Upregulation Of Adhesion Molecules Research Articles

Thrombosis Mechanisms in Obese and Ischemic Stroke COVID-19 Patients: A Literature Review

Highlight: The ongoing Coronavirus disease 2019 also affects multiorgan, including cardiovascular disease with several factors. Mechanism of thrombus in the patient that induces the subject such as obesity with increased BMI, thrombotic pathway modulator and pathophysiologist. An increase in acute CVD incidence, including ischemic stroke in COVID-19 patients, has been a new concern in the ongoing pandemic. ABSTRACT Coronavirus disease 2019 (COVID-19), despite being a respiratory infection, also causes neurological manifestations such as stroke due to thrombosis formation. Prior investigations have examined the correlation between COVID-19 and ischemic stroke, as well as COVID-19 and obesity. However, the mechanism of thrombosis in obese COVID-19 patients remains elusive. This review aims to examine the mechanism of thrombosis in COVID-19 patients with ischemic stroke and obesity. Chronic inflammation and impaired fibrinolysis are two major pathways responsible for thrombosis in people with obesity. Chronic inflammation activates prothrombic signaling pathways in vascular cells, resulting in procoagulant factors and adhesion molecules upregulation, anticoagulant proteins downregulation, platelet activation enhancement, and increased thrombin generation. SARS-CoV-2 enters human cells utilizing the angiotensin-converting enzyme 2 (ACE-2) receptors, which results in inflammation, which has been suggested as one of the factors contributing to thrombotic complications in COVID-19 patients. The infection also causes cytokine storm that induces atherosclerosis, plaque rupture, and superimposed thrombosis leading to brain damage. Together with endothelial injury, the cytokine storm might increase the expression of tissue factors and further promote a prothrombic state. In conclusion, the mechanisms of thrombosis in COVID-19 patients are related to direct infection of SARS-CoV-2 into the ACE-2 receptor and the cytokine storm that results in chronic inflammation and thrombosis formation. Obesity will further boost the inflammation process that leads to the formation of thrombosis and increase the risk of ischemic stroke among individuals with COVID-19 with obesity.

The pharmacology of blinatumomab: state of the art on pharmacodynamics, pharmacokinetics, adverse drug reactions and evaluation in clinical trials.

Bispecific drugs (BDs) belong to the family of immunotherapies along with checkpoint inhibitors and CAR-T cells. In the field of oncology, BDs are designed to simultaneously bind a tumour antigen on the one side and an antigen present on the surface of effector cells on the other. This review summarizes the information available to date on the first marketed BiTE-format bispecific antibody, blinatumomab BLINCYTO® in acute lymphoblastic leukaemia. A literature search was conducted in the PubMed database by including studies published in English using the term blinatumomab. Furthermore, bibliographies of selected references were also evaluated for relevant articles. Clinical trial (CT) data were retrieved from clinicaltrials.gov (ongoing trials, adverse events [AEs]) and global pharmacovigilance data were retrieved from VigiBase®. Blinatumomab is a fusion protein which consists of two single-chain variable fragments arranged in tandem: the first binds the CD19 surface antigen of all B cells and the second targets the CD3 antigen of T cells. Binding of blinatumomab to B and T cells induces apoptosis of B cells after secretion of granzymes and perforins by T cells. T-cell activation results in secretion of pro-inflammatory cytokines and upregulation of activation markers and adhesion molecules on the surface of T cells. The major CTs that led to an indication show increased overall survival with blinatumomab with better efficacy in patients in haematological remission with minimal residual disease ≥10-3 . The major AEs are cytokine release syndrome, neurotoxicity and hypogammaglobulinemia. The three most frequent system organ classes in CTs are haematological, gastrointestinal and general disorders. These results are also found in VigiBase® but neurological disorders and infections appear more frequently in real life. This review summarizes the current knowledge of blinatumomab in the literature. The subject of many CTs is to improve the route of administration and expand the indications for treatment.

