The prognostic role of M2 tumor-associated macrophages in non-small-cell lung cancer.

Lung cancer is a high-risk tumor and is a main cause of death worldwide. The tumor aggressiveness and degree of malignancy depend not only on the tumor itself, but also on the microenvironment. The inflammatory microenvironment is one of the key factors in promoting the progression of lung cancer. It has been found that macrophages are the most abundant immune cells in the tumor microenvironment, with strong plasticity and heterogeneity. Tumor-Associated Macrophages (TAMs) are important components of the tumor immune microenvironment. TAMs are thought to be polarized into two main phenotypes: inflammatory or classically activated (M1) and antiinflammatory or alternatively activated (M2) macrophages. Their phenotype and function change according to environment and the appearance of tumor cells. M2 macrophages have been reported to be protumorigenic, because they can promote the formation of blood vessels in the tumor microenvironment, helping tumor cells escape the body's immune defense and promote their growth, by releasing a variety of cytokines, including chemokines, inflammatory factors and growth factor. However, the prognostic impact of TAMs and their phenotypes in non-small-cell lung cancer (NSCLC) remains to be fully elucidated. Some reports of the association between the characteristics of macrophages in lung tumor and patients' survival outcomes show contradicting results. In order to explore the prognostic role of TAMs in NSCLS, the association between the phenotype, density and distribution of macrophages and the prognosis of human NSCLC, as well as the potential mechanisms of M2 macrophages leading to poor prognosis in NSCLC, are reviewed in this study.

Astrocytoma progression scoring system based on the WHO 2016 criteria.

Diffuse astrocytoma (including glioblastoma) is morbid with a worse prognosis than other types of glioma. Therefore, we sought to build a progression-associated score to improve malignancy and prognostic predictions for astrocytoma. The astrocytoma progression (AP) score was constructed through bioinformatics analyses of the training cohort (TCGA RNA-seq) and included 18 genes representing distinct aspects of regulation during astrocytoma progression. This classifier could successfully discriminate patients with distinct prognoses in the training and validation (REMBRANDT, GSE16011 and TCGA-GBM Microarray) cohorts (P < 0.05 in all cohorts) and in different clinicopathological subgroups. Distinct patterns of somatic mutations and copy number variation were also observed. The bioinformatics analyses suggested that genes associated with a higher AP score were significantly involved in cancer progression-related biological processes, such as the cell cycle and immune/inflammatory responses, whereas genes associated with a lower AP score were associated with relatively normal nervous system biological processes. The analyses indicated that the AP score was a robust predictor of patient survival, and its ability to predict astrocytoma malignancy was well elucidated. Therefore, this bioinformatics-based scoring system suggested that astrocytoma progression could distinguish patients with different underlying biological processes and clinical outcomes, facilitate more precise tumour grading and possibly shed light on future classification strategies and therapeutics for astrocytoma patients.

Distribution and function of voltage-gated sodium channels in the nervous system.

Voltage-gated sodium channels (VGSCs) are the basic ion channels for neuronal excitability, which are crucial for the resting potential and the generation and propagation of action potentials in neurons. To date, at least nine distinct sodium channel isoforms have been detected in the nervous system. Recent studies have identified that voltage-gated sodium channels not only play an essential role in the normal electrophysiological activities of neurons but also have a close relationship with neurological diseases. In this study, the latest research findings regarding the structure, type, distribution, and function of VGSCs in the nervous system and their relationship to neurological diseases, such as epilepsy, neuropathic pain, brain tumors, neural trauma, and multiple sclerosis, are reviewed in detail.

Microsurgical Outcomes of Secondary Epilepsy from Hippocampal Lesions: A Report of 56 Cases and Literature Review.

