OBJECTIVES:To identify drug-associated risk signals for neovascular age-related macular degeneration (nAMD) and explore their biological basis. METHODS:We analysed the US FDA Adverse Event Reporting System (FAERS) to detect drugs with disproportionate nAMD reporting. Drug targets were mapped and causality was assessed by integrating summary-based Mendelian randomisation (SMR) and colocalisation analyses using cis-pQTL data. Single-cell RNA sequencing from nAMD patients evaluated cell type-specific gene expression. Protein-protein interaction and pathway enrichment analyses elucidated underlying mechanisms. RESULTS:FAERS analysis identified five drugs (apixaban, carbamazepine, latanoprost, rituximab and semaglutide) significantly associated with higher reporting risks of nAMD. SMR implicated six genes (IGFBP6, MAPKAPK2, NFKB1, RGMA, RNASE1 and WARS1) in nAMD risk, with evidence supporting colocalisation for WARS1. Most candidate genes were predominantly expressed in vascular remodelling endothelial cells, while WARS1 was also highly specific to monocytes. Enrichment analysis highlighted their critical involvement in immune and inflammatory responses, particularly within the Toll-like receptor, TNF and NF-kappa B signalling pathways. CONCLUSIONS:This study suggests a potential association between specific drugs and nAMD and reveals six genes as their possible molecular basis, thereby providing prioritised candidate targets and testable biological hypotheses for subsequent experimental validation.

OBJECTIVE:To compare the efficacy and safety of 0.50% and 0.75% pilocarpine ophthalmic solutions for treating presbyopia. METHODS:In this prospective study, 22 presbyopic subjects (44 eyes) were assigned to use 0.50% or 0.75% pilocarpine bilaterally, once daily for 2 weeks. Primary outcomes included distance-corrected intermediate visual acuity (DCIVA) at 66 cm and distance-corrected near visual acuity (DCNVA) at 40 cm under photopic and mesopic conditions, pupil size, refractive error, intraocular pressure (IOP) and patient-reported adverse events. Assessments were conducted at baseline, day 1 (after 1 and 6 h) and week 2 (after 1 h). RESULTS:No serious adverse events occurred. Neither formulation affected IOP or refractive error significantly. Pupil constriction was greater in the 0.75% group than the 0.50% group (2.8 ± 1.1 vs. 2.0 ± 0.8 mm, p = 0.02). After 2 weeks, the gain in photopic DCNVA was 0.18 logMAR for both concentrations (p = 0.70). The respective gain in visual acuity measures for the 0.75% and 0.50% groups was: mesopic DCNVA, 0.14 and 0.19 logMAR (p = 0.25); photopic DCIVA, 0.14 and 0.09 logMAR (p = 0.02); mesopic DCIVA, 0.12 and 0.10 logMAR (p = 0.18). CONCLUSION:Both 0.50% and 0.75% pilocarpine improved visual performance in presbyopia significantly, suggesting it is a promising treatment option. CLINICAL TRIAL REGISTRATION:Chinese Clinical Trial Registry (ChiCTR), 2023/3/2, No.ChiCTR2300068971.

Introduction:Skin squamous cell carcinoma (SCC) arises from dysregulated epidermal homeostasis characterized by aberrant keratinocyte proliferation and pathological angiogenesis. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) functions as a critical suppressor of cap-dependent translation by interacting with eIF4E, thereby constraining protein synthesis and cell growth. However, its role in SCC remains elusive. Methods:To address the role of 4E-BP1 function in SCC pathogenesis, we employed a two-stage chemical carcinogenesis model in 4E-BP1-deficient mice. Results:4E-BP1-deficient mice exhibited a significantly increased papilloma burden compared to wild-type controls, accompanied by enhanced keratinocyte proliferation and augmented tumor vascularization. Analysis of human SCC specimens revealed elevated 4E-BP1 phosphorylation together with increased proliferative and angiogenic markers and activation of the mTOR signaling pathway, mirroring molecular features observed in 4E-BP1-deficient tumors. Discussion:Collectively, these findings establish 4E-BP1 as a tumor suppressor in skin carcinogenesis that constrains both proliferative and angiogenic processes, underscoring the contribution of dysregulated translation to SCC development.

