Activation Factor Research Articles

Smooth muscle cell Piezo1 is essential for phenotypic switch and neointimal hyperplasia.

Disturbed blood flow is a critical factor in activation of vascular smooth muscle cells (VSMCs) and initiation of neointimal hyperplasia. The Piezo1 channel is a recent yet well-characterised mechanosensor that plays a vital role in vascular development and homeostasis. However, the role of VSMC Piezo1 in neointima development remains largely unknown. The purpose of this study is to investigate the functional role of Piezo1 channel in neointimal hyperplasia. We measured the expression of Piezo1 in VSMC-rich neointima from human coronary artery samples and two mouse neointimal hyperplasia models which were induced by cast implantation or guidewire injury. We utilised VSMC-specific Piezo1 knockout mice to explore its function and the underlying mechanism of neointimal hyperplasia, both in vivo and in vitro. In human and mouse neointima samples, we observed a significant up-regulation of Piezo1 expression in the VSMC-rich neointima compared to the medial layer. VSMC-specific knockout of Piezo1 significantly reduced neointimal hyperplasia in both animal models. Activation of Piezo1 facilitates, whereas Piezo1 deficiency inhibits disturbed flow-induced cell proliferation, migration and synthetic phenotype switch. Mechanistic studies suggest that Piezo1 activates YAP and TAZ through Ca2+ and its downstream effectors calmodulin kinase II and calcineurin, which in turn drive VSMC proliferation and migration, thereby facilitating neointimal hyperplasia. These findings demonstrate a critical role of mechanosensitive Piezo1 channel in neointimal hyperplasia via modulating VSMC phenotype. Piezo1 channels may represent a novel therapeutic target for maladaptive vascular remodelling and occlusive vascular diseases.

Nepetin limits NLRP3 inflammasome activation and alleviates NLRP3-driven inflammatory diseases via PINK1-dependent mitophagy.

The NLRP3 inflammasome plays a pivotal role in the progression of inflammatory diseases. Mitochondrial damage, oxidative stress and mitochondrial DNA (mtDNA) leak are the key upstream factors for NLRP3 inflammasome activation. Nepetin (Nep), a naturally occurring flavonoid found with anti-inflammatory properties; however, whether it can affect the NLRP3 inflammasome activation and its precise anti-inflammatory mechanism remains unclear. In this study, we demonstrated that Nep enhances PINK1-mediated ubiquitin phosphorylation, which promotes mitophagy and subsequently inhibits NLRP3 inflammasome activation and pyroptosis in macrophages. The administration of Nep to macrophages alleviated of mitochondrial damage, reduced mitochondrial superoxide production, restored mitochondrial membrane potential and prevented the mtDNA leakage. These findings provide compelling evidence for the antioxidant effect of Nep. Furthermore, the pivotal function of mitophagy in the NLRP3 inflammasome inhibitory impact of Nep was substantiated through the utilisation of mitophagy inhibitors and siRNA techniques. Notably, Nep increased survival and reduced organ damage in mice with systemic inflammation by inhibiting NLRP3 inflammasome activation. In addition, Nep suppressed NLRP3 inflammasome activation in obese mice, which led to reduced white adipose and liver inflammation, thereby ameliorating insulin resistance. In conclusion, our findings suggest that Nep is a potent NLRP3 inflammasome inhibitor and a promising candidate for the development of anti-inflammatory therapies.

