Endosialin-positive CAFs promote hepatocellular carcinoma progression by suppressing CD8+ T cell infiltration.

BACKGROUND AND AIMS: Endosialin, also known as tumor endothelial marker1 or CD248, is a transmembrane glycoprotein that is mainly expressed in cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known. APPROACH AND RESULTS: The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (ENKO) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from ENKO mice had increased CD8+ T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8+ T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9/10 expression and secretion, resulting in the suppression of CD8+ T cell infiltration. High level of endosialin protein expression was correlated with low CD8+ T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually. CONCLUSIONS: Endosialin could inhibit CD8+ T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.

Risk factors and outcomes associated with systolic dysfunction following traumatic brain injury.

Systolic dysfunction has been observed following isolated moderate-severe traumatic brain injury (Ims-TBI). However, early risk factors for the development of systolic dysfunction after Ims-TBI and their impact on the prognosis of patients with Ims-TBI have not been thoroughly investigated. A prospective observational study among patients aged 16 to 65 years without cardiac comorbidities who sustained Ims-TBI (Glasgow Coma Scale [GCS] score ≤12) was conducted. Systolic dysfunction was defined as left ventricular ejection fraction <50% or apparent regional wall motion abnormality assessed by transthoracic echocardiography within 24 hours after admission. The primary endpoint was the incidence of systolic dysfunction after Ims-TBI. The secondary endpoint was survival on discharge. Clinical data and outcomes were assessed within 24 hours after admission or during hospitalization. About 23 of 123 patients (18.7%) developed systolic dysfunction after Ims-TBI. Higher admission heart rate (odds ratios [ORs]: 1.05, 95% confidence interval [CI]: 1.02-1.08; P = .002), lower admission GCS score (OR: 0.77, 95% CI: 0.61-0.96; P = .022), and higher admission serum high-sensitivity cardiac troponin T (Hs-cTnT) (OR: 1.14, 95% CI: 1.06-1.22; P < .001) were independently associated with systolic dysfunction among patients with Ims-TBI. A combination of heart rate, GCS score, and serum Hs-cTnT level on admission improved the predictive performance for systolic dysfunction (area under curve = 0.85). Duration of mechanical ventilation, intensive care unit length of stay, and in-hospital mortality of patients with systolic dysfunction was higher than that of patients with normal systolic function (P < .05). Lower GCS (OR: 0.66, 95% CI: 0.45-0.82; P = .001), lower admission oxygen saturation (OR: 0.82, 95% CI: 0.69-0.98; P = .025), and the development of systolic dysfunction (OR: 4.85, 95% CI: 1.36-17.22; P = .015) were independent risk factors for in-hospital mortality in patients with Ims-TBI. Heart rate, GCS, and serum Hs-cTnT level on admission were independent early risk factors for systolic dysfunction in patients with Ims-TBI. The combination of these 3 parameters can better predict the occurrence of systolic dysfunction.

Endosialin in Cancer: Expression Patterns, Mechanistic Insights, and Therapeutic Approaches.

Endosialin, also known as tumor endothelial marker 1 (TEM1) or CD248, is a single transmembrane glycoprotein with a C-type lectin-like domain. Endosialin is mainly expressed in the stroma, especially in cancer-associated fibroblasts and pericytes, in most solid tumors. Endosialin is also expressed in tumor cells of most sarcomas. Endosialin can promote tumor progression through different mechanisms, such as promoting tumor cell proliferation, adhesion and migration, stimulating tumor angiogenesis, and inducing an immunosuppressive tumor microenvironment. Thus, it is considered an ideal target for cancer treatment. Several endosialin-targeted antibodies and therapeutic strategies have been developed and have shown preliminary antitumor effects. Here, we reviewed the endosialin expression pattern in different cancer types, discussed the mechanisms by which endosialin promotes tumor progression, and summarized current therapeutic strategies targeting endosialin.

Prognosis of comatose patients with reduced EEG montage by combining quantitative EEG features in various domains.

