ELK4 targets CHMP6 to inhibit ferroptosis and enhance malignant properties of skin cutaneous melanoma cells.

Ferroptosis, a key factor in tumor progression, is poorly understood at the molecular level. This study investigates how ELK4 and CHMP6 regulate skin cutaneous melanoma (SKCM) cell proliferation and ferroptosis. Analysis of TCGA data reveals high expression of ELK4 and CHMP6 in SKCM. Overexpression of ELK4 or CHMP6 enhances cell proliferation, invasion, and migration while reducing ROS and Fe2 + levels. It also increases GPX4 and xCT expression and decreases ACSL4 levels in SKCM cells. The opposite effects are observed with ELK4 or CHMP6 knockdown. ELK4 binds to the CHMP6 promoter, promoting CHMP6 transcription. Knockdown of CHMP6 reverses the oncogenic effects of ELK4 overexpression. In conclusion, ELK4 enhances proliferation, invasion, and migration while inhibiting ferroptosis in SKCM cells by upregulating CHMP6 transcription. This study sheds light on the intricate mechanisms involved in SKCM progression and identifies potential therapeutic targets in melanoma treatment.

MicroRNA-650 promotes melanoma metastasis via targeting inhibitor of growth family member 4.

Objective: This study aimed to evaluate the effects of microRNA-650 (miR-650) on melanoma metastasis and reveal the regulatory relationship between miR-650 and the inhibitor of growth family member 4 (ING4). Methods: miR-650 expression was determined in human melanoma WM115 and A-375 cells. WM115 cells were transfected with miR-650 mimic or mimic control. The invasion and migration abilities of transfected WM115 cells were analyzed using Transwell and wound healing assays, respectively. Then, miR-650-overexpression lentivirus vector was constructed and transfected into WM115 cells. After injection into the mice, the number of micro-metastatic foci in the lung tissues was counted. A regulatory relationship between miR-650 and ING4 was identified in WM115 and A-375 cells. Results: The miR-650 expression was upregulated in WM115 and A-375 cells. WM115 cells transfected with the miR-650 mimic exhibited higher invasive and migratory abilities than mock cells or cells transfected with negative control (NC). The number of micro-metastatic foci was significantly higher in mice injected with Lenti-miR-650 than that in those injected with mock or NC controls. Transfection with miR-650 mimic observably inhibited the expression of ING4 in WM115 and A-375 cells, whereas transfection with miR-650 inhibitor had the opposite effect. Dual-luciferase reporter gene assay showed that the miR-650 mimic inhibited the luciferase activity of ING4. Conclusion: miR-650 promotes melanoma metastasis by downregulating ING4 expression.

Internal Brace Fixation Technique for Lisfranc Injury: A Retrospective Study.

BACKGROUND The Lisfranc ligament is crucial for maintaining the transverse and longitudinal arch of the foot. Owing to the disruption between the medial cuneiform bone and the base of the second metatarsal bone, the currently preferred fixation method remains controversial. Our fixation technique involves screwing one anchor to the medial and intermediate cuneiform bones and using the anchor to carry the ligament to bind the Lisfranc joint and first and second metatarsal joints altogether for elastic fixation. This study evaluated the clinical and functional outcomes of InternalBrace fixation for Lisfranc injury. MATERIAL AND METHODS This retrospective study included 58 patients who underwent InternalBrace fixation for Lisfranc injury between January 2019 and September 2022 by an experienced surgeon. One-way analysis of variance or t test was used. Preoperative classification was performed according to the Myerson classification with imaging data. Postoperative follow-up was performed based on intraoperative blood loss, fracture healing time, visual analog scale (VAS) score, the American Orthopedic Foot and Ankle Society (AOFAS) score, Tegner score, and complications. RESULTS Surgery was completed in all patients, and follow-up was performed. The patients' ages ranged from 19 to 62 years (average: 34.6±9.4 years). The postoperative follow-up time was 12-24 months (average: 16.9±3.0 months). The average time for fracture healing was 12.8±3.0 (10-24) weeks. The VAS, AOFAS, and Tegner scores significantly improved postoperatively (from 5.33±1.0 (3-7) to 1.24±0.57 (0-2); 28.02±6.70 (18-51) to 91.59±4.76 (82-96); and 2.40±0.67 (1-4) to 6.53±0.54 (6-7), respectively), which was statistically significant (P<0.01), and the good rate of AOFAS was 91.4%. The postoperative complications were traumatic arthritis, incision infection, and temporary dorsal foot numbness, which gradually recovered. No other rejection reactions or Lisfranc fracture/dislocations recurrence occurred during the follow-up period. CONCLUSIONS InternalBrace fixation for Lisfranc injury is beneficial for restoring Lisfranc joint stability and function and allows for early and more aggressive rehabilitation for patients, with fewer surgical complications.

