Fluid Clearance Research Articles

Resveratrol alleviates blast lung injury by modulating the epithelial sodium channel (ENaC) via the PI3K/AKT pathway.

Blast lung injury (BLI) is a major cause of death in blast injuries, largely due to pulmonary edema. Effective clearance of alveolar fluid is critical for resolving pulmonary edema, with the epithelial sodium channel (ENaC) playing a key role in this process. Resveratrol (RES), a natural compound with known antioxidant and anti-inflammatory properties, has shown promise in treating respiratory diseases. However, its potential protective effects against BLI, particularly through ENaC modulation, remain unclear. In this study, complementary in vivo and in vitro models were used to investigate mechanisms underlying pulmonary edema following a gas explosion. We discovered that RES significantly alleviated BLI by decreasing pulmonary edema, pulmonary index, W/D ratio, oxidative stress, inflammatory cell infiltration, and TNF-α and IL-1β expression levels in rat lung tissue. RES upregulated the expression of ENaC and PI3K/AKT both in rats and in A549 cells. The knockout of the PI3K-p85 gene suppressed RES-induced upregulation of p-AKT and ENaC, reversing protein expression in A549 cells. Altogether, RES shows potential to attenuate blast-induced lung injury by upregulating ENaC, partly through the PI3K/AKT signaling pathway. This study highlights RES as a potential therapeutic agent for BLI and offers new insights into its mechanisms of action.

Huashi baidu granule alleviates inflammation and lung edema by suppressing the NLRP3/caspase-1/GSDMD-N pathway and promoting fluid clearance in a porcine reproductive and respiratory syndrome (PRRS) model.

Huashi Baidu Granule (HSBDG), a traditional Chinese medicine (TCM), is used for treating coronavirus disease 2019 (COVID-19). Porcine reproductive and respiratory syndrome (PRRS) is considered the "COVID-19" for swine. According to the TCM theory, "dampness" is the main pathogenic factor in COVID-19 and PRRS, and "Huashi" means that this formula is good at removing "dampness". Studies have demonstrated that HSBDG's effect in COVID-19; but the mechanism of removing "dampness" remains elusive. We aimed to assess the effect of HSBDG on PRRS, and elucidate its potential mechanism in removing "dampness". We established a PRRS-virus (PRRSV)-infected Marc-145cells model, and performed qRT-PCR, Western blot analysis, and indirect immunofluorescence assay to examine the anti-PRRSV effects of HSBDG in vitro. PRRSV-infected pig model was established and used to investigate HSBDG's effect in PRRS and explore underlying mechanisms in removing "dampness" using ELISA and immunohistochemistry assay methods. HSBDG exhibited anti-PRRSV activity and suppressed the viral replication and release phases. HSBDG treatment alleviated PRRS, lowered rectal temperature, reduced histopathological changes and viral load in lung tissues, and ameliorated organ lesions. Moreover, IL-1β, IL-6, IL-8, and TNF-α expressions were decreased in lung tissues. Mechanistically, HSBDG inhibited the NLRP3/Caspase-1/GSDMD-N pathway to reduce the inflammatory response and upregulated AQP1, AQP5, α-ENaC, and Na-K-ATPase expressions to promote lung fluid clearance. HSBDG exerted anti-PRRSV effects and could attenuate PRRS. HSBDG potentially removes "dampness" by attenuating inflammation by suppressing the NLRP3/Caspase-1/GSDMD-N pathway and inhibiting pulmonary edema by upregulating the expression of AQP1, AQP5, α-ENaC, and Na-K-ATPase.