Keratoconus is a progressive ocular disorder characterized by the cornea gradually thinning and protruding into a conical shape, resulting in distorted vision. The underlying pathogenesis of keratoconus is multifactorial and involves a loss of corneal collagen cross-linking, leading to structural instability and the conical deformation of the cornea. Currently, the mainstay treatments for keratoconus include surgical interventions, such as corneal cross-linking, and the use of contact lenses for vision correction. However, there are no approved direct pharmacological treatments available. In this review, we provide an overview of innovative medical therapies that target various pathogenic mechanisms of keratoconus. These treatments aim to enhance collagen cross-linking, reduce corneal degradation, and modulate inflammatory factors. Advances in drug formulations and delivery vehicles have played a significant role in the development of these novel treatments. Some of these therapies are in advanced stages of clinical development, demonstrating promising results, while others remain in preclinical stages. In addition to directly targeting the pathogenesis of keratoconus, preventive measures, such as medical treatments that reduce eye rubbing or mitigate corneal hydrops, have shown potential in halting disease progression and alleviating symptoms. This review aims to update the current landscape of medical treatments for keratoconus, offering insights into future noninvasive therapeutic approaches for managing this condition.

Satralizumab, an interleukin-6 receptor monoclonal antibody, is an established therapy for neuromyelitis optica spectrum disorder (NMOSD). While randomized trials have demonstrated their efficacy and short-term safety, real-world data characterizing report-level associations and severe adverse outcomes remain limited. We performed a retrospective pharmacovigilance study using the U.S. FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q3 2025. Disproportionality analyses (reporting odds ratios [RORs], information components [ICs]), subgroup analyses, co-medication analysis, time-to-onset evaluation, and multivariable logistic regression for most severe outcomes (death/life-threatening events) were conducted. Among 1174 satralizumab-related reports, infections were the most prominent signals, with key signals including atypical mycobacterial infection (ROR 109.24, 95

PURPOSE:Atropine is an important medicine for myopia control in clinical practice, yet individual therapeutic responses vary widely, potentially due to differences in metabolic processes. Atropinesterase (AE), the enzyme catalyzing atropine hydrolysis, may critically influence its bioavailability and efficacy. This study investigated the role of AE in intraocular atropine metabolism. METHODS:In total, 28 New Zealand White rabbits were screened for plasma AE activity using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). From these, 14 rabbits [7 AE-positive (AE+) and 7 AE-negative (AE-)] were selected for the drug administration study. A single 50-μL dose of 1% atropine sulfate was administered topically to the right conjunctival sac of each animal. Then 24 h post-administration, ocular tissues (including cornea, iris, retina, choroid, aqueous humor, vitreous, and anterior/posterior sclera) were collected. Tissue atropine concentrations were quantified by validated HPLC-MS/MS methods. For statistical analysis, tissue-specific atropine distributions were evaluated using generalized linear mixed-effects models. RESULTS:Briefly, 35.71% of rabbits were identified as AE+. AE activity significantly reduced atropine levels in aqueous humor (P = 0.001), iris (P = 0.030), choroid (P = 0.031), and vitreous (P = 0.001) in AE+ rabbits than in AE- rabbits. In both AE- and AE+ eyes, the top 3 atropine-concentrated tissues were anterior sclera, cornea, and posterior sclera. CONCLUSIONS:AE markedly accelerates intraocular atropine metabolism, leading to significant concentration disparities across ocular tissues. The metabolic principle revealed in rabbits-that higher enzymatic activity limits drug availability-likely applies to humans and offers a new perspective on interindividual efficacy variations of atropine in myopic children.