Establishing a Ten Disulfidptosis-related Gene Signature for Prognostic Prediction in Skin Cutaneous Melanoma.

AIM: Disulfidptosis is a new metabolic-related regulated cell death associated with cancer growth. This study aimed to investigate the molecular mechanisms associated with disulfidptosis in skin cutaneous melanoma (SKCM) and establish a disulfidptosis-related gene signature for prognostic prediction in SKCM. METHODS: Disulfidptosis-associated genes were identified from RNA-seq data of SKCM. A risk score signature was developed and validated through univariate Cox and LASSO analyses. Additionally, the immune microenvironment related to the risk score signature was investigated. Finally, a disulfidptosis-related genes-transcription factor -miRNA network was developed, and the expression levels of five disulfidptosis-related genes were initially verified in SKCM cell lines. RESULTS: A total of 107 disulfidptosis-related differentially expressed genes in SKCM samples were identified. A ten-disulfidptosis-gene signature was established, including BIN2, CCL3L3, CCL8, CD79A, CIITA, CXCR3, DEFB1, GPR171, IL2RB, and SOCS1. The SKCM samples were divided into high- and low-risk groups, of which samples in the low-risk group showed better survival performance. The receiver operating characteristic curve analysis confirmed the good potency of the disulfidptosis-related gene prognostic model. Except for DEFB1, the other nine genes were positively related with T cell CD8+, T cell CD4+ memory activated, T cell gamma delta, NK cell activated, and macrophage M1, and they were all negatively related with NK cell resting, macrophage M0, macrophage M2, and mast cell activated. Finally, we verified downregulated levels of SOCS1 and DEFB1 and upregulated CXCR3, BIN2, and CCL3L3 in A875 and A375. CONCLUSION: We successfully established ten disulfidptosis-related genes' prediction prognostic signatures for SKCM patients.

The effects of fatty acids on psoriasis: A two-sample mendelian randomization study.

BACKGROUND: Some studies indicated an association between fatty acids (FA) and psoriasis. While definitive correlation between FA and psoriasis is still unclear. Therefore, our objective is to ascertain whether fatty acid levels are causally related to psoriasis using a Mendelian randomization approach. METHOD: We investigated the causal relationship between psoriasis and multiple types of FA by mendelian randomization. All data were acquired from Genome-Wide Association Study. We also performed additional analysis to assess the validity of the causal connection. RESULTS: Our mendelian analysis suggests that n-3 fatty acid levels are associated with a lower risk of psoriasis. [IVW, OR/95% CI: 0.998/(0.997, 0.999), p (2.479 × 10-4)] Complementary analyses returned similar results, indicating consistency in our findings. No horizontal pleiotropy was found in our analysis. There was no indication of causal effects from other varieties of FA on psoriasis. CONCLUSION: Our studies found that n-3 FA may lower the likelihood of developing psoriasis. We also need well-designed prospective studies and related large-scale, multicenter RCTs to confirm our findings.

Unsupervised Conditional Diffusion Models in Video Anomaly Detection for Monitoring Dust Pollution.

Video surveillance is widely used in monitoring environmental pollution, particularly harmful dust. Currently, manual video monitoring remains the predominant method for analyzing potential pollution, which is inefficient and prone to errors. In this paper, we introduce a new unsupervised method based on latent diffusion models. Specifically, we propose a spatio-temporal network structure, which better integrates the spatial and temporal features of videos. Our conditional guidance mechanism samples frames of input videos to guide high-quality generation and obtains frame-level anomaly scores, comparing generated videos with original ones. We also propose an efficient compression strategy to reduce computational costs, allowing the model to perform in a latent space. The superiority of our method was demonstrated by numerical experiments in three public benchmarks and practical application analysis in coal mining over previous SOTA methods with better AUC, of at most over 3%. Our method accurately detects abnormal patterns in multiple challenging environmental monitoring scenarios, illustrating the potential application possibilities in the environmental protection domain and beyond.