Impaired Sphenoparietal Venous Drainage Is Associated With Increased Risk of Vasospasm in Aneurysmal Subarachnoid Hemorrhage

BACKGROUND Adequate venous drainage of brain parenchyma is essential to maintain cerebral perfusion and clearance of cerebrospinal fluid. The cortical vein opacification score (COVES) is a radiographic metric calculated from a computed tomography angiogram that provides a measure of venous drainage using 3 cortical veins in each hemisphere. Emerging evidence indicates that longitudinal declines in COVES correlates with poor outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), but the clinical factors associated with a low COVES, and the relationship between COVES and other outcomes remains poorly understood. METHODS We performed a single‐center retrospective analysis of 54 patients with aSAH to characterize the relationship between the COVES score and radiographic vasospasm. RESULTS We found that patients with high‐grade aSAH (Hunt and Hess 4–5) had worse cortical venous drainage (mean total COVES±SEM, 10.2±0.2, n = 21) compared with patients with lower grade aSAH (Hunt and Hess 2–3, n = 33, 9.5±0.3, P <0.05, 2‐tailed t ‐test) and that venous drainage improves at longitudinal follow‐up after discharge (mean increase in total COVES: 1.3±0.3, P <0.01). Logistic regression revealed that patients whose admission computed tomography angiogram showed impairment in sphenoparietal drainage were at the highest risk for radiographic vasospasm (odds ratio, 0.34 [95% CI, 0.13–0.84]). CONCLUSION These results suggest a potential mechanistic link between impaired venous drainage and radiographic vasospasm and provide the basis for further study of COVES as a prognostic tool in patients with aSAH. We found that patients with more severe presentations of aneurysmal subarachnoid hemorrhage had impairment in cortical venous drainage. Impairments in venous drainage were associated with a higher likelihood of radiographic vasospasm.

New Insights on Mechanisms and Therapeutic Targets of Cerebral Edema.

Cerebral Edema (CE) is the final common pathway of brain death. In severe neurological disease, neuronal cell damage first contributes to tissue edema, and then Increased Intracranial Pressure (ICP) occurs, which results in diminishing cerebral perfusion pressure. In turn, anoxic brain injury brought on by decreased cerebral perfusion pressure eventually results in neuronal cell impairment, creating a vicious cycle. Traditionally, CE is understood to be tightly linked to elevated ICP, which ultimately generates cerebral hernia and is therefore regarded as a risk factor for mortality. Intracranial hypertension and brain edema are two serious neurological disorders that are commonly treated with mannitol. However, mannitol usage should be monitored since inappropriate utilization of the substance could conversely have negative effects on CE patients. CE is thought to be related to bloodbrain barrier dysfunction. Nonetheless, a fluid clearance mechanism called the glial-lymphatic or glymphatic system was updated. This pathway facilitates the transport of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and later into the brain interstitium. After removing solutes from the neuropil into meningeal and cervical lymphatic drainage arteries, the route then directs flows into the venous perivascular and perineuronal regions. Remarkably, the dual function of the glymphatic system was observed to protect the brain from further exacerbated damage. From our point of view, future studies ought to concentrate on the management of CE based on numerous targets of the updated glymphatic system. Further clinical trials are encouraged to apply these agents to the clinic as soon as possible.

The role of lymphatic vessels in cardiac injury and repair

Abstract The cardiac lymphatic system plays a vital role in maintaining interstitial fluid balance, immune cell homeostasis, and overall cardiac health. Despite its importance, the involvement of cardiac lymphatics in heart disease has only recently garnered significant research attention. This review explores the structural, molecular, and functional characteristics of the cardiac lymphatic network and its role in cardiac injury and the subsequent repair process, including conditions such as myocardial infarction, ischemia-reperfusion injury, infective endocarditis, atherosclerosis, heart failure, and atrial fibrillation. Studies demonstrate that cardiac lymphatics facilitate the clearance of interstitial fluid, proteins, and immune cells, contributing to inflammation resolution and tissue repair. However, dysfunctions in the lymphatic system can exacerbate pathological processes, leading to myocardial edema, fibrosis, and cardiac remodeling. Emerging evidence suggests that targeted modulation of lymphangiogenesis and lymphatic function may offer new therapeutic avenues for treating cardiovascular diseases. This review provides a comprehensive understanding of the cardiac lymphatic system’s contribution to cardiac injury and repair, aiming to lay the groundwork for future research and therapeutic development in this burgeoning field.

The "Hedgehog-Halo Sign" Is Associated with Gait Symptom Severity and Tap Response in Normal Pressure Hydrocephalus.