Background Postoperative endophthalmitis (POE) is a severe complication of intraocular surgery. This study aimed to evaluate the impact of a surgical safety intervention on the POE rate. Methods In late 2019, a multifaceted surgical safety intervention was established and implemented at the study hospital, targeting all staff involved in ophthalmic surgery. The intervention comprised five components: surgical safety visual cues, periodic training and educational meetings, regulation of surgical instruments, surface microbial sampling, and video-based performance review. We included all patients who underwent inpatient ophthalmic surgery between January 1, 2017 and December 31, 2023, and compared the POE incidence before (2017–2019) and after (2020–2023) implementation. Results A total of 191,657 patients were included. The POE incidence decreased by 64.4% after intervention (pre-intervention: 0.038% [27/71,978], 95% confidence interval [CI]: 0.025–0.055%; post-intervention: 0.013% [16/119,679], 95% CI: 0.008–0.022%; P < 0.001). Poisson regression confirmed a significant downward trend in annual POE incidence with continued implementation (incidence rate ratio [IRR] = 0.619, 95% CI: 0.523–0.733, P < 0.001). The highest POE incidence across the study period occurred in patients undergoing cataract and crystalline lens surgery (0.055% [15/27,098], 95% CI: 0.031–0.091%), and this subspecialty showed a more than six-fold reduction after intervention (pre: 0.132% [11/8344], 95% CI: 0.066–0.236%; post: 0.021% [4/18,754], 95% CI: 0.006–0.055%; P < 0.001). Conclusions Promoting surgical safety through a multifaceted approach is effective and sustainable in reducing the POE rate. This study offers a highly accessible intervention framework to improve the safety of ophthalmic surgeries.

To compare the efficacy and safety of 0.50

Background:The prospective prescription review system can improve prescription rationality, but its effectiveness in high-volume specialty care settings is not well established. Objective:We aimed to evaluate the effectiveness of the prospective prescription review system in reducing irrational prescriptions and to analyze factors associated with successful interception. Methods:This retrospective cohort study analyzed all outpatient and emergency prescriptions issued between January 1 and December 31, 2024, at an eye, ear, nose, and throat tertiary hospital in Shanghai, China. Among 2,559,342 prescriptions, 123,914 (4.84%) flagged as irrational by the prospective prescription review system were included. Results:The overall interception success rate was 32.99% (40,877/123,914). The prescription rationality rate increased from 95.23% (2,476,305/2,600,219) to 96.79% (2,477,144/2,559,342) after excluding intercepted prescriptions (P<.001). Higher review levels were strongly associated with higher interception success rates: 0.99% (517/52,146) for reminder, 54.2% (37,039/68,341) for warning, and 96.91% (3321/3427) for mandatory (P<.001). Revised prescriptions had a higher interception success rate than prescriptions without revision (35,008/50,418, 69.44% vs 5869/73,496, 7.99%; P<.001). Prescriptions without documented reasons showed a higher interception success rate than those with documented reasons (40,086/98,070, 40.87% vs 791/25,844, 3.06%; P<.001). Physician acceptance of pharmacist disapproval was associated with a successful interception rate of 85.63% (137/160), compared with 3.33% (2/60) when the disapproval was rejected (P<.001). Multivariable logistic regression showed that inappropriate dosage or frequency (odds ratio [OR] 3.11, 95% CI 2.99-3.24) and inappropriate prescription quantity (OR 2.09, 95% CI 2-2.18) were most likely to be intercepted, whereas inappropriate indications (OR 0.04, 95% CI 0.03-0.04) and radiation oncology (OR 0.01, 95% CI 0.01-0.02; P<.001) were more likely to be issued. Pharmacist-led rule revision for mometasone furoate nasal spray led to a 1000-fold increase in identified irrational prescriptions (from 2-4 per month to 3022 in May). The interrupted time series analysis showed that the April revision was associated with an immediate and statistically significant increase in the monthly overall interception success rate (intervention coefficient = 0.15; P =.005). Conclusions:The prospective prescription review system substantially reduced irrational prescriptions and improved prescription rationality. Higher review levels were associated with higher interception rates, and physicians' attitudes also played a critical role. Paired-organ dose standardization emerged as an important consideration in ophthalmology and otolaryngology practice. Collaboration between the prospective prescription review system and pharmacists is essential for optimizing prescription review outcomes.