Construction and validation of m6A-related diagnostic model for psoriasis.

Background: Psoriasis is a chronic immune-mediated inflammatory disease. N6-methyladenosine (m6A) is involved in numerous biological processes in both normal and diseased states. Herein, we aimed to explore the potential role of m6A regulators in the diagnosis of psoriasis and predict molecular mechanisms by which m6A regulators impact psoriasis. Methods: GSE30999 (170 human skin tissue samples) and GSE13355 (180 human skin tissue samples) were downloaded as the training analysis dataset and validation dataset respectively. M6A-related genes were obtained from the literature and their expression levels in GSE30999 samples were measured to identify M6A-related DEGs between psoriasis lesions (LS) and non-lesional lesions (NL). We identified m6A-related DEGs using differential expression analysis and assessed their interactions through correlation analysis and network construction. A logistic regression analysis followed by LASSO optimization was employed to select m6A-related DEGs for the construction of a diagnostic model. The performance of the model was validated using support vector machine (SVM) methodology with sigmoid kernel function and extensive cross-validation. Additionally, the correlation between m6A-related DEGs and immune cell infiltration was analyzed, as well as the association of these DEGs with psoriasis subtypes. Functional analysis of the m6A-related DEGs included the construction of regulatory networks involving miRNAs, transcription factors (TFs), and small-molecule drugs. The m6A modification patterns were also explored by examining the gene expression differences between psoriasis subtypes and their enriched biological pathways. Finally, the expression of significant m6A regulators involved in the diagnostic model was examined by RT-qPCR. Results: In this study, ten optimal m6A-related DEGs were identified, including FTO, IGF2BP2, METTL3, YTHDC1, ZC3H13, HNRNPC, IGF2BP3, LRPPRC, YTHDC2, and HNRNPA2B1. A diagnostic model based on these m6A-related DEGs was constructed, demonstrating high diagnostic accuracy with an area under the curve (AUC) in GSE30999 and GSE13355 of 0.974 and 0.730, respectively. Meanwhile, the expression level of m6A regulators verified by RT-qPCR was consistent with the results in GSE30999. The infiltration of activated mast cells and NK cells was significantly associated with all ten m6A-related DEGs in psoriasis. Among them, YTHDC1, HNRNPC, and FTO were targeted by most miRNAs and were regulated by nine related TFs. Therefore, patients may benefit from dorsomorphin and cyclosporine therapy. Between the two subgroups, 1,592 DEGs were identified, including LRPPRC and METTL3. These DEGs were predicted to be involved in neutrophil activation, cytokine-cytokine receptor interactions, and chemokine signaling pathways. Conclusions: A diagnostic model based on ten m6A-related DEGs in patients with psoriasis was constructed, which may provide early diagnostic biomarkers and therapeutic targets for psoriasis.

Functional connectivity disruption of insular subregions in the cirrhotic patients with minimal hepatic encephalopathy.

We investigated abnormal functional connectivity (FC) patterns of insular subregions in patients with minimal hepatic encephalopathy (MHE) and examined their relationships with cognitive dysfunction using resting-state functional magnetic resonance imaging (fMRI). We collected resting-state fMRI data in 54 patients with cirrhosis [20 with MHE and 34 without MHE (NHE)] and 25 healthy controls. After defining six subregions of insula, we mapped whole-brain FC of the insular subregions and identified FC differences through three groups. FC of the insular subregions was correlated against clinical parameters (including venous blood ammonia level, Child-Pugh score, and cognitive score). The discrimination performance between the MHE and NHE groups was evaluated by performing a classification analysis using the FC index. Across three groups, the observed FC differences involved four insular subregions, including the left-ventral anterior insula, left-dorsal anterior insula, right-dorsal anterior insula, and left-posterior insula (P < 0.05 with false discovery rate correction). Moreover, the FC of these four insular subregions progressively attenuated from NHE to MHE. In addition, hypoconnectivity of insular subregions was correlated with the poor neuropsychological performance and the evaluated blood ammonia levels in patients (P < 0.05 with Bonferroni correction). The FC of insular subregions yielded moderate discriminative value between the MHE and NHE groups (AUC = 0.696-0.809). FC disruption of insular subregions is related to worse cognitive performance in MHE. This study extended our understanding about the neurophysiology of MHE and may assist for its diagnosis.

