Determining the Optimal Dosage of Dexmedetomidine for Smooth Emergence in Older Patients Undergoing Spinal Surgery: A Study of 44 Cases.

BACKGROUND Emergence agitation, or delirium, occurs during early recovery from general anesthesia and involves disorientation, excitation, and uncontrolled physical movements. Dexmedetomidine is an alpha agonist that has sedative, anxiolytic, analgesic, and sympatholytic activities and is used as a continuous infusion to prevent emergence agitation. This study aimed to evaluate patients aged 65 years and older undergoing general anesthesia to determine the 90% effective dose (ED90) of dexmedetomidine continuous intraoperative infusion to prevent emergence agitation. MATERIAL AND METHODS We enrolled 44 patients aged 65 years and older undergoing spinal surgery under general anesthesia. Dexmedetomidine administration commenced 30 minutes before surgery completion, with a predetermined infusion dose (µg/kg/h), without a loading dose. The initial dose was 0.2 µg/kg/h, and subsequent step size was ±0.05 µg/kg/h. We tried to find ED90 of dexmedetomidine using the biased-coin design. Vital signs, extubation quality scores, extubation-related complications, and postoperative outcomes were monitored. RESULTS Dexmedetomidine ED90 for smooth emergence in older patients was 0.34 µg/kg/h. Peri-extubation vital signs remained within 20% of baseline values, without requiring pharmacological intervention. No hypoxia, hypoventilation, or post-extubation agitation occurred. In the recovery room, 1 patient briefly exhibited excitement but quickly calmed. Nine patients initially unresponsive in the recovery room fully awoke and were promptly discharged. CONCLUSIONS For older patients who are vulnerable to adverse effects of anesthetics and opioids, dexmedetomidine enables gentle awakening without adverse vital sign changes, respiratory depression, excessive sedation, or emergence agitation (ED90=0.34 µg/kg/h). Further studies should involve a larger patient cohort, considering diverse medical conditions in older individuals.

Quantification of tire wear particles in road dust based on synthetic/natural rubber ratio using pyrolysis-gas chromatography-mass spectrometry across diverse tire types.

Increase in road traffic leads to increased concentrations of tire-wear particles (TWPs), a prominent source of microplastics from vehicles, in road dust. These particles can re-enter the atmosphere or move into aquatic ecosystems via runoff, impacting the environment. Consequently, accurately assessing and managing TWP levels in road dust is crucial. However, the ISO method (ISO/TS 20593 and 21396) uses a constant ratio of styrene-butadiene rubber (SBR) to natural rubber (NR) for all tires, disregarding the variability in tire composition across different types and brands. Our study found substantial SBR content (15.7 %) in heavyweight truck tires, traditionally believed to be predominantly NR. We evaluated the SBR/NR content in 15 tire types and proposed a method to more accurately evaluate TWP concentrations in road dust from five different locations. Our findings suggest that the conventional ISO method may underestimate the concentrations of TWP due to its reliance on a static ratio of SBR/NR. This study underscores the necessity for a more flexible approach that can adapt to the variability in SBR and NR content across different tire types. By delineating the limitations inherent in current assessment methods, our research contributes to a more adaptable understanding of TWP concentrations in road dust. This advancement prompts the development of a revised methodology that more accurately reflects the diverse compositions of tire rubber in environmental samples.

A Lung Cancer Mouse Model Database.

Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance.

The Defined TLR3 Agonist, Nexavant, Exhibits Anti-Cancer Efficacy and Potentiates Anti-PD-1 Antibody Therapy by Enhancing Immune Cell Infiltration.

Nexavant was reported as an alternative to the TLR3 agonist of Poly(I:C) and its derivatives. The physicochemical properties, signaling pathways, anti-cancer effects, and mechanisms of Nexavant were investigated. The distinctive characteristics of Nexavant compared to that of Poly(I:C) were demonstrated by precise quantification, enhanced thermostability, and increased resistance to RNase A. Unlike Poly(I:C), which activates TLR3, RIG-I, and MDA5, Nexavant stimulates signaling through TLR3 and RIG-I but not through MDA5. Compared to Poly(I:C), an intratumoral Nexavant treatment led to a unique immune response, immune cell infiltration, and suppression of tumor growth in various animal cancer models. Nexavant therapy outperformed anti-PD-1 antibody treatment in all the tested models and showed a synergistic effect in combinational therapy, especially in well-defined cold tumor models. The effect was similar to that of nivolumab in a humanized mouse model. Intranasal instillation of Nexavant led to the recruitment of immune cells (NK, CD4+ T, and CD8+ T) to the lungs, suppressing lung metastasis and improving animal survival. Our study highlighted Nexavant's defined nature for clinical use and unique signaling pathways and its potential as a standalone anti-cancer agent or in combination with anti-PD-1 antibodies.

