Generalizability of PGS313 for breast cancer risk in a Los Angeles biobank.

Polygenic scores (PGS) summarize the combined effect of common risk variants and are associated with breast cancer risk in patients without identifiable monogenic risk factors. One of the most well-validated PGSs in breast cancer to date is PGS313, which was developed from a Northern European biobank but has shown attenuated performance in non-European ancestries. We further investigate the generalizability of the PGS313 for American women of European (EA), African (AFR), Asian (EAA), and Latinx (HL) ancestry within one institution with a singular EHR system, genotyping platform, and quality control process. We found that the PGS313 achieved overlapping Areas under the ROC Curve (AUCs) in females of Lantix (AUC, 0.68; 95 CI, 0.65-0.71) and European ancestry (AUC, 0.70; 95 CI, 0.69-0.71) but lower AUCs for the AFR and EAA populations (AFR: AUC, 0.61; 95 CI, 0.56-0.65; EAA: AUC, 0.64; 95 CI, 0.60-0.680). While PGS313 is associated with Hormone Positive (HR+) disease in European Americans (OR, 1.42; 95 CI, 1.16-1.64), this association is lost in African, Latinx, and Asian Americans. In summary, we found that PGS313 was significantly associated with breast cancer but with attenuated accuracy in women of African and Asian descent within a singular health system in Los Angeles. Our work further highlights the need for additional validation in diverse cohorts prior to clinical implementation of polygenic scores.

Conservative treatment of congenital radial head subluxation and non-traumatic elbow locking: A case report.

Congenital radial head subluxation is relatively rare and may be overlooked due to mild symptoms. The diagnosis mainly relies on imaging and history. Observation is an option for those with insignificant symptoms, while surgical intervention, such as ulnar osteotomy or arthroscopy, is often required when dysfunction exists. A 30-year-old man was admitted with congenital radial head dislocation, which was treated with manipulative repositioning. During follow-up, the patient regained the original mobility of the elbow joint and had no recurrence of dislocation. In conclusion, in adults with congenital dislocation of the radial head, we recommend conservative treatment as a first step.

Interactions between MDSCs and the Autonomic Nervous System: Opportunities and Challenges in Cancer Neuroscience.

Myeloid-derived suppressor cells (MDSC) are a population of heterogeneous immune cells that are involved in precancerous conditions and neoplasms. The autonomic nervous system (ANS), which is composed of the sympathetic nervous system and the parasympathetic nervous system, is an important component of the tumor microenvironment that responds to changes in the internal and external environment mainly through adrenergic and cholinergic signaling. An abnormal increase of autonomic nerve density has been associated with cancer progression. As we discuss in this review, growing evidence indicates that sympathetic and parasympathetic signals directly affect the expansion, mobilization, and redistribution of MDSCs. Dysregulated autonomic signaling recruits MDSCs to form an immunosuppressive microenvironment in chronically inflamed tissues, resulting in abnormal proliferation and differentiation of adult stem cells. The two components of the ANS may also be responsible for the seemingly contradictory behaviors of MDSCs. Elucidating the underlying mechanisms has the potential to provide more insights into the complex roles of MDSCs in tumor development and lay the foundation for the development of novel MDSC-targeted anticancer strategies.

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis.

BACKGROUND: Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis in NSCLC patients. Here, we performed functional studies to unravel the mechanism underlying the "metastasis-suppressor" effect of HERC5, with a focus on mitochondrial metabolism pathways. METHODS: We assessed cell proliferation, colony formation potential, anchorage-independent growth, migration, and wound healing in NSCLC cell line models with HERC5 overexpression (OE) or knockout (KO). To study early tumor cell dissemination, we used these cell line models in zebrafish experiments and performed intracardial injections in nude mice. Mass spectrometry (MS) was used to analyze protein changes in whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, and lactate production were used to investigate the relationships with mitochondrial energy metabolism pathways. RESULTS: Using different in vitro NSCLC cell line models, we showed that NSCLC cells with low HERC5 expression had increased malignant and invasive properties. Furthermore, two different in vivo models in zebrafish and a xenograft mouse model showed increased dissemination and metastasis formation (in particular in the brain). Functional enrichment clustering of MS data revealed an increase in mitochondrial proteins in vitro when HERC5 levels were high. Loss of HERC5 leads to an increased Warburg effect, leading to improved adaptation and survival under prolonged inhibition of oxidative phosphorylation. CONCLUSIONS: Taken together, these results indicate that low HERC5 expression increases the metastatic potential of NSCLC in vitro and in vivo. Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene.