Metabolic diversity shapes vegetation-enhanced methane oxidation in landfill covers: Multi-omics study of rhizosphere microorganisms.

Vegetation root exudates have the ability to shape soil microbial community structures, thereby enhancing CH4 bio-oxidation capacity in landfill cover systems. In this study, the CH4 oxidation capacity of indigenous vegetation rhizosphere microorganisms within operational landfill covers in Chongqing, China, was investigated for the first time, with the objective of identifying suitable plant candidates for CH4 mitigation initiatives within landfill cover systems. Furthermore, a multi-omics methodology was employed to explore microbial community structures and metabolic variances within the rhizospheric environment of diverse vegetation types. The primary aim was to elucidate the fundamental factors contributing to divergent CH4 oxidation capacities observed in rhizosphere soils. The findings demonstrated that herbaceous vegetation predominated in landfill covers. Notably, Rumex acetosa exhibited the highest CH4 oxidation capacity in the rhizosphere soil, approximately 20 times greater than that in non-rhizosphere soil. Root exudates played a crucial role in inducing the colonization of CH4-oxidizing functional microorganisms in the rhizosphere, subsequently prompting the development of specific metabolic pathways. This process, in turn, enhanced the functional activity of the microorganisms while concurrently bolstering their tolerance to microbial pollutants. Consequently, the addition of substances like Limonexic acid strengthened the CH4 bio-oxidation process, thereby underscoring the suitability of Rumex acetosa and similar vegetation species as preferred choices for landfill cover vegetation restoration.

Physiologically based pharmacokinetic model combined with reverse dose method to study the nephrotoxic tolerance dose of tacrolimus.

Nephrotoxicity is the most common side effect that severely limits the clinical application of tacrolimus (TAC), an immunosuppressive agent used in kidney transplant patients. This study aimed to explore the tolerated dose of nephrotoxicity of TAC in individuals with different CYP3A5 genotypes and liver conditions. We established a human whole-body physiological pharmacokinetic (WB-PBPK) model and validated it using data from previous clinical studies. Following the injection of 1 mg/kg TAC into the tail veins of male rats, we developed a rat PBPK model utilizing the drug concentration-time curve obtained by LC-MS/MS. Next, we converted the established rat PBPK model into the human kidney PBPK model. To establish renal concentrations, the BMCL5 of the in vitro CCK-8 toxicity response curve (drug concentration range: 2-80 mol/L) was extrapolated. To further investigate the acceptable levels of nephrotoxicity for several distinct CYP3A5 genotypes and varied hepatic function populations, oral dosing regimens were extrapolated utilizing in vitro-in vivo extrapolation (IVIVE). The PBPK model indicated the tolerated doses of nephrotoxicity were 0.14-0.185 mg/kg (CYP3A5 expressors) and 0.13-0.155 mg/kg (CYP3A5 non-expressors) in normal healthy subjects and 0.07-0.09 mg/kg (CYP3A5 expressors) and 0.06-0.08 mg/kg (CYP3A5 non-expressors) in patients with mild hepatic insufficiency. Further, patients with moderate hepatic insufficiency tolerated doses of 0.045-0.06 mg/kg (CYP3A5 expressors) and 0.04-0.05 mg/kg (CYP3A5 non-expressors), while in patients with moderate hepatic insufficiency, doses of 0.028-0.04 mg/kg (CYP3A5 expressors) and 0.022-0.03 mg/kg (CYP3A5 non-expressors) were tolerated. Overall, our study highlights the combined usage of the PBPK model and the IVIVE approach as a valuable tool for predicting toxicity tolerated doses of a drug in a specific group.