Nutritional Habits in Crohn’s Disease Onset and Management

Crohn’s disease (CD)’s activation factors are still unclear. However, they are reported to involve an interaction between genetic susceptibility and unhealthy lifestyle factors like smoking, alcohol consumption, low physical activity, low BMI (<18.5 kg/m2), and probably unbalanced nutritional habits. Therefore, the aim of the present narrative review is to demonstrate the possible effects of different nutritional habits, before the occurrence of the disease, as crucial factors for the inception of CD activation. The structure of the present narrative review was conducted following the instructions of the “Narrative Review Academy of Nutrition and Dietetics Checklist”. It is well established that the consumption of specific foods and drinks, such as spicy and fatty foods, raw vegetables and fruits, dairy products, carbonated beverages, and coffee or tea, can provoke the exacerbation of CD symptoms. On the other hand, Mediterranean-oriented diets seem to provide an inverse association with the incidence of CD. Moreover, patients seem to have the knowledge to select foods that contribute to the remission of their symptoms. However, it is not clearly reported whether the inception of CD activation is due to lifelong unbalanced nutritional habits and their subsequent effect on gut microbiota secretion, which seems to be the gold standard for CD’s investigation. Therefore, more future studies should record, examine, and compare the nutritional habits between patients with CD (immediately after the disease’s diagnosis) and healthy populations in a lifelong manner, in order to reveal the possible influence of foods on CD inception.

Characterization of motor nerve stimulation using sinusoidal low frequency alternating currents and cuff electrodes.

Direct electrical neurostimulation using continuous sinusoidal low frequency alternating currents (LFAC) is an emerging modality for neuromodulation. As opposed to the traditional rectangular pulse stimulation, there is limited background on the characteristics of peripheral nerves responses to sinusoidal LFAC stimulation; especially within the low frequency range (<50Hz). In this study, we demonstrate LFAC activation as a means to activate motor nerves by direct bipolar nerve stimulation via cuff electrodes, and characterize the factors of activation. We study and quantify the effects of sinusoidal frequency and electrode geometry on the motor nerve activation threshold in-vivo and in computational models, in-silico. Acute in-vivo experiments (N=34) were conducted on isoflurane-anaesthetized rats. A pure tone continuous sinusoidal current was applied to the rat sciatic nerve in bipolar configurations via bipolar or tripolar nerve cuff electrodes (different contact separations). LFAC activation thresholds were quantified by measuring the electromyogram (EMG) response of the triceps surae muscles and the induced twitch force to LFAC stimulation at six frequencies (1, 2, 3, 4, 8, and 20Hz). Computationally, we utilized a volume conductor model of a bipolar cuff electrode around a single rat-size fascicle and projected the potentials to the McIntyre-Richardson-Grill (MRG) models of myelinated motor nerve fibers. We compared the in-silico responses of a range of fiber diameters (5.7 to 16μm) to LFAC stimulation and their activation thresholds to the in-vivo findings. Sinusoidal LFAC stimulation elicited motor nerve activity in-vivo and in-silico, with a remarkable convergence of the in-silico predictions to the in-vivo observations. The EMG activity showed that muscle responses to LFAC stimulation were phase-locked to the sinusoidal cycle but exhibited two distinct activation modes. These modes were classified as burst and unitary, indicating the presence of two distinct patterns of muscle activation during LFAC stimulation. The LFAC motor activation threshold was significantly dependent on frequency and influenced by the contact separation of the cuff electrode, with a greater extent of reduction at a higher frequency or wider separation. Moreover, the order of fiber recruitment was found to be normal-physiological (small-to-large caliber) given the nature of the induced EMG activity and in-silico predictions. These findings provide significant insights into the nature of sinusoidal LFAC stimulation, at the explored range of frequency, and the expected mammalian peripheral motor nerve responses to LFAC. The characteristics of sinusoidal LFAC stimulation would facilitate selectivity approaches in a broader range of therapeutic and rehabilitative neuromodulation applications.

Building a Bridge Between the Mechanism of EBV Reactivation and the Treatment of EBV-Associated Cancers.

Epstein-Barr virus (EBV) infection is closely associated with the development of various tumors such as lymphomas and epithelial cancers. EBV has a discrete life cycle with latency and lytic phases. In recent years, significant progress has been made in the understanding of the mechanism underlying the transition of EBV from latency to lytic replication. Multiple new lytic activation factors have been emerged and promoted our understanding of this field. In addition, we have comprehensively presented the existing therapeutic strategies and their relationship to the mechanism underlying the transition of EBV from latency to lytic replication in this review, such as lytic induction therapy and drugs to prevent EBV from entering the lytic phase fully utilize the EBV reactivation mechanisms. This year marks the 60th anniversary of the discovery of EBV, and building a bridge between the mechanism of EBV reactivation and the treatment may help us to design new approaches for treating EBV-associated diseases.