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

BackgroundThe immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear.ResultsChronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8+ memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly.ConclusionsOur research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

131 Mediators of capillary-to-venule conversion in psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and hyperkeratosis, immune cell infiltration and vascular remodeling. Despite the emerging recognition of vascular normalization as a novel strategy in managing psoriasis, an in-depth delineation of the remodeled dermal vasculature has been missing. In the present study, we exploited 5’ single-cell RNA-sequencing (scRNA-seq) to investigate the transcriptomic alterations in different subpopulations of blood vascular and lymphatic endothelial cells (ECs) directly isolated from psoriatic and healthy human skin. Individual subtypes of ECs underwent specific molecular repatterning associated with cell adhesion and extracellular matrix organization. Blood capillaries, in particular, showed upregulation of the melanoma cell adhesion molecule (MCAM) as well as its binding partners and adopted post-capillary venule-like characteristics during chronic inflammation that are more permissive to leukocyte transmigration. We also identified psoriasis-specific interactions between cis-regulatory enhancers and promoters for each EC subtype, revealing the dysregulated gene regulatory networks in psoriasis. Together, our results provide new insights into the specific transcriptional responses and epigenetic signatures of ECs lining different vessel compartments in chronic skin inflammation.

Porcine cytomegalovirus in xenotransplantation: The new frontier in human transplantation?

Porcine cytomegalovirus in xenotransplantation: The new frontier in human transplantation?

The Effect of Diammonium Glycyrrhizinate Lipid Ligand on Nonalcoholic Fatty Liver Disease Induced Leukocyte Infiltration in Rat Model

Objective: To investigate the effects of diammonium glycyrrhizinate lipid ligand (DGLL) on nonalcoholic fatty liver disease (NAFLD)-induced leukocyte infiltration in rat and underlying mechanisms. Methods: Sixty SD rats were randomly distributed into six groups, control group, NAFLD model group, DGLL (30, 60, 120 mg/kg) treatment group and positive control (biphenyl biester tablets (BDP), 200 mg/kg) group. The expression and activity of myeloperoxidase (MPO) in liver tissues were measured by immunohistochemistry and ELISA, respectively. The expressions of leukocyte adhesion molecules in whole blood were determined by flow cytometry. The intercellular adhesion molecule-1 (ICAM-1) expressions in liver tissues was detected by western blotting. Results: Compared with NAFLD model groups, the expression and activity of MPO in liver tissues of DGLL (30, 60, 120 mg/kg) treatment group were all significantly ameliorated by the administration of DGLL (P < 0.05). Meanwhile, the up-regulation of adhesion molecules expressed on monocytes and neutrophils in whole blood, as well as endothelial ICAM-1 expression in NAFLD model groups were eliminated by DGLL treatment (P < 0.05). Conclusion: DGLL ameliorated leukocyte activation and infiltration in rat liver with NAFLD, which might be related to suppression of adhesion molecules expression on leukocyte and endothelium.

4-Ethylguaiacol Modulates Neuroinflammation and Promotes Heme Oxygenase-1 Expression to Ameliorate Brain Injury in Ischemic Stroke.

Ischemic stroke is caused by a sudden reduction in cerebral blood flow that subsequently induces a complex cascade of pathophysiological responses, leading to brain inflammation and irreversible infarction. 4-ethylguaiacol (4-EG) is reported to suppress inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects in ischemic stroke remains unexplored. We evaluated the therapeutic potential of 4-EG and examined the cellular and molecular mechanisms underlying the protective effects of 4-EG in ischemic stroke. The effect of 4-EG in ischemic stroke was determined by using a transient middle cerebral artery occlusion (MCAO) animal model followed by exploring the infarct size, neurological deficits, microglia activation, inflammatory cytokine production, blood–brain barrier (BBB) disruption, brain endothelial cell adhesion molecule expression, and microglial heme oxygenase-1 (HO-1) expression. Nrf2-/- and HO-1 inhibitor ZnPP-treated mice were also subjected to MCAO to evaluate the role of the Nrf2/HO-1 pathway in 4-EG-mediated protection in ischemic stroke. We found that 4-EG attenuated infarct size and neurological deficits, and lessened BBB disruption in ischemic stroke. Further investigation revealed that 4-EG suppressed microglial activation, peripheral inflammatory immune cell infiltration, and brain endothelial cell adhesion molecule upregulation in the ischemic brain. Finally, we identified that the protective effect of 4-EG in ischemic stroke was abolished in Nrf2-/– and ZnPP-treated MCAO mice. Our results identified that 4-EG confers protection against ischemic stroke and reveal that the protective effect of 4-EG in ischemic stroke is mediated through the induction of the Nrf2/HO1 pathway. Thus, our findings suggest that 4-EG could be developed as a novel therapeutic agent for the treatment of ischemic stroke.