Efficacy and safety of upadacitinib for the treatment of moderate-to-severe atopic dermatitis: a systematic review and meta-analysis.

Introduction: Upadacitinib, an oral selective-JAK1 inhibitor, has been used in clinical trials to treat atopic dermatitis (AD). Aim: To evaluate the efficacy and safety of upadacitinib in moderate-to-severe AD. Material and methods: We searched clinical trials from PubMed, Embase, Cochrane Library databases, and Web of Science. All randomized controlled trials (RCTs) of upadacitinib treatment on patients with moderate-to-severe AD were included. A meta-analysis was performed using the fixed- or random-effects models to calculate pooled standard mean differences or relative risks (SMD or RR, respectively). Results: Compared with the placebo group, our meta-analysis revealed that upadacitinib was related to a significant decrease in Eczema Area and Severity Index (EASI) scores, and pruritus numeric rating scale (NRS) scores. A higher response rate in Investigator's Global Assessment (IGA) and EASI-75 were also detected in the upadacitinib group. Although patients treated with upadacitinib experienced a higher incidence of adverse events (AEs), these AEs were mild and tolerated. As for serious adverse events (SAEs), there was no difference between the placebo group and the upadacitinib group. Conclusions: This meta-analysis demonstrated that upadacitinib is a safe and effective treatment for moderate-to-severe AD. Further long-term trials are required for confirmation.

Anterior Talofibular Ligament All-Inside Arthroscopic Reconstruction with InternalBrace™ for Chronic Lateral Ankle Instability.

BACKGROUND Anterior talofibular ligament (ATFL) is the most easily injured or even broken of ankle sprain. Patients who fail to receive conservative treatment, resulting in persistent ankle swelling, painful and functional decline that it is so-called chronic lateral ankle instability (CLAI). It makes sense to investigate all-inside arthroscopic reconstruction of ATFL with InternalBrace™ for CLAI. MATERIAL AND METHODS We included 108 patients who underwent all-inside arthroscopic ATFL reconstruction with InternalBrace™ for CLAI from January 2018 to April 2020 through a retrospective study. Patients age ranged from 19 to 58 years (mean 35.6±8.7 years). Several elements are used to evaluate the clinical consequences of ankle function, including the American Orthopedic Foot and Ankle Society (AOFAS), Japanese Society for Surgery of the Foot Ankle-Hindfoot (JSSF), Kofoed, Tegner scores and complications, and the tilt angle of talus (TT) and the anterior displacement of talus (ADT) with stressing radiographs were taken to measure in follow-ups. RESULTS All 108 patients had all-inside arthroscopic procedures performed smoothly without serious complications. During the follow-up period (26.7±2.6 months on average), no recurrence of ankle instability and other serious complications happened. The AOFAS, JSSF, Kofoed, and Tegner scores significantly increased as time went by postoperatively, which proved statistically significant (P<0.01). Regarding stress-radiographic measurements, TT significantly decreased from (9.5±1.1)° preoperatively to (2.6±0.6)° at the latest follow-up (P<0.01), while ADT significantly decreased from (9.5±1.0) mm preoperatively to (2.6±0.6) mm at the latest examination (P<0.01). CONCLUSIONS All-inside arthroscopic ATFL reconstruction with the InternalBrace™ for CLAI is beneficial for ankle stability, allowing earlier return to activities.

Hsa-let-7c-5p, hsa-miR-130b-3p, and hsa-miR-142-3p as Novel miRNA Biomarkers for Melanoma Progression.

