Cholesterol metabolism in T-cell aging: Accomplices or victims.

Aging has a significant impact on the function and metabolism of T cells. Cholesterol, the most important sterol in mammals, is known as the "gold of the body" because it maintains membrane fluidity, rigidity, and signal transduction while also serving as a precursor of oxysterols, bile acids, and steroid hormones. Cholesterol homeostasis is primarily controlled by uptake, biosynthesis, efflux, and regulatory mechanisms. Previous studies have suggested that there are reciprocal interactions between cholesterol metabolism and T lymphocytes. Here, we will summarize the most recent advances in the effects of cholesterol and its derivatives on T-cell aging. We will furthermore discuss interventions that might be used to help older individuals with immune deficiencies or diminishing immune competence.

Analysis of Pathological Factors of Long Head of Biceps Tendinopathy Based on Network Pharmacology.

OBJECTIVES: To investigate the therapeutic effect and mechanism of Danggui Buxue Tang in the treatment of biceps longus tendon lesions, and to preliminarily explore the relevant factors affecting this injury. METHODS: Using network pharmacology analysis methods, the potential mechanism of Danggui Buxue Tang in treating key lesions of the long head of the biceps brachii muscle was studied. RESULTS: Model analysis revealed 44 protein-protein interactions associated with long head binding. The distribution of 19 strongly correlated targets is Pharmaper>SEA>Stitch>Swiss. Further discovery revealed 17 immune system and inflammation related KEGG pathways with P values less than 0.01. The TNF and sphingolipid signaling pathways are associated with inflammation, while the MAPK signaling pathway is associated with immunity. Finally, it was found that the FoxO and HIF-1 signaling pathways are directly associated with long head restraint injury in the biceps brachii muscle. CONCLUSION: Danggui Buxue Tang inhibits related pathways, regulates the immune system, reduces inflammation, and alleviates disease progression. Danggui Buxue Tang can be an effective choice for treating combined lesions of the long head of the biceps brachii muscle.

Glycolysis mediates the association between phthalate exposure and the prevalence of childhood asthma: The National Health and Nutrition Examination Survey 2009-2018.

Identified as a critical risk factor for childhood asthma, environmental pollution plays a pivotal role. However, research on the effects and mechanisms of phthalates mixture and their interactions in relation to childhood asthma is still lacking. In the National Health and Nutrition Examination Survey (NHANES) conducted from 2009 to 2018, our research explored the link between phthalates in urine and the prevalence of childhood asthma. In this study, which involved 810 participants, we used four different statistical analysis methods to investigate the association between urinary phthalate levels and childhood asthma. Additionally, we conducted a mediation analysis to explore whether the impact mechanism of phthalate exposure on childhood asthma operates through the glycolysis. Among the participants, 525 (64.81 %) individuals were diagnosed with asthma, with 330 (40.74 %) individuals undergoing testing for glycolytic markers. Through Spearman correlation analysis and weighted principal component analysis (W-PCA), it was found that mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) are the four most highly correlated phthalates. In addition, comprehensive analysis by the weighted generalized linear models (W-GLM), weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models showed that phthalates mixture were positively associated with the prevalence of childhood asthma, especially MECPP, MEHHP and MEOHP. More importantly, glycolysis participated as a mediator in the relationship between MECPP, MEHHP and MEOHP exposure and the prevalence of childhood asthma, explaining 41.194 %, 38.322 % and 39.871 % of the effects respectively. Therefore, our study revealed that phthalate exposure is a risk factor for asthma in children, and glycolysis may be involved as a potential mediator in this process. This conclusion will be verified through more prospective studies in the future.

Morphology and classification of the second mesiobuccal canal in maxillary first molars: a cone-beam computed tomography analysis in a Chinese population.