Luminal flow in the connecting tubule induces afferent arteriole vasodilation.

Renal autoregulatory mechanisms modulate renal blood flow. Connecting tubule glomerular feedback (CNTGF) is a vasodilator mechanism in the connecting tubule (CNT), triggered paracrinally when high sodium levels are detected via the epithelial sodium channel (ENaC). The primary activation factor of CNTGF-whether NaCl concentration, independent luminal flow, or the combined total sodium delivery-is still unclear. We hypothesized that increasing luminal flow in the CNT induces CNTGF via O2- generation and ENaC activation. Rabbit afferent arterioles (Af-Arts) with adjacent CNTs were microperfused ex-vivo with variable flow rates and sodium concentrations ranging from < 1 to 80mM and from 5 to 40 nL/min flow rates. Perfusion of the CNT with 5mM NaCl and increasing flow rates from 5 to 10, 20, and 40 nL/min caused a flow-rate-dependent dilation of the Af-Art (P < 0.001). Adding the ENaC blocker benzamil inhibited flow-induced Af-Art dilation, indicating a CNTGF response. In contrast, perfusion of the CNT with < 1mM NaCl did not result in flow-induced CNTGF vasodilation (P > 0.05). Multiple linear regression modeling (R2 = 0.51; P < 0.001) demonstrated that tubular flow (β = 0.163 ± 0.04; P < 0.001) and sodium concentration (β = 0.14 ± 0.03; P < 0.001) are independent variables that induce afferent arteriole vasodilation. Tempol reduced flow-induced CNTGF, and L-NAME did not influence this effect. Increased luminal flow in the CNT induces CNTGF activation via ENaC, partially due to flow-stimulated O2- production and independent of nitric oxide synthase (NOS) activity.

Novel Insights into Hg0 Oxidation in Rice Leaf: Catalase Functions and Transcriptome Responses.

Rice leaves can assimilate atmospheric mercury (Hg0), which is accumulated by grains and causes health risks to rice consumers. However, the molecular mechanisms underlying Hg0 assimilation in rice leaves remain poorly understood. Here, we investigated catalase's (CAT) function in Hg0 oxidation within rice leaves, as well as the Hg speciation and transcriptomic profiles of rice leaves exposed to Hg0. The inactivation of catalase reduced Hg0 oxidation by 91% in the leaf homogenate and the Hg0 oxidation rate increased along with CAT activity, showing the CAT's function in Hg0 oxidation. Hg0 was converted to Hg(cysteine)2 complexes in the leaf. Transcriptomic results revealed that the expression levels of both OsCATA and OsCATB (catalase-encoding genes) increased with Hg concentration, suggesting the involvement of catalase-related molecular network in Hg0 oxidation. Upstream transcription factors, including NAC (NAM-no apical meristem, ATAF-Arabidopsis transcription activation factor, and CUC-cup-shaped cotyledon), and ethylene-responsive transcription factor, are likely involved in catalase expression. Genes related to cysteine metabolism and amino acid transport appeared to regulate Hg accumulation. Our findings demonstrate the important function of catalase in Hg0 oxidation within rice and are fundamental for developing genetically modified rice cultivars to minimize human Hg exposure health risks.

The Role of Indoxyl Sulfate in Exacerbating Colorectal Cancer During Chronic Kidney Disease Progression: Insights into the Akt/β-Catenin/c-Myc and AhR/c-Myc Pathways in HCT-116 Colorectal Cancer Cells.