Is the Direct Fixation of Displaced Quadrilateral Plates in Acetabular Fractures Necessary?

Quadrilateral plate fractures represent a heterogeneous group of acetabular fractures. Accurate reduction is required to prevent post-traumatic arthritis. The purpose of this study is to determine the reduction effect of the direct fixation of quadrilateral plates in acetabular fractures, and to evaluate the strength of direct fixation compared to indirect fixation. Between 2005 and 2021, 49 patients underwent surgery for open reduction and internal fixation in acetabular fractures with severely displaced quadrilateral plates. Twenty-nine patients comprised the indirect fixation group, and twenty patients comprised the direct fixation group. In a comparison of primary outcome between two groups, 10 out of 29 indirect-group patients and 1 out of 20 direct-group patients developed post-traumatic osteoarthritis, wherein the difference between the two groups is statistically significant. In the assessment of postoperative Matta's radiological reduction status, 19 out of 20 patients in the direct group had achieved anatomical and congruent reduction. The treatment using a direct reduction and internal fixation improved the reduction quality of articular displacement and offered a better survivorship of the affected hip joint.

An implantable ionic therapeutic platform for photodynamic therapy with wireless capacitive power transfer.

In this work, we describe the development of an implantable ionic device that can deliver a spatially targeted light source to tumor tissues in a controllable manner. The motivation behind our approach is to overcome certain limitations of conventional approaches where light is delivered from the outside of the body and only achieves low penetration depths. Also, to avoid the issues that come from the periodic need to replace the device's battery, we utilize a wireless power transfer system synchronized with light operation in an implantable structure. In our testing of this implanted, soft ionic, gel-based device that receives power wirelessly, we were able to clearly observe its capability to effectively deliver light in a harmonious and stable configuration to adjacent tissues. This approach reduces the mechanical inconsistencies seen in conventional systems that are induced by mismatches between the mechanical strength of conventional metallic components and that of biological tissues. The light delivering performance of our device was studied in depth under the various conditions set by adjusting the area of the gel receivers, the ion concentration and the ion types used in the gel components. The enhanced antitumor effects of our device were observed through in vitro cell tests, in comparison with treatments using the conventional approach of using direct light from outside the body. Full encapsulation using biocompatible elastomers enables our device to provide good functional stability, while implantation for about 3 weeks in the in vivo model showed the effective targeted photodynamic treatments made possible by our approach. Our advanced approach of designing the implantable platform based on ionic gel components allows us to iteratively irradiate a target with light whenever required, making the technology particularly suited to long-term treatment of residual tumors while facilitating further practical and clinical development.

A novel defined TLR3 agonist as an effective vaccine adjuvant.

Synthetic double-stranded RNA analogs recognized by Toll-like receptor 3 (TLR3) are an attractive adjuvant candidate for vaccines, especially against intracellular pathogens or tumors, because of their ability to enhance T cell and antibody responses. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been limited due to heterogeneous molecular size, inconsistent activity, poor stability, and toxicity. To overcome these limitations, we developed a novel dsRNA-based TLR3 agonist named NexaVant (NVT) by using PCR-coupled bidirectional in vitro transcription. Agarose gel electrophoresis and reverse phase-HPLC analysis demonstrated that NVT is a single 275-kDa homogeneous molecule. NVT appears to be stable since its appearance, concentration, and molecular size were unaffected under 6 months of accelerated storage conditions. Moreover, preclinical evaluation of toxicity under good laboratory practices showed that NVT is a safe substance without any signs of serious toxicity. NVT stimulated TLR3 and increased the expression of viral nucleic acid sensors TLR3, MDA-5, and RIG-1. When intramuscularly injected into C57BL/6 mice, ovalbumin (OVA) plus NVT highly increased the migration of dendritic cells (DCs), macrophages, and neutrophils into inguinal lymph node (iLN) compared with OVA alone. In addition, NVT substantially induced the phenotypic markers of DC maturation and activation including MHC-II, CD40, CD80, and CD86 together with IFN-ß production. Furthermore, NVT exhibited an appropriate adjuvanticity because it elevated OVA-specific IgG, in particular, higher levels of IgG2c (Th1-type) but lower IgG1 (Th2-type). Concomitantly, NVT increased the levels of Th1-type T cells such as IFN-γ+CD4+ and IFN-γ+CD8+ cells in response to OVA stimulation. Collectively, we suggest that NVT with appropriate safety and effectiveness is a novel and promising adjuvant for vaccines, especially those requiring T cell mediated immunity such as viral and cancer vaccines.