OBJECTIVE:The influence of obesity on the interplay between Klotho and age-related hearing loss (ARHL) requires further exploration. This study investigates the impact of obesity on the correlation between Serum Klotho levels and ARHL prevalence in a large cohort. METHODS:The present study analyzed data from the National Health and Nutrition Examination Survey (NHANES) involving 3355 participants. Participants were stratified based on body mass index (BMI) into non-obese (BMI < 30 kg/m²) and obese (BMI ≥ 30 kg/m²) groups. We then assessed the interaction between serum Klotho levels and the risk of ARHL using multivariable logistic regression. Restricted cubic splines were employed to evaluate the dose-response relationship between serum Klotho and ARHL in both non-obese and obese groups. RESULTS:In non-obese participants, serum Klotho levels were significantly associated with ARHL in both univariate (OR = 0.84, 95 % CI 0.77-0.93, p < 0.001) and multivariable analyses (OR = 0.88, 95 % CI 0.79-0.99, p = 0.034). A restricted cubic spline model confirmed a linear relationship between serum Klotho and ARHL in this group (p for non-linearity = 0.969). Conversely, no significant association was found in obese participants. These findings underscore a persistent association between serum Klotho and ARHL in non-obese individuals after adjusting for confounding factors. CONCLUSION:Obesity appears to modulate the association between serum Klotho levels and age-related hearing loss, offering potential insights for improving prevention and management strategies for hearing impairment.

Cataracts remain the leading cause of blindness globally. They manifest as lens opacification triggered by various factors, leading to blurred vision. In severe cases, patients may eventually lose their vision entirely. There are many types of cataracts, and their pathogenesis has not been fully clarified. Currently, oxidative stress is widely acknowledged as the primary influencing factor. Pharmacological intervention remains a significant clinical challenge in cataract management. At present, there are no drugs on the market capable of truly reversing cataracts; existing medications can only alleviate the progression of the condition to a certain extent. Surgical treatment remains the only effective approach at this stage. However, economic limitations and the risks of postoperative complications hinder its accessibility for certain patient groups. The treatment of cataracts has consistently been a research hotspot in the field of ophthalmology. Current research mainly centers on two strategic approaches: optimizing surgical techniques alongside improved perioperative pharmaceutical regimens to minimize complications, and conducting basic researches on disease mechanisms to facilitate drug discovery. Effective drug treatment has long been a major gap in current clinical treatment. In recent years, significant progress has been achieved in the exploration of cataract mechanisms and the development of new drugs. Despite the remarkable advancements in uncovering cataract pathogenesis and identifying novel therapeutic targets in recent years, substantial challenges remain in translating these discoveries into clinically applicable medications. This article reviews the progress in mechanism research, the current state of pharmacological interventions, and the clinical research developments of several promising cataract drugs, aiming to provide the latest reference for the research and development of new cataract drugs.

BackgroundDistant metastasis is the main cause of treatment failure and death in patients with nasopharyngeal carcinoma (NPC). The aim of this study was to explore the risk factors for distant metastasis in NPC patients using machine learning (ML) methods.MethodsWe collected data from NPC patients who were treated at the Eye Ear Nose Throat Hospital of Fudan University between September 2017 and June 2024. Seven ML methods were employed to construct the predictive models. By comparing the predictive performance of different ML models, the best one was selected to establish a predictive model for distant metastasis of NPC. The SHapley Additive exPlanation (SHAP) method was utilized to ascertain the ranking of feature importance and to provide explanations for the predictive model.ResultsA total of 1,845 NPC patients were included in this study. Among the seven models, Logistic Regression (LR) performed best in the test dataset (Area Under the ROC Curve [AUC] = 0.8499). SHAP analysis indicated that the most important variables for distant metastasis in NPC patients were targeted therapy, immunotherapy, N stage, Epstein-Barr virus (EBV), hypertension, T stage, lymphocyte count (LY) and lactate dehydrogenase (LDH) level.ConclusionTargeted therapy, N stage, immunotherapy, EBV, hypertension, T stage, LY and LDH level are significantly associated with the risk of distant metastasis in NPC and could be used to identify high-risk populations for distant metastasis in NPC patients. For high-risk patients, early interventions such as targeted therapy and immunotherapy might be considered to reduce the risk of distant metastasis in NPC.

