Gender-specific prognosis models reveal differences in subarachnoid hemorrhage patients between sexes.

BACKGROUND: Subarachnoid hemorrhage (SAH) represents a severe stroke subtype. Our study aims to develop gender-specific prognostic prediction models derived from distinct prognostic factors observed among different-gender patients. METHODS: Inclusion comprised SAH-diagnosed patients from January 2014 to March 2016 in our institution. Collected data encompassed patients' demographics, admission severity, treatments, imaging findings, and complications. Three-month post-discharge prognoses were obtained via follow-ups. Analyses assessed gender-based differences in patient information. Key factors underwent subgroup analysis, followed by univariate and multivariate analyses to identify gender-specific prognostic factors and establish/validate gender-specific prognostic models. RESULTS: A total of 929 patients, with a median age of 57 (16) years, were analyzed; 372 (40%) were male, and 557 (60%) were female. Differences in age, smoking history, hypertension, aneurysm presence, and treatment interventions existed between genders (p < 0.01), yet no disparity in prognosis was noted. Subgroup analysis explored hypertension history, aneurysm presence, and treatment impact, revealing gender-specific variations in these factors' influence on the disease. Screening identified independent prognostic factors: age, SEBES score, admission GCS score, and complications for males; and age, admission GCS score, intraventricular hemorrhage, treatment interventions, symptomatic vasospasm, hydrocephalus, delayed cerebral ischemia, and seizures for females. Evaluation and validation of gender-specific models yielded an AUC of 0.916 (95% CI: 0.878-0.954) for males and 0.914 (95% CI: 0.885-0.944) for females in the ROC curve. Gender-specific prognostic models didn't significantly differ from the overall population-based model (model 3) but exhibited robust discriminative ability and clinical utility. CONCLUSION: Variations in baseline and treatment-related factors among genders contribute partly to gender-based prognosis differences. Independent prognostic factors vary by gender. Gender-specific prognostic models exhibit favorable prognostic performance.

Comparison of conventional (basketing + dusting) and Moses (pop-dusting) holmium lasers during flexible ureteroscopy in the treatment of renal stones between 2 and 3 cm: a randomized clinical trial.

To investigate the feasibility of conventional (basketing + dusting) and Moses (pop-dusting) holmium lasers during flexible ureteroscopy (FURS) in the treatment of 2-3 cm renal calculi and to compare the efficiency and safety of the two methods, a total of 230 patients with 2-3 cm kidney stones who underwent FURS were randomly divided into the conventional group and the Moses group. The mode of lithotripsy in the conventional group was fragmentation and dusting. The mode of lithotripsy in the Moses group was dusting and pop-dusting. Clinical and perioperative variables and complications were compared between the two cohorts. Multivariate analyses of factors contributing to the stone-free rate (SFR) and operation time were performed. No statistically significant differences were found in the demographics, renal stone-related data, SFR, or complications between the cohorts. The laser energy was higher in the Moses cohort than in the conventional cohort (119.3 ± 15.2 vs. 92.8 ± 15.1 kJ; P < 0.001), and the operation time was shorter in the Moses cohort than in the conventional cohort (99.5 ± 18.9 vs. 105.3 ± 13.7 min; P = 0.009). When there was isolated stone, the operation time was shorter in the Moses cohort than in the conventional cohort (99.6 ± 17.5 vs. 111.4 ± 10.7 min; P < 0.001), while there was no significant difference between the two cohorts when there were multiple stones (99.5 ± 20 vs. 101.2 ± 14 min; P = 0.415). Multivariate analyses found that an increase in stone volume can decrease the SFR and prolong the operation time, and use of a Moses laser can shorten the operation time. Both holmium laser modes during FURS can effectively treat 2-3 cm renal calculi. The Moses mode is recommended as the first choice for the treatment of isolated 2-3 cm renal stones. When treating multiple stones, the efficiency of these two laser modalities is the same. TRIAL REGISTRATION: ChiCTR2200056091.

Bone marrow lesion and 5-year incident joint surgery in patients with knee osteoarthritis: a retrospective cohort study.