This study aimed to screen miRNA biomarkers for melanoma progression. Raw melanoma data were downloaded from the Gene Expression Omnibus (GSE34460, GSE35579, GSE18509, and GSE24996) and the Cancer Genome Atlas (TCGA). Then, all differentially expressed miRNAs (DEmiRNAs) between benign vs. primary, metastatic vs. benign, and metastatic vs. primary groups were obtained in the GSE34460 and GSE35579 datasets, and the miRNAs related to disease progression were further screened. Then, the miRNA-gene network was constructed, followed by enrichment, survival, and cluster analyses. Differentially expressed genes (DEGs), tumor-infiltrating immune cells, and tumor mutation burden (TMB) between subtypes were analyzed. miRNAs were verified in the GSE18509 and GSE24996 datasets. A total of 132 and 209 DEmiRNAs were obtained in the GSE34460 and GSE35579 datasets, respectively, and 27 DEmiRNAs related to disease progression were screened. hsa-miR-106b-5p, hsa-miR-27b-3p, and hsa-miR-141-3p had a higher degree and were regulated by numerous genes in the miRNA-gene network. Moreover, four miRNAs were associated with prognosis: hsa-let-7c-5p, hsa-miR-130b-3p, hsa-miR-142-3p, and hsa-miR-509-3p. Furthermore, the bidirectional hierarchical clustering of 27 miRNAs was classified into three subtypes, and TMB and four types of immune cells, including activated dendritic cells, naïve CD4 T cells, M1 macrophages, and plasma cells, showed significant differences among the three subtypes. The expression levels of most miRNAs in the GSE18509 and GSE24996 datasets were consistent with those in the training dataset. These miRNAs, including hsa-let-7c-5p, hsa-miR-130b-3p, and hsa-miR-142-3p, and activated dendritic cells, naïve CD4 T cells, M1 macrophages, and plasma cells may play vital roles in the pathogenesis of melanoma.

Aberrant stability of brain functional architecture in cirrhotic patients with minimal hepatic encephalopathy.

To investigate the stability changes of brain functional architecture and the relationship between stability change and cognitive impairment in cirrhotic patients. Fifty-one cirrhotic patients (21 with minimal hepatic encephalopathy (MHE) and 30 without MHE (NHE)) and 29 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and neurocognitive assessment using the Psychometric Hepatic Encephalopathy Score (PHES). Voxel-wise functional connectivity density (FCD) was calculated as the sum of connectivity strength between one voxel and others within the entire brain. The sliding window correlation approach was subsequently utilized to calculate the FCD dynamics over time. Functional stability (FS) is measured as the concordance of dynamic FCD. From HCs to the NHE and MHE groups, a stepwise reduction of FS was found in the right supramarginal gyrus (RSMG), right middle cingulate cortex, left superior frontal gyrus, and bilateral posterior cingulate cortex (BPCC), whereas a progressive increment of FS was observed in the left middle occipital gyrus (LMOG) and right temporal pole (RTP). The mean FS values in RSMG/LMOG/RTP (r = 0.470 and P = 0.001; r = -0.458 and P = 0.001; and r = -0.384 and P = 0.005, respectively) showed a correlation with PHES in cirrhotic patients. The FS index in RSMG/LMOG/BPCC/RTP showed moderate discrimination potential between the NHE and MHE groups. Changes in FS may be linked to neuropathological bias of cognitive impairment in cirrhotic patients and could serve as potential biomarkers for MHE diagnosis and monitoring the progression of hepatic encephalopathy.

Dynamic Alterations in Functional Connectivity Density in Amyotrophic Lateral Sclerosis: A Resting-State Functional Magnetic Resonance Imaging Study.

Background and Aims: Current knowledge on the temporal dynamics of the brain functional organization in amyotrophic lateral sclerosis (ALS) is limited. This is the first study on alterations in the patterns of dynamic functional connection density (dFCD) involving ALS. Methods: We obtained resting-state functional magnetic resonance imaging (fMRI) data from 50 individuals diagnosed with ALS and 55 healthy controls (HCs). We calculated the functional connectivity (FC) between a given voxel and all other voxels within the entire brain and yield the functional connection density (FCD) value per voxel. dFCD was assessed by sliding window correlation method. In addition, the standard deviation (SD) of dFCD across the windows was computed voxel-wisely to measure dFCD variability. The difference in dFCD variability between the two groups was compared using a two-sample t-test following a voxel-wise manner. The receiver operating characteristic (ROC) curve was used to assess the between-group recognition performance of the dFCD variability index. Results: The dFCD variability was significantly reduced in the bilateral precentral and postcentral gyrus compared with the HC group, whereas a marked increase was observed in the left middle frontal gyrus of ALS patients. dFCD variability exhibited moderate potential (areas under ROC curve = 0.753-0.837, all P < 0.001) in distinguishing two groups. Conclusion: ALS patients exhibit aberrant dynamic property in brain functional architecture. The dFCD evaluation improves our understanding of the pathological mechanisms underlying ALS and may assist in its diagnosis.