BACKGROUND: Understanding the tooth anatomy is crucial for ensuring effective endodontic treatment. This study investigated the root canal morphology of the second mesiobuccal (MB2) canal in maxillary first molars (MFMs) in a Chinese population using cone-beam computed tomography (CBCT). METHODS: This study evaluated 486 MFMs with MB2 canals from 285 participants undergoing CBCT examination and determined the Vertucci's classification and position of the MB2 canal orifice. The prevalence of the MB2 canal was correlated with the sex, age, and tooth side. The correlations between the prevalence of the MB2 canal and sex and tooth side were assessed using the Fisher's exact test. The chi-square test was used for evaluating the correlation between the prevalence of the MB2 canal and age. RESULTS: The number of type II, III, IV, V, VI, VII, and other root canals in the MFMs was 30.9%, 0.6%, 65.0%, 1.2%, 1.2%, 0.4%, and 0.6%, respectively. Among the 201 cases with bilateral inclusion, 87.6% showed consistent canal configuration. Results of the first clear apparent position (FCAP) of the MB2 canals showed that 434, 44, and 3 teeth had FCAP at the upper, middle, and bottom one-third of the root, respectively. The FCAPs of the MB2 canal in the MFMs with types II, IV, and VI, as well as types III and V canals showed significant differences (p<0.05). The horizontal distance between the MB1 and MB2 canal orifices in the type II canals of MFMs was significantly lesser than those in the type IV canals of MFMs (p < 0.01). The longitudinal distance between the pulp chamber floor plane and MB2 canal orifice significantly correlated with age (p < 0.05). CONCLUSIONS: The morphology of the mesiobuccal root canal in the MFMs is complex. Complete understanding of the anatomical morphology of the root canal combined with the CBCT and dental operating microscope is necessary for the accurate detection of the MB2 canal and consequently improved success rate of root canal treatment. Our study findings can help endodontists improve endodontic treatment outcomes.

Highly efficient overexpression and purification of multisubunit tethering complexes in Saccharomyces cerevisiae.

Vesicle trafficking is a fundamental cellular process that ensures proper material exchange between organelles in eukaryotic cells, and multisubunit tethering complexes (MTCs) are essential in this process. The heterohexameric homotypic fusion and protein sorting (HOPS) complex, which functions in the endolysosomal pathway, is a member of MTCs. Despite its critical role, the complex composition and low-expression level of HOPS have made its expression and purification extremely challenging. In this study, we present a highly efficient strategy for overexpressing and purifying HOPS from Saccharomyces cerevisiae. We achieved HOPS overexpression by integrating a strong promoter TEF1 before each subunit using the gRNA-tRNA array for CRISPR-Cas9 (GTR-CRISPR) system. The HOPS complex was subsequently purified using Staphylococcus aureus protein A (ProtA) affinity purification and size-exclusion chromatography, resulting in high purity and homogeneity. We obtained two-fold more HOPS using this method than that obtained using the commonly used GAL1 promoter-controlled HOPS overexpression. Negative staining electron microscopy analysis confirmed the correct assembly of HOPS. Notably, we also successfully purified two other MTCs, class C core vacuole/endosome tethering (CORVET) and Golgi-associated retrograde protein (GARP) using this approach. Our findings facilitate further in vitro biochemical characterization and functional studies of MTCs and provide a useful guide for the preparation of other heterogenic multisubunit complexes.

Effects of trunk neuromuscular electrical stimulation on the motor circuits of able-bodied individuals.

Upper- and lower-limb neuromuscular electrical stimulation (NMES) is known to modulate the excitability of the neural motor circuits. However, it remains unclear whether short-duration trunk muscle NMES could achieve similar neuromodulation effects. We assessed motor evoked potentials (MEPs) elicited through transcranial magnetic stimulation of the primary motor cortex representation of the trunk extensor muscles to evaluate corticospinal excitability. Moreover, cervicomedullary motor evoked potentials (CMEPs) were assessed through cervicomedullary junction magnetic stimulation to evaluate subcortical excitability. Twelve able-bodied individuals participated in the MEP study, and another twelve in the CMEP study. During the interventions, NMES was applied bilaterally to activate the erector spinae muscle and produce intermittent contractions (20 s ON/20 s OFF) for a total of 20 min while participants remained seated. Assessments were performed: (i) before; (ii) during (in brief periods when NMES was OFF); and (iii) immediately after the interventions to compare MEP or CMEP excitability. Our results showed that MEP responses were not affected by trunk NMES, while CMEP responses were facilitated for approximately 8 min during the intervention, and returned to baseline before the end of the 20 min stimulating period. Our findings therefore suggest that short-duration NMES of the trunk extensor muscles likely does not affect the corticospinal excitability, but it has a potential to facilitate subcortical neural circuits immediately after starting the intervention. These findings indicate that short-duration application of NEMS may be helpful in rehabilitation to enhance neuromodulation of the trunk subcortical neural motor circuits.