Epidemiological studies suggest an increased risk of colorectal cancer (CRC) aggravation in patients with chronic kidney disease (CKD). Our previous study demonstrated that indoxyl sulfate, a uremic toxin whose concentration increases with CKD progression, exacerbates CRC through activation of the AhR and Akt pathways. Consequently, indoxyl sulfate has been proposed to be a significant link between CKD progression and CRC aggravation. The present study aimed to investigate the roles of c-Myc and β-Catenin, which are hypothesized to be downstream factors of indoxyl sulfate-induced AhR and Akt activation, in CRC cell proliferation and EGF sensitivity in HCT-116 CRC cells. Indoxyl sulfate significantly induced CRC cell proliferation at concentrations exceeding 62.5 µM, a process suppressed by the c-Myc inhibitor 10058-F4. Indoxyl sulfate activated the Akt/β-Catenin/c-Myc pathway as evidenced by the Akt inhibitor MK2206, which decreased both β-Catenin and c-Myc protein levels, and the β-Catenin inhibitor XAV-939, which reduced c-Myc protein levels. The AhR antagonist CH223191 also inhibited c-Myc upregulation, indicating involvement of the AhR/c-Myc pathway. MK2206 partially attenuated the indoxyl sulfate-induced AhR transcriptional activity, suggesting that Akt activation influences the AhR/c-Myc pathway. MK2206, CH223191, and 10058-F4 suppressed the increase in EGFR protein levels induced by indoxyl sulfate, indicating that the Akt/β-Catenin/c-Myc and AhR/c-Myc pathways enhance the sensitivity of HCT-116 CRC cells to EGF. These findings indicate that the elevation of indoxyl sulfate levels in the blood, due to CKD progression, could worsen CRC by promoting the proliferation of CRC cells and enhancing EGF signaling. Therefore, indoxyl sulfate could potentially serve as a therapeutic target for CRC aggravation in patients with CKD.

N-acetyl-l-cysteine stimulates bone healing by recovering the age-associated degenerative complications relative to osteoblastic Wntless ablation.

Dysregulated Wnt signaling causes age-related characteristics such as oxidative stress, stem cell senescence, and abnormal bone homeostasis. Here we explored whether supplemental n-acetyl-l-cysteine (NAC) recovers the age-associated complications relative to osteoblastic Wntless (Wls) ablation and examined the possible mechanisms therein. For this work, we administered Col2.3-Cre;Wlsfl/fl mutant and littermate control (Wlsfl/fl) mice (14 weeks of age) with NAC (40 mM)-supplemented or NAC-free water for four weeks. A proportion of these mice received non-critical-sized femoral defects at 16 weeks of age. Blood, bone, and bone marrow (BM) samples were collected and adjusted for in vivo, ex vivo, and in vitro analyses. Osteoblastic Wls deletion delayed bone mass accrual and the healing of bone defects, stimulated osteoclastic activation and inflammatory factor expression, and decreased antioxidant enzyme activity in the BM. Osteoblastic Wls deletion also promoted oxidative stress, apoptosis, and senescence in BM stromal cells (BMSCs) and decreased BMSC' multipotencies. Supplementation of Wlsfl/fl mice with NAC enhanced bone mass accrual and regenerative bone healing via a Wnt signal-associated osteogenic activation. However, supplemental NAC induced new bone formation in the mutant mice by inhibiting the age-related complications of BM/BMSCs, as well as by restoring endogenous antioxidant system without any alterations in Wnt ligand secretion, hematopoiesis, and expression of osteogenic and growth factors. This study indicates that supplemental NAC protects mice against Wnt deficiency-mediated and age-associated degenerative complications. Overall, this study highlights the therapeutic potency of NAC for restoring the antioxidant system, stem cell function, and regenerative bone homeostasis in osteoblastic Wls-dispensable manner.

Two glycoside hydrolase family 1 proteins mediate glycosylated modification at the 5-position of anthocyanin in grape hyacinth.