BACKGROUND: It is beneficial for society to discover the risk factors associated with surgery and to carry out some early interventions for patients with these risk factors. Few studies specifically explored the relationship between bone marrow lesions (BMLs) and long-term incident joint surgery. OBJECTIVE: To investigate the association between BML severity observed in knee osteoarthritis (OA) patients' first MRI examination and incident knee surgery within 5 years. Additionally, to assess the predictive value of BMLs for the incident knee surgery. DESIGN: Retrospective cohort study. METHODS: We identified patients diagnosed with knee OA and treated at our institution between January 2015 and January 2018, and retrieved their baseline clinical data and first MRI examination films from the information system. Next, we proceeded to determine the Max BML grades, BML burden grades and Presence BML grades for the medial, lateral, patellofemoral, and total compartments, respectively. Multi-variable logistic regression models examined the association of the BML grades with 5-year incident knee surgery. Positive and negative predictive values (PPVs and NPVs) were determined for BML grades referring to 5-year incident knee surgery. RESULTS: Totally, 1011 participants (knees) were found eligible to form the study population. Within the 5 years, surgery was performed on 74 knees. Max BML grade 2 and grade 3 of medial, patellofemoral and total compartments were strongly and significantly associated with incident surgery. None of the BML grades from lateral compartment was associated with incident surgery. The PPV was low and NPV was high for BMLs. CONCLUSIONS: BMLs found in the first MRI examination were associated with 5-year incident joint surgery, except for those allocated in lateral compartments. The high NPVs imply that patients without BMLs have a low risk of requiring surgery within 5 years.

Atrial lead perforation early after device implantation-a case report and literature review.

We report three patients with screw-in lead perforation in the right atrial free wall not long after device implantation. All the patients complained of intermittent stabbing chest pain associated with deep breathing during the implantation. The "dry" epicardial puncture was utilized to avoid hemopericardium during lead extraction in the first case. The atrial electrode was repositioned in all cases and replaced by a new passive fixation lead in two patients with resolution of the pneumothorax or pericardial effusion. A literature review of 50 reported cases of atrial lead perforation was added to the findings in our case report.

Cascaded All-Fiber Gas Raman Laser Oscillator in Deuterium-Filled Hollow-Core Photonic Crystal Fibers.

Hollow-core photonic crystal fibers (HC-PCFs) provide an ideal transmission medium and experimental platform for laser-matter interaction. Here, we report a cascaded all-fiber gas Raman laser based on deuterium (D2)-filled HC-PCFs. D2 is sealed into a gas cavity formed by a 49 m-long HC-PCF and solid-core fibers, and two homemade fiber Bragg gratings (FBGs) with the Raman and pump wavelength, respectively, are further introduced. When pumped by a pulsed fiber amplifier at 1540 nm, the pure rotational stimulated Raman scattering of D2 occurs inside the cavity. The first-order Raman laser at 1645 nm can be obtained, realizing a maximum power of ~0.8 W. An all-fiber cascaded gas Raman laser oscillator is achieved by adding another 1645 nm high-reflectivity FBG at the output end of the cavity, reducing the peak power of the cascaded Raman threshold by 11.4%. The maximum cascaded Raman power of ~0.5 W is obtained when the pump source is at its maximum, and the corresponding conversion efficiency inside the cavity is 21.4%, which is 1.8 times that of the previous configuration. Moreover, the characteristics of the second-order Raman lasers at 1695 nm and 1730 nm are also studied thoroughly. This work provides a significant method for realizing all-fiber cascaded gas Raman lasers, which is beneficial for expanding the output wavelength of fiber gas lasers with a good stability and compactivity.

Deep learning model for the detection of prostate cancer and classification of clinically significant disease using multiparametric MRI in comparison to PI-RADs score.