The LysM receptor-like kinase SlLYK10 controls lipochitooligosaccharide signaling in inner cell layers of tomato roots.

Establishment of arbuscular mycorrhiza (AM) relies on a plant signaling pathway that can be activated by fungal chitinic signals such as short chain chitooligosaccharides (CO) and lipo-chitooligosaccharides (LCOs). The tomato LysM receptor-like kinase (LysM RLK) SlLYK10 has high affinity for LCOs and is involved in root colonization by arbuscular mycorrhizal fungi (AMF), however its role in LCO responses has not yet been studied. Here, we show that SlLYK10 proteins produced by the Sllyk10-1 and Sllyk10-2 mutant alleles, which both cause decreases in AMF colonization, and carry mutations in LysM1 and 2 respectively, have similar LCO binding affinities compared to the WT SlLYK10. However, the mutant forms were no longer able to induce cell death in Nicotiana benthamiana when co-expressed with MtLYK3, a Medicago truncatula LCO co-receptor, while they physically interacted with MtLYK3 in co-purification experiments. This suggests that the LysM mutations affect the ability of SlLYK10 to trigger signaling through a potential co-receptor rather than its ability to bind LCOs. Interestingly, tomato lines that contain a calcium (Ca2+) concentration reporter (Genetically Encoded Ca2+ indicators, GECO), showed Ca2+ spiking in response to LCO applications, but this occurred only in inner cell layers of the roots, while short chain COs also induced Ca2+ spiking in the epidermis. Moreover, LCO-induced Ca2+spiking was decreased in Sllyk10-1*GECO plants, suggesting that the decrease in AMF colonization in Sllyk10-1 is due to abnormal LCO signaling.

Gemfibrozil-Platinum(IV) Precursors for New Enhanced-Starvation and Chemotherapy In Vitro and In Vivo.

A brand-new enhanced starvation is put forward to trigger sensitized chemotherapy: blocking tumor-relation blood vessel formation and accelerating nutrient degradation and efflux. Following this concept, two cisplatin-like gemfibrozil-derived Pt(IV) prodrugs, GP and GPG, are synthesized. GP and GPG had nanomolar IC50 against A2780 cells and higher selectivity against normal cells than cisplatin. Bioactivity results confirmed that GP and GPG highly accumulated in cells and induced DNA damage, G2-phase arrest, and p53 expression. Besides, they could increase ROS and MDA levels and reduce mitochondrial membrane potential and Bcl-2 expression to promote cell apoptosis. In vivo, GP showed superior antitumor activity in A2780 tumor-bearing mice with no observable tissue damage. Mechanistic studies suggested that highly selective chemotherapy could be due to the new enhanced starvation effect: blocking vasculature formation via inhibiting the CYP2C8/EETs pathway and VEGFR2, NF-κB, and COX-2 expression and cholesterol efflux and degradation acceleration via increasing ABCA1 and PPARα.

Photosensitive Hydrogel with Temperature-Controlled Reversible Nano-Apertures for Single-Cell Protein Analysis.

Single cell western blot (scWB) is one of the most important methods for cellular heterogeneity profiling. However, current scWB based on conventional photoactive polyacrylamide hydrogel material suffers from the tradeoff between in-gel probing and separation resolution. Here, a highly sensitive temperature-controlled single-cell western blotting (tc-scWB) method is introduced, which is based on a thermo/photo-dualistic-sensitive polyacrylamide hydrogel, namely acrylic acid-functionalized graphene oxide (AFGO) assisted, N-isopropylacrylamide modified polyacrylamide (ANP) hydrogel. The ANP hydrogel is contracted at high-temperature to constrain protein band diffusion during microchip electrophoretic separation, while the gel aperture is expanded under low-temperature for better antibody penetration into the hydrogel. The tc-scWB method enables the separation and profiling of small-molecule-weight proteins with highly crosslinked gel (12% T) in SDS-PAGE. The tc-scWB is demonstrated on three metabolic and ER stress-specific proteins (CHOP, MDH2 and FH) in four pancreatic cell subtypes, revealing the expression of key enzymes in the Krebs cycle is upregulated with enhanced ER stress. It is found that ER stress can regulate crucial enzyme (MDH2 and FH) activities of metabolic cascade in cancer cells, boosting aerobic respiration to attenuate the Warburg effect and promote cell apoptosis. The tc-scWB is a general toolbox for the analysis of low-abundance small-molecular functional proteins at the single-cell level.