Glycosylation modification of anthocyanins is important as a preceding step to acylation modification. Cyanidin-3-O-(p-coumaroyl)glucoside-5-O-malonylglucoside (Cy3pCG5MaG) is one of the major anthocyanin substances in blue-flowered grape hyacinth, but its 5-position glycosylation is unknown. Here, we identified two glycoside hydrolase family 1 genes, MaAGGT1 and MaAGGT5, which use acyl-glucose as a donor and are involved in the glycosylation modification of anthocyanins in grape hyacinth. MaAGGT1 and MaAGGT5 are localized in vacuoles and primarily expressed in the flowers, coinciding roughly with the accumulation of total anthocyanins and Cy3pCG5MaG. In vitro enzyme activity assays of recombinant proteins showed that MaAGGT1 is substrate-specific for Cy3G and Pt3G, while MaAGGT5 is substrate-specific for Mv3G. Suppressing the expression of MaAGGT1 or MaAGGT5 significantly inhibits the accumulation of total anthocyanins in blue-flowered grape hyacinth, but only MaAGGT1 affects the accumulation of Cy3pCG5MaG. Additionally, the anthocyanin activation factor MaMybA can bind to the promoters of MaAGGT1 and MaAGGT5, positively regulating their transcription, while MaAN2 binds only to the promoter of MaAGGT5, significantly enhancing its expression. In summary, our results provide evidence that two glycoside hydrolase family 1 proteins mediate the glycosylation modification at the 5-position of anthocyanins in grape hyacinth, with MaAGGT1 playing a key catalytic role in the formation of Cy3pCG5MaG.

Serum BAFF levels are associated with the prognosis of idiopathic membranous nephropathy

Objective High serum levels of B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) have been observed in patients with idiopathic membranous nephropathy (iMN); however, their relationships with disease severity and progression remain unclear. Methods Patients with iMN diagnosed via renal biopsy were enrolled in this study. The concentrations of BAFF and APRIL were determined using ELISA kits. Proteinuria remission, including complete remission (CR) and partial remission (PR), and renal function deterioration were defined as clinical events. The Cox proportional hazards method was used to analyze the relationship between cytokine levels and disease progression. Results Seventy iMN patients were enrolled in this study, with a median follow-up time of 24 months (range 6–72 months). The serum levels of BAFF and APRIL were higher in iMN patients than in healthy controls but lower than those in minimal change disease (MCD) patients. The serum BAFF level was positively correlated with the serum APRIL level, serum anti-phospholipase A2 receptor (anti-PLA2R) antibody level, and 24-h proteinuria and negatively correlated with the serum albumin (ALB) level. However, no significant correlation was observed between the serum APRIL level and clinical parameters. According to the multivariate Cox proportional hazards regression model adjusted for sex, age, systolic blood pressure (SBP), estimated glomerular filtration rate (eGFR), immunosuppressive agent use, 24-h proteinuria, APRIL level, and anti-PLA2R antibody, only the serum BAFF level was identified as an independent predictor of PR (HR, 0.613; 95% CI, 0.405–0.927; p = 0.021) and CR of proteinuria (HR, 0.362; 95% CI, 0.202–0.648; p < 0.001). Conclusions A high serum BAFF level is associated with severe clinical manifestations and poor disease progression in patients with iMN.

A Reliability and Validity of the Korean Version of Behavioral Activation for Depression Scale-Short Form: A Community Sample of Adults

Background: The behavioral activation method is a short-term, evidence-based approach that promotes functional activation by reinforcing adaptive behaviors and eliminating avoidance behaviors. This study aims to validate the Korean version of the Behavior Activation for Depression Scale-Short Form (K-BADS-SF) among Korean community adults, providing an objective measure of behavioral activation.Methods: A total of 471 participants, ranging in age from 18 to 69 years, completed an online survey. They filled out the K-BADS-SF and its long-form version, the K-BADS, as well as the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scales, the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7). The K-BADS-SF was subject to a thorough psychometric evaluation, which included analyzing internal consistency, test-retest reliability, exploratory and confirmatory factor analyses, and both convergent and discriminant validity analyses.Results: Exploratory and confirmatory factor analyses show that the model fit of the K-BADS-SF improves when certain items from the original scale are moved from the activation factor to the avoidance factor.Conclusions: The K-BADS-SF exhibits sufficient reliability and validity in the Korean community sample, confirming its effectiveness as a valuable tool for assessing behavioral activation.