Mediators of Capillary-to-Venule Conversion in the Chronic Inflammatory Skin Disease Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and hyperkeratosis, immune cell infiltration and vascular remodeling. Despite the emerging recognition of vascular normalization as a potential strategy for managing psoriasis, an in-depth delineation of the remodeled dermal vasculature has been missing. In this study, we exploited 5' single-cell RNA sequencing to investigate the transcriptomic alterations in different subpopulations of blood vascular and lymphatic endothelial cells directly isolated from psoriatic and healthy human skin. Individual subtypes of endothelial cells underwent specific molecular repatterning associated with cell adhesion and extracellular matrix organization. Blood capillaries, in particular, showed upregulation of the melanoma cell adhesion molecule as well as its binding partners and adopted postcapillary venule‒like characteristics during chronic inflammation that are more permissive to leukocyte transmigration. We also identified psoriasis-specific interactions between cis-regulatory enhancers and promoters for each endothelial cell subtype, revealing the dysregulated gene regulatory networks in psoriasis. Together, our results provide more insights into the specific transcriptional responses and epigenetic signatures of endothelial cells lining different vessel compartments in chronic skin inflammation.

SVCAM1 in the Hippocampus Contributes to Postoperative Cognitive Dysfunction in Mice by Inducing Microglial Activation Through the VLA-4 Receptor.

Postoperative cognitive dysfunction (POCD) is a severe postsurgical complication, but its underlying mechanisms remain unclear. Neuroinflammation mediated by microglial activation plays a major role in POCD pathophysiology. Upregulation of vascular cell adhesion molecule 1 (VCAM1) on brain endothelial cells is closely correlated with microglial activation in the mouse hippocampus. However, the role of VCAM1 upregulation in microglial activation remains unknown. Soluble VCAM1 (sVCAM1) activates the very late antigen-4 (VLA-4) receptor under inflammatory conditions. Therefore, we hypothesized that sVCAM1 which is shed from VCAM1 contributes to POCD by triggering hippocampal microglial activation through the VLA-4 receptor. We found that VCAM1 and sVCAM1 expression in the mouse hippocampus was upregulated after surgery, and the upregulation was accompanied by hippocampal microglial activation. sVCAM1 levels in mouse and human serum were increased after surgery. Anti-VCAM1 treatment inhibited microglial activation, proinflammatory cytokine production, VLA-4 expression and P38 mitogen-associated protein kinase (MAPK) pathway activation and attenuated hippocampal-dependent cognitive dysfunction. In vitro, recombinant sVCAM1 promoted M1 polarization in BV2 cells, increased VLA-4 expression and activated the P38 MAPK pathway. These effects were reversed by VLA-4 receptor blockade. Anti-VLA-4 treatment ameliorated hippocampal-dependent cognitive dysfunction after surgery by inhibiting microglial activation, proinflammatory cytokine production and P38 pathway activation. In conclusion, increased sVCAM1 in the hippocampus is involved in microglial activation and cognitive dysfunction induced by surgery. Inhibiting the sVCAM1-VLA-4 interaction in microglia may be a therapeutic strategy for POCD.