Does long-term care insurance reduce the disability among middle-aged and older adults? Evidence from China.

This study aimed to examine whether the implementation of Long-Term Care Insurance (LTCI) policy could reduce the disability among middle-aged and older adults in China, and to test the heterogeneity of the effects. Data came from four waves of the China Health and Retirement Longitudinal Study (CHARLS, 2011 to 2018). The Difference-In-Differences (DID) method and the panel data fixed effect model were used to estimate the effect of implementation of LTCI policy on disability among individuals aged 45 years and above. The LTCI policy had a positive impact on reducing disability among middle-aged and older people. Females, younger adults, city dwellers, and individuals living alone benefited the most from LTCI policy. The results provided empirical evidence for the implementation of LTCI policy in China and other similar countries as China. The implementation of LTCI policy should also pay more attention to inequity of the effects on reducing disability among different demographic groups.

Effectiveness and safety of intracardiac electrocardiogram guidance for epicutaneo-cava catheters via the lower extremity in preterm infants: a retrospective study.

INTRODUCTION: In recent years, intracardiac electrocardiogram (IC-ECG) technology has been widely used for epicutaneo-cava catheter (ECC) placement and has shown many potential advantages. However, evidence about the quantitative changes, effectiveness, and safety of IC-ECG for lower extremity ECC is sparse. This study aimed to explore the quantitative changes in IC-ECG for lower extremity ECC and determine its effectiveness and safety. METHODS: A retrospective study was conducted on 303 premature infants who underwent successful IC-ECG-guided lower extremity ECC placement between January 2019 and December 2021. All patients underwent chest X-ray postoperatively to verify the position of the catheter tip. The amplitudes of the surface electrocardiogram and IC-ECG QRS waves and the difference between the two amplitudes were measured. The effectiveness (matching rate between IC-ECG and chest X-ray) and safety (incidence of catheter-related complications) of IC-ECG for lower extremity ECC were evaluated. RESULTS: The matching rate between IC-ECG and chest X-ray was 95.0%. When the catheter tip was optimally positioned, the QRS amplitude of the IC-ECG was 0.85 ± 0.56 mv higher than that of the surface electrocardiogram. The overall incidence of catheter-related complications was 10.6%. The actual ECC insertion length was associated with a noticeably increased risk of catheter-related complications. CONCLUSIONS: This study suggests that IC-ECG is an effective and safe method by observing the dynamic changes in both QRS complexes and P wave to locate the tip of lower extremity ECC in preterm infants. Our findings would facilitate the application of IC-ECG for ECC localization.

Dual trajectories of depression and social participation among Chinese older adults.

OBJECTIVES: This study aimed to investigate the dual trajectories of social participation (SP) and depression among older adults, and explore common factors that may influence both trajectories. METHODS: The study utilized data from four waves of the China Health and Retirement Longitudinal Study (CHARLS, 2011 to 2018). The dual-trajectory model was employed to estimate the dual trajectories of SP and depression. RESULTS: This study identified two SP and three depression trajectories. The results revealed that the reciprocal relationship between SP and depression trajectories is confirmed in all sub-groups of the dual trajectories. Our study identified six distinct sub-groups of individuals based on their SP and depression trajectories and some commen risk factors of SP and depression trajectories. CONCLUSIONS: Related intervention policies should consider the dual trajectories of SP and depression and focus on subgroups with high vulnerability, such as high depression but low SP. Additionally, attention should be given to addressing the common risk factors that underlie these trajectories.