BACKGROUND: The Prostate Imaging Reporting and Data System (PI-RADS) is an established reporting scheme for multiparametric magnetic resonance imaging (mpMRI) to distinguish clinically significant prostate cancer (csPCa). Deep learning (DL) holds great potential for automating csPCa classification on mpMRI. METHOD: To compare the performance between a DL algorithm and PI-RADS categorization in PCa detection and csPCa classification, we included 1,729 consecutive patients who underwent radical prostatectomy or biopsy in Tongji hospital. We developed DL models by integrating individual mpMRI sequences and employing an ensemble approach for distinguishing between csPCa and CiSPCa (specifically defined as PCa with a Gleason group 1 or benign prostate disease, training cohort: 1,285 patients vs. external testing cohort: 315 patients). RESULTS: DL-based models exhibited higher csPCa detection rates than PI-RADS categorization (area under the curve [AUC]: 0.902; sensitivity: 0.728; specificity: 0.906 vs. AUC: 0.759; sensitivity: 0.761; specificity: 0.756) (P < 0.001) Notably, DL networks exhibited significant strength in the prostate-specific antigen (PSA) arm < 10 ng/ml compared with PI-RADS assessment (AUC: 0.788; sensitivity: 0.588; specificity: 0.883 vs. AUC: 0.618; sensitivity: 0.379; specificity: 0.763) (P = 0.041). CONCLUSIONS: We developed DL-based mpMRI ensemble models for csPCa classification with improved sensitivity, specificity, and accuracy compared with clinical PI-RADS assessment. In the PSA-stratified condition, the DL ensemble model performed better than PI-RADS in the detection of csPCa in both the high PSA group and the low PSA group.

EXO1/P53/SREBP1 axis-regulated lipid metabolism promotes prostate cancer progression.

Prostate cancer (PCa) is one of the most common malignant tumors affecting the male genitourinary system. However, there is currently a lack of effective treatments for patients with advanced prostate cancer, which significantly impacts men's overall health. Exonuclease 1 (EXO1), a protein with mismatch repair and recombination functions, has been found to play a vital role in various diseases. In our study, we discovered that EXO1 acts as a novel biomarker of PCa, which promotes prostate cancer progression by regulating lipid metabolism reprogramming in prostate cancer cells. Mechanistically, EXO1 promotes the expression of SREBP1 by inhibiting the P53 signaling pathway. In summary, our findings suggest that EXO1 regulated intracellular lipid reprogramming through the P53/SREBP1 axis, thus promoting PCa progression. The result could potentially lead to new insights and therapeutic targets for diagnosing and treating PCa.

A nanoporous organic polymer using 1, 3-dibromoadamantane as a crosslinker for adsorption/separation of benzene and cyclohexane.

The development of nanoporous organic polymers with cycloaliphatic components for effective benzene (Bz) and cyclohexane (Cy) adsorption/separation poses a significant challenge. This work focuses on synthesizing NOP-Ad-1, a nanoporous organic polymer derived from a Friedel-Crafts reaction between cycloaliphatic 1,3-dibromadantane and aromatic hexaphenylbenzene. At 298 K and P/P0 = 0.95, NOP-Ad-1 can uptake 989 mg g-1 benzene and 441 mg g-1 cyclohexane. Moreover, as the benzene vapor ratio increased from 20% to 80%, the Bz/Cy selectivity of NOP-Ad-1 gradually decreased from 1.75 to 1.24. These findings highlight the potential application of NOP-Ad-1 in the adsorption/separation of Bz/Cy mixtures.

Anti-depressant medication use is a risk factor for incident knee surgery and opioid use in patients with knee osteoarthritis.

Objective: To investigate whether depression and exposure to anti-depressant medication are independent risk factors for incident knee surgery and opioid use in knee osteoarthritis (KOA) patients. Methods: We identified all patients who visited our outpatient department and were clinically diagnosed with KOA between January 2010 and January 2018. We retrieved their demographic, clinical, and radiographic data from the database of our hospital. Next, we analyzed the effect of depression and anti-depressant medication on the incident knee surgery and opioid use in KOA patients. Results: A total of 4,341 KOA patients were found eligible to form the study population. Incident knee surgery and opioid use for the purpose of treating osteoarthritis were observed in 242 and 568 patients, respectively. Incident knee surgery was significantly associated with age (OR [95%CI], 1.024 [1.009-1.039], P = 0.002), BMI (OR [95%CI], 1.090 [1.054-1.128], P < 0.001), baseline K-L grade 3 (OR [95%CI], 1.977 [1.343-2.909], P = 0.001), baseline K-L grade 4 (OR [95%CI], 1.979 [1.241-3.157], P = 0.004), depression (OR [95%CI], 1.670 [1.088-2.563], P = 0.019), and exposure to anti-depressant medication (OR [95%CI], 2.004 [1.140-3.521], P = 0.016). Incident opioid use was significantly associated with depression (OR [95%CI], 1.554 [1.089-2.215], P = 0.015) and exposure to anti-depressant medication (OR [95%CI], 1.813 [1.110-2.960], P = 0.017). Conclusion: Depression and anti-depressant drug exposure were independently associated with incident knee surgery, highlighting the need for more attention on comorbid depression in KOA management.

