Prognostic value of tumor markers ProGRP, NSE and CYFRA 21-1 in patients with small cell lung cancer and chemotherapy-induced remission.

BACKGROUND: Despite successful response to first line therapy, patients with small-cell lung cancer (SCLC) often suffer from early relapses and disease progression. OBJECTIVE: To investigate the relevance of serum tumor markers for estimation of prognosis at several time points during the course of disease. METHODS: In a prospective, single-center study, serial assessments of progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1) and carcino-embryogenic antigen (CEA) were performed during and after chemotherapy in 232 SCLC patients, and correlated with therapy response and overall survival (OS). RESULTS: ProGRP, NSE and CYFRA 21-1 levels decreased quickly after the first chemotherapy cycle and correlated well with the radiological response. Either as single markers or in combination they provided valuable prognostic information regarding OS at all timepoints investigated: prior to first-line therapy, after two treatment cycles in patients with successful response to first-line therapy, and prior to the start of second-line therapy. Furthermore, they were useful for continuous monitoring during and after therapy and often indicated progressive disease several months ahead of radiological changes. CONCLUSIONS: The results indicate the great potential of ProGRP, NSE and CYFRA 21-1 for estimating prognosis and monitoring of SCLC patients throughout the course of the disease.

Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.

Neuron-specific enolase in hypertension patients with acute ischemic stroke and its value forecasting long-term functional outcomes.

BACKGROUND: Neuron Specific Enolase (NSE), a neuro-biochemical protein marker, may correlate with the prognosis of stroke patients. Moreover, hypertension is the most common comorbidities in patients with acute ischemic stroke (AIS), and the relationship between NSE levels and long-term functional outcomes in such an increasingly large population is unclear. The aim of the study was to investigate the relationships mentioned above and optimize the prediction models. METHODS: From 2018 to 2020, 1086 admissions for AIS were grouped as hypertension and non-hypertension, while hypertension group was randomly divided into development and validation cohorts for internal validation. The severity of the stroke was staged by National Institutes of Health Stroke Scale (NIHSS) score. Stroke prognosis after 1 year of follow up was documented by modified Rankin Scale (mRS) score. RESULTS: Analysis revealed the following findings:(i) Serum NSE levels increased greatly in hypertension subjects with poor functional outcomes(p = 0.046). However, there was no association in non-hypertension individuals(p = 0.386). (ii) In addition to the conventional factors (age and NIHSS score), NSE (OR:1.241, 95% CI: 1.025-1.502) and prothrombin time were significantly related to the incidence of unfavorable outcomes. (iii)Based on the above four indicators, a novel nomogram was established to predict the prognosis of stoke in hypertension patients with the c-index values of 0.8851. CONCLUSIONS: Overall, high baseline NSE is associated with poor 1-year AIS outcomes in hypertension patients, suggesting NSE may be a potential prognostic and therapeutic target for stroke in hypertension patients.

Effect of digoxin, sodium valproate, and celecoxib on the cerebral cyclooxygenase pathway and neuron-specific enolase under the pentylenetetrazole-induced kindling in mice.

Neuroinflammation plays an important role in the pathogenesis of epilepsy, so it is necessary to clarify the influence of standard antiepileptic drugs as well as adjuvant agents (e.g., cardiac glycoside digoxin, which previously showed a clear anticonvulsant potential) on cyclooxygenase pathway and neuron-specific enolase under the conditions of chronic epileptogenesis. The aim of the article is to determine the effect of digoxin, sodium valproate, and celecoxib per se, as well as the combination of digoxin with sodium valproate on the content of cyclooxygenase 1 and 2 types, prostaglandins E2, F2α, I2, thromboxane B2, 8-isoprostane and neuron-specific enolase in the brain of mice in the pentylenetetrazole-induced kindling model. It was found that only the combination of sodium valproate with digoxin provides a complete protective effect (absence of seizures) and shows the clearest influence on neuroinflammation markers and neuronal damage than monotherapy with each of these drugs and celecoxib, which appeared to be an ineffective anticonvulsant. The obtained results indicate that digoxin is a promising adjuvant drug to classical antiepileptic drugs (mostly sodium valproate) in epilepsy treatment.c.

Glioblastoma glycolytic signature predicts unfavorable prognosis, immunological heterogeneity, and ENO1 promotes microglia M2 polarization and cancer cell malignancy.