Reduced cerebrospinal fluid (CSF) clearance may play a vital role in the pathogenesis of normal pressure hydrocephalus (NPH), but the radiologic marker is yet to be elucidated. This open-label study presents two novel neuroimaging biomarkers based on enlarged perivascular spaces (ePVS) of the sub-insular territory: the Hedgehog and Hedgehog-Halo (H-H) sign, designed to predict gait symptom severity and tap response in NPH. We retrospectively reviewed 203 patients with possible NPH with baseline magnetic resonance imaging and gait analyses before and after lumbar puncture (LP). The Hedgehog/H-H sign was scored using T2-weighted images. The clinical severity at baseline and post-tap gait improvement was compared in patients with and without Hedgehog/H-H sign. The association between Hedgehog/H-H sign and post-tap gait outcomes was assessed using multivariate regression. The diagnostic performance of Hedgehog/H-H sign was compared with conventional radiological markers. Patients with H-H showed higher global disability and more severe gait impairment than those without any signs. Following LP, patients with Hedgehog/H-H sign significantly improved in various gait parameters, unlike those with neither sign. Additionally, sub-insular ePVS was significantly associated with post-tap gait improvement after adjusting covariates. Finally, the Hedgehog/H-H sign showed a higher performance than conventional markers in predicting post-tap gait response. The Hedgehog/H-H sign is a useful neuroimaging biomarker related to the severity and tap response in NPH. This biomarker can be readily applied in clinical practice before undergoing LP, independent of conventional radiological signs. Further research is warranted to determine applicability in predicting post-shunt gait response.

Resting-state functional MRI of the nose as a novel investigational window into the nervous system

Besides being responsible for olfaction and air intake, the nose contains abundant vasculature and autonomic nervous system innervations, and it is a cerebrospinal fluid clearance site. Therefore, the nose is an attractive target for functional MRI (fMRI). Yet, nose fMRI has not been possible so far due to signal losses originating from nasal air-tissue interfaces. Here, we demonstrated feasibility of nose fMRI by using novel ultrashort/zero echo time (TE) MRI. Results obtained in the resting-state from 13 healthy participants at 7T and in 5 awake mice at 9.4T revealed a highly reproducible resting-state nose functional network that likely reflects autonomic nervous system activity. Another network observed in humans involves the nose, major brain vessels and CSF spaces, presenting a temporal dynamic that correlates with heart rate and breathing rate. These resting-state nose functional signals should help elucidate peripheral and central nervous system integrations.

Sex-specific age-related differences in cerebrospinal fluid clearance assessed by resting-state functional magnetic resonance imaging

Cerebrospinal fluid (CSF) flow may assist the clearance of brain wastes, such as amyloid-β (Aβ) and tau, and thus play an important role in aging and dementias. However, a lack of non-invasive tools to assess the CSF dynamics-related clearance in humans hindered the understanding of the relevant changes in healthy aging. The global infra-slow (<0.1 Hz) brain activity measured by the global mean resting-state fMRI signal (gBOLD) was recently found to be coupled by large CSF movements. This coupling has been found to correlate with various pathologies of Alzheimer's disease (AD), particularly Aβ pathology, linking it to waste clearance. Using resting-state fMRI data from a group of 719 healthy aging participants, we examined the sex-specific differences of the gBOLD-CSF coupling over a wide age range between 36–100 years of age. We found that this coupling index remains stable before around age 55 and then starts to decline afterward, particularly in females. Menopause may contribute to the accelerated decline in females.

Nasal lymphatic obstruction of CSF drainage as a possible cause of Alzheimer's disease and dementia.