AIM: To explore the treatment efficacy of microsurgery for secondary epilepsy from hippocampal lesions. MATERIAL AND METHODS: The clinical data, pathological findings, surgical methods and surgical outcomes of 56 patients with secondary epilepsy from hippocampal lesions were retrospectively analyzed. RESULTS: Postoperative pathological examinations confirmed that 27 patients had gliomas, 17 patients had vascular malformations and 12 patients had hippocampal sclerosis. Twenty-nine patients underwent selective resection of the lesioned tissue and the surrounding infiltrated tissue, and 26 patients underwent a more generous removal of the anterior temporal lobe, lesioned tissue, infiltrated tissue and medial structures of the temporal lobe. Fifty patients were followed up with an average follow-up duration of 25.5 months. At postoperative one year, the remission rate of epilepsy that achieved Engel grade I was 80.8% (21/26) and 83.3% (20/24) for the selective resection and more generous resection, respectively, indicating that the difference between the two methods was insignificant. CONCLUSION: Microsurgery is the first choice for the treatment of secondary epilepsy from hippocampal lesions. Various operative routes and methods can be selected based on the lesion natures. Long-term favorable outcome of seizure control following microsurgery can be achieved in most of the patients.

Multiple intracranial and spinal metastases from a nonfunctioning pituitary adenoma following multiple surgeries: an illustrative case with 16 years of follow-up.

Pituitary adenomas are the third most common primary intracranial tumor; however, those with postoperative metastases are very rare and are classically considered as pituitary carcinomas. The field of neurosurgery has struggled with diagnosing and treating these unusual lesions. In this report, we retrospectively analyze the clinical features, imaging findings, pathological characteristics and prognosis of one patient with non-hormone-secreting pituitary adenoma who had multiple intracranial and spinal metastases and underwent four surgeries in a 16-year follow-up period. In addition, on the basis of the existing literature, we explore the underlying mechanisms of, as well as the preventive and therapeutic strategies used to treat, pituitary carcinomas and postoperative metastasis of pituitary tumors.

Ecdysterone protects gerbil brain from temporal global cerebral ischemia/reperfusion injury via preventing neuron apoptosis and deactivating astrocytes and microglia cells.

Ecdysterone (EDS), a common derivative of ecdysteroid, has shown its effects on alleviating cognitive impairment and improving the cognition and memory. However, the mechanisms remain unknown. Using temporal global forebrain ischemia and reperfusion-induced brain injury as a model system, we investigated the roles of EDS in improving cognitive impairment in gerbil. Our results demonstrated that intraperitoneal injection of EDS obviously increased the number of surviving neuron cells by Nissl and neuronal nuclei (NeuN) staining. Indeed, the protecting effects of EDS are because of its ability to prevent the apoptosis of neuron cells as evidenced by TUNEL staining and caspase-3 deactivation in the brain of temporal global forebrain ischemia/reperfusion-treated gerbil. Moreover, EDS administration suppressed the ischemia stimulated activity of astrocytes and microglia cells by inhibiting the production of tumor necrosis alpha (TNF-α) in the brain of gerbil. More importantly, these actions of neurons and astrocytes/microglia cells in response to EDS treatment played pivotal roles in ameliorating the cognitive impairment in the ischemia/reperfusion-injured gerbil. In view of these observations, we not only decipher the mechanisms of EDS in reducing the syndrome of ischemia, but also provide novel perspectives to combat ischemic stroke.

Microsurgical management of bronchogenic cysts in the thalamus: an illustrative case and literature review.

Intracranial bronchogenic cysts are extremely rare. This is the first reported case of a bronchogenic cyst arising from the thalamus. Complete microsurgical resection was undertaken. A literature review was conducted to explore the etiologies, diagnostic approaches, and therapeutic strategies for this type of rare disease.

Plasma levels of tissue inhibitor of matrix metalloproteinase-1 correlate with diagnosis and prognosis of glioma patients.