Glioblastomas are the most malignant brain tumors, whose progress was promoted by aberrate aerobic glycolysis. The immune environment was highly engaged in glioblastoma formation, while its interaction with aerobic glycolysis remained unclear. Herein, we build a 7-gene Glycolytic Score (GS) by Elastic Net in the training set and two independent validating sets. The GS predicted malignant features and poor survival with good performances. Immune functional analyses and Cibersort calculation identified depressed T cells, B cells, natural killer cells immunity, and high immunosuppressive cell infiltration in the high-GS group. Also, high expressions of the immune-escape genes were discovered. Subsequently, the single-cell analyses validated the glycolysis-related immunosuppression. The functional results manifested the high-GS neoplastic cells' association with T cells, NK cells, and macrophage function regulation. The intercellular cross-talk showed strong associations between high-GS neoplastic cells and M2 macrophages/microglia in several immunological pathways. We finally confirmed that ENO1, the key gene of the GS, promoted M2 microglia polarization and glioblastoma cell malignant behaviors via immunofluorescence, clone formation, CCK8, and transwell rescue experiments. These results indicated the interactions between cancerous glycolysis and immunosuppression and glycolysis' role in promoting glioblastoma progression. Conclusively, we built a robust model and discovered strong interaction between GS and immune, shedding light on prognosis management improvement and therapeutic strategies development for glioblastoma patients.

Comparison of frequency of silent cerebral infarction as assessed by serum neuron specific enolase in patients with non-valvular atrial fibrillation: Warfarin versus direct oral anticoagulant.

BACKGROUND: Cerebral infarction in patients with atrial fibrillation (AF) may clinically vary from being silent to catastrophic. Silent cerebral infarction (SCI) is the neuronal injury in the absence of clinically appearent stroke or transient ischaemic attack. Serum neuron specific enolase (NSE) is suggested to be a valid surrogate biomarker that allows to detect recent neuronal injury. We aimed to evaluate the incidence of recent SCI by positive NSE levels in patients with non-valvular AF (NVAF) on oral anticoagulants. METHODS: Blood samples for NSE were collected from 197 consecutive NVAF patients. NSE levels of greater than 12 ng/ml was considered as positive and suggestive of SCI. RESULTS: Patients were mainly female with a mean age of 69 years. Ninety-eight of them (49.7%) were taking warfarin. Mean INR level was 2.3 ± 0.9. Mean CHA2DS2-VASc score of the study population was 3.5 ± 1.5. Seventy-two patients (36.5%) were found to have NSE elevation. They were more likely to have history of chronic heart failure and previous stroke/TIA. Increased left atrial diameter and higher CHA2DS2-VASc were other factors associated with SCI. Patients on DOACs and patients taking aspirin on top of oral anticoagulant treatment were less likely to have SCI. Multivariate analysis demonstrated that increased left atrial diameter (OR: 2.5; 95% CI: 1.52-4; p < 0.001) and use of warfarin (OR: 2.8; 95% CI: 1.37-5.61; p = 0.005) were detected as independent predictors of SCI. CONCLUSIONS: Our study revealed that DOACs were associated with significantly reduced SCIs compared with warfarin, probably due to more effective and consistent therapeutic level of anticoagulation.

MULTIMODAL TREATMENT APPROACHES TO COMBINED TRAUMATIC BRAIN INJURY AND HEMORRHAGIC SHOCK ALTER POSTINJURY INFLAMMATORY RESPONSE.