Abstract 3874: Engineered microphysiological systems for testing effectiveness of cell-based cancer immunotherapies in small cell lung cancer

Abstract Background: Immune cell trafficking into solid tumors has proven challenging due to immune cell exclusion by vascular barriers. Additionally, testing next-generation immune therapies remains difficult in animal models and requires sophisticated ex vivo systems to study human tumor biology and predict treatment response in real time. SCLC comprises approximately 15% of all lung cancer cases and despite recent incorporation of immune checkpoint blockade (ICB) into first line treatment, patients with SCLC continue to have a poor prognosis and limited treatment options. Notably, recent transcriptomic profiling of SCLC has indicated significant inter-tumoral and intra-tumoral heterogeneity. We have previously demonstrated that neuroendocrine SCLC subpopulations downregulate MHC I, whereas non-neuroendocrine SCLC subpopulations exhibit increased innate immune signaling and robust upregulation of MHC I antigen presentation. Here we interrogate the vulnerability of SCLC populations to NK cells and investigate their trafficking using a novel microphysiological ex vivo model. Methods: We developed a 3-dimensional (3D) microphysiological TME model of vascularized SCLC, comprising tumor spheroids embedded in a microvascular network self-assembled by endothelial cells and lung fibroblasts. Real time fluorescence imaging, cell-titer Glo and flow cytometry were used to quantify tumor cell viability in 2D and 3D microfluidic co-culture cytotoxicity assays, using primary NK cells and the NK92 cell line. Results: We demonstrated robust targeting of MHC-I low SCLC cells by primary human NK cells and NK92, and found that MHC-I high SCLC subpopulations show resistance to NK cell-mediated killing. To dissect the influence of vascular barriers on immune cell trafficking, we developed a 3D microphysiological TME model of vascularized SCLC, which successfully recapitulated tumor-vascular-immune interactions in a human-relevant platform as evidenced by vascular perfusion by NK cells. Using this model, we were able to demonstrate that the activation of cGAS-STING signaling in endothelial cells results in the secretion of CXCL10 and upregulation of adhesion molecules (ICAM-1, VCAM-1, E-selectin), promoting immune cell recruitment. Conclusions: We successfully developed a 3D microphysiological model of vascularized SCLC TME and show proof of principle that this model can be used for preclinical studies of cell therapies. Using this novel microphysiological system, we revealed that co-opting STING signaling can promote NK cell recruitment to the SCLC TME. Taken together, we show that microphysiological systems can be used to identify and test therapeutic vulnerabilities while studying immune infiltration and killing in the TME, offering an accurate and adaptable platform for biologic discovery and therapeutic development. Citation Format: Marco Campisi, Minyue Chen, Nathaniel Spicer, Patrick Lizotte, Erik H. Knelson, Cloud P. Paweletz, David A. Barbie, Navin R. Mahadevan. Engineered microphysiological systems for testing effectiveness of cell-based cancer immunotherapies in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3874.

Abstract 3859: Remodeling the extracellular matrix environment enables the dissemination of primary tumor cells through a chemokine gradient to establish brain metastasis in non-small cell lung cancer adenocarcinoma

