and poor patient prognosis. Following DNA damage, ATM kinase phosphorylated TGS1 at serine residues S389 and S531, which mediated its direct interaction with BRCA1 and subsequent recruitment of BRCA1 to DNA damage sites. The phosphorylation-dependent interaction enhanced HR repair efficiency, enabling cancer cells to survive genotoxic stress. Depletion or pharmacologic inhibition of TGS1 induced HR deficiency and markedly enhanced sensitivity to DNA-damaging agents, particularly PARP inhibitors, in pancreatic adenocarcinoma cell lines in vitro and in both cell line– and patient-derived xenograft models in vivo. Collectively, these findings uncover an ATM–TGS1–BRCA1 signaling axis that promotes DNA repair and resistance to genotoxic therapies in pancreatic cancer, positioning TGS1 as a promising predictive biomarker and therapeutic target to enhance treatment efficacy. Significance: The ATM–TGS1–BRCA1 signaling axis is a critical regulator of DNA repair that can be targeted to overcome genotoxic therapy resistance, providing a promising therapeutic strategy that could transform pancreatic cancer treatment.

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Background: Femoroacetabular impingement (FAI) is a common cause of hip pain in female athletes. There are limited data on midterm outcomes for female athletes undergoing hip arthroscopic surgery. Purpose: To evaluate return-to-sport rates and clinical outcomes in female athletes with FAI after primary hip arthroscopic surgery with labral repair and femoral osteochondroplasty. Study Design: Case series; Level of evidence, 4. Methods: A retrospective analysis of a single institution’s database was performed to identify female athletes who underwent primary hip arthroscopic surgery with labral repair and femoral osteochondroplasty from July 2011 to October 2019 with a minimum 5-year follow-up. Preoperative radiographs were evaluated for the lateral center-edge angle, Tonnis angle, Tonnis grade, and alpha angle. Patient-reported outcome measure (PROM) scores, including those for the modified Harris Hip Score, Hip Outcome Score, Tegner Activity Scale, and visual analog scale for pain, as well as patient satisfaction with surgery were analyzed postoperatively. Results: A total of 63 hips (27 left, 36 right) in 56 female patients (mean age, 21.6 ± 8.0 years; mean body mass index, 24.7 ± 4.8 kg/m 2 ) were included and followed for a mean of 8.4 ± 2.1 years (range, 5.0-13.2 years). Preoperatively, patients participated in basketball (n = 18), dance (n = 21), hockey (n = 8), and soccer (n = 12). Of the 56 patients, 41 attempted to return to sport. There were 28 (68%) female athletes who successfully returned to their preoperative sport. Of the total cohort, 21 (38%) patients cited non–hip-related factors for discontinuing their sport. All postoperative PROM scores improved significantly compared with preoperatively ( P ≤ .002) for patients with available preoperative data. Those who returned to sport had significantly improved Hip Outcome Score values compared with those who did not return to sport ( P ≤ .010). Conclusion: Female athletes who underwent primary hip arthroscopic surgery for FAI had significant improvements in PROM scores and moderate return-to-sport rates at a minimum 5-year follow-up. Most athletes discontinued sports because of non–hip-related factors, although hip-related issues were also cited. Our analysis highlights the need for thorough perioperative counseling and establishing appropriate patient expectations for female athletes before hip arthroscopic surgery.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Abstract The acetabular labrum is a fibrocartilaginous structure that deepens the acetabular socket and helps maintain a suction seal. In patients with hip dysplasia, a distinct labral tear pattern called an inside‐out labral tear is often seen. This tear pattern is particularly challenging to correct via conventional techniques since the labrum can potentially remain everted and insufficiently restore the native hip labral suction seal after repair. An inverted hip labral repair technique is performed for this pathology at our institution and focuses on achieving optimal labral orientation to enhance the suction seal and joint stability, particularly in dysplastic hips. This Technical Note aims to describe the key surgical principles and clinical considerations of inverted hip labral repair. Technique Video video See video under supplementary data.

Objectives: To evaluate return-to-sport (RTS) rates and patient reported outcome measures (PROMs) following hip arthroscopy for femoroacetabular impingement (FAI) in active football players with a minimum of 5-years follow-up. Methods: All active football players who underwent hip arthroscopy for FAI from 2010-2019 were identified. Preoperative radiographic measures including lateral center edge angle, Tönnis angle, alpha angle, and acetabular depth were obtained. Patients were evaluated for post-operative RTS and revision surgery data at final follow-up. Modified Harris Hip Score (mHHS), Hip Outcome Score (HOS), HOS Activities of Daily Living (HOS-ADL), HOS Sports Specific Subscale (HOS-Sports), Tegner Activity Scores, Visual Analogue Scale (VAS) for pain, and surgery satisfaction were collected at a minimum 5-year follow-up. Descriptive and comparative statistical analysis was performed using R software (version 4.4.1). Results: Sixty-six hips from 53 male patients were included. The mean age was 20.4 ± 6.4 years and mean BMI was 27.3 ± 6.6 kg/m² (Table 1). Mean follow-up was 8.7 ± 2.8 years. The majority (60%) were high school players and 19% were college players. Figure 1 displays the most commonly affected positions which included wide receiver (32%), defensive lineman (26%), and tight end or offensive lineman (16%). There were 11 bilateral cases and 2 revisions. The mean lateral center edge angle was 31.6º ± 6.4, the mean Tönnis angle was 5.0º ± 5, and the mean alpha angle was 63.2º ± 12.7. There was significant improvement in all PROMs from baseline to a minimum 5-year follow-up (p<0.04). Fifty-four percent of athletes returned to football postoperatively and the average overall surgery satisfaction rating was 8.1/10. Among those who didn’t return, 14% cited hip-related reasons, while 67% cited non-hip related reasons such as priorities changing or graduating (Figure 2). Athletes who returned to football had significantly higher mean HOS-ADL (p=0.049), HOS-Sport (p=0.042), and Tegner level before surgery (p=0.023) compared to those who did not return (Table 2). Conclusions: Football players undergoing hip arthroscopy for FAI demonstrate significant improvements in outcome scores at a minimum 5-year follow-up with a moderate return-to-sport rate. Athletes who are able to return to football report higher patient reported outcomes compared to those who do not. Player position may also influence incidence and outcomes. Although football players demonstrate significant improvements following hip arthroscopy, the moderate RTS rates highlights the demanding nature of the sport and need for improved perioperative counseling.