To objectively and subjectively assess eye drop instillation in patients with glaucoma, and identified factors associated with eye drop instillation failure. This cross-sectional observational study included patients who visited an outpatient clinic between August and November 2023. Patients were objectively assessed by observing a demonstration, and subjectively assessed through interview responses. A total of 187 individuals diagnosed with glaucoma participated, with an average age of 63.1 ± 10.5 years. During the demonstration, 84.5

BackgroundThe precise mechanisms by which alpha-lipoic acid (LA) alleviates nab-paclitaxel (nab-PTX)-induced peripheral neuropathy have yet to be fully elucidated. The objective of this study was to investigate the mechanisms underlying the neuroprotective effects of LA in mitigating nab-PTX-induced peripheral neuropathy.MethodsWe established a rat model of nab-PTX-induced peripheral neuropathy to evaluate the efficacy of LA. To systematically elucidate the mechanisms by which LA alleviates nab-PTX-induced peripheral neuropathy, we utilized an integrated approach that combined network toxicology and network pharmacology. Subsequently, molecular docking analysis was performed to assess the binding affinity of the LA to the target proteins involved in the key signaling pathway. Furthermore, experimental validation was conducted to confirm the role of the key signaling pathway in the neuroprotective mechanism of LA.ResultsLA was demonstrated to effectively alleviate nab-PTX-induced peripheral neuropathy. The network analysis indicated that LA ameliorated nab-PTX-induced peripheral neuropathy primarily through the AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, fluid shear stress and atherosclerosis, NOD-like receptor signaling pathway, and pathways of neurodegeneration - multiple diseases. The molecular docking indicated a potential impact of LA on the IL-17 signaling pathway. Further experiment validation revealed that nab-PTX activated the IL-17 signaling pathway, whereas LA could mitigate nab-PTX-induced peripheral neuropathy by inhibiting this pathway.ConclusionBy integrating network toxicology analysis, network pharmacology analysis, and experimental validation, this study provides a clearer understanding of the mechanisms by which LA ameliorates nab-PTX-induced peripheral neuropathy.

Objective: This study aimed to investigate the etiology, pathogens, antibiotic susceptibility, treatments, and factors influencing the visual prognosis of pediatric post-traumatic endophthalmitis (PTE) to provide valuable insights for clinical diagnosis and treatment. Results: A total of 301 children were included, with 142 (47.2%) cultures yielding positive results. Gram-positive cocci were the predominant pathogens (71.1%), with high sensitivity to vancomycin (95.4%). Pars plana vitrectomy (PPV) was performed in 216 eyes (71.8%), with emergency or immediate vitrectomy within 24 h of hospitalization performed on 171 eyes (56.8%). The first intravitreal antibiotic injection, consisting of ceftazidime and norvancomycin, was administered to 248 patients (82.4%). The absence of retinal detachment (OR, 0.191; 95% CI, 0.065-0.560; p = 0.002), normal intraocular pressure (OR, 1.894; 95% CI, 1.151-3.117; p = 0.012), and no lens extraction (OR, 0.187; 95% CI, 0.069-0.504; p < 0.001) were found to be independent factors associated with better visual outcomes (BCVA) in pediatric PTE patients. Methods: A retrospective analysis was conducted on pediatric PTE patients treated between January 2012 and June 2022. Data were collected on clinical characteristics, causative pathogens, antibiotic sensitivity, treatments, and visual outcomes. Conclusions: Gram-positive cocci are the most common pathogens in pediatric PTE, with early vitrectomy and intravitreal ceftazidime and norvancomycin being the most effective treatments. Favorable visual outcomes are strongly associated with the absence of retinal detachment, normal intraocular pressure, and no lens extraction. These findings highlight the need for timely surgical and antimicrobial interventions tailored to each patient to improve visual prognosis.