Abstract Dissemination of tumor cells from the primary site of the lung to distant sites in non-small cell lung cancer (NSCLC) is poorly understood. With distinct mutation signatures in patients, altering pathways is critical to preventing tumor cell dissemination to distant sites. Towards this, we characterized 21 "trios" patient-matched brain metastases (BT), primary tumors (LT), and normal samples (LN), revealing a pattern of extracellular matrix remodeling which suppressed immune cell infiltration. Our objectives were to (i) determine if clinically sampled primary lung tumors encode gene expression patterns distinct from normal tissue, suggestive of increased tumor invasiveness including brain metastasis (ii) determine the biologic underpinning of immune-suppressive information carryover from primary lung tumor to brain metastasis and (iii) determine if synchronous and metachronous (time to disease) clinically sample brain metastases tumors converge on a common signaling mechanism. Transformation of the normal lung cells to primary tumor cells suggested a breakdown in ECM axes primarily governed by upregulation of collagen (COL1A1, COL1A2, COL3A1, COL10A1), fibronectin (FN1), and matrix metalloproteinases (MMP7, MMP9, MMP11, MMP12, MMP13, MMP14) genes. Collectively, the primary tumor cells used MMPs to break down the main components of lung ECM and reorganized collagen and fibronectin in the tumor microenvironment to facilitate migration and invasion. With a disorganized ECM present in LT, a chemokine gradient from LT to BT was discernable with sustained FN1 expression that allowed dissemination into the brain microenvironment. Migration and subsequent cell adhesion in the brain microenvironment revealed upregulation of neural cell adhesion molecule (NCAM1) and phosphoprotein 1 (SPP1). These changes in ECM profiles between LT and BT signify primary tumor cells' adaptation in the brain microenvironment. Further computational deconvolution revealed reduced HLA class II gene expression (HLA-DMA, HLA-DOB, HLA-DPA1, HLADPB1, HLA-DQA2, HLA-DQB2, HLA-DRA) correlated with a lower immune enrichment score of CD4+ T cells in synchronous tumors while metachronous tumors had distinct HLA expression profile. Overall, using the matched sequencing information, we will present the underlying signaling gradients that dictate dissemination of primary lung tumor cells to the brain environment in the background of altered ECM environment using cellular models harboring EGFR, KRAS, and ALK driver mutations cocultured with other cell types such as liver and breast. Citation Format: Albert R. Wang, Saniya Khullar, Jared Brown, Andrew Baschnagel, Darya Buehler, Christina Kendziorski, Gopal Iyer. Remodeling the extracellular matrix environment enables the dissemination of primary tumor cells through a chemokine gradient to establish brain metastasis in non-small cell lung cancer adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3859.

Abstract 6382: Targeting mast cells restores T cell infiltration and sensitizes sarcomas to PD-L1 inhibition

Abstract Despite recent advances in cancer research, developments in sarcoma treatment have been slow. The efficacy of chemotherapy in sarcoma is limited by the pathophysiology of surrounding tumor stroma. Abnormalities in the tumor microenvironment (TME) result in stiffening of the tumor and accumulation of mechanical stresses which in turn cause the extreme deformation and collapse of intratumoral vessels. Strategies to induce TME reprogramming with the aim to restore mechanical properties of the tissue as well as tumor blood vessel functionality involve the use of “mechanotherapeutics”. Herein, we exploited the potential of the antihistamine drug and mast cell stabilizer, ketotifen, to induce mechanotherapeutic effects in murine models of soft tissue and bone sarcoma. Mast cells are the first population of immune cells drawn to the tumorigenic nidus where they interact with multiple components of the TME. Yet, their role in tumor stroma remains enigmatic as they either promote or inhibit tumor development depending on the conditions. In agreement with other mechanotherapeutics, we found that ketotifen induces vascular normalization in a dose dependent manner as indicated by the increase in perfusion, higher open lumen fraction and pericyte coverage of the vessels. Moreover, in vivo ultrasound shear wave elastography confirmed the mechanotherapeutic properties of ketotifen in reducing tissue stiffness, while further ex vivo validation indicated that TME reprogramming is mediated by a significant reduction in cancer associated fibroblast and inhibition of collagen synthesis as well as of that of other extracellular matrix components. Furthermore, we found that ketotifen modulates the immune microenvironment to promote immunostimulation. Immune stimulation was mediated by both intratumoral T cell accumulation and higher cytotoxic to regulatory T cell ratio concomitantly with a pronounced reduction in tissue hypoxia and upregulation of leukocyte adhesion molecules on endothelium. As a result of ketotifen-induced TME reprogramming, the addition of ketotifen to doxorubicin-aPDL1 combination treatment exhibited therapeutic superiority as opposed to doxorubicin-aPDL1, offering a durable tumor remission and immunological memory following tumor rechallenge experiments. Taken together, our findings demonstrate that ketotifen has a dual role in shaping the TME: i) reducing intratumoral physical forces to improve perfusion and ii) establishing favorable immunogenic conditions. Therefore, incorporating such agents in clinical practice holds great promise in the treatment of refractory, advanced sarcomas. Citation Format: Myrofora Panagi, Fotios Mpekris, Chrysovalantis Voutouri, Christina Michael, Anastasia Constantinidou, John D. Martin, Triantafyllos Stylianopoulos. Targeting mast cells restores T cell infiltration and sensitizes sarcomas to PD-L1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6382.