Poly (ADP-ribose) Polymerase Inhibitors in Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis of Randomized Controlled Trials.

Context: Several recent randomized controlled trials (RCTs) have reported on the survival benefits of poly (ADP-ribose) polymerase inhibitors (PARPi) compared to standard-of-care (SOC) treatment (enzalutamide, abiraterone, or docetaxel) in patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is a limited integrated analysis of high-quality evidence comparing the efficacy and safety of PARPi and SOC treatments in this context. Objective: This study aims to comprehensively analyze the survival benefits and adverse events associated with PARPi and SOC treatments through a head-to-head meta-analysis in mCRPC. Evidence acquisition: A systematic review search was conducted in PubMed, Embase, Clinical trials, and the Central Cochrane Registry in July 2023. RCTs were assessed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review was prospectively registered on PROSPERO (CRD42023441034). Evidence synthesis: A total of 8 studies, encompassing 2341 cases in the PARPi treatment arm and 1810 cases in the controlled arm, were included in the qualitative synthesis. The hazard ratio (HR) for radiographic progression-free survival (rPFS) and overall survival (OS) were 0.74 (95% CI, 0.61-0.90) and 0.89 (95% CI, 0.80-0.99), respectively, in the intention-to-treatment patients. For subgroup analysis, HRs for rPFS and OS in the BRCA-mutated subgroup were 0.39 (95% CI, 0.28-0.55) and 0.62 (95% CI, 0.38-0.99), while in the HRR-mutated subgroup, HR for rPFS was 0.57 (95% CI, 0.48-0.69) and for OS was 0.77 (95% CI, 0.64-0.93). The odds ratio (OR) for all grades of adverse events (AEs) and AEs with severity of at least grade 3 were 3.86 (95% CI, 2.53-5.90) and 2.30 (95% CI, 1.63-3.26), respectively. Conclusions: PARP inhibitors demonstrate greater effectiveness than SOC treatments in HRR/BRCA-positive patients with mCRPC. Further research is required to explore ways to reduce adverse event rates and investigate the efficacy of HRR/BRCA-negative patients.

Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery.

Thalidomide and its analogs are molecular glues (MGs) that lead to targeted ubiquitination and degradation of key cancer proteins via the cereblon (CRBN) E3 ligase. Here, we develop a direct-to-biology (D2B) approach for accelerated discovery of MGs. In this platform, automated, high throughput, and nano scale synthesis of hundreds of pomalidomide-based MGs was combined with rapid phenotypic screening, enabling an unprecedented fast identification of potent CRBN-acting MGs. The small molecules were further validated by degradation profiling and anti-cancer activity. This revealed E14 as a potent MG degrader targeting IKZF1/3, GSPT1 and 2 with profound effects on a panel of cancer cells. In a more generalized view, integration of automated, nanoscale synthesis with phenotypic assays has the potential to accelerate MGs discovery.

Alcoholic drink produced by pea is a risk factor for incident knee surgery in patients with knee osteoarthritis.