Characterizing Sensorimotor-Related Area Abnormalities in Amyotrophic Lateral Sclerosis: An Intravoxel Incoherent Motion Magnetic Resonance Imaging Study.

RATIONALE AND OBJECTIVES: To investigate the microperfusion and water molecule diffusion alterations in sensorimotor-related areas in amyotrophic lateral sclerosis (ALS) using intravoxel incoherent motion (IVIM) magnetic resonance imaging. MATERIALS AND METHODS: IVIM data were obtained from 43 ALS patients and 31 controls. This study employed the revised ALS Functional Rating Scale (ALSFRS-R) in evaluating disease severity. IVIM-derived metrics were calculated, including diffusion coefficient (D), pseudo-diffusion coefficient, and perfusion fraction. Conventional apparent diffusion coefficient was also computed. Atlas-based analysis was conducted to detect between-group difference in these metrics in sensorimotor-related gray/white matter areas. Spearman correlation analysis was employed to establish correlation between various metrics and ALSFRS-R. RESULTS: ALS patients had perfusion fraction (× 10-3) reduction in the left presupplementary motor area (60.72 ± 16.15 vs. 71.15 ± 12.98, p = 0.016), right presupplementary motor area (61.35 ± 17.02 vs. 72.18 ± 14.22, p = 0.016), left supplementary motor area (55.73 ± 12.29 vs. 64.12 ± 9.17, p = 0.015), and right supplementary motor area (56.53 ± 11.93 vs. 63.67 ± 10.03, p = 0.020). Patients showed D (× 10-6 mm2/s) increase in a white matter tract projecting to the right ventral premotor cortex (714.20 ± 39.75 vs. 691.01 ± 24.53, p = 0.034). A negative correlation between D of right ventral premotor cortex tract and ALSFRS-R score was observed (r = -0.316, p = 0.039). CONCLUSION: These findings suggest aberrant microperfusion and water molecule diffusion in the sensorimotor-related areas in ALS patients, which are associated with motor impairment in ALS.

Abnormal Stability of Dynamic Functional Architecture in Amyotrophic Lateral Sclerosis: A Preliminary Resting-State fMRI Study.

Purpose: Static and dynamic analyses for identifying functional connectivity (FC) have demonstrated brain dysfunctions in amyotrophic lateral sclerosis (ALS). However, few studies on the stability of dynamic FC have been conducted among ALS patients. This study explored the change of functional stability in ALS and how it correlates with disease severity. Methods: We gathered resting-state functional magnetic resonance data from 20 patients with ALS and 22 healthy controls (HCs). The disease severity was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R). We used a sliding window correlation approach to identify dynamic FC and measured the concordance of dynamic FC over time to obtain the functional stability of each voxel. We assessed the between-group difference in functional stability by voxel-wise two-sample t-test. The correlation between the functional stability index and ALSFRS-R in ALS patients was evaluated using Spearman's correlation analysis. Results: Compared with the HC group, the ALS group had significantly increased functional stability in the left pre-central and post-central gyrus and right temporal pole while decreased functional stability in the right middle and inferior frontal gyrus. The results revealed a significant correlation between ALSFRS-R and the mean functional stability in the right temporal pole (r = -0.452 and P = 0.046) in the ALS patients. Conclusions: ALS patients have abnormal stability of brain functional architecture, which is associated with the severity of the disease.

Administration of Nrf-2-Modified Hair-Follicle MSCs Ameliorates DSS-Induced Ulcerative Colitis in Rats.

Ulcerative colitis (UC) is a common chronic nonspecific intestinal inflammation of unknown etiology associated with a low cure rate and a high relapse rate. Hair follicle mesenchymal stem cells (HF-MSCs) are a class of pluripotent stem cells that have differentiation potential and strong proliferation ability. Nuclear factor red system related factor (Nrf-2) is a key factor in the oxidative stress response. Dextran sulfate sodium- (DSS-) induced rat UC models closely mimic human UC in terms of symptoms and histological changes. Animals were divided into five groups, including a healthy group and UC model rats treated with normal saline, Nrf-2, HF-MSCs, or Nrf-2-expressing HF-MSC group. Based on the expression of intestinal stem cells, inflammatory factors, anti-inflammatory factors, and disease activity index scores, Nrf-2-expressing HF-MSCs had the most obvious therapeutic effect under the same treatment regimen. This study provided a new potential clinical treatment option for ulcerative colitis.