A novel HDAC6 inhibitor attenuate APAP-induced liver injury by regulating MDH1-mediated oxidative stress.

Glutathione (GSH) depletion, mitochondrial damage, and oxidative stress have been implicated in the pathogenesis of acetaminophen (APAP) hepatotoxicity. Here, we demonstrated that the expression of histone deacetylase 6 (HDAC6) is highly elevated, whereas malate dehydrogenase 1 (MDH1) is downregulated in liver tissues and AML-12 cells induced by APAP. The therapeutic benefits of LT-630, a novel HDAC6 inhibitor on APAP-induced liver injury, were also substantiated. On this basis, we demonstrated that LT-630 improved the protein expression and acetylation level of MDH1. Furthermore, after overexpression of MDH1, an upregulated NADPH/NADP+ ratio and GSH level and decreased cell apoptosis were observed in APAP-stimulated AML-12 cells. Importantly, MDH1 siRNA clearly reversed the protection of LT-630 on APAP-stimulated AML-12 cells. In conclusion, LT-630 could ameliorate liver injury by modulating MDH1-mediated oxidative stress induced by APAP.

COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment: A Randomized Clinical Trial.

Importance: With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective: To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants: This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions: Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures: The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results: The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance: In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.

Numerical Simulation Study on the Effect of Preinjected CO2 on the Hydraulic Fracturing Behavior of Shale Oil Reservoirs.

Due to the low permeability and apparent mechanical anisotropy of shale reservoirs, shale oil production highly depends on the performance of hydraulic fracturing of the tight reservoir. Pre-injection of CO2 before hydraulic fracturing treatment has been proven beneficial to enhance shale oil production. A comprehensive understanding of the effect of changes in the properties of shale reservoirs after preinjected CO2 on the hydraulic fracturing behavior of shale reservoirs is essential to improve the stimulated reservoir volume (SRV) of shale oil reservoirs. In this study, comprehensive evaluating parameters were proposed to specify the variation of mechanical properties of shale rock at different soaking times of CO2 based on published testing parameters of shale. Accordingly, a three-dimensional (3D) numerical model was established and three groups of horizontal well fracturing cases with different cluster spacings were conducted based on the adaptive FE-DE method to simulate and compare the hydraulic fracturing behavior in the reservoirs with different mechanical properties. We established a quantitative relationship between the alterations in reservoir properties and the stimulated reservoir volume. The results indicate that both the brittleness and conductivity properties of shale rock are dramatically improved as the increment of soaking time of CO2. It is beneficial to improve the SRV, and the initiation pressure is reduced with the increment of soaking time of CO2. However, as the stress shadow effect is involved in the horizontal well fracturing, the complexity of the hydrofracturing crack is significantly enhanced to restrain the development of hydrofracturing crack. When the cluster spacing is larger, the stress shadow effect is weakened, and the weakening effect of CO2 soaking on reservoir is more obvious.

SpiDe-Sr: blind super-resolution network for precise cell segmentation and clustering in spatial proteomics imaging.

Spatial proteomics elucidates cellular biochemical changes with unprecedented topological level. Imaging mass cytometry (IMC) is a high-dimensional single-cell resolution platform for targeted spatial proteomics. However, the precision of subsequent clinical analysis is constrained by imaging noise and resolution. Here, we propose SpiDe-Sr, a super-resolution network embedded with a denoising module for IMC spatial resolution enhancement. SpiDe-Sr effectively resists noise and improves resolution by 4 times. We demonstrate SpiDe-Sr respectively with cells, mouse and human tissues, resulting 18.95%/27.27%/21.16% increase in peak signal-to-noise ratio and 15.95%/31.63%/15.52% increase in cell extraction accuracy. We further apply SpiDe-Sr to study the tumor microenvironment of a 20-patient clinical breast cancer cohort with 269,556 single cells, and discover the invasion of Gram-negative bacteria is positively correlated with carcinogenesis markers and negatively correlated with immunological markers. Additionally, SpiDe-Sr is also compatible with fluorescence microscopy imaging, suggesting SpiDe-Sr an alternative tool for microscopy image super-resolution.