Long-term effects of obstructive sleep apnea and its treatment on open-angle glaucoma: a big-data cohort study.

STUDY OBJECTIVES: The relationship between open-angle glaucoma (OAG) and obstructive sleep apnea (OSA) is unclear. The long-term risk for OAG after OSA diagnosis has not been investigated. Therefore, we assessed the risk for OAG among patients with OSA over a 12-year follow-up period using nationwide, population-based data. METHODS: The OSA group was randomly selected from among 3.5 million individuals registered with the National Health Insurance Service. The non-OSA group was obtained through propensity score matching considering several variables. The primary endpoint was glaucoma diagnosis. RESULTS: The OSA and non-OSA groups both included 6,369 individuals. The overall hazard ratio for OAG in the OSA group was 1.42 (95% confidence interval [CI]: 1.19-1.69). In subgroup analysis, the hazard ratio for OAG was 1.94 (95% CI: 1.57-2.41) for those aged > 60 years, 1.50 (95% CI: 1.20-1.89) for those with diabetes mellitus, 1.53 (95% CI: 1.26-1.86) for those with hypertension, and 0.71 (95% CI: 0.52-0.96) for those with a history of OSA surgery. CONCLUSIONS: Over the 12-year follow-up, the risk for OAG increased after OSA diagnosis. Further research will be necessary to determine if treating OSA can mitigate this association. CITATION: Lee T-E, Kim JS, Yeom SW, Lee MG, Lee JH, Lee H-J. Long-term effects of obstructive sleep apnea and its treatment on open-angle glaucoma: a big-data cohort study. J Clin Sleep Med. 2023;19(2):339-346.

Nuclear S6K1 Enhances Oncogenic Wnt Signaling by Inducing Wnt/ß-Catenin Transcriptional Complex Formation.

Ribosomal protein S6 kinase 1 (S6K1), a key downstream effector of the mammalian target of rapamycin (mTOR), regulates diverse functions, such as cell proliferation, cell growth, and protein synthesis. Because S6K1 was previously known to be localized in the cytoplasm, its function has been mainly studied in the cytoplasm. However, the nuclear localization and function of S6K1 have recently been elucidated and other nuclear functions are expected to exist but remain elusive. Here, we show a novel nuclear role of S6K1 in regulating the expression of the Wnt target genes. Upon activation of the Wnt signaling, S6K1 translocated from the cytosol into the nucleus and subsequently bound to ß-catenin and the cofactors of the Wnt/ß-catenin transcriptional complex, leading to the upregulation of the Wnt target genes. The depletion or repression of S6K1 downregulated the Wnt target gene expression by inhibiting the formation of the Wnt/ß-catenin transcriptional complex. The S6K1-depleted colon cancer cell lines showed lower transcription levels of the Wnt/ß-catenin target genes and a decrease in the cell proliferation and invasion compared to the control cell lines. Taken together, these results indicate that nuclear S6K1 positively regulates the expression of the Wnt target genes by inducing the reciprocal interaction of the subunits of the transcriptional complex.

Association of adenotonsillar disease and adenotonsillectomy with the development of vitiligo: A nationwide population-based cohort study.