BACKGROUND: There is no validated blood biomarker available for glioma management. Invasive growth is the key feature of glioma. We assessed the clinical usefulness of plasma tissue inhibitor of metalloproteinase 1 (TIMP-1), which has less molecular weight than metalloproteinases, as a potential blood biomarker for glioma. METHODS: A total of 285 patients and 59 normal subjects were studied. Plasma concentration of TIMP-1 was measured with enzyme-linked immunosorbent assay. Plasma TIMP-1 was compared between normal and glioma patients, between patients with different pathological grades, and between patients with different prognoses. Longitudinal changes in plasma TIMP-1 during treatment were also evaluated. Plasma matrix metalloproteinase (MMP)-9 level was also assayed and its clinical usefulness was compared with that of TIMP-1. RESULTS: Plasma TIMP-1 and MMP-9 were both increased in glioma patients compared with normal controls (TIMP-1: P < 0.001; MMP-9: P = 0.007). Plasma TIMP-1 increases with increased tumor grade. In Grade IV gliomas, plasma TIMP-1 significantly increased after "successful removal" of the tumor (paired samples t-test, before operation vs. during chemotherapy without recurrence, t = -2.131, P = 0.038), but did not change significantly at the time of tumor recurrence (during chemotherapy without recurrence vs. after tumor recurrence, t = -0.652, P = 0.632). High plasma TIMP-1 level correlated with better survival in Grade IV glioma patients (hazard ratio: 0.550, 95% CI: 0.101-1.000, P = 0.036). In Grade IV gliomas, patients with higher plasma TIMP-1 had significantly longer survival time than those with lower plasma TIMP-1 level (25.23 vs. 18.95 months, log-rank P = 0.045). Plasma MMP-9 did not show significant association with either the pathological grade or the prognosis of glioma patients. CONCLUSIONS: Plasma TIMP-1 is associated with the diagnosis and prognosis of glioma patients. It appears to have better usefulness for guiding clinical decision making than plasma MMP-9. Further studies in an expanded patient population are needed to better define its clinical usefulness.

Microsurgical management of giant malignant peripheral nerve sheath tumor of the scalp: two case reports and a literature review.

Malignant peripheral nerve sheath tumors of the scalp are rare lesions of the nervous system. Only 14 cases have been reported to date. The field of neurosurgery has struggled with diagnosing and treating these tumors. In this report, we present two cases of giant malignant peripheral nerve sheath tumors of the scalp and retrospectively analyze the clinical features, imaging findings, pathological features, and prognoses of these two patients. Each underwent microsurgery and radiotherapy. In addition, based on a literature review, we discuss the diagnostic and therapeutic strategies used to treat these unusual lesions.

Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: Shikonin, a natural naphthoquinone pigment extracted from the root of Lithospermum erythrorhizon, has shown a variety of pharmacologic properties including anti-inflammatory effect. In the present study, we analyzed the role of shikonin in acute lung injury induced by lipopolysaccharide (LPS) in mice. MATERIALS AND METHODS: Sixty male BALB/C mice were randomly allocated into six groups (n = 10, each): control group, shikonin group (50 mg/kg), LPS group, and three different doses (12.5, 25, and 50 mg/kg) for shikonin-treated groups. Shikonin or vehicle was given with an intragastric administration 1 h before an intratracheal instillation of LPS (5 mg/kg). The severity of pulmonary injury was evaluated 6 h after LPS challenge. RESULTS: Shikonin pretreatment significantly attenuated LPS-induced pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration. The lung wet-to-dry weight ratios, as the index of pulmonary edema, were markedly decreased by shikonin pretreatment. Moreover, shikonin decreased the productions of the proinflammatory cytokines including tumor necrosis factor alpha and interleukin 1ß and the concentration of total proteins in the bronchoalveolar lavage fluid. Shikonin pretreatment also reduced the concentrations of myeloperoxidase and nitric oxide in lung tissues. In addition, shikonin pretreatment significantly suppressed LPS-induced activation of cyclooxygenase 2 and inducible nitric oxide synthase and the nuclear factor κB DNA-binding activity in lung tissues. CONCLUSIONS: This study indicates that shikonin may have a protective effect against LPS-induced acute lung injury, and the potential mechanism of this action may attribute partly to the inhibition of inducible nitric oxide synthase and cyclooxygenase 2 expression by downregulating nuclear factor κB activation.

[An experimental study on chemoprevention of esophageal adenocarcinoma by celecoxib, a selective cyclooxygenase-2 inhibitor].