Objective: As the frontoparietal network underlies recovery from coma, a limited frontoparietal montage was used, and the prognostic values of EEG features for comatose patients were assessed. Methods: Collected with a limited frontoparietal EEG montage, continuous EEG recordings of 81 comatose patients in ICU were used retrospectively. By the 60-day Glasgow outcome scale (GOS), the patients were dichotomized into favorable and unfavorable outcome groups. Temporal-, frequency-, and spatial-domain features were automatically extracted for comparison. Partial correlation analysis was applied to eliminate redundant factors, and multiple correspondence analysis was used to explore discrimination between groups. Prognostic characteristics were calculated to assess the performance of EEG feature-based predictors established by logistic regression. Analyses were performed on all-patients group, strokes subgroup, and traumatic brain injury (TBI) subgroup. Results: By analysis of all patients, raised burst suppression ratio (BSR), suppressed root mean square (RMS), raised power ratio of ß to α rhythm (ß/α), and suppressed phase-lag index between F3 and P4 (PLI [F3, P4]) were associated with unfavorable outcome, and yielded AUC of 0.790, 0.811, 0.722, and 0.844, respectively. For the strokes subgroup, the significant variables were BSR, RMS, θ/total, θ/δ, and PLI (F3, P4), while for the TBI subgroup, only PLI (F3, P4) was significant. BSR combined with PLI (F3, P4) gave the best predictor by cross-validation analysis in the all-patients group (AUC = 0.889, 95% CI: 0.819-0.960). Conclusion: Features extracted from limited frontoparietal montage EEG served as valuable coma prognostic tools, where PLI (F3, P4) was always significant. Combining PLI (F3, P4) with features in other domains may achieve better performance. Significance: A limited-montage EEG coupled with an automated algorithm is valuable for coma prognosis.

Atomistic Insights into Interfacial Optimization Mechanism for Achieving Ultralow-Friction Amorphous Carbon Films under Solid-Liquid Composite Conditions.

The combination of fluid lubricants and textured amorphous carbon (a-C) can provide an ultralow friction state, which can improve the reliability and service life of dynamic machinery. However, the coupling effects of the contact pressure and oil content on the friction-reducing efficiency is still lack of study, and the corresponding friction mechanism is also not fully understood, which cannot be achieved by experiment due to the limitation of in situ characterization. In this study, using the reactive molecular dynamics simulation, the insight into the evolution of interfacial structures induced by both contact pressures and oil contents on a-C surface was systematically investigated to explore the fundamental mechanism. In particular, the friction difference between textured and untextured a-C films was evaluated comparatively. Results indicate that the tribological performance strongly depends on the interfacial lubrication state, which is jointly determined by the oil content and contact pressure; the best operating condition to achieve ultralow friction coefficient (0.002) is obtained, and the evolution of friction coefficient with oil content and contact pressure is highly dominated by the lubricant mobility, cross-linking between mating a-C surfaces, or competition/synergy of the H stress state from the lubricant with interfacial passivation. Furthermore, the difference in friction reduction between textured and untextured systems is unveiled; with the increase of contact pressure, the role of texturing a-C surface in antifriction changes from positive to negative effect, which is related to the transformation of interfacial hybridized structure and anomalous flow of lubricant. These results can significantly enhance the understanding of composite lubrication systems through computation and also provide a roadmap for the R&D of the advanced lubrication system according to the working conditions.

Interplay between Vitamin D and Adipose Tissue: Implications for Adipogenesis and Adipose Tissue Function.

Adipose tissue encompasses various types, including White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and beige adipose tissue, each having distinct roles in energy storage and thermogenesis. Vitamin D (VD), a fat-soluble vitamin, maintains a complex interplay with adipose tissue, exerting significant effects through its receptor (VDR) on the normal development and functioning of adipocytes. The VDR and associated metabolic enzymes are widely expressed in the adipocytes of both rodents and humans, and they partake in the regulation of fat metabolism and functionality through various pathways. These encompass adipocyte differentiation, adipogenesis, inflammatory responses, and adipokine synthesis and secretion. This review primarily appraises the role and mechanisms of VD in different adipocyte differentiation, lipid formation, and inflammatory responses, concentrating on the pivotal role of the VD/VDR pathway in adipogenesis. This insight furnishes new perspectives for the development of micronutrient-related intervention strategies in the prevention and treatment of obesity.

Atomic-Scale Understanding on the Tribological Behavior of Amorphous Carbon Films under Different Contact Pressures and Surface Textured Shapes.