VASCULAR BIOMARKERS IN RELATION TO INDICES OF AORTIC STIFFNESS AND RENAL FUNCTION IN PRIMARY HYPERTENSION

Objective: Degradation of the glycocalyx (GC), the innermost layer protecting the vascular endothelium, and up-regulation of adhesion molecules is associated with subclinical atherosclerosis and endothelial dysfunction, while aortic stiffness is related to early structural vascular changes and decline in renal function. However, few studies have investigated vascular biomarkers in relation to central and peripheral hemodynamics, and renal function in hypertension. Design and method: 107 patients (58 ± 13 years) with hypertension (mean 149/87 mmHg; 31% on antihypertensive treatment) and a wide range of renal function (eGFR 130 to 21 ml/min x 1.73 m2, mean 74 ml/min), were investigated. Indices of aortic stiffness were central systolic blood pressure (cSBP), central pulse pressure (cPP), carotid/brachial pulse pressure ratio (cPP/brPP), augmentation index (AIx), carotid-femoral pulse wave velocity (PWV), and aortic-brachial PWV ratio, assessed by applanation tonometry (SphygmoCor, AtCor Medical). Endothelial function was studied by forearm post-ischemic flow mediated vasodilatation. The GC glycoproteins hyaluronan (HA) and syndecan-1 (Syn-1), and adhesion molecules (ICAM-1, VCAM-1, and E-selectin), were analysed with ELISA. Results: Median[range] HA, Syn-1, ICAM-1, VCAM-1, and E-selectin were 15 [11–20], 38[27–54], 302[264–345], 347[304–408], and 32[26–41] ng/mL, respectively. HA was related to cPP (r = 0.31; P = 0.002), cPP/brPP (r = 0.21; P = 0.002), AIx (r = 0.21; P = 0.034), PWV (r = 0.31; P = 0.003), and aortic-brachial PWV ratio (r = 0.27; P = 0.011). Syn-1 was inversely related to cSBP (r = –0.17; P = 0.043). E-selectin tended to be inversely related to cSBP (p = 0.10) and to cPP (p = 0.071). HA and VCAM-1 were inversely related to eGFR (r = –0.45 and r = –0.43; both P < 0.001). All vascular biomarkers were unrelated to flow-mediated vasodilation. Conclusions: Vascular biomarkers were associated with indices of aortic stiffness, and impaired renal function, but was unrelated to peripheral endothelial function. HA showed association with increased stiffness, compared to Syn-1 that was unrelated to stiffness, and both HA and VCAM-1 were inversely related to renal function, where elevation of HA and VCAM-1 may reflect endothelial dysfunction of the kidneys. Thus, our results suggest that functional vascular biomarkers may relate to early structural and functional vascular changes in uncomplicated hypertension with impaired renal function.

Tryptophan hydroxylase 1 drives glioma progression by modulating the serotonin/L1CAM/NF-\u03baB signaling pathway

BackgroundGlioma is one of the main causes of cancer-related mortality worldwide and is associated with high heterogeneity. However, the key players determining the fate of glioma remain obscure. In the present study, we shed light on tumor metabolism and aimed to investigate the role of tryptophan hydroxylase 1 (TPH-1) in the advancement of glioma.MethodHerein, the levels of TPH-1 expression in glioma tissues were evaluated using The Cancer Genome Atlas (TCGA) database. Further, the proliferative characteristics and migration ability of TPH-1 overexpressing LN229/T98G cells were evaluated. Additionally, we performed a cytotoxicity analysis using temozolomide (TMZ) in these cells. We also examined the tumor growth and survival time in a mouse model of glioma treated with chemotherapeutic agents and a TPH-1 inhibitor.ResultsThe results of both clinical and experimental data showed that excess TPH-1 expression resulted in sustained glioma progression and a dismal overall survival in these patients. Mechanistically, TPH-1 increased the production of serotonin in glioma cells. The elevated serotonin levels then augmented the NF-κB signaling pathway through the upregulation of the L1-cell adhesion molecule (L1CAM), thereby contributing to cellular proliferation, invasive migration, and drug resistance. In vivo experiments demonstrated potent antitumor effects, which benefited further from the synergistic combination of TMZ and LX-1031.ConclusionTaken together, these data suggested that TPH-1 facilitated cellular proliferation, migration, and chemoresistance in glioma through the serotonin/L1CAM/NF-κB pathway. By demonstrating the link of amino acid metabolic enzymes with tumor development, our findings may provide a potentially viable target for therapeutic manipulation aimed at eradicating glioma.