OBJECTIVE: To study the feasibility of chemoprevention of esophageal adenocarcinoma by celecoxib, a selective cyclooxygenase-2(COX-2) inhibitor using a rat model. METHODS: Rats were divided into 3 groups: model group, celecoxib group, and control group. The rat surgical model was established by performing a gastrojejunostomy plus an esophagojejunostomy 5 mm distal to the gastrojejunal anastomosis. Twenty-eight weeks after surgery, all the animals were sacrificed and the pathological changes in the esophagus were examined macroscopically. COX-2 expression was analyzed by immunohistochemistry. Prostaglandin E2(PGE2) level was measured by enzyme-linked immunosorbent assay(ELISA). RESULTS: The incidence of Barrett's esophagus and esophageal adenocarcinoma in the model group was 84% and 57% respectively, significantly higher than those in the control group(P<0.01). The incidence of esophageal adenocarcinoma in the celecoxib-treated group was significantly lower than that in the model group(P<0.01), and no esophageal adenocarcinoma was detected in the control group. COX-2 expression was detected in 100% of reflux esophagitis, Barrett esophagus and esophageal adenocarcinoma, but not found in the normal tissue from the esophagus and the jejunum(P<0.01). The PGE2 level in the esophageal tissue in the model group was significantly higher than that in the control group(P<0.01). Rats in the celecoxib-treated group had significantly lower PGE2 level than that in the model group(P<0.01). The PGE2 levels were significantly higher in rats with cancer than those without cancer(P<0.01). CONCLUSION: Celecoxib successfully prevents the development of esophageal adenocarcinoma in a rat surgical model with mixed reflux of acid and duodenal juice and significantly decreases the risk of Barrett esophagus developing esophageal adenocarcinoma. COX-2 maybe an effective selective target of chemoprevention for esophageal adenocarcinoma.

Cloning and expression of the two new variants of Nav1.5/SCN5A in rat brain.

The α-subunit of tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel (VSGC, Nav1.5/SCN5A) has been found from the rat heart and human neuroblastoma cell line NB-1, but its expression in rat brain has not been identified radically. In this study, a reverse transcriptase-polymerase chain reaction was used to clone the full sequence of Nav1.5 (designated as rN1) α-subunit in rat brain and compared the distribution in different lobe of brain in different developmental stages. The open reading frame of rN1 encodes 2,016 amino acid residues and sequence analysis indicated that rN1 is highly homologous with 96.53% amino acids identity to rat cardiac Nav1.5 (rH1) and 96.13% amino acids identity to human neuroblastoma Nav1.5 (hNbR1). It has all the structural features of a VSGC and the presence of a cysteine residue (C373) in the pore loop region of domain I suggests that this channel is resistant to TTX. A new exon (exon6A) that is distinct from rH1 was found in DI-S3-S4, meanwhile an isomer of alternative splicing that deleted 53 amino acids (exon18) was found for the first time in domain DII-III in rN1. (designated as rN1-2). Distribution results demonstrated that rN1 expressed discrepancy in different ages and lobe in brain. The expression level of rN1 was gradually more stable in adult than in neonatal; these results suggest that rN1 has a newly identified exon for alternative splicing that is differentfrom rat heart and is more widely expressed in rat brain than previously thought.

Bag3 promotes resistance to apoptosis through Bcl-2 family members in non-small cell lung cancer.

In non-small cell lung cancer (NSCLC) certain molecular characteristics, which are related to molecular alterations have been investigated. These are responsible for both the initiation and maintenance of the malignancy in lung cancer. The aim of this study was to evaluate the influence of Bag3 (Bcl-2 associated athanogene 3) in the regulation of apoptosis on NSCLC. Bag3 and Hsp70 expression were examined by immunohistochemistry to confirm their potential roles in the prevalence of NSCLC. We also established human normal bronchial epithelial cells and HOP-62 cell line as the model to analyze cell apoptosis and the expression of Hsp70, Bcl-XL and Bcl-2, which were affected by Bag3. In this study, we found that Bag3 and Hsp70 are highly expressed in few tissues and cell lines of NSCLC. Bag3 inhibits apoptosis in human normal bronchial epithelial cell lines and sustain the survival of NSCLC cells. Bag3, Hsp70, Bcl-XL and Bcl-2 are up-regulated in NSCLC cell lines. At the same time, the silencing of Bag3 results in diminishing protein levels of Bcl-XL and Bcl-2. The results of immunoprecipitation identified that Bag3 could interact with Hsp70, Bcl-XL and Bcl-2 NSCLC cells directly or indirectly. We conclude that NSCLC cells were protected from apoptosis through increasing Bag3 expression and consequently promoted the expression of Bcl-XL and Bcl-2.