CLINICAL RELEVANCE:Accommodation is crucial for clear near vision and is predominantly affected by presbyopia. The ability to modulate accommodative function with eye drops could offer a pharmacological approach to manage presbyopia. BACKGROUND:To investigate the effects of different concentrations of pilocarpine eye drops on ocular accommodation in young volunteers. METHODS:In this prospective study, healthy volunteers with mild or moderate myopia with corrected visual acuity of no less than 20/20 were recruited. Participants underwent four visits for baselining and administration of low (0.75%), medium (1.00%), and high (1.25%) concentrations of pilocarpine eye drops respectively. One eye of each participant was chosen and analysed. Ophthalmologic examinations included objective and subjective refraction, corrected distance visual acuity, intraocular pressure, and pupil size. Accommodation was assessed using the WAM-5500 binocular autorefractor. Accommodation facility and the defocus curve were measured. RESULTS:Volunteers (n = 24, mean age 23.7 ± 1.5 years) with a mean spherical equivalent of -2.91 ± 1.54 dioptres (D) were recruited. No serious adverse events occurred. All pilocarpine concentrations showed similar pupil constriction without significant intraocular pressure changes (p > 0.05). Pilocarpine induced greater objective refraction changes with higher concentrations (-1.12 ± 1.07D, -1.56 ± 1.38D, -1.68 ± 1.60D for low, medium, and high concentrations, respectively; p < 0.01). Subjective refraction showed a similar dose-response. Accommodative response decreased significantly at the 20 cm stimulus for medium and high concentrations (p < 0.05). Corrected distance visual acuity improved beyond -1.00D to + 0.50D defocus after all three pilocarpines. Accommodative facility improved more by 1.25% than 0.75% (p = 0.04). CONCLUSIONS:Pilocarpine eye drops are effective in improving ocular accommodation, with higher concentrations leading to greater accommodative changes. Pilocarpine has potential for managing presbyopia.

Developing a mathematical model to predict the distribution and bioavailability of atropine in human eyes is an insight approach for clinical practice. This study aims to develop a human ocular physiologically based pharmacokinetic (PBPK) modeling for the ophthalmic drug atropine and explore possible mechanisms by which atropine reduces myopia progression in children. The Ocular Compartment Absorption and Transit (OCAT™) model was employed to describe the ocular distribution of atropine following administration at different dosages in both rabbits and humans. The PBPK model enables the extrapolation of pharmacokinetic characteristics among different species depending on theirphysiology and anatomy. The developed and validated OCAT-PBPK model demonstrated good agreement with observed data from rabbit ocular tissues and human aqueous humor. Fifty-eight percent of simulations fell within the standard deviation range of experimental data. The extrapolated human PBPK model for accurately predicted the ocular exposure and distribution following the administration of low-concentration atropine. This study confirms the performance of the ocular PBPK model in predicting ocular pharmacokinetic behavior among different species. Model’s predictions indicate that atropine shows significant potential to penetrate the posterior eye segment, providing underlying insights into its mechanisms of action in the eye.

The safety information of netarsudil primarily comes from clinical trials experience. This study aimed to explore the ocular and systemic safety of netarsudil through data mining the FDA Adverse Event Reporting System (FAERS) database. Adverse event (AE) reports submitted to FAERS between January 2018 and September 2024 were extracted. The reporting odd ratio was used to identify netarsudil-related AE signals. Subgroup analysis, time to onset (TTO) analysis and sensitivity analysis were conducted to comprehensively assess the safety profile of netarsudil. A total of 63 AE signals were identified. Thirty-eight were ocular AEs listed in netarsudil’s label, with conjunctival hyperemia, vision blurred and eye irritation ranking the top three in reporting frequency. Twenty-one were new ocular AE signals, including allergic blepharitis, eye pruritus, dacryostenosis, myopic shift, corneal hemorrhage, etc. The rest four were unexpected systemic AE signals, including hypersensitivity, swelling face, dermatitis allergic and dermatitis contact. Subgroup analysis showed that patients ≥ 65 years were more likely to develop inflammation-related AEs, whereas the other adult patients were more prone to experience cataract subcapsular, dry eye, refraction disorder and ocular discomfort. The median TTO of netarsudil-related AEs was 1 day (IQR: 0–13 days), with the majority of AEs (82.65