Multi-omics Profiling Shows BAP1 Loss Is Associated with Upregulated Cell Adhesion Molecules in Uveal Melanoma.

BAP1 mutations and increased metastasis may be due to upregulation of CAMs.

Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities.

Maintaining blood-brain barrier (BBB) integrity is crucial for the homeostasis of the central nervous system. Structurally comprising the BBB, brain endothelial cells interact with pericytes, astrocytes, neurons, microglia, and perivascular macrophages in the neurovascular unit. Brain ischemia unleashes a profound neuroinflammatory response to remove the damaged tissue and prepare the brain for repair. However, the intense neuroinflammation occurring during the acute phase of stroke is associated with BBB breakdown, neuronal injury, and worse neurological outcomes. Here, we critically discuss the role of neuroinflammation in ischemic stroke pathology, focusing on the BBB and the interactions between central nervous system and peripheral immune responses. We highlight inflammation-driven injury mechanisms in stroke, including oxidative stress, increased MMP (matrix metalloproteinase) production, microglial activation, and infiltration of peripheral immune cells into the ischemic tissue. We provide an updated overview of imaging techniques for in vivo detection of BBB permeability, leukocyte infiltration, microglial activation, and upregulation of cell adhesion molecules following ischemic brain injury. We discuss the possibility of clinical implementation of imaging modalities to assess stroke-associated neuroinflammation with the potential to provide image-guided diagnosis and treatment. We summarize the results from several clinical studies evaluating the efficacy of anti-inflammatory interventions in stroke. Although convincing preclinical evidence suggests that neuroinflammation is a promising target for ischemic stroke, thus far, translating these results into the clinical setting has proved difficult. Due to the dual role of inflammation in the progression of ischemic damage, more research is needed to mechanistically understand when the neuroinflammatory response begins the transition from injury to repair. This could have important implications for ischemic stroke treatment by informing time- and context-specific therapeutic interventions.

Endothelial cells of pulmonary origin display unique sensitivity to the bacterial endotoxin lipopolysaccharide.

Acute respiratory distress syndrome (ARDS) is a major clinical problem without available therapies. Known risks for ARDS include severe sepsis, SARS‐CoV‐2, gram‐negative bacteria, trauma, pancreatitis, and blood transfusion. During ARDS, blood fluids and inflammatory cells enter the alveoli, preventing oxygen exchange from air into blood vessels. Reduced pulmonary endothelial barrier function, resulting in leakage of plasma from blood vessels, is one of the major determinants in ARDS. It is, however, unknown why systemic inflammation particularly targets the pulmonary endothelium, as endothelial cells (ECs) line all vessels in the vascular system of the body. In this study, we examined ECs of pulmonary, umbilical, renal, pancreatic, and cardiac origin for upregulation of adhesion molecules, ability to facilitate neutrophil (PMN) trans‐endothelial migration (TEM) and for endothelial barrier function, in response to the gram‐negative bacterial endotoxin LPS. Interestingly, we found that upon LPS stimulation, pulmonary ECs showed increased levels of adhesion molecules, facilitated more PMN‐TEM and significantly perturbed the endothelial barrier, compared to other types of ECs. These observations could partly be explained by a higher expression of the adhesion molecule ICAM‐1 on the pulmonary endothelial surface compared to other ECs. Moreover, we identified an increased expression of Cadherin‐13 in pulmonary ECs, for which we demonstrated that it aids PMN‐TEM in pulmonary ECs stimulated with LPS. We conclude that pulmonary ECs are uniquely sensitive to LPS, and intrinsically different, compared to ECs from other vascular beds. This may add to our understanding of the development of ARDS upon systemic inflammation.