The textured design of amorphous carbon (a-C) film can significantly improve the tribological performance and service life of moving mechanical components. However, its friction dependence on different texture shapes, especially under different load conditions, remains unclear. In particular, due to the lack of information regarding the friction interface, the underlying friction mechanism has still not been unveiled. Therefore, the effects of contact pressure and textured shapes on the tribological behavior of a-C films under dry friction conditions were comparatively studied in this work by reactive molecular dynamics simulation. The results show that under low contact pressure, the tribological property of a-C film is sensitive to the textured shape, and the system with a circular textured surface exhibits a lower friction coefficient than that with a rectangular textured surface, which is attributed to the small fraction of unsaturated bonds. However, the increase of contact pressure results in the serious reconstruction and passivation of the friction interface. On the one hand, this induces a growth rate of friction force that is much smaller than that of the normal load, which is followed by a significant decrease in the friction coefficient with contact pressure. On the other hand, the destruction or even disappearance of the textured structure occurs, weakening the difference in the friction coefficient caused by different textured shapes of the a-C surface. These results reveal the friction mechanism of textured a-C film and provide a new way to functionalize the a-C as a protective film for applications in hard disks, MEMS, and NEMS.

Association between N-acetylcysteine treatment and in-hospital mortality in adult patients with acquired thrombotic thrombocytopenic purpura: a cohort study.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a fatal hematologic disease. Despite the currently high standards of care, some patients who develop refractory or recurrent disease still have a poor prognosis. Although N-acetylcysteine (NAC) is recommended for the treatment of aTTP, its use in aTTP treatment is still controversial. We aimed to evaluate the association of NAC with mortality in patients with aTTP. This was a retrospective cohort study of patients with aTTP with in-hospital mortality as the primary outcome and time to platelet recovery and neurological recovery as secondary outcomes. We used multifactorial COX regression analysis to check for an association of NAC with mortality. Moreover, we performed a sensitivity analysis check the stability of our results. Finally, 89 patients with aTTP were enrolled. After adjusting for potential confounders, we found NAC to be associated with 75% lower in-hospital mortality (HR = 0.25, 95% CI = 0.1-0.64). The results of sensitivity analyses performed remained stable as the risk of in-hospital mortality in patients reduced in patients with comorbid neurological symptoms (HR = 0.23, 95% CI = 0.06-0.89). However, NAC use did not affect the time to platelet recovery (HR = 1.19, 95% CI = 0.57-2.5) or neurological recovery (HR = 0.32, 95% CI = 0.08-1.25) in patients with aTTP. NAC treatment reduces in-hospital mortality in patients with aTTP but does not shorten the time to platelet recovery or neurological recovery.

The selective regulation of immune responses by matrix metalloproteinase MMP14 in Ostrinia furnacalis.

Matrix metalloproteinases (MMPs) are crucial for tissue remodeling and immune responses in insects, yet it remains unclear how MMPs affect the various immune processes against pathogenic infections and whether the responses vary among insects. In this study, we used the lepidopteran pest Ostrinia furnacalis larvae to address these questions by examining the changes of immune-related gene expression and antimicrobial activity after the knockdown of MMP14 and bacterial infections. We identified MMP14 in O. furnacalis using the rapid amplification of complementary DNA ends (RACE), and found that it was conserved and belonged to the MMP1 subfamily. Our functional investigations revealed that MMP14 is an infection-responsive gene, and its knockdown reduces phenoloxidase (PO) activity and Cecropin expression, while the expressions of Lysozyme, Attacin, Gloverin, and Moricin are enhanced after MMP14 knockdown. Further PO and lysozyme activity determinations showed consistent results with gene expression of these immune-related genes. Finally, the knockdown of MMP14 decreased larvae survival to bacterial infections. Taken together, our data indicate that MMP14 selectively regulates the immune responses, and is required to defend against bacterial infections in O. furnacalis larvae. Conserved MMPs may serve as a potential target for pest control using a combination of double-stranded RNA and bacterial infection.

Roles of syntaphilin and armadillo repeat-containing X-linked protein 1 in brain injury after experimental intracerebral hemorrhage.