Mechanisms of HIV-immunologic non-responses and research trends based on gut microbiota.

With the increasing number of people with HIV (PWH) and the use of antiretroviral treatment (ART) for PWH, HIV has gradually become a chronic infectious disease. However, some infected individuals develop issues with immunologic non-responses (INRs) after receiving ART, which can lead to secondary infections and seriously affect the life expectancy and quality of life of PWH. Disruption of the gut microbiota is an important factor in immune activation and inflammation in HIV/AIDS, thus stabilizing the gut microbiota to reduce immune activation and inflammation and promoting immune reconstitution may become a direction for the treatment of HIV/AIDS. This paper, based on extensive literature review, summarizes the definition, mechanisms, and solutions for INRs, starting from the perspective of gut microbiota.

Development of a multi-scale nanofiber scaffold platform for structurally and functionally replicated artificial perforating arteries.

Experimental models for exploring abnormal brain blood vessels, including ischemic stroke, are crucial in neuroscience; recently, significant attention has been paid to artificial tissues through tissue engineering. Nanofibers, although commonly used as tissue engineering scaffolds, undergo structural deformations easily, making it challenging to create uniform tissue, especially for the smallest-diameter ones such as perforating arteries. This study focused on the development of a platform capable of reconstructing structurally and functionally replicated perforating arteries. To ensure structural consistency, 3D-printed modules were developed to minimize the structural deformation of nanofibrous scaffolds when integrated into a 3D-printed vessel culture dish. Surface structures and physical characteristics of the nanofibers before and after installation were compared using scanning electron microscopy, contact angle analysis, surface area analysis, and universal testing machine (UTM) analysis. The results showed a uniform thickness distribution, topography, maximum load, tensile strain, tensile strength, surface area, pore size, and pore volume of the nanofibers. For consistency in tissue culture, smooth muscle, endothelial, and astrocyte cells were co-cultured by continuously measuring the pH of the medium and replenishing the depleted glucose using the Kalman filter control system. The functional efficacy and consistency of the artificial perforating vessels were confirmed under oxidative stress induced by exposure to hydrogen peroxide. Transcriptional mRNA expression trends were similar to those in vivo for antioxidant enzymes, neurotrophic factors, inflammatory factors, and endothelial cell activation factors, with very low variation between tissues. This study provides a research platform for studying the oxidative stress environments related to stroke by mass-producing perforating arteries with consistent structures and functions.

Investigating the role of Wnt3a and Wnt5a as critical factors of hepatic stellate cell activation in acute toxicant-induced liver injury

Toxicant exposure can lead to acute liver injury, characterized by hepatic reprogramming and wound healing. Hepatic stellate cells (HSC) play a key role in liver regeneration during wound healing by secreting fibrogenic factors and production of extracellular matrix (ECM). However, repetitive injury to the liver can lead to extensive scarring and liver fibrosis, indicating HSCs coordinate both regeneration and disease. Because the factors contributing to HSC reprogramming during wound healing are not fully defined, we sought to further characterize morphogenic pathways of regeneration in an acute model of toxicant-induced liver injury1. Wnt/β-catenin signaling has been recently associated with progressive liver fibrosis, but its role in HSC reprogramming is not well defined. Here, we investigated the canonical role of Wnt3a/Wnt5a on β-catenin-dependent HSC transdifferentiation and find that hepatic ECM gene expression is increased and associated with Wnt3a, Wnt5a, and their transducers (Frizzled-2 and Frizzled-7) after an acute exposure of the hepatotoxin, carbon tetrachloride(CCl4). Moreover, we find exogenous Wnt3a and Wnt5a can accelerate spontaneous, culture-induced HSC activation in vitro as evidenced by increased total expression of fibrogenic factors, including Col1a1 and α-SMA. Challenge with Wnt3a induced canonical β-catenin-dependent transcription of axin2, which was attenuated by the Wnt coreceptor antagonist, Dickkopf-1 (DKK-1). These data support a role for canonical Wnt signaling as an additional mechanism by which HSCs dynamically respond to liver injury during the early wound healing response. New & noteworthy. This study elucidates novel mechanisms of fibrotic gene reprogramming in the liver. Specifically, we describe that Wnts and their transducers are increased during early liver injury which are associated with early fibrogenic responses and for the first time, causally link Wnts as direct inducers of HSC activation in the liver.Graphical abstract