Proinflammatory CD20+ T cells contribute to CNS-directed autoimmunity.

The origin and function of CD20+ T cells are poorly understood. Here, we characterized CD20+ T cells in mice and humans and investigated how they are affected by anti-CD20 antibody treatment. We report that murine CD20+ T cells are unable to endogenously express the B cell lineage marker CD20; the development of CD20+ T cells in rodents requires the presence of CD20-expressing B cells. Our results demonstrated that both murine and human T cells acquire CD20 from B cells via trogocytosis while being activated by an antigen-presenting B cell. In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), expression of CD20 on T cells is associated with an up-regulation of activation markers, proinflammatory cytokines, and adhesion molecules, suggesting high pathogenic potential. Supporting this hypothesis, CD20+ T cells expand during active EAE in rodents; furthermore, adoptive transfer of CD20+ T cells into EAE-diseased mice worsened histological and clinical severity. Of direct therapeutic relevance, we demonstrate that the exclusive therapeutic elimination of CD20+ T cells effectively ameliorates EAE, independent of B cells. The results support the hypothesis that CD20+ T cells arise upon B cell-T cell interaction and that depletion of CD20+ T cells might contribute to the success of anti-CD20 antibody therapies in MS and other inflammatory disorders.

Loss of IRF7 accelerates acute myeloid leukemia progression and induces VCAM1-VLA-4 mediated intracerebral invasion

Interferon regulatory factor 7 (IRF7) is widely studied in inflammatory models. Its effects on malignant progression have been documented mainly from the perspective of the microenvironment. However, its role in leukemia has not been established. Here we used MLL-AF9-induced acute myeloid leukemia (AML) mouse models with IRF7 knockout or overexpression and xenograft mouse models to explore the intrinsic effects of IRF7 in AML. AML-IRF7−/− mice exhibited accelerated disease progression with intracerebral invasion of AML cells. AML-IRF7−/− cells showed increased proliferation and elevated leukemia stem cell (LSC) levels. Overexpression of IRF7 in AML cells decreased cell proliferation and LSC levels. Furthermore, overexpression of transforming growth-interacting factor 1 (TGIF1) rescued the enhanced proliferation and high LSC levels caused by IRF7 deficiency. Moreover, upregulation of vascular cell adhesion molecule 1 (VCAM1), which correlated with high LSC levels, was detected in AML-IRF7−/− cells. In addition, blocking VCAM1-very late antigen 4 (VLA-4) axis delayed disease progression and attenuated intracerebral invasion of AML cells. Therefore, our findings uncover the intrinsic effects of IRF7 in AML and provide a potential strategy to control central nervous system myeloid leukemia.

Endothelial cells: potential novel regulators of renal inflammation.

Substantial evidence has supported the role of endothelial cell (EC) activation and dysfunction in the development of hypertension, chronic kidney disease (CKD), and lupus nephritis (LN). In both humans and experimental models of hypertension, CKD, and LN, ECs become activated and release potent mediators of inflammation including cytokines, chemokines, and reactive oxygen species that cause EC dysfunction, tissue damage, and fibrosis. Factors that activate the endothelium include inflammatory cytokines, mechanical stretch, and pathological shear stress. These signals can activate the endothelium to promote upregulation of adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which promote leukocyte adhesion and migration to the activated endothelium. More importantly, it is now recognized that some of these signals may in turn promote endothelial antigen presentation through major histocompatibility complex II. In this review, we will consider in-depth mechanisms of endothelial activation and the novel mechanism of endothelial antigen presentation. Moreover, we will discuss these proinflammatory events in renal pathologies and consider possible new therapeutic approaches to limit the untoward effects of endothelial inflammation in hypertension, CKD, and LN.