Alzheimer's disease, the most common form of dementia among older adults, slowly destroys memory and thinking skills. In recent years, scientists have made tremendous progress in understanding Alzheimer's disease, still, they do not yet fully understand what causes the disease. This article proposes a novel etiology for Alzheimer's disease. Our hypothesis developed from a review of nuclear medicine scans, in which the authors observed a significant increase in nasal turbinate vasodilation and blood pooling in patients with hypertension, sleep apnea, diabetes and/or obesity, all risk factors for Alzheimer's disease. The authors propose that nasal turbinate vasodilation and resultant blood pooling lead to the obstruction of normal nasal lymphatic clearance of cerebrospinal fluid and its waste products from the brain. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs alongside the well-established increased sympathetic activity of the cardiovascular system as seen in patients with hypertension. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of highly processed food associated with dysregulation of the glucose regulatory system. The authors' hypothesis offers a novel mechanism and a new paradigm for the etiology of Alzheimer's disease and helps explain the rapid worldwide rise in the disease and other dementias which are expected to double in the next 20 years. This new paradigm provides compelling evidence for the modulation of the parasympathetic nervous system as a novel treatment strategy for Alzheimer's disease and other degenerative brain diseases, specifically targeting nasal turbinate lymphatic flow.

The Thyroid Hormone Analog GC-1 Mitigates Acute Lung Injury by Inhibiting M1 Macrophage Polarization.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high mortality rate of ≈40%. Thyroid hormones (THs) play crucial roles in maintaining homeostasis of the cellular microenvironment under stress. The previous studies confirmed that the clinical-stage TH analog GC-1 significantly alleviates pulmonary fibrosis by improving the function of mitochondria in epithelial cells. However, the effects of GC-1 on macrophages in lung injury and the related mechanisms remain unclear. This study evaluated the therapeutic effects of GC-1 in two murine models of lipopolysaccharide (LPS)- or hydrochloric acid (HCl)-induced ALI. Additionally, mouse alveolar macrophages (AMs) and human THP-1-derived macrophages are utilized to investigate the impact of GC-1 on macrophage polarization. GC-1 effectively reduces the inflammatory response and lung injury in ALI mice, as evidenced by neutrophil infiltration, cytokine levels, alveolar fluid clearance, and pulmonary pathology. Notably, GC-1 selectively inhibits M1 macrophage polarization, which may be achieved by impeding NF-κB signaling activation through the DNMT3b-PPARγ-NF-κB pathway in a TH receptor β1 (TRβ1)-dependent manner, consequently suppressing the polarization of macrophages toward the M1 phenotype and overproduction of inflammatory cytokines. Overall, these findings highlight the immunomodulatory property of GC-1 as an anti-inflammatory strategy for ALI/ARDS and inflammation-related diseases.

Quantitative systems pharmacology model of α-synuclein pathology in Parkinson's disease-like mouse for investigation of passive immunotherapy mechanisms.

The main pathophysiological hallmark of Parkinson's disease (PD) is the accumulation of aggregated alpha-synuclein (αSyn). Microglial activation is an early event in PD and may play a key role in pathological αSyn aggregation and transmission, as well as in clearance of αSyn and immunotherapy efficacy. Our aim was to investigate how different proposed mechanisms of anti-αSyn immunotherapy may contribute to pathology reduction in various PD-like mouse models. Our mechanistic model of PD pathology in mouse includes αSyn production, aggregation, degradation and distribution in neurons, secretion into interstitial fluid, internalization, and subsequent clearance by neurons and microglia. It describes the influence of neuroinflammation on PD pathogenesis and dopaminergic neurodegeneration. Multiple data from mouse PD models were used for calibration and validation. Simulations of anti-αSyn passive immunotherapy adequately reproduce preclinical data and suggest that (1) immunotherapy is efficient in the reduction of aggregated αSyn in various models of PD-like pathology; (2) prevention of aSyn spread only does not reduce the pathology; (3) a decrease in microglial inflammatory activation and aSyn aggregation may be alternative therapy approaches in PD-like pathology.

Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation.

Advances and controversies in meningeal biology.

The dura, arachnoid and pia mater, as the constituent layers of the meninges, along with cerebrospinal fluid in the subarachnoid space and ventricles, are essential protectors of the brain and spinal cord. Complemented by immune cells, blood vessels, lymphatic vessels and nerves, these connective tissue layers have held many secrets that have only recently begun to be revealed. Each meningeal layer is now known to have molecularly distinct types of fibroblasts. Cerebrospinal fluid clearance through peripheral lymphatics and lymph nodes is well documented, but its routes and flow dynamics are debated. Advances made in meningeal immune functions are also debated. This Review considers the cellular and molecular structure and function of the dura, arachnoid and pia mater in the context of conventional views, recent progress, and what is uncertain or unknown. The hallmarks of meningeal pathophysiology are identified toward developing a more complete understanding of the meninges in health and disease.