ABSTRACT: Introduction: The optimal management strategies for patients with polytraumatic injuries that include traumatic brain injury (TBI) are not well defined. Specific interventions including tranexamic acid (TXA), propranolol, and hypertonic saline (HTS) have each demonstrated benefits in patient mortality after TBI, but have not been applied to TBI patients with concomitant hemorrhage. The goals of our study were to determine the inflammatory effects of resuscitation strategy using HTS or shed whole blood (WB) and evaluate the cerebral and systemic inflammatory effects of adjunct treatment with TXA and propranolol after combined TBI + hemorrhagic shock. Methods: Mice underwent TBI via weight drop and were subsequently randomized into six experimental groups: three with HTS resuscitation and three with WB resuscitation. Mice were then subjected to controlled hemorrhagic shock for 1 h to a goal MAP of 25 mmHg. Mice were then treated with an i.p. dose of 4 mg/kg propranolol, 100 mg/kg TXA, or normal saline (NS) as a control. Mice were killed at 1, 6, or 24 h for serum and cerebral biomarker evaluation by multiplex ELISA and serum neuron-specific enolase, a biomarker of cerebral cellular injury. Results: Mice resuscitated with HTS had elevated serum proinflammatory cytokines compared with WB resuscitated groups at 6 and 24 h after injury, with no significant difference in cerebral cytokine levels. Within the TBI/shock + HTS groups, the addition of propranolol or TXA did not significantly alter serum cytokine concentration, but cerebral IL-2, IL-12, and macrophage inflammatory protein-1α (MIP-1α) decreased after propranolol administration. In the TBI/shock + WB cohorts, the addition of both propranolol and TXA increased systemic proinflammatory cytokine levels at 6 and 24 h after injury as demonstrated by serum IL-2, IL-12, MIP-1α, and IL-1ß compared with NS control. By contrast, TBI/shock + WB mice demonstrated a significant reduction in cerebral IL-2, IL-12, and MIP-1α in propranolol treated mice 6 h after injury compared with NS group. While serum neuron-specific enolase was significantly increased 1 and 24 h after injury in TBI/shock + HTS + TXA cohorts compared with NS control, it was significantly reduced in the TBI/shock + WB + propranolol mice compared with NS control 24 h after injury. Conclusions: Whole blood resuscitation can reduce the acute postinjury neuroinflammatory response after combined TBI/shock compared with HTS. The addition of either propranolol or TXA may modulate the postinjury systemic and cerebral inflammatory response with more improvements noted after propranolol administration. Multimodal treatment with resuscitation and pharmacologic therapy after TBI and hemorrhagic shock may mitigate the inflammatory response to these injuries to improve recovery.

rEnolase maternal immunization confers caries protection on offspring.

Therapeutic vaccination with Streptococcus sobrinus recombinant enolase (rEnolase) protects rats from dental caries. Here, we investigated the effect that maternal rEnolase vaccination before pregnancy had on the offspring's immune response to S. sobrinus oral infection and dental caries progression. Female Wistar rats were immunized by intranasal and subcutaneous routes with rEnolase adsorbed onto aluminum hydroxide as adjuvant or similarly treated with the adjuvant alone (sham-immunized). Ten days after the last administration, the immunized females were paired with a male rat. The oral immune responses to S. sobrinus infection and dental caries in the offspring were evaluated. The results showed that pups born from rEnolase-immunized mothers had higher levels of rEnolase-specific salivary IgA and IgG antibodies (indicating a placental antibody transfer) and lower sulcal and proximal enamel caries scores than rats born from sham-immunized mothers. In conclusion, rEnolase maternal immunization before pregnancy provides offspring with protection against S. sobrinus-induced dental caries.

α-Enolase: a promising therapeutic and diagnostic tumor target.

α-enolase (ENOA) is a metabolic enzyme involved in the synthesis of pyruvate. It also acts as a plasminogen receptor and thus mediates activation of plasmin and extracellular matrix degradation. In tumor cells, ΕΝΟΑ is upregulated and supports anaerobic proliferation (Warburg effect), it is expressed at the cell surface, where it promotes cancer invasion, and is subjected to a specific array of post-translational modifications, namely acetylation, methylation and phosphorylation. Both ENOA overexpression and its post-translational modifications could be of diagnostic and prognostic value in cancer. This review will discuss recent information on the biochemical, proteomics and immunological characterization of ENOA, particularly its ability to trigger a specific humoral and cellular immune response. In our opinion, this information can pave the way for effective new therapeutic and diagnostic strategies to counteract the growth of the most aggressive human disease.

Oral therapeutic vaccination with Streptococcus sobrinus recombinant enolase confers protection against dental caries in rats.

Dental caries is among the more prevalent chronic human infections for which an effective human vaccine has not yet been achieved. Enolase from Streptococcus sobrinus has been identified as an immunomodulatory protein. In the present study, we used S. sobrinus recombinant enolase (rEnolase) as a target antigen and assessed its therapeutic effect in a rat model of dental caries. Wistar rats that were fed a cariogenic solid diet on day 18 after birth were orally infected with S. sobrinus on day 19 after birth and for 5 consecutive days thereafter. Five days after infection and, again, 3 weeks later, rEnolase plus alum adjuvant was delivered into the oral cavity of the rats. A sham-immunized group of rats was contemporarily treated with adjuvant alone. In the rEnolase-immunized rats, increased levels of salivary IgA and IgG antibodies specific for this recombinant protein were detected. A significant decrease in sulcal, proximal enamel, and dentin caries scores was observed in these animals, compared with sham-immunized control animals. No detectable histopathologic alterations were observed in all immunized animals. Furthermore, the antibodies produced against bacterial enolase did not react with human enolase. Overall, these results indicate that rEnolase could be a promising and safe candidate for testing in trials of vaccines against dental caries in humans.