Background: Vitiligo is a common acquired skin depigmentation disorder and is associated with various other autoimmune diseases which include thyroid disease and rheumatoid arthritis. Similarly, adenotonsillar disease (ATD) may induce inflammatory or autoimmune diseases in other organs which include the skin. However, the influence of ATD on the development of vitiligo has not been studied. Objectives: To determine the association between ATD and adenotonsillectomy, and the development of vitiligo. Design and methods: Using data from the National Health Insurance Service database, patients diagnosed with ATD between 2008 and 2010 were included in the study. We performed two rounds of 1:1 propensity score matching in the ATD and adenotonsillectomy groups. The ATD and non-ATD groups both included 206,514 individuals. Among the ATD group, the adenotonsillectomy and non-adenotonsillectomy groups both included 23,354 individuals. Each individual was monitored until 2019. The primary end point was the risk of vitiligo. Using the Cox Proportional Hazards model, the incidence of vitiligo and the hazard ratio (HR) were calculated. Results: The incidence of vitiligo was 1.16-fold higher in the ATD group than in the non-ATD group [adjusted HR (aHR), 1.16; 95% confidence interval (CI), 1.09-1.24] and 0.82-fold lower in the adenotonsillectomy group than in the non-adenotonsillectomy group (aHR, 0.82; 95% CI, 0.68-0.99). Additionally, the other risk factors for developing vitiligo included thyroid disease (aHR, 1.48; 95% CI, 1.11-1.98), age younger than 30 years (aHR, 1.18; 95% CI, 1.09-1.27), and age over 60 years (aHR, 1.22; 95% CI, 1.06-1.41), whereas factors including rural residency (aHR, 0.91; 95% CI, 0.85-0.98) and low economic status (aHR 0.87; 95% CI, 0.82-0.93) were associated with decreased incidence of vitiligo. Conclusion: In this study, ATD increases the risk of vitiligo and adenotonsillectomy attenuates its development. Clinicians should consider ATD as a pathogenic factor for vitiligo and the potential effect of adenotonsillectomy in its management.

Prevalence and comorbidities of bronchiolitis in adults: A population-based study in South Korea.

ABSTRACT: Bronchiolitis generally refers to inflammation and/or fibrosis of the non-cartilaginous small airways located approximately from the 8th airway generation down to the terminal and respiratory bronchioles. In contrast to young children, the frequency of small airway infection in adult bronchiolitis appears less frequent and a number of other pathophysiological conditions have been implicated in adult bronchiolitis. However, little information is available on the exact medical burden of bronchiolitis such as its prevalence and comorbidities in the adult population. The aim of this study is to elucidate the prevalence and comorbidities of bronchiolitis. We used the Korea National Health Insurance Service-National Sample Cohort, which provides data for 1,000,000 individuals out of the entire population by 2% stratified random sampling according to age, sex, residential area, and level of household income. We defined the cause of bronchiolitis other than acute infection as a patient with diagnostic code J448 or J684 and over 20 years of age who visited a clinic or hospital in South Korea. Then, 1:1 propensity score matching was performed to define a non-bronchiolitis (control) group to compare the comorbidities and mortality in the 2 groups. The overall prevalence of bronchiolitis was 688 cases/1,000,000 population during the study period (95% confidence interval, 625-751). The most common comorbid clinical condition in adults with bronchiolitis was rhinitis (52.3%), followed by bronchial asthma (52.23%), hypertension (43.69%), gastroesophageal reflux disease (30.56%), sinusitis (28.72%), diabetes (22.77%), and osteoporosis (17.85%). Other common bronchiolitis-associated comorbidities were cerebrovascular disease (16.86%), angina (14.37%), peripheral vascular disease (13.42%), congestive heart failure (11.9%), and malignancy in any organ (10.6%). Healthcare costs for bronchiolitis increased steeply during the same period. Malignancy in any organ was the leading cause of mortality in the patient group, followed by bronchiolitis itself. Further larger prospective multiethnic cohort studies should be carried out in the near future.

ΔNp63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer.