Plasticity changes in dorsolateral prefrontal cortex associated with procedural sequence learning are hemisphere-specific.

Corticocortical neuroplastic changes from higher-order cortices to primary motor cortex (M1) have been described for procedural sequence learning. The dorsolateral prefrontal cortex (DLPFC) plays critical roles in cognition, including in motor learning and memory. However, neuroplastic changes in the DLPFC and their influence on M1 and on motor learning are not well understood. The present study examined bilateral DLPFC-M1 changes in plasticity induced by procedural motor sequence learning in a serial reaction time task. DLPFC plasticity induced by procedural sequence learning was examined by comparing before vs. after training assessments of ipsilateral/contralateral DLPFC-M1 interactions between sequence order and random order trials performed using either the left or right hand. Intra-hemispheric (inter-stimulus interval [ISI] = 10 ms) and inter-hemispheric (ISI = 10 or 50 ms) DLPFC-M1 interactions and single-pulse motor-evoked potentials (MEPs) were measured with transcranial magnetic stimulation (TMS). The reaction times of participants measured during motor training were faster for sequence learning than for random learning with either hand. Paired-pulse TMS induced DLPFC-M1 interactions that were disinhibited after motor sequence learning, especially for left DLPFC-left M1 interactions with right hand task performance and for left DLPFC-right M1 interactions with left hand task performance. These findings indicate that motor sequence learning induces neuroplastic changes to enhance DLPFC-M1 interactions. This manifestation of plasticity showed hemispheric specificity, favoring the left DLPFC. DLPFC plasticity may be a useful index of DLPFC function and may be a treatment target for enhancing DLPFC function and motor learning.

Acoustics-Controlled Microdroplet and Microbubble Fusion and Its Application in the Synthesis of Hydrogel Microspheres.

Droplet fusion technology is a key technology for many droplet-based biochemical medical applications. By integrating a symmetrical flow channel structure, we demonstrate an acoustics-controlled fusion method of microdroplets using surface acoustic waves. Different kinds of microdroplets can be staggered and ordered in the symmetrical flow channel, proving the good arrangement effect of the microfluidic chip. This method can realize not only the effective fusion of microbubbles but also the effective fusion of microdroplets of different sizes without any modification. Further, we investigate the influence of the input frequency and peak-to-peak value of the driving voltage on microdroplets fusion, giving the effective fusion parameter conditions of microdroplets. Finally, this method is successfully used in the preparation of hydrogel microspheres, offering a new platform for the synthesis of hydrogel microspheres.

Short-term facilitation effects elicited by cortical priming through theta burst stimulation and functional electrical stimulation of upper-limb muscles.

Non-invasive theta burst stimulation (TBS) can elicit facilitatory or inhibitory changes in the central nervous system when applied intermittently (iTBS) or continuously (cTBS). Conversely, neuromuscular electrical stimulation (NMES) can activate the muscles to send a sensory volley, which is also known to affect the excitability of the central nervous system. We investigated whether cortical iTBS (facilitatory) or cTBS (inhibitory) priming can affect subsequent NMES-induced corticospinal excitability. A total of six interventions were tested, each with 11 able-bodied participants: cortical priming followed by NMES (iTBS + NMES and cTBS + NMES), NMES only (iTBSsham + NMES and cTBSsham + NMES), and cortical priming only (iTBS + rest and cTBS + rest). After iTBS or cTBS priming, NMES was used to activate right extensor capri radialis (ECR) muscle intermittently for 10 min (5 s ON/5 s OFF). Single-pulse transcranial magnetic stimulation motor evoked potentials (MEPs) and maximum motor response (Mmax) elicited by radial nerve stimulation were compared before and after each intervention for 30 min. Our results showed that associative facilitatory iTBS + NMES intervention elicited greater MEP facilitation that lasted for at least 30 min after the intervention, while none of the interventions alone were effective to produce effects. We conclude that facilitatory iTBS priming can make the central nervous system more susceptible to changes elicited by NMES through sensory recruitment to enhance facilitation of corticospinal plasticity, while cTBS inhibitory priming efficacy could not be confirmed.