White matter microstructural impairments in amyotrophic lateral sclerosis: A mean apparent propagator MRI study.

BACKGROUND: White matter (WM) impairment is a hallmark of amyotrophic lateral sclerosis (ALS). This study evaluated the capacity of mean apparent propagator magnetic resonance imaging (MAP-MRI) for detecting ALS-related WM alterations. METHODS: Diffusion images were obtained from 52 ALS patients and 51 controls. MAP-derived indices [return-to-origin/-axis/-plane probability (RTOP/RTAP/RTPP) and non-Gaussianity (NG)/perpendicular/parallel NG (NG⊥/NG||)] were computed. Measures from diffusion tensor/kurtosis imaging (DTI/DKI) and neurite orientation dispersion and density imaging (NODDI) were also obtained. Voxel-wise analysis (VBA) was performed to determine differences in these parameters. Relationship between MAP parameters and disease severity (assessed by the revised ALS Functional Rating Scale (ALSFRS-R)) was evaluated by Pearson's correlation analysis in a voxel-wise way. ALS patients were further divided into two subgroups: 29 with limb-only involvement and 23 with both bulbar and limb involvement. Subgroup analysis was then conducted to investigate diffusion parameter differences related to bulbar impairment. RESULTS: The VBA (with threshold of P < 0.05 after family-wise error correction (FWE)) showed that ALS patients had significantly decreased RTOP/RTAP/RTPP and NG/ NG⊥/NG|| in a set of WM areas, including the bilateral precentral gyrus, corona radiata, posterior limb of internal capsule, midbrain, middle corpus callosum, anterior corpus callosum, parahippocampal gyrus, and medulla. MAP-MRI had the capacity to capture WM damage in ALS, which was higher than DTI and similar to DKI/NODDI. RTOP/RTAP/NG/NG⊥/NG|| parameters, especially in the bilateral posterior limb of internal capsule and middle corpus callosum, were significantly correlated with ALSFRS-R (with threshold of FWE-corrected P < 0.05). The VBA (with FWE-corrected P < 0.05) revealed the significant RTAP reduction in subgroup with both bulbar and limb involvement, compared with those with limb-only involvement. CONCLUSIONS: Microstructural impairments in corticospinal tract and corpus callosum represent the consistent characteristic of ALS. MAP-MRI could provide alternative measures depicting ALS-related WM alterations, complementary to the common diffusion imaging methods.

ID1 mediates resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer through epithelial-mesenchymal transition.

BACKGROUND: ID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, the effect of ID1 expression on osimertinib resistance in EGFR T790M-positive NSCLC is not clear. METHODS: We established a drug-resistant cell line, H1975/OR, from the osimertinib-sensitive cell line H1975. Alterations in ID1 protein expression and Epithelial-mesenchymal transition (EMT)-related proteins were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA levels. ID1 silencing and overexpression were used to investigate the effects of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess the proliferation rate in cells with altered of ID1 expression. Transwell assay was used to evaluate the invasion ability of different cells. The effects on the cell cycle and apoptosis were also compared using flow cytometry. RESULTS: In our study, we found that in osimertinib-resistant NSCLC cells, the expression level of the EMT-related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin were higher than those of sensitive cells. ID1 expression levels was closely related to E-cadherin and vimentin in both osimertinib-sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression in H1975/OR cells could inhibit cell proliferation, reduce cell invasion, promote cell apoptosis and arrested the cell cycle in the G1/G0 stage phase. Our study suggests that ID1 may induce EMT in EGFR T790M-positive NSCLC, which mediates drug resistance of osimertinib. CONCLUSIONS: Our study revealed the mechanism of ID1 mediated resistance to osimertinib in EGFR T790M-positive NSCLC through EMT, which may provide new ideas and methods for the treatment of EGFR mutated NSCLC after osimertinib resistance.