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ΔNp63, the p53 family member and p63 isoform, guides the maturation of these stem cells through the regulation of their self-renewal and terminal differentiation; however, the underlying mechanistic role regulated by ∆Np63 in lung cancer development has remained elusive. By utilizing a ΔNp63-specific conditional knockout mouse model and xenograft models of LUAD and LUSC, we found that ∆Np63 promotes non-small cell lung cancer by maintaining the lung stem cells necessary for lung cancer cell initiation and progression in quiescence. ChIP-seq analysis of lung basal cells, alveolar type 2 (AT2) cells, and LUAD reveals robust ∆Np63 regulation of a common landscape of enhancers of cell identity genes. Importantly, one of these genes, BCL9L, is among the enhancer associated genes regulated by ∆Np63 in Kras-driven LUAD and mediates the oncogenic effects of ∆Np63 in both LUAD and LUSC. Accordingly, high BCL9L levels correlate with poor prognosis in LUAD patients. Taken together, our findings provide a unifying oncogenic role for ∆Np63 in both LUAD and LUSC through the regulation of a common landscape of enhancer associated genes.

Cancer stem cells, not bulk tumor cells, determine mechanisms of resistance to SMO inhibitors.

The emergence of treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Although both genetic and epigenetic mechanisms of drug resistance have been reported, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown. Here, we report that the dependence of cancer stem cells (CSCs), not bulk tumor cells, on the targeted pathway determines the molecular mechanism of resistance in individual tumors. Using both spontaneous and transplantable mouse models of sonic hedgehog (SHH) medulloblastoma (MB) treated with an SHH/Smoothened inhibitor, sonidegib/LDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs (SD-CSCs). In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC MBs alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including histone acetylation machinery components, resulting in global reductions in H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies. This insight provides a new conceptual framework to understand responses and resistance to SMOis and other targeted therapies.

Cancer-epigenetic function of the histone methyltransferase KMT2D and therapeutic opportunities for the treatment of KMT2D-deficient tumors.

Epigenetic mechanisms are central to understanding the molecular basis underlying tumorigenesis. Aberrations in epigenetic modifiers alter epigenomic landscapes and play a critical role in tumorigenesis. Notably, the histone lysine methyltransferase KMT2D (a COMPASS/ Set1 family member; also known as MLL4, ALR, and MLL2) is among the most frequently mutated genes in many different types of cancer. Recent studies have demonstrated how KMT2D loss induces abnormal epigenomic reprograming and rewires molecular pathways during tumorigenesis. These findings also have clinical and therapeutic implications for cancer treatment. In this review, we summarize recent advances in understanding the role of KMT2D in regulating tumorigenesis and discuss therapeutic opportunities for the treatment of KMT2D-deficient tumors.

Author Correction: SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis.

A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00686-x.

Broad genic repression domains signify enhanced silencing of oncogenes.

Cancers result from a set of genetic and epigenetic alterations. Most known oncogenes were identified by gain-of-function mutations in cancer, yet little is known about their epigenetic features. Through integrative analysis of 11,596 epigenomic profiles and mutations from >8200 tumor-normal pairs, we discover broad genic repression domains (BGRD) on chromatin as an epigenetic signature for oncogenes. A BGRD is a widespread enrichment domain of the repressive histone modification H3K27me3 and is further enriched with multiple other repressive marks including H3K9me3, H3K9me2, and H3K27me2. Further, BGRD displays widespread enrichment of repressed cis-regulatory elements. Shortening of BGRDs is linked to derepression of transcription. BGRDs at oncogenes tend to be conserved across normal cell types. Putative tumor-promoting genes and lncRNAs defined using BGRDs are experimentally verified as required for cancer phenotypes. Therefore, BGRDs play key roles in epigenetic regulation of cancer and provide a direction for mutation-independent discovery of oncogenes.

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma.

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors.

Effect of the Fluorination of Graphene Nanoflake on the Dispersion and Mechanical Properties of Polypropylene Nanocomposites.

In order to investigate the effect of fluorination of graphene nanoflake on the dispersibility in polypropylene (PP) composites, fluorinated graphene oxide (FGO) was prepared by solvo-thermal reaction and applied as a filler of the PP nanocomposite. Due to the weakened inter-particle attraction among the graphene nanoflake and reduced surface energy difference between PP and the filler, PP/FGO composites showed better exfoliation and dispersion state of the filler compared with that of PP/graphene oxide (GO) or PP/reduced graphene oxide (RGO) composites. The improved exfoliation and dispersion of graphene nanoflake resulted in a significant reinforcement on the composites. The Young's modulus and tensile strength of PP composites filled with 2 wt% of FGO increased by 31% and 15%, respectively, compared with those of PP.

KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer.

Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.