Investigating Optic Nerve Sheath Diameter in Prone Position Spinal Surgery Patients: A Pilot Study.

This study aimed to evaluate the effect of intraoperative positioning and ocular immobility on the amount of cerebrospinal fluid around the optic nerve in patients undergoing prone spinal surgery by measuring the optic nerve sheath diameter (ONSD) using ultrasound. Consecutive participants (n = 15 patients, 30 eyes) were scanned preoperatively, intraoperatively approximately 20 minutes before the end of the surgery, and postoperatively in the post-anesthesia care unit at least 10 min after the completion of the surgery at one academic hospital. On average, patients who underwent prone spinal surgery had a 21% increase in ONSD intraoperatively, with a positive time-dependent relationship with the overall length of surgery (P 0.001). ONSDs postoperatively returned to baseline and were not significantly different from preoperative measurements. Our findings suggest pooling and inadequate clearance of perioptic cerebrospinal fluid during prone spinal surgery that improves following termination of the procedure and return of the patient to an upright position.

Left atrial strain assessment unveils left ventricular diastolic dysfunction in neonates with transient tachypnea of the newborn: A prospective observational study.

An inadequate clearance of lung fluid plays a key role in the pathogenesis of transient tachypnea of the newborn (TTN). To evaluate if left ventricular diastolic dysfunction contributes to reduced clearance of lung fluid in TTN. This was a prospective, observational study. Echocardiography and lung ultrasound were performed at 2, 24 and 48 h of life (HoL) to assess biventricular function and calculate lung ultrasound score (LUS). Left atrial strain reservoir (LASr) provided surrogate measurement of left ventricular diastolic function. Twenty-seven neonates with TTN were compared with 27 controls with no difference in gestation (36.1 ± 2 vs. 36.9 ± 2 weeks) or birthweight (2508 ± 667 vs. 2718 ± 590 g). Biventricular systolic function was normal in both groups. LASr was significantly lower in cases at 2 (21.0 ± 2.7 vs. 38.1 ± 4.4; p < 0.01), 24 (25.2 ± 4.5 vs. 40.6 ± 4.0; p < 0.01) and 48 HoL (36.5 ± 5.8 and 41.6 ± 5.2; p < 0.01), resulting in a significant group by time interaction (p < 0.001), after adjusting for LUS and gestational diabetes. A logistic regression model including LUS, birth weight and gestational diabetes as covariates, showed that LASr at 2 HoL was a predictor of respiratory support at 24 HoL, with an adjusted odds ratio of 0.60 (CI 0.36-0.99). LASr was reduced in neonates with TTN, suggesting diastolic dysfunction, that may contribute to the delay in lung fluid clearance.

Capsular bag distension syndrome with sulcus IOL acting as a seal

Capsular bag distension syndrome (CBDS) is a rare complication following cataract surgery with posterior chamber intraocular lens (IOL) implantation. We describe the case of a 68-year-old female who developed early-onset CBDS of her left eye after manual small-incision cataract surgery with implantation of posterior chamber IOL in the sulcus (Excel PMMA IOL (polymethyl methacrylate), Manufactured by Excel Optics (P) Limited, Chennai). The patient had an uneventful cataract surgery performed by a resident in training. Her immediate postoperative uncorrected vision was 20/40, but it decreased to finger counting 1 m on postoperative day 7, for which she presented back to hospital. Slit-lamp examination revealed a quiet anterior chamber without any cells–flare with IOL in the sulcus with a relatively smaller capsulorhexis of about 5 mm, and IOL optic was covering the capsulorhexis in a symmetric fashion, thus causing a block. Distension of capsular bag was further confirmed by Anterion anterior segment optical coherence tomography (Heidelberg Engineering Technology, Germany), which showed a confined hyperechogenic fluid trapped between the IOL and the posterior capsule. She was diagnosed with CBDS secondary to retention of turbid fluid. Phased treatment was done; neodymium-doped yttrium aluminum garnet capsulotomy was tried in the first attempt, but failed as the posterior capsule was far too behind. This was followed by anterior chamber wash with redialing of the lens in the bag, which thereby improved vision to 20/20 (best corrected visual acuity) at 1-week postoperatively. Even with IOL in the sulcus, the postoperative CBDS may rarely happen at any point of time with a small capsulorrhexis and an intumescent mature cataract. Immense cortex wash should always be kept in mind in such a case, as the liquefied cortex is sometimes stuck at the equator and a little more duration of irrigation is required in such scenarios. Hence, complete clearance of turbid fluid of intumescent mature cataract variety also holds due importance similar to the need of removing viscoelastic substance to prevent CBDS.