Microsurgical management of cerebral parenchymal cysticercosis.

OBJECTIVE: Microsurgery is an optional way to treat parenchymal neurocysticercosis. The aim of this study is to evaluate the therapeutic efficacy of microsurgery in cerebral parenchymal cysticercosis. MATERIALS AND METHODS: A retrospective analysis was performed of the clinical data and outcomes of microsurgery in 20 cases of cerebral parenchymal cysticercosis. RESULTS: All head segments found in cysticercus cysts were removed completely. Total resection of the cystic wall was achieved in 16 cases and subtotal resection in 4 cases. Twelve patients recovered from intracranial hypertension soon after the operation. No novel complications or deaths occurred postoperatively. The patients were followed up for 3 months to 10 years; among them, 14 patients who had epilepsy before surgery were markedly improved and controlled, 4 of 5 patients recovered from hemiparesis within 6 months after surgery, and 2 patients with cerebellar ataxia showed improvement. Two patients were lost to follow-up. CONCLUSIONS: Despite a high rate of misdiagnosis of cerebral parenchymal cysticercosis, microsurgery is associated with satisfactory clinical outcomes in appropriately selected patients.

Increase of plasma IgE during treatment correlates with better outcome of patients with glioblastoma.

BACKGROUND: Previous studies have shown that glioma patients have lower blood IgE levels than controls. To evaluate its potential as a surrogate biomarker for glioma, we measured plasma IgE levels in glioma patients and healthy controls, and correlated them with clinicopathological factors and the patients' outcome. METHODS: We used enzyme-linked immunosorbant assay (ELISA) to determine the plasma IgE levels of 25 normal subjects and 252 glioma patients (85 patients with grade II glioma, 46 patients with grade III glioma, and 121 patients with glioblastoma). We also collected longitudinal plasma samples from glioblastoma patients and compared the plasma IgE levels before operation, one week after operation, in the middle of radiotherapy, after two cycles of chemotherapy, and after recurrence. The correlations between plasma IgE levels and the outcomes of the patients were determined. RESULTS: Plasma IgE levels were significantly lower in glioma patients (P = 0.004); patients with low-grade glioma have lower IgE levels than patients with high-grade glioma do (P = 0.029). In 24 patients with both preoperative plasma and two-cycle chemotherapy plasma samples, IgE levels increased after successful removal of the tumor (P = 0.021), and the increase correlated with the patients' survival (increase > 100 ng/ml vs. ≤ 100 ng/ml, 127.5 weeks vs. 62.3 weeks. P = 0.012, log-rank). Plasma IgE level increase of > 100 ng/ml has a specificity of 80% and a sensitivity of 78% to predict the patients' long survival (> 18 months). CONCLUSIONS: Our results suggest that plasma IgE level correlates with clinical and pathological factors in glioma patients. It has the potential to be a biomarker for glioma patients.

17Beta-estradiol differentially protects cortical pericontusional zone from programmed cell death after traumatic cerebral contusion at distinct stages via non-genomic and genomic pathways.

Pericontusional zone (PCZ) of traumatic cerebral contusion is a target of pharmacological intervention. Our previous study indicated that 17beta-estradiol has a protective role in PCZ after traumatic cerebral contusion via the upregulation of estrogen receptor (ER) alpha mRNA induction and protein expression as well as inhibition of caspase-3 activation, suggesting that genomic signaling pathway is implicated in the protective effect of 17beta-estrodiol. Recent findings demonstrated that 17beta-estradiol also acts on the extranuclear/membrane ER to activate non-genomic signaling pathway to regulate cellular functions and exert the protective effect in the brain. It is still unclear how and whether genomic and non-genomic pathways of 17beta-estradiol are involved in the neuroprotection in PCZ. Our current study demonstrates that 17beta-estradiol activates ERK1/2 and Akt at the early stage and induces ERalpha and survivin mRNA at the late stage to modulate its protection via the suppression of caspase-3 activation in PCZ. These findings suggest that 17beta-estrodiol differentially plays its protective roles via genomic and non-genomic signaling pathways in PCZ after traumatic cerebral contusion.