Studies have indicated that neuronal mitochondrial injury may be involved in the brain injury caused by intracerebral hemorrhage (ICH). Syntaphilin (SNPH) is associated with mitochondrial anchoring and Armadillo repeat-containing X-linked protein 1 (Armcx1) is linked to mitochondrial transport. This study aimed to analyze the contribution of SNPH and Armcx1 to the neuronal damage resulting from ICH. Primary cultured neuron cells were exposed to oxygenated hemoglobin to replicate the effects of ICH stimulation, while a mouse model of ICH was established by injecting autoblood into the basal ganglia. Specific SNPH knockout or Armcx1 overexpression in neurons is achieved by stereolocalization injection of adeno-associated virus vectors carrying hsyn specific promoters. First, it was confirmed that there is a correlation between SNPH/Armcx1 and ICH pathology, as evidenced by the rise of SNPH and the decrease of Armcx1 in neurons exposed to ICH both in vitro and in vivo. Second, our research revealed the protective effects of SNPH knockdown and Armcx1 overexpression on brain cell death around the hematoma in mice. In addition, the efficacy of SNPH knockdown and Armcx1 overexpression in improving neurobehavioral deficits was also demonstrated in mouse ICH model. Thus, moderate adjusting the levels of SNPH and Armcx1 may be an effective way to improve the outcome of ICH.

CD248 promotes migration and metastasis of osteosarcoma through ITGB1-mediated FAK-paxillin pathway activation.

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents. Frequent tumor metastasis and high postoperative recurrence are the most common challenges in OS. However, detailed mechanism is largely unknown. METHODS: We examined the expression of CD248 in OS tissue microarrays by immunohistochemistry (IHC) staining. We studied the biological function of CD248 in cell proliferation, invasion and migration of OS cells by CCK8 assay, transwell and wound healing assay. We also studied its function in the metastasis of OS in vivo. At last, we explored the potential mechanism how CD248 promotes OS metastasis by using RNA-seq, western blot, immunofluorescence staining and co-immunoprecipitation using CD248 knockdown OS cells. RESULTS: CD248 was highly expressed in OS tissues and its high expression was correlated with pulmonary metastasis of OS. Knockdown of CD248 in OS cells significantly inhibited cell migration, invasion and metastasis, while had no obvious effect on cell proliferation. Lung metastasis in nude mice was significantly inhibited when CD248 was knocked down. Mechanistically, we found that CD248 could promote the interaction between ITGB1 and extracellular matrix (ECM) proteins like CYR61 and FN, which activated the FAK-paxillin pathway to promote the formation of focal adhesion and metastasis of OS. CONCLUSION: Our data showed that high CD248 expression is correlated with the metastatic potential of OS. CD248 may promote migration and metastasis through enhancing the interaction between ITGB1 and certain ECM proteins. Therefore, CD248 is a potential marker for diagnosis and effective target for the treatment of metastatic OS.

Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression.

Background: Cancer-associated fibroblasts (CAFs) promote tumor progression through extracellular matrix (ECM) remodeling and extensive communication with other cells in tumor microenvironment. However, most CAF-targeting strategies failed in clinical trials due to the heterogeneity of CAFs. Hence, we aimed to identify the cluster of tumor-promoting CAFs, elucidate their function and determine their specific membrane markers to ensure precise targeting. Methods: We integrated multiple single-cell RNA sequencing (scRNA-seq) datasets across different tumors and adjacent normal tissues to identify the tumor-promoting CAF cluster. We analyzed the origin of these CAFs by pseudotime analysis, and tried to elucidate the function of these CAFs by gene regulatory network analysis and cell-cell communication analysis. We also performed cell-type deconvolution analysis to examine the association between the proportion of these CAFs and patients' prognosis in TCGA cancer cohorts, and validated that through IHC staining in clinical tumor tissues. In addition, we analyzed the membrane molecules in different fibroblast clusters, trying to identify the membrane molecules that were specifically expressed on these CAFs. Results: We found that COL11A1+ fibroblasts specifically exist in tumor tissues but not in normal tissues and named them cancer-specific fibroblasts (CSFs). We revealed that these CSFs were transformed from normal fibroblasts. CSFs represented a more activated CAF cluster and may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. High CSF proportion was associated with poor prognosis in bladder cancer (BCa) and lung adenocarcinoma (LUAD), and IHC staining of COL11A1 confirmed their specific expression in tumor stroma in clinical BCa samples. We also identified that CSFs specifically express the membrane molecules LRRC15, ITGA11, SPHK1 and FAP, which could distinguish CSFs from other fibroblasts. Conclusion: We identified that CSFs is a tumor specific cluster of fibroblasts, which are in active state, may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. Membrane molecules LRRC15, ITGA11, SPHK1 and FAP could be used as therapeutic targets for CSF-targeting cancer treatment.

Single-cell analysis of multiple cancer types reveals differences in endothelial cells between tumors and normal tissues.