MRI free water mediates the association between water exchange rate across the blood brain barrier and executive function among older adults.

Vascular risk factors contribute to cognitive aging, with one such risk factor being dysfunction of the blood brain barrier (BBB). Studies using non-invasive magnetic resonance imaging (MRI) techniques, such as diffusion prepared arterial spin labeling (DP-ASL), can estimate BBB function by measuring water exchange rate (kw). DP-ASL kw has been associated with cognition, but the directionality and strength of the relationship is still under investigation. An additional variable that measures water in extracellular space and impacts cognition, MRI free water (FW), may help explain prior findings. A total of 94 older adults without dementia (Mean age = 74.17 years, 59.6% female) underwent MRI (DP-ASL, diffusion weighted imaging (DWI)) and cognitive assessment. Mean kw was computed across the whole brain (WB), and mean white matter FW was computed across all white matter. The relationship between kw and three cognitive domains (executive function, processing speed, memory) was tested using multiple linear regression. FW was tested as a mediator of the kw-cognitive relationship using the PROCESS macro. A positive association was found between WB kw and executive function [F(4,85) = 7.81, p < .001, R2= 0.269; β = .245, p = .014]. Further, this effect was qualified by subsequent results showing that FW was a mediator of the WB kw-executive function relationship (indirect effect results: standardized effect = .060, bootstrap confidence interval = .0006 to .1411). Results suggest that lower water exchange rate (kw) may contribute to greater total white matter (WM) FW which, in turn, may disrupt executive function. Taken together, proper fluid clearance at the BBB contributes to higher-order cognitive abilities.

Ultrasonic cerebrospinal fluid clearance improves outcomes in hemorrhagic brain injury models.

Impaired clearance of the byproducts of aging and neurologic disease from the brain exacerbates disease progression and severity. We have developed a noninvasive, low intensity transcranial focused ultrasound protocol that facilitates the removal of pathogenic substances from the cerebrospinal fluid (CSF) and the brain interstitium. This protocol clears neurofilament light chain (NfL) - an aging byproduct - in aged mice and clears red blood cells (RBCs) from the central nervous system in two mouse models of hemorrhagic brain injury. Cleared RBCs accumulate in the cervical lymph nodes from both the CSF and interstitial compartments, indicating clearance through meningeal lymphatics. Treating these hemorrhagic brain injury models with this ultrasound protocol reduced neuroinflammatory and neurocytotoxic profiles, improved behavioral outcomes, decreased morbidity and, importantly, increased survival. RBC clearance efficacy was blocked by mechanosensitive channel antagonism and was effective when applied in anesthetized subjects, indicating a mechanosensitive channel mediated mechanism that does not depend on sensory stimulation or a specific neural activity pattern. Notably, this protocol qualifies for an FDA non-significant risk designation given its low intensity, making it readily clinically translatable. Overall, our results demonstrate that this low-intensity transcranial focused ultrasound protocol clears hemorrhage and other harmful substances from the brain via the meningeal lymphatic system, potentially offering a novel therapeutic tool for varied neurologic disorders.