Microsurgical management of dumbbell C1 and C2 schwannomas via the far lateral approach.

Dumbbell C1 and C2 schwannomas are rare and have a distinctive presentation and anatomical features. To study the clinical characteristics of these tumors, we reviewed the microsurgical management of 18 patients with dumbbell C1 and C2 schwannomas by the far lateral approach. Data regarding clinical manifestations, radiological findings and surgical results were analyzed retrospectively. Total and subtotal resection of the tumor was achieved in 15 and three patients, respectively. At the time of discharge, 12 patients showed improvement while five patients remained the same. The average follow-up duration was 43 months (range = 3-110 months); six of seven patients had recovery from local pain or numbness. With the exception of one patient with hemiplegia or hemiparesthesia preoperatively, all patients recovered within 6 months postoperatively. The far lateral approach offers adequate exposure and access with minimal neural manipulation for treating dumbbell C1 and C2 schwannomas, and is considered the preferred surgical approach for resection of these tumors located ventrally or ventrolaterally to the first two cervical vertebrae.

Glycyrrhizin treatment is associated with attenuation of lipopolysaccharide-induced acute lung injury by inhibiting cyclooxygenase-2 and inducible nitric oxide synthase expression.

Glycyrrhizin (GL), a major active constituent of licorice root, has been attributed numerous pharmacologic effects, including anti-inflammatory, anti-viral, anti-tumor, and hepatoprotective activities. In this study, we investigated the anti-inflammatory effect of GL on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in Balb/c mice by intratracheal instillation of LPS (1 mg/kg). Before 1 h of LPS administration, the mice received intraperitoneal injection of GL at varied doses (10, 25, and 50 mg/kg). The severity of pulmonary injury was evaluated 12 h after LPS administration. GL pretreatment led to significant attenuation of LPS induced evident lung histopathologic changes, alveolar hemorrhage, and neutrophil infiltration with evidence of reduced myeloperoxidase (MPO) activity. The lung wet/dry weight ratios, as an index of lung edema, were markedly reduced by GL pretreatment. The concentrations of pro-inflammatory cytokines interleukin (IL)-1ß and tumor necrosis factor (TNF)-α were elevated in bronchoalveolar lavage fluid (BALF) after LPS administration, which were significantly inhibited by GL pretreatment. GL pretreatment also reduced the concentrations of nitric oxide (NO) in lung tissues. Furthermore, the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was suppressed by GL pretreatment. In conclusion, GL potently protected against LPS-induced ALI, and the protective effects of GL may attribute partly to the suppression of COX-2 and iNOS expression.

Protective effect of nicotine on lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: Recently, nicotine administration has been shown to be a potent inhibitor of a variety of innate immune responses, including endotoxin-induced sepsis. OBJECTIVE: It was the aim of this study to evaluate the effect of nicotine on attenuating lung injury and improving the survival in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: ALI was induced in mice by intratracheal instillation of LPS (3 mg/ml). The mice received intratracheal instillation of nicotine (50, 250 and 500 µg/kg) before or after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain, and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and high mobility group box (HMGB)-1, as well as myeloperoxidase (MPO) activity were measured by enzyme-linked immunosorbent assay. The mortality rate was recorded and analyzed by the Kaplan-Meier method. RESULTS: Nicotine pretreatment significantly attenuated the severity of lung injury and inhibited the production of TNF-α, IL-1ß and HMGB-1 in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by nicotine pretreatment. Early treatment with a high dose of nicotine (500 µg/kg) after LPS administration decreased the mortality in mice with ALI, even when treatment was started 24 h after LPS administration. CONCLUSION: Nicotine attenuated the lung injury and reduced mortality in mice with LPS-induced ALI.