To identify novel susceptibility genes and drug targets for basal cell carcinoma (BCC). We performed a transcriptome-wide association study (TWAS) to identified the susceptibility genes and potential drug targets for BCC. The cross-tissue TWAS was conducted to discover the candidate genes for BCC. Functional Summary-based Imputation (FUSION) analysis was used to validate these genes in the single tissues. Multimarker Analysis of Genomic Annotation (MAGMA) was employed to further screen candidate genes. Summary data-based Mendelian randomization (SMR) and colocalization analyses were applied to infer causal relationships between candidate genes and BCC. The expression pattern of the identified genes in single-cell types was also investigated. Function, pathway enrichment and disease connection analyses were performed to understand the biological implication of identified genes. Additionally, druggability of the identified genes was evaluated to discover potential candidate drugs for BCC. Ninety-five genes were identified by cross-tissue TWAS analysis. Among them, 24 genes were confirmed by FUSION and MAGMA methods. Ten genes were further confirmed by SMR and colocalization analyses. Three genes were replicated by using another GWAS data. The potential interacting gene networks constructed with these identified genes were mainly involved in viral life cycle-HIV-1, GABAergic synapse, nicotine addiction, ether lipid metabolism, and mineral absorption pathways. AN-9 and amooranin might be candidate drugs for BCC. We have identified 10 susceptibility genes associated with BCC risk, which might deepen our comprehension of BCC pathogenesis and illuminating new avenues for therapeutic and preventive drug development.

B-cell lymphoma extra large (BCL-XL) is an important anti-apoptotic protein of BCL-2 family. It is frequently overexpressed in various hematologic and solid tumors, often positively correlated with chemotherapy resistance in tumors. However, the clinical development of the small molecule BCL-XL inhibitor ABT-263 has been challenged on account of its on-target and dose-limiting toxicity. We have previously reported that SIAIS361034, a Proteolysis Targeting Chimera (PROTAC) specifically targeting BCL-XL to cereblon (CRBN) E3 ligase for degradation, represents a novel Hedgehog (Hh) inhibitor and inhibits tumors addiction to the Hh pathway activity with little influence on platelets. However, the inhibitory effect of SIAIS361034 on tumors independent on Hh pathway remains to be fully elucidated. In the present study, we explored its inhibitory effect on the growth of hematologic malignancies and small cell lung cancer (SCLC). Our results showed that SIAIS361034 selectively and efficiently degraded BCL-XL in tumor cells via a CRBN- and proteasome-dependent manner, with the halfmaximal degradation concentration (DC50) of below 10 nM. Moreover, SIAIS361034 effectively killed BCL-XLdependent MOLT-4 acute lymphoblastic leukemia (ALL) cells in vitro, with the half-maximal effective concentration (EC50) of 16.09 nM, and triggered apoptosis of MOLT-4 cells. SIAIS361034 obviously inhibited the growth of MOLT-4 xenografts with tumor growth inhibition rate (TGI) of 96.1 %, and did not induce acute and severe thrombocytopenia at therapeutic dosages. Furthermore, SIAIS361034 potently boosted the response of SCLC cells to Paclitaxel (PTX) and yielded more apoptosis in vitro by concurrently reduced the expression of BCL-XL and myeloid cell leukemia 1 (MCL-1), respectively. Meanwhile, we observed that SIAIS361034 significantly synergized with PTX to inhibit the growth of SCLC xenografts in vivo, without causing exacerbating PTX-induced neutropenia. Taken together, SIAIS361034, shows great potentiality in killing tumors cells, both as a monotherapy and in combination with PTX.