The LAMMER Kinase MoKns1 Regulates Growth, Conidiation and Pathogenicity in Magnaporthe oryzae.

Magnaporthe oryzae is an important pathogen that causes a devastating disease in rice. It has been reported that the dual-specificity LAMMER kinase is conserved from yeast to animal species and has a variety of functions. However, the functions of the LAMMER kinase have not been reported in M. oryzae. In this study, we identified the unique LAMMER kinase MoKns1 and analyzed its function in M. oryzae. We found that in a MoKNS1 deletion mutant, growth and conidiation were primarily decreased, and pathogenicity was almost completely lost. Furthermore, our results found that MoKns1 is involved in autophagy. The ΔMokns1 mutant was sensitive to rapamycin, and MoKns1 interacted with the autophagy-related protein MoAtg18. Compared with the wild-type strain 70-15, autophagy was significantly enhanced in the ΔMokns1 mutant. In addition, we also found that MoKns1 regulated DNA damage stress pathways, and the ΔMokns1 mutant was more sensitive to hydroxyurea (HU) and methyl methanesulfonate (MMS) compared to the wild-type strain 70-15. The expression of genes related to DNA damage stress pathways in the ΔMokns1 mutant was significantly different from that in the wild-type strain. Our results demonstrate that MoKns1 is an important pathogenic factor in M. oryzae involved in regulating autophagy and DNA damage response pathways, thus affecting virulence. This research on M. oryzae pathogenesis lays a foundation for the prevention and control of M. oryzae.

The Amino Acid Permease MoGap1 Regulates TOR Activity and Autophagy in Magnaporthe oryzae.

Rice is an important food crop all over the world. It can be infected by the rice blast fungus Magnaporthe oryzae, which results in a significant reduction in rice yield. The infection mechanism of M. oryzae has been an academic focus for a long time. It has been found that G protein, AMPK, cAMP-PKA, and MPS1-MAPK pathways play different roles in the infection process. Recently, the function of TOR signaling in regulating cell growth and autophagy by receiving nutritional signals generated by plant pathogenic fungi has been demonstrated, but its regulatory mechanism in response to the nutritional signals remains unclear. In this study, a yeast amino acid permease homologue MoGap1 was identified and a knockout mutant of MoGap1 was successfully obtained. Through a phenotypic analysis, a stress analysis, autophagy flux detection, and a TOR activity analysis, we found that the deletion of MoGap1 led to a sporulation reduction as well as increased sensitivity to cell wall stress and carbon source stress in M. oryzae. The ΔMogap1 mutant showed high sensitivity to the TOR inhibitor rapamycin. A Western blot analysis further confirmed that the TOR activity significantly decreased, which improved the level of autophagy. The results suggested that MoGap1, as an upstream regulator of TOR signaling, regulated autophagy and responded to adversities such as cell wall stress by regulating the TOR activity.

Contribution of stochastic processes to the microbial community assembly on field-collected microplastics.

A growing body of evidence suggests that microplastics may be colonized with a unique microbiome, termed 'plastisphere', in aquatic environments. However, the deep mechanisms (deterministic and/or stochastic processes) underlying the community assembly on microplastics are still poorly understood. Here, we took the estuary of Hangzhou Bay (Zhejiang, China) as an example and examined the assembly mechanisms of bacterial communities in water and microplastic samples. Results from high-throughput sequencing showed that Proteobacteria, Firmicutes, and Actinobacteria were the dominant phyla across all samples. Additionally, microorganisms from plastisphere and planktonic communities exhibited contrasting taxonomic compositions, with greater within-group variation for microplastic samples. The null model analysis indicated the plastisphere bacterial communities were dominantly driven by the stochastic process of drift (58.34%) and dispersal limitation (23.41%). The normalized stochasticity ratio (NST) also showed that the community assembly on microplastics was more stochastic (NST > 50%). Based on the Sloan neutral community model, the migration rate for plastisphere communities (0.015) was significantly lower than that for planktonic communities (0.936), potentially suggesting that it is the stochastic balance between loss and gain of bacteria (e.g., stochastic births and deaths) critically shaping the community assembly on microplastics and generating the specific niches. This study greatly enhanced our understanding of the ecological patterns of microplastic-associated microbial communities in aquatic environments.