Endothelial cells (ECs) play an important role in tumor progression. Currently, the main target of anti-angiogenic therapy is the vascular endothelial growth factor (VEGF) pathway. Some patients do benefit from anti-VEGF/VEGFR therapy; however, a large number of patients do not have response or acquire drug resistance after treatment. Moreover, anti-VEGF/VEGFR therapy may lead to nephrotoxicity and cardiovascular-related side effects due to its action on normal ECs. Therefore, it is necessary to identify targets that are specific to tumor ECs and could be applied to various cancer types. We integrated single-cell RNA sequencing data from six cancer types and constructed a multi-cancer EC atlas to decode the characteristic of tumor ECs. We found that tip-like ECs mainly exist in tumor tissues but barely exist in normal tissues. Tip-like ECs are involved in the promotion of tumor angiogenesis and inhibition on anti-tumor immune responses. Moreover, tumor cells, myeloid cells, and pericytes are the main sources of pro-angiogenic factors. High proportion of tip-like ECs is associated with poor prognosis in multiple cancer types. We also identified that prostate-specific membrane antigen (PSMA) is a specific marker for tip-like ECs in all the cancer types we studied. In summary, we demonstrate that tip-like ECs are the main differential EC subcluster between tumors and normal tissues. Tip-like ECs may promote tumor progression through promoting angiogenesis while inhibiting anti-tumor immune responses. PSMA was a specific marker for tip-like ECs, which could be used as a potential target for the diagnosis and treatment of non-prostate cancers.

Endosialin-positive tumor-derived pericytes promote tumor progression through impeding the infiltration of CD8+ T cells in clear cell renal cell carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) therapy can be effective against clear cell renal cell carcinoma (ccRCC), but many patients show no benefit. Tumor-derived pericytes (TDPs) may promote tumor progression by influencing T cells and are an immunotherapy target; however, they may comprise functionally distinct subtypes. We aimed to identify markers of tumor-promoting TDPs and develop TDP-targeting strategies to enhance ICB therapy effectiveness against ccRCC. METHODS: We analyzed the relationship between endosialin (EN) expression and cytotoxic T-lymphocyte (CTL) infiltration in ccRCC tumor samples using flow cytometry and in a ccRCC-bearing mice inhibited for EN via knockout or antibody-mediated blockade. The function of ENhigh TDPs in CTL infiltration and tumor progression was analyzed using RNA-sequencing (RNA-seq) data from ccRCC tissue-derived TDPs and single-cell RNA-seq (scRNA-seq) data from an online database. The role of EN in TDP proliferation and migration and in CTL infiltration was examined in vitro. Finally, we examined the anti-tumor effect of combined anti-EN and anti-programmed death 1 (PD-1) antibodies in ccRCC-bearing mice. RESULTS: High EN expression was associated with low CTL infiltration in ccRCC tissues, and inhibition of EN significantly increased CTL infiltration in ccRCC-bearing mice. RNA-seq and scRNA-seq analyses indicated that high EN expression represented the TDP activation state. EN promoted TDP proliferation and migration and impeded CTL infiltration in vitro. Finally, combined treatment with anti-EN and anti-PD-1 antibodies synergistically enhanced anti-tumor efficacy. CONCLUSION: ENhigh TDPs are in an activated state and inhibit CTL infiltration into ccRCC tissues. Combined treatment with anti-EN and anti-PD-1 antibodies may improve ICB therapy effectiveness against ccRCC.

Fat-poor renal angiomyolipoma with prominent cystic degeneration: A case report and review of the literature.

BACKGROUND: Angiomyolipoma (AML), the most common benign tumor of the kidney, is usually composed of dysmorphic blood vessels, smooth muscle, and mature adipose tissue. To our knowledge, AML with cystic degeneration has rarely been documented. Cystic degeneration, hemorrhage, and a lack of fat bring great challenges to the diagnosis. CASE SUMMARY: A 60-year-old man with hypertension presented with a 5-year history of cystic mass in his left kidney. He fell 2 mo ago. A preoperative computed tomography (CT) scan showed a mixed-density cystic lesion without macroscopic fat density, the size of which had increased compared with before, probably due to hemorrhage caused by a trauma. Radical nephrectomy was performed. Histopathological studies revealed that the lesion mainly consisted of tortuous, ectatic, and thick-walled blood vessels, mature adipose tissue, and smooth muscle-like spindle cells arranged around the abnormal blood vessels. The tumor cells exhibited positivity for human melanoma black-45, Melan-A, smooth muscle actin, calponin, S-100, and neuron-specific enolase, rather than estrogen receptor, progesterone receptor, CD68, and cytokeratin. The Ki-67 labeling index was less than 5%. The final diagnosis was a fat-poor renal AML (RAML) with prominent cystic degeneration. CONCLUSION: When confronting a large renal cystic mass, RAML should be included in the differential diagnosis.