Objective: The objective of this study is to investigate whether alcohol exposure and specific alcoholic drinks are independent risk factors for incident knee surgery in knee osteoarthritis (KOA) patients. Methods: We identified all patients who were clinically diagnosed as KOA between January 2010 and January 2018 in our outpatient department. Demographic, clinical, and radiographic data were collected from the database of our hospital. Next, we analyzed the association between alcohol consumption and incident knee surgery. Results: A total of 4,341 KOA patients completed the current study and were included in the final analysis. Incident knee surgery for the purpose of treating osteoarthritis was observed in 242 patients. Incident knee surgery was significantly associated with age (OR [95%CI], 1.023 [1.009-1.039], P = 0.002), BMI (OR [95%CI], 1.086 [1.049-1.123], P < 0.001), baseline K-L grade 3 (OR [95%CI], 1.960 [1.331-2.886], P = 0.001), baseline K-L grade 4 (OR [95%CI], 1.966 [1.230-3.143], P = 0.005), 7.1-14 drinks per week (OR [95%CI], 2.013 [1.282-3.159], P = 0.002), >14 standard drinks per week (OR [95%CI], 2.556 [1.504-4.344], P = 0.001), and the most common alcoholic drink produced by pea (OR [95%CI], 3.133 [1.715-5.723], P < 0.001). Conclusion: KOA patients who consumed more than seven standard drinks per week were at substantial risk of incident knee surgery. In addition, alcoholic drink produced by pea is also an independent risk factor.

Long-Read Sequencing Reveals Alternative Splicing-Driven, Shared Immunogenic Neoepitopes Regardless of SF3B1 Status in Uveal Melanoma.

Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, the identification of functional tumor-specific neoepitopes remains challenging. In addition to the most common source, single-nucleotide variants (SNV), alternative splicing (AS) represents another rich source of neoepitopes and can be utilized in cancers with low SNVs such as uveal melanoma (UM). UM, the most prevalent adult ocular malignancy, has poor clinical outcomes due to a lack of effective therapies. Recent studies have revealed the promise of harnessing tumor neoepitopes to treat UM. Previous studies have focused on neoepitope targets associated with mutations in splicing factor 3b subunit 1 (SF3B1), a key splicing factor; however, little is known about the neoepitopes that are commonly shared by patients independent of SF3B1 status. To identify the AS-derived neoepitopes regardless of SF3B1 status, we herein used a comprehensive nanopore long-read-sequencing approach to elucidate the landscape of AS and novel isoforms in UM. We also performed high-resolution mass spectrometry to further validate the presence of neoepitope candidates and analyzed their structures using the AlphaFold2 algorithm. We experimentally evaluated the antitumor effects of these neoepitopes and found they induced robust immune responses by stimulating interferon (IFN)γ production and activating T cell-based UM tumor killing. These results provide novel insights into UM-specific neoepitopes independent of SF3B1 and lay the foundation for developing therapies by targeting these actionable neoepitopes.

PUF60 promotes cell cycle and lung cancer progression by regulating alternative splicing of CDC25C.

Alternative splicing (AS) has been implicated in cell cycle regulation and cancer, but the underlying mechanisms are poorly understood. The poly(U)-binding splicing factor 60 (PUF60) is essential for embryonic development and is overexpressed in multiple types of cancer. Here, we report that PUF60 promotes mitotic cell cycle and lung cancer progression by controlling AS of the cell division cycle 25C (CDC25C). Systematic analysis of splicing factors deregulated in lung adenocarcinoma (LUAD) identifies that elevated copy number and expression of PUF60 correlate with poor prognosis. PUF60 depletion inhibits LUAD cell-cycle G2/M transition, cell proliferation, and tumor development. Mechanistically, PUF60 knockdown leads to exon skipping enriched in mitotic cell cycle genes, including CDC25C. Exon 3 skipping in the full-length CDC25C results in nonsense-mediated mRNA decay and a decrease of CDC25C protein, thereby inhibiting cell proliferation. This study establishes PUF60 as a cell cycle regulator and an oncogenic splicing factor in lung cancer.

Regulation of alternative splicing: Functional interplay with epigenetic modifications and its implication to cancer.