Effect of transcutaneous electrical acupoint stimulation based on the theory of "qi ascending and descending movement" on autonomic nervous system and gastrointestinal function in patients after general anesthesia laparoscopic cholecystectomy. / 基于"气机升降"ç†è®ºç»çš®ç©´ä½ç”µåˆºæ¿€å¯¹å ¨éº»è ¹è ”é•œèƒ†å›Šåˆ‡é™¤æœ¯åŽæ‚£è€ è‡ªä¸»ç¥žç»å’Œèƒƒè‚ åŠŸèƒ½çš„å½±å“.

OBJECTIVES: To observe the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) based on the theory of "qi ascending and descending movement" in patients after general anesthesia laparoscopic cholecystectomy, so as to explore the impact of TEAS on the autonomic nervous system and gastrointestinal function of patients. METHODS: A total of 204 patients scheduled to undergo general anesthesia laparoscopic cholecystectomy were selected and randomly divided into control, double acupoints and multiple acupoints groups, with 68 cases in each group. For patients in the multiple acupoints group, TEAS was applied at Zusanli (ST36), Tiantu (CV22), Danzhong (CV17), Zhongwan (CV12), Taichong (LR3), and Neiguan (PC6) 30 min before anesthesia induction until the end of the surgery. In the double acupoints group, TEAS was applied only at ST36 and PC6. No electrical stimulation was applied in the control group. The postoperative bloating, bowel sound recovery time, first farting time, first defecation time, length of hospital stay, nausea and vomiting were compared among the three groups. Heart rate variability was monitored by twelve-lead electrocardiogram to evaluate the autonomic nervous function of the patients, including the low frequency power/high frequency power ratio (LF/HF), the standard deviation of all sinus RR intervals (SDNN), and the root mean square of difference between successive normal RR intervals (RMSSD). RESULTS: At 6 h and 24 h after surgery, the symptoms of bloating, nausea and vomiting in the multiple acupoints group and double acupoints group were significantly improved compared to the control group (P<0.05), and the multiple acupoints group was superior to the double acupoints group (P<0.05). Compared with the control group, the bowel sound recovery time, first farting time, first defecation time, and length of hospital stay were significantly shorter (P<0.05) in the multiple acupoints group and double acupoints group, and the multiple acupoints group was superior to the double acupoints group (P<0.05). At 1 d and 2 d after surgery, compared with the control group, LF/HF was decreased (P<0.05) while SDNN and RMSSD were increased (P<0.05) in the multiple acupoints group and double acupoints group, and there was a significant difference between the two groups (P<0.05). CONCLUSIONS: TEAS treatment based on the theory of "qi ascending and descending movement" can relieve gastrointestinal dysfunction, reduce early postoperative sympathetic nerve excitement and maintain parasympathetic nerve tension in patients after general anesthesia laparoscopic cholecystectomy, thereby promoting gastrointestinal function recovery.

Identification and characterization of a novel CASR mutation causing familial hypocalciuric hypercalcemia.

Context: Although a monoallelic mutation in the calcium-sensing receptor (CASR) gene causes familial hypocalciuric hypercalcemia (FHH), the functional characterization of the identified CASR mutation linked to the clinical response to calcimimetics therapy is still limited. Objective: A 45-year-old male presenting with moderate hypercalcemia, hypocalciuria, and inappropriately high parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium (Ca2+) from 12.5 to 10.1 mg/dl). We identified the genetic mutation and characterized the functional and pathophysiological mechanisms, and then linked the mutation to calcimimetics treatment in vitro. Design: Sanger sequencing of the CASR, GNA11, and AP2S1 genes was performed in his family. The simulation model was used to predict the function of the identified mutant. In vitro studies, including immunoblotting, immunofluorescence, a cycloheximide chase study, Calbryte™ 520 Ca2+ detection, and half-maximal effective concentration (EC50), were examined. Results: This proband was found to carry a de novo heterozygous missense I554N in the cysteine-rich domain of CASR, which was pathogenic based on the different software prediction models and ACGME criteria. The simulation model showed that CASR I554N mutation decreased its binding energy with Ca2+. Human CASR I554N mutation attenuated the stability of CASR protein, reduced the expression of p-ERK 1/2, and blunted the intracellular Ca2+ response to gradient extracellular Ca2+ (eCa2+) concentration. The EC50 study also demonstrated the correctable effect of calcimimetics on the function of the CASR I554N mutation. Conclusion: This novel CASR I554N mutation causing FHH attenuates CASR stability, its binding affinity with Ca2+, and the response to eCa2+ corrected by therapeutic calcimimetics.

EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer.

AIMS: Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. MAIN METHODS: We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. KEY FINDINGS: Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. CONCLUSIONS: Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.

Efficacy of 2% Hydroxypropyl Methylcellulose and Bandage Contact Lens for the Management of Dry Eye Disease after Cataract Surgery.

Objectives: To investigate the effect of 2% hydroxypropyl methylcellulose (HPMC) and bandage contact lens (BCL) on dry eye disease after cataract surgery. Methods: This prospective randomized controlled trial included 63 eyes which were divided into the balanced salt solution (BSS), HPMC, BCL, and combined HPMC and BCL (H&B) groups. The Ocular Surface Disease Index (OSDI), tear meniscus height (TMH), and average tear break-up time were measured before cataract surgery and 30 days postoperatively. Differences in corneal nerve fiber (CNF) and dendritic cell (DC) density in various directions were evaluated and compared. The CNFs and DCs in central and infratemporal directions were observed using in vivo confocal microscopy. Data were evaluated using the Kruskal-Wallis rank-sum test and analysis of variance. Results: The differences in variations in OSDI and TMH after cataract surgery between the four groups were statistically significant (P < 0.05). The postoperative OSDI of the HPMC group decreased compared with their preoperative OSDI. A statistically significant difference in the variations of OSDI score was observed between the HPMC and other groups (P < 0.05). The postoperative variations in TMH in the HPMC group were significantly higher than those observed preoperatively and significantly differed between HPMC and BCL groups and between BCL and H&B groups (P < 0.05). Postoperatively, the density of corneal DCs decreased in BSS and HPMC groups and increased in BCL and H&B groups (P < 0.001). Conclusions: The application of 2% HPMC in cataract surgery has a certain effect on managing dry eye after cataract surgery. Although the use of BCLs after cataract surgery has some benefits, it may cause mild ocular surface inflammation. Nevertheless, using 2% HPMC with BCLs in the perioperative phase of cataract surgery can alleviate the subjective discomfort of patients and can safely and effectively replace eye patch after cataract surgery.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. RESULTS: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10-15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10-46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74). CONCLUSIONS: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

Primary Lacrimal Sac Tumors with Extension into Vicinity: Outcomes with Endoscopy-Assisted Modified Weber-Ferguson's Approach.

PURPOSE: To evaluate the outcomes of endoscopy-assisted modified Weber-Ferguson's approach in the management of primary lacrimal sac tumors with extension into the neighboring tissues. METHODS: A retrospective interventional study was performed on all patients with lacrimal sac tumors treated with the endoscopy-assisted modified Weber-Ferguson approach between January 2010 and June 2022 at the Shanghai Ninth People's Hospital, China. Data assessed include demographics, clinical presentations, imaging features, surgical techniques, histopathology, adjuvant modalities of management, complications, and outcomes. RESULTS: A total of 13 patients were included in the analysis. Epiphora and palpable mass lesion were the presenting complaint in 84.6% (11/13) of the patients. Nearly half of the patients (46.1%, 6/13) were misdiagnosed as lacrimal duct obstruction. All the lacrimal sac tumors in the present series showed uneven enhancement on T1-weighted MRI imaging. Postoperatively, 84.6% (11/13) patients recovered well with excellent esthetics and were disease-free after a mean follow-up of 58.6 months. Two patients who underwent additional exenteration developed recurrence and succumbed (at 41 and 96 months follow up) while they were on palliative chemoradiation. CONCLUSION: The endoscopic-assisted modified Weber-Fergusson surgical approach is effective in providing better visibility and accessibility to lacrimal sac tumors with extension into neighboring tissue.