SZ168 treats LPS-induced acute lung injury by inhibiting the activation of NF-κB and MAPKs pathways.

BACKGROUND: This study aimed to elucidate the effect and underlying molecular mechanisms of SZ168 (Podoplanin (PDPN) monoclonal antibody) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and LPS-induced MH-S cells. METHODS: The survival rate was calculated by recording the death of mice in each group. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)- 6 and tumor necrosis factor-alpha (TNF-α) in blood and bronchoalveolar lavage fluid (BALF) of mice. Hematoxylin-eosin (H&E) staining were performed to evaluate the pathological changes in pulmonary tissues. Additionally, the phagocytosis of cells was tested by flow cytometry, and the expression levels of caveolin-1 (CAV-1) and Occludin proteins in lung tissue and the expression of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway-related proteins in MH-S cells were determined by western blot. RESULTS: SZ168 significantly improved the survival rate of ALI mice. Briefly speaking, SZ168 protected pulmonary vascular permeability, reduced the level of pro-inflammatory cytokines, improved the pathological changes of lung tissue, reduced the infiltration of inflammatory cells, increased CAV-1 and Occludin protein expression, and then effectively relieved lung injury. In addition, SZ168 could significantly reduce the phagocytic ability of LPS-induced MH-S cells and inhibit the expression of hospho-extracellular regulated protein kinases (p-ERK), Phospho-Jun N-terminal kinase (p-JNK), Phospho-NF-κB p65 (p-p65) and Phospho-IkappaB-alpha (p-IκBα). CONCLUSION: SZ168 can treat ALI by inhibiting the activation of NF-κB and MAPK signaling pathways and restoring tight junction protein expression.

Application of metagenomic next-generation sequencing for the diagnosis of intracranial infection of Listeria monocytogenes.

Background: Intracranial infection of Listeria monocytogenes (LM) can lead to various manifestations, including meningitis, meningoencephalitis, brainstem encephalitis, and brain abscess, which often have a poor prognosis. Metagenomic next-generation sequencing (mNGS) is a promising new tool for the diagnosis of intracranial infection of LM. We describe the typical clinical manifestations of LM intracranial infection and highlight its rarity and severity to help physicians better understand the disease characteristics. Methods: Six cases of severe LM intracranial infection were diagnosed by mNGS. We conducted a retrospective analysis of the data on disease progression, diagnostic tools, treatments, and outcomes, and summarized the findings. We compared the differences in diagnostic accuracy and timeliness between mNGS and etiological cultures. Results: Among the 6 patients, 5 were males and 1 was female (age range 32-83). Three patients had a history of immunosuppressive therapy. Common symptoms included fever (100%) and a stiff neck (100%). Coma occurred early in severe patients (66%). Two healthy young patients had previously developed with meningitis, while coma occurred in 3 immunosuppressed patients and 1 elderly patient. Three immunosuppressed patients presented with brain abscess, brainstem encephalitis, and meningitis. 1 elderly patient presented with meningitis. Two patients developed septic shock complications early. Laboratory data showed normal or slightly increased leukocytes, neutrophils, and procalcitonin, and cerebrospinal fluid (CSF) tests were consistent with bacterial CSF infection. All 6 patients were examined for blood culture and CSF culture. The positive rate of blood culture and CSF culture was 50% and 16%. The average time from admission to positive culture findings was 91 h. All 6 patients were examined for CSF mNGS. Two were also examined for whole-blood mNGS. The positive rate for CSF mNGS and whole-blood mNGS results was 100%. The mean time from admission to positive mNGS report was 47 h. After diagnosis and treatment with sensitive antibiotics, 1 patient with brain abscess developed neurological sequelae, while the other 5 patients completely recovered. Conclusions: mNGS can improve accuracy in the diagnosis of LM intracranial infection and reduce the delay in diagnosis. Intracranial infection of Listeria monocytogenes responds well to the timely use of appropriate antibiotics.