Objectives: Periacetabular osteotomy (PAO) is utilized for the treatment of hip dysplasia, with a growing trend towards hip arthroscopy at the time of PAO or in a planned, staged manner prior to PAO in order to address intra-articular pathology such as labral tears. For patients with persistent or new pain following isolated PAO, a subset undergo unplanned, primary hip arthroscopy. To date, there is a paucity of available evidence regarding the risk factors for and outcomes of unplanned hip arthroscopy for persistent or new pain after PAO. The purpose of this study was to determine demographic and radiographic characteristics of patients undergoing hip arthroscopy for persistent pain after PAO and also to compare radiographic parameters, surgical characteristics, and postoperative PROMs between patients that underwent hip arthroscopy following PAO and a demographically similar group of controls without acetabular dysplasia that underwent primary hip arthroscopy. Methods: An institutional database of 3014 hip arthroscopies performed between 1988 and 2022 was reviewed for patients having undergone unplanned (i.e. non-staged) first-time hip arthroscopy after PAO. These patients were propensity-matched on a 1:2 ratio with demographically similar, non-dysplastic patients undergoing primary hip arthroscopy with labral repair. All patients were contacted at final-follow-up to collect outcomes including subsequent procedures, progression to THA, and patient-reported outcome measures (PROMs), including modified Harris Hip Score (mHHS), Hip Outcome Score (HOS), International Hip Outcome Tool (iHOT), Tegner Activity Scores, Visual Analogue Scale (VAS) for pain, and surgery satisfaction. Demographics, radiographic characteristics, and postoperative outcomes were compared. All statistical analysis and Kaplan-Meier survival curve analysis was performed using R software (version 4.4.1). Results: We identified 22 hips in 21 patients (17 female, 4 male; age: 24.6 ± 8.5 years; BMI: 29.3 ± 7.4 kg/m²) who underwent first-time arthroscopy after ipsilateral PAO and were followed for a mean of 7.2 ± 2.8 years (Table 1). The median post-PAO LCEA was 28° (IQR: 24.6 – 31.7) and the mean Tönnis angle was 4.2° ± 5.9. The median time from the date of PAO to date of subsequent hip arthroscopy was 1.6 years (IQR: 1.1 - 3.4). Compared to the control group, there was a significantly lower rate of femoral osteochondroplasty (50% vs, 86%, p < 0.01), as well as trends towards lower rate of labral repair (77% vs. 95% p = 0.11), and higher rate of capsular repair (64% vs. 75%, p = 0.34). No differences were found between the PAO and control groups in any of the postoperative PROMs (Table 2). Among the PAO patients, 3 (20%) progressed to total hip arthroplasty (THA) compared to 1 (9%) in the control group (p=0.62). Conclusions: Hip arthroscopy after prior PAO was associated with postoperative improvements in pain and moderate rates of conversion to THA. When patients undergoing hip arthroscopy following PAO were compared to a demographically similar matched cohort of nondysplastic hips who underwent primary hip arthroscopy without a prior PAO, similar postoperative outcome scores were observed. This data provides valuable counselling information for clinicians discussing hip arthroscopy in the setting of patients with persistent pain following PAO.

Background Intracranial occlusions in embolic stroke of undetermined source are histopathologically similar to cardiac sources of embolism. Whether patients with embolic stroke of undetermined source and intracranial occlusion benefit from anticoagulation is unknown. Methods A multicenter retrospective cohort of adults with cryptogenic stroke was queried for patients with proximal or medium/distal vessel occlusion. The primary outcome was recurrent ischemic stroke, which was assessed in unadjusted and adjusted Cox proportional hazards models and repeated following 1:1 propensity score matching and biweight kernel density matching. Results Of the 2328 patients who were followed over a median of 1.31 years (interquartile range, 0.34–2.85), 999 (42.6%) had an intracranial occlusion. When compared with patients without an intracranial occlusion, those with an occlusion had fewer atherosclerotic vascular risk factors, more severe symptoms, and less severe cerebral microvascular disease. The rate of recurrent stroke was similar between patients with versus without an intracranial occlusion (6.8%/year [95% CI, 5.7–8.2] versus 7.0%/year [95% CI 6.0–8.1]; adjusted hazard ratio [HR], 1.09 [95% CI, 0.77–1.55]). There was no association between occlusion and recurrent stroke in the adjusted propensity score matching (HR, 1.01 [95% CI, 0.64–1.59]) or kernel density models (HR, 0.95 [95% CI, 0.62–1.45]). There was no interaction between occlusion and treatment with anticoagulation, sex, age, or high‐risk sources of embolism for the primary outcome in the unmatched and matched analyses. Conclusions Intracranial occlusion in patients with embolic stroke of undetermined source is not associated with a greater risk of recurrence when compared with patients without an intracranial occlusion. There was no difference in rate of recurrent stroke with anticoagulation when stratified by presence or absence of occlusion.