Eukaryotic gene expression is intricately regulated at multiple levels. The protein-coding genes are first transcribed as pre-mRNAs in the nucleus and undergo a series of RNA processing steps before being transported into the cytoplasm for translation. During RNA processing, most human genes (>95%) undergo alternative splicing to generate multiple mRNA isoforms from a single gene, which effectively diversifies the genome complexity. Since the splicing of most genes occurs co-transcriptionally, the regulation layers of gene expression often show functional interactions with each other. In this review, we provide a brief overview of alternative splicing regulation in three different layers (controlled by the splicing machinery, transcription process, and chromatin structure), emphasizing the regulatory roles of epigenetic modifications and the crosstalk between these layers. Specifically, we categorize the major effects of the epigenetic modifications on alternative splicing into three different types: by affecting transcription rate, splicing factor recruitment, or the expression/activity of splicing factor. The dysregulation of epigenetics and splicing are extremely common in cancer, we also discuss the potential mechanisms of how epigenetic changes can lead to splicing dysregulation and their functional consequences. We aim to provide insights into the complicated regulation of different gene expression layers, which will shed light on the novel approaches to modulate disease-related splicing dysregulation. This article is categorized under: RNA Processing > 3' End Processing RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease.

Experimental investigation of the optimal driving pressure for a larger-volume controllable jet injection system.

Jet injection technology has become the alternative drug delivery method of conventional needle-based injection due to its obvious advantages. In order to meet the demand for larger volume injection, the pneumatic jet injection systems have efficiently administrated vaccine up to 1 mL in human. Our recent study has also demonstrated that controlling the driving pressure enabled the pneumatic jet injection system to deliver larger volumes of drugs to target sites at desired rates and times. This work continues to explore the optimal two-phase driving pressure combination with better injection efficiency for typical larger-volume (1.0 mL) jet injection with controllable pneumatic jet injection system. Under the combination of a first phase driving pressure of 1.00 MPa and a second phase driving pressure ranging from 0.25 to 0.90 MPa, dynamic characteristics, dispersion characteristics and pharmacokinetic characteristics of this controllable jet injection system were quantitatively analyzed. In all experiments, it was confirmed that the optimal driving pressure combination of 1.0 mL ejection volume was close to (1.00-0.50) MPa. That is, the injection velocities of 151.85 m/s and 102.01 m/s for the first and second phase respectively facilitated better injection performance with a controlled release of 1.0 mL ejection volume. This strategy is practical for facilitating the clinical application of large-volume controllable jet injection systems.

An Inflammatory Checkpoint Generated by IL1RN Splicing Offers Therapeutic Opportunity for KRAS-Mutant Intrahepatic Cholangiocarcinoma.

KRAS mutations are causally linked to protumor inflammation and are identified as driving factors in tumorigenesis. Here, using multiomics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS-mutant iCCA. In KRAS-mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant antitumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS-mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in patients with KRAS-mutant iCCA were significantly associated with superior response to anti-PD-1 immunotherapy. SIGNIFICANCE: This work describes a novel inflammatory checkpoint mediated by IL1RN alternative splicing variants that may serve as a promising basis to develop therapeutic options for KRAS-mutant iCCA and other cancers. This article is featured in Selected Articles from This Issue, p. 2109.

RBM10 Loss Promotes EGFR-Driven Lung Cancer and Confers Sensitivity to Spliceosome Inhibition.

In lung adenocarcinoma (LUAD), loss-of-function mutations in the splicing factor RBM10 frequently co-occur with oncogenic EGFR mutations. A detailed understanding of the functional consequences and therapeutic impact of RBM10 loss in EGFR-mutant LUAD could help identify more effective treatment strategies. Here, analysis of LUAD data sets indicated that RBM10 mutations are mutually exclusive with mutations in the tumor suppressor gene TP53. In an EGFR-driven LUAD mouse model, lung-specific ablation of either Rbm10 or Trp53 similarly promoted tumor development, leading to overlapping gene expression changes enriched in cancer-related pathways. RBM10 loss induced key RNA splicing changes concordant in mice and LUAD patients. Importantly, RBM10 deficiency conferred high sensitivity to spliceosome inhibition in EGFR-mutated LUAD cells. Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in RBM10-deficient LUAD. Together, this study establishes RBM10 as a tumor suppressor akin to p53 and provides a therapeutic strategy of targeting the splicing machinery in EGFR-driven LUAD. SIGNIFICANCE: Loss of the splicing factor RBM10 is mutually exclusive with p53 mutations, promotes tumorigenesis, and enhances the efficacy of spliceosome inhibition in EGFR-driven lung cancer.