Lycopene-Loaded Microemulsion Regulates Neurogenesis in Rats with Aß-Induced Alzheimer's Disease Rats Based on the Wnt/ß-catenin Pathway.

Objective: To investigate the effects of lycopene-loaded microemulsion (LME) on the cognitive function and neurogenesis in the dentate gyrus (DG) of the hippocampus and subventricular (SVZ) region of rats with amyloid ß- (Aß-) induced Alzheimer's disease (AD) and its mechanism based on the Wnt/ß-catenin pathway. Methods: Healthy Wistar rats were divided into four groups: the blank control (CON), AD control, traditional lycopene (LOO), and LME groups. The CON and AD groups were fed with normal saline, while the LOO group was fed with traditional lycopene, and the LME group was fed with lycopene-loaded microemulsion. Behavioral tests were performed after three weeks of gastric administration. Immunofluorescence-labeled cells were used to observe the differentiation and maturation of new nerve cells in the DG of the hippocampus and SVZ region. qRT-PCR and Western blotting detected the expression of neurogenesis genes and Wnt/ß-catenin pathway-related proteins, respectively. Results: On the Morris water maze test, LME rats had significantly shortened movement trajectory on the searching platform, reduced escape latency time, and increased residence time on the original platform quadrant. In addition, more LME rats crossed the platform when it was removed. Thus, LME can improve the spatial learning and memory of Aß-induced AD rats. On qRT-PCR, LME significantly increased Reelin, Nestin, and Pax6 gene expressions, which regulate neurogenesis. Immunofluorescence showed that LME could significantly increase BrdU+, Dcx+, BrdU+/Neun+, BrdU+/Dcx+ cells in the DG and SVZ regions, thus promoting neurogenesis. LME also reduced the number of Iba1+ and Iba1+/BrdU+ cells, thus reducing the neuroinflammatory response. On Western blot, LME upregulated the Wnt/ß-catenin pathway by upregulating Wnt3a, ß-catenin, Disheveled (Dvl), and p-GSK3ß and downregulating p-ß-catenin and GSK3ß. Conclusion: LME attenuates cognitive impairment in Aß-induced AD rats by promoting neurogenesis in the hippocampus and SVZ region through upregulating the Wnt/ß-catenin pathway.

Multiple root canals in the maxillary molar: an unusual case report.

BACKGROUND: The objective of this report was to highlight the importance of using a dental operating microscope (DOM) to locate supernumerary canals and diagnose variations in root canals using cone-beam computed tomographic (CBCT) images. CASE PRESENTATION: A 35-year-old Chinese female had repeated swelling in the upper right posterior maxilla for 3 months and was referred to evaluate symptomatic apical periodontitis and mesotaurodonts for upper right first permanent molar and upper right second permanent molar. Root canal therapy was proposed and conducted with the use of DOM and CBCT. CONCLUSIONS: Proper diagnosis and careful clinicoradiological examination are necessary, and it is essential to reinforce the knowledge of the rare morphology of root canals for clinicians.

A Highly Selective Supramolecule Array Membrane Made of Zero-Dimensional Molecules for Gas Separation.

We orderly assembled zero-dimensional 2-methylimidazole (mim) molecules into unprecedented supramolecule array membranes (SAMs) through solvent-free vapor processing, realizing the intermolecular spacing of mim at ca. 0.30 nm available as size-sieving channels for distinguishing the tiny difference between H2 (kinetic diameter: 0.289 nm) and CO2 (kinetic diameter: 0.33 nm). The highly oriented and dense membranes yield a separation factor above 3600 for equimolar H2 /CO2 mixtures, which is one order of magnitude higher than those of the state-of-the-art membranes defining 2017's upper bound for H2 /CO2 separation. These SAMs define a new benchmark for molecular sieve membranes and are of paramount importance to precombustion carbon capture. Given the range of supramolecules, we anticipate SAMs with variable intermolecular channels could be applied in diversified separations that are prevalent in chemical processes.