The efficacy and safety of furmonertinib in patients with advanced EGFR-mutated NSCLC and leptomeningeal metastases.

e20525 Background: Leptomeningeal metastasis (LM) is a common and fatal complication in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR) mutation. This retrospective study aimed to evaluate the efficacy and safety of furmonertinib in patients with advanced EGFR-mutated ( EGFRm) NSCLC and LM. Methods: Eligible patients with confirmed advanced EGFRm NSCLC and LM were treated with furmonertinib. The primary endpoints were LM response rate and progression-free survival (PFS). Secondary endpoints were overall survival (OS) and adverse events (AEs). Results: This retrospective study analyzed the efficacy and safety of 31 EGFRm advanced NSCLC patients with LM at two hospitals between February 2020 to March 2023. The median age was 56 years (rang: 31-75), 22 (71.0%) were females. 19 (61.3%) patients had ECOG PS≥2 and all 31 patients (100%) had adenocarcinoma histology. For the treatment of LM, 19 (61.3%) patients received furmonertinib as first-line treatment, 8 (25.8%) patients as second-line treatment. 16 (51.6%) patients were treated with 240 mg of furmonertinib and 12 (38.7%) patients with 160 mg of furmonertinib. The median follow-up duration was 16.80 months (95% CI 12.71-20.89 months). LM objective response rate (ORR) was 75.0% and LM disease control rate (DCR) was 95.0% according to RANO-LM radiologic criteria. Overall ORR was 22.6% and DCR was 96.8%. Median LM duration of response (DoR) was 12.00 months (95% CI 7.40-16.60 months) and median overall DoR was 7.20 months (95% CI 3.60-10.80 months). 23 (74.2%) of the 31 patients had progressed or died by data cutoff. The median PFS was 11.70 months (95% CI 9.48-13.92 months) and the median OS was 18.40 months (95% CI 12.49-24.21 months). There was no significant difference in survival (median PFS: 11.70 months vs 10.90 months, p = 0.335; median OS: 18.40 months vs 13.50 months, p = 0.196) between the 19 patients who treated with furmonertinib as first-line therapy and those who treated with furmonertinib as second-line therapy. Although data on cerebrospinal fluid (CSF) clearance were not available, we observed improved neurologic function in 18 (75%) of 24 patients with baseline neurologic abnormalities. Logistic regression analysis showed that the therapeutic dose of furmonertinib was a positive predictor of OS in NSCLC patients harboring EGFR mutation with LM [HR: 2.679 (1.004-7.147), P = 0.049]. The most common AEs were rash, diarrhea and decreased appetite. However, most AEs were grade 1-2. Conclusions: Our study provides real-world clinical evidence that furmonertinib shows an encouraging efficacy and a manageable safety profile in patients with EGFRm NSCLC and LM.

Protein interactome analysis of ATP1B1 in alveolar epithelial cells using Co-Immunoprecipitation mass spectrometry and parallel reaction monitoring assay

AimsAlveolar epithelial barrier integrity is essential for lung homeostasis. Na, K-ATPase β1 subunit (ATP1B1) involves alveolar edema fluid clearance and alveolar epithelial barrier stability. However, the underlying molecular mechanism of ATP1B1 in alveolar epithelial cells still needs to be understood. Main methodsWe utilized Co-Immunoprecipitation mass spectrometry proteomic analysis, protein-protein interaction (PPI) analysis, enrichment analysis, and parallel reaction monitoring (PRM) analysis to investigate proteins interacting with ATP1B1 in A549 cells. Key findingsA total of 159 proteins were identified as significant proteins interacting with ATP1B1 in A549 cells. Ribosomal and heat shock proteins were major constituents of the two main functional modules based on the PPI network. Enrichment analysis showed that significant proteins were involved in protein translation, posttranslational processing, and function regulation. Moreover, 10 proteins of interest were verified by PRM, and fold changes in 6 proteins were consistent with proteomics results. Finally, HSP90AB1, EIF4A1, TUBB4B, HSPA8, STAT1, and PLEC were considered candidates for binding to ATP1B1 to function in alveolar epithelial cells. SignificanceOur study provides new insights into the role of ATP1B1 in alveolar epithelial cells and indicates that six proteins, in particular HSP90AB1, may be key proteins interacting with and regulating ATP1B1, which might be potential targets for the treatment of acute respiratory distress syndrome.