ATAD2 and TWIST1 Interaction Promotes MYC Activation in Colorectal Carcinoma.

ATPase family AAA domain-containing protein 2 (ATAD2) is significantly up-regulated in many cancer types and contributes to poor patient outcomes. ATAD2 exhibits a multidomain architecture comprising an N-terminal acidic domain, two AAA+ ATPase domains, a bromodomain, and a C-terminal domain. The AAA+ ATPase domain facilitates protein oligomerization and ATP binding, while the bromodomain recognizes acetylated lysine in histones and nonhistone proteins. ATAD2 involvement in cancer extends across multiple signaling pathways, such as Rb-E2F1, PI3K/AKT, and TGF-β1/Smad3, which promotes cell proliferation and cancer progression. Herein, we report that ATAD2 directly interacts with TWIST1, and both N-terminal regions of proteins mediate the interaction. Immunofluorescence experiments suggested that ATAD2 and TWIST1 primarily colocalize in the nucleus. Notably, our qPCR results revealed the functional significance of ATAD2-TWIST1 interaction by demonstrating their synergistic effect on the transcriptional activation of MYC in colorectal carcinoma cell lines. Moreover, the ChIP-qPCR result further indicates that ATAD2 and TWIST1 significantly localize in the promoter of the MYC gene. In addition, analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) data suggests a correlation between ATAD2, TWIST1, and MYC overexpression and poor survival rates in colorectal carcinoma. Lastly, the overexpression of ATAD2 and TWIST1 enhances cell proliferation, emphasizing their role in colorectal carcinoma progression through MYC activation. Together, these results suggest that ATAD2 is a crucial factor in TWIST1-dependent MYC gene activation, resulting in an active ATAD2-TWIST1-MYC axis that contributes to colon cancer cell proliferation.

Brown adipose tissue activation in paediatric and adolescent oncological (Hodgkin lymphoma or sarcoma) cases visualised on FDG PET/CT

AbstractObjectiveWe aimed to study the possible factors influencing visualisation of brown adipose tissue (BAT) on FDG PET/CT at diagnosis in children.MethodA total of 92 children or adolescents were included (63 patients with Hodgkin lymphoma (HL) and 29 patients with sarcoma). We examined FDG PET/CT images obtained at diagnosis and searched for FDG uptake in BAT. We analysed the relationship between BAT activation and different possible influencing factors, such as age, sex, outside temperature or season, histological type of malignancy (HL or sarcoma), and volumetric and metabolic values of the tumour tissue. Mann-Whitney, Chi-2 and Fischer's exact tests, and logistic regression analysis were used.ResultsWe found no significant difference in the BAT activation frequency between patients with HL and those with sarcoma (P = 0.12). BAT visualization on FDG PET/CT in the HL subgroup showed a trend towards lower TMTV (P = 0.06) and TLG (P = 0.09).The logistic regression analysis did not show a significant correlation between BAT visualisation on FDG PET/CT and TMTV values.In terms of age, we found a slightly significant correlation for the whole group (P = 0.06) and for the subgroup of HL patients (P = 0.04) in logistic regression. In terms of seasons, the majority (45%) of BAT positive cases were found in autumn.ConclusionsBAT visualisation may be associated with a low HL tumour mass. Multivariate analysis revealed a correlation between BAT activation and age in paediatric patients. BAT visualisation do not differ between boys and girls.