Tuning of Delicate Host-Guest Interactions in Hydrated MIL-53 and Functional Variants for Furfural Capture from Aqueous Solution.

Capture of high-boiling-point furfural from diluted aqueous solution is a critical but challenging step in sustainable bio-refinery processes, but conventional separation methods such as distillation and liquid-liquid extraction requires prohibitive energy consumption. We report control over the microenvironment of hydrated MIL-53 and isoreticular variants with diversified functional terephthalic acid linkers for the purpose of preferential binding of furfural through delicate host-guest interactions. Methyl-bounded MIL-53 with improved binding energy in the hydrated form results in highly efficient capture ratio (ca. 98 %) in the extremely low concentration of furfural solution (0.5-3 wt %) and 100 % furfural specificity over xylose. The distinct hydrogen bonding sites and multiple Van de Wall interactions for furfural adsorption was testified by computational modeling. Furthermore, the recovery ratio of furfural reaches ca. 93 % in desorption.

NFE2L2/KEAP1 Mutations Correlate with Higher Tumor Mutational Burden Value/PD-L1 Expression and Potentiate Improved Clinical Outcome with Immunotherapy.

BACKGROUND: Abnormalities in the KEPA1-NRF2 pathway have a role in cancer progression, metastasis, and resistance to chemo- and radiotherapies. Persistent activation of NRF2 associates with poor prognosis across different cancer types. However, the beneficial therapeutic strategy to harness this pathway in cancer remains unclear. This study aimed to investigate the clinical outcome with immunotherapy in NFE2L2/KEAP1 mutant population. MATERIALS AND METHODS: We investigated the correlation between NFE2L2/KEAP1 mutations and tumor mutational burden (TMB) and programmed death-ligand 1 (PD-L1) expression status to identify the therapeutic vulnerability. For this purpose, relevance analysis with TMB value was performed in 9,040 patients with cancer, and relevance analysis with PD-L1 expression was performed in 3,457 patients. The Memorial Sloan Kettering Cancer Center (MSKCC) database and real-world evidence were used to assess the immunotherapy response in NFE2L2/KEAP1 mutant subsets. RESULTS: NFE2L2/KEAP1 mutations occurred in various cancers, and the highest mutation incidences occurred in lung squamous cell carcinoma (LUSC) at 19.16% (NFE2L2) and 10.31% (KEAP1). We confirmed that higher TMB value and PD-L1 expression were associated with NFE2L2/KEAP1 mutations compared with wild-type, especially in non-small lung cancer. MSKCC database analysis showed the improved survival of patients with NFE2L2/KEAP1 mutant with immunotherapy compared with other treatments (median overall survival 22.52 VS 12.89, p = .0034). Real-world evidence further confirmed the efficacy of immunotherapy in the mutant population. CONCLUSION: Our study revealed that patients with NFE2L2/KEAP1 mutant could achieve improved outcomes from immunotherapy than the other treatments. These findings may broaden the application of immune checkpoint blockade to patients harboring NFE2L2/KEAP1 mutations. IMPLICATIONS FOR PRACTICE: NFE2L2/KEAP1 alterations occur frequently in multiple cancer types and are associated with poor prognosis; however, the efficacious strategy to inhibit this pathway in cancer is poorly understood. This study was designed to analyze the mutational characteristics of NFE2L2/KEAP1 alterations in 9,243 Chinese patients. The highest mutation incidences occurred in lung squamous cell carcinoma at 19.16% (NFE2L2) and 10.31% (KEAP1). Relevance analysis showed the NFE2L2/KEAP1 mutant subsets were associated with higher tumor mutational burden value and programmed death-ligand 1 expression. Clinical data further confirmed NFE2L2/KEAP1 mutations correlate with improved outcome with immunotherapy. These findings suggest the clinical application of immunotherapy in the NFE2L2/KEAP1 mutant population.