Heparin Resistance in Patients Receiving Extracorporeal Membrane Oxygenation: A Review.

Heparin resistance (HR) in patients on extracorporeal membrane oxygenation (ECMO) exacerbates bleeding and thrombogenesis. Thus far, there is no universal definition of what this condition entails and no unified strategy for assessing heparin's efficacy in ECMO patients. The most frequent discrepancy when it comes to defining HR is the difference in the reported doses: units per day (U/d) or per kilogram per hour (U/kg/h). Another disagreement arises with regard to the various methods of measuring unfractionated heparin (UFH) efficacy. Due to numerous processes that begin with ECMO initiation, including protein layer formation on the surface of circuits, the recruitment of immune cells, the activation of complement and contact activation systems, and platelets, assessing pure antithrombin consumption is complicated. Moreover, there is an alternative anticoagulation procedure performed by a serine protease inhibitor named heparin cofactor II, which could also contribute to heparin consumption. Considering simultaneously launched processes of inflammation and thrombogenesis in response to contact with artificial surfaces on ECMO, we listed the possible mechanisms contributing to additional antithrombin consumption. The effect of the flow on the platelets' activation and von Willebrand factor (vWF) assembly was also described. We reviewed the scientific literature from PubMed and Embase to identify possible definitions of heparin resistance during ECMO treatment among pediatric and adult cohorts. We identified 13 records describing different approaches to assessing HR and described our vision of delineating HR on ECMO.

Mediators of Filgotinib Treatment Effects in Ulcerative Colitis: Exploring Circulating Biomarkers in the Phase 2b/3 SELECTION Study.

We utilized patient samples from the large, phase 2b/3 SELECTION trial to identify circulating biomarkers of ulcerative colitis (UC) and potential early mediators of filgotinib treatment effects. Samples were collected at baseline and during the induction phase of the SELECTION trial. Evaluated biomarkers comprised serum and stool proteins (measured by enzyme-linked immunosorbent assay), whole-blood cell counts, and whole-blood RNA-seq-derived gene-expression factors identified via exploratory factor analysis. Biomarker levels were assessed by baseline disease severity (endoscopy/bleeding/stool and Mayo Clinic Score) and biologic status (naive vs experienced). Effects of filgotinib on biomarker levels, including week 4 biomarker changes that may mediate week 10 clinical improvements, were assessed. The biomarker analysis set included 598 biologic-naive patients and 592 biologic-experienced patients. Systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], serum amyloid A [SAA], and platelet cell counts) had the strongest positive correlations with baseline UC disease severity. CRP, IL-6, SAA, and neutrophil activation biomarkers (including neutrophil gelatinase-associated lipocalin [NGAL], tumor necrosis factor ɑ, and oncostatin M [OSM]), as well as platelet, neutrophil, and monocyte cell counts were increased in biologic-experienced versus biologic-naive patients. Gene-expression-derived plasmablast and cell proliferation factors were positively correlated with disease severity; B cell, T-cell activation, and plasmacytoid dendritic cell factors were negatively correlated. Filgotinib reduced nearly all proinflammatory biomarkers correlated with baseline UC disease activity; reduced SAA, CRP, IL-6, NGAL, and OSM at week 4 were identified as mediators of improved week 10 clinical scores. Filgotinib significantly impacted circulating biomarkers related to UC pathology. Several proinflammatory and neutrophil activation biomarkers may be early mediators of filgotinib treatment effects. NCT02914522.

In situ blockade of TNF-TNFR2 axis via oncolytic adenovirus improves antitumor efficacy in solid tumors.

Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8+ T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4+ T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma, and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.