Functions of Heparin Sodium Injection in the Prevention of Peripherally Inserted Central Catheter-Related Venous Thrombosis in NSCLC Patients during Postoperative Chemotherapy.

Objective: This study intended to analyze hazardous factors of venous thrombosis by comparing the effect of different doses of heparin sodium injection on the incidence rate of peripherally inserted central catheter (PICC)-related venous thrombosis in non-small cell lung carcinoma (NSCLC) patients during postoperative chemotherapy. Methods: 425 NSCLC patients who received PICC catheterization in Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Hospital from July 2019 to July 2021 were collected. Based on their different pathological types, patients were given two different chemotherapy regimens: pemetrexed+cisplatin or paclitaxel+cisplatin. Patients were grouped according to the different doses of heparin sodium injection adopted. Control group (n = 140). Catheters were sealed with 10 mL saline only. Group I (n = 142). In addition to routine maintenance with normal saline, 2 mL of 10 IU/mL heparin sodium injection was sealed in the catheters under positive pressure every time after catheterization. Group II (n = 143). In addition to routine maintenance with normal saline, 5 mL of 10 IU/mL heparin sodium injection was sealed in the same manner as Group I. The baseline characteristics of the three groups of patients were compared by statistical means. Doppler ultrasonography was applied to check the venous thrombosis. The hazardous factors of venous thrombosis were analyzed through correlation analysis and binary logistic regression method. Results: The incidence rates of thrombosis in the control group, Group I, and Group II were 20.00%, 7.04%, and 2.09%, respectively, with statistically significant differences (P < 0.01). Additionally, through the collinear correlation analysis of baseline characteristics, a significant correlation between the dosage of heparin sodium injection and the incidence of thrombosis was observed (P < 0.05), but there were no significant differences between other baseline data and the incidence of thrombosis (P > 0.05). Binary logistic regression analysis revealed that postoperative use of heparin sodium injection (Group I: OR = 0.312; P = 0.003; Group II: OR = 0.082, P < 0.001) was a protective factor for preventing thrombosis. In addition, the thromboprophylaxis effect of Group II was better than that of Group I. No serious adverse reactions were found in safety analysis. Conclusion: Heparin sodium could significantly lower the incidence rate of PICC-related venous thrombosis in NSCLC patients during postoperative chemotherapy. Heparin sodium injection is safe enough to be promoted among PICC patients with a high risk of venous thrombosis.

A longitudinal observational retrospective study on risk factors and predictive model of PICC associated thrombosis in cancer patients.

To analyze the incidence of PICC associated venous thrombosis. To predict the risk factors of thrombosis. To validate the best predictive model in predicting PICC associated thrombosis. Consecutive oncology cases in 341 who initially naive intended to be inserted central catheter for chemotherapy, were recruited to our dedicated intravenous lab. All patients used the same gauge catheter, Primary endpoint was thrombosis formation, the secondary endpoint was infusion termination without thrombosis. Two patients were excluded. 339 patients were divided into thrombosis group in 59 (17.4%) and non-thrombosis Group in 280 (82.6%), retrospectively. Tumor, Sex, Age, Weight, Height, BMI, BSA, PS, WBC, BPC, PT, D-dimer, APTT, FIB, Smoking history, Location, Catheter length, Ratio and Number as independent variables were analyzed by Fisher's scoring, then Logistic risk regression, ROC analysis and nomogram was introduced. Total incidence was 17.4%. Venous mural thrombosis in 2 (3.4%), "fibrin sleeves" in 55 (93.2%), mixed thrombus in 2 (3.4%), symptomatic thrombosis in 2 (3.4%), asymptomatic thrombosis in 57 (96.6%), respectively. Height (χ² = 4.48, P = 0.03), D-dimer (χ² = 37.81, P < 0.001), Location (χ² = 7.56, P = 0.006), Number (χ² = 43.64, P < 0.001), Ratio (χ² = 4.38, P = 0.04), and PS (χ² = 58.78, P < 0.001), were statistical differences between the two groups analyzed by Fisher's scoring. Logistic risk regression revealed that Height (ß = -0.05, HR = 0.95, 95%CI: 0.911-0.997, P = 0.038), PS (ß = 1.07, HR = 2.91, 95%CI: 1.98-4.27, P < 0.001), D-dimer (ß0.11, HR = 1.12, 95%CI: 1.045-1.200, P < 0.001), Number (ß = 0.87, HR = 2.38, 95% CI: 1.619-3.512, P < 0.001) was independently associated with PICC associated thrombosis. The best prediction model, D-dimer + Number as a novel co-variable was validated in diagnosing PICC associated thrombosis before PICC. Our research revealed that variables PS, Number, D-dimer and Height were risk factors for PICC associated thrombosis, which were slightly associated with PICC related thrombosis, in which, PS was the relatively strongest independent risk factor of PICC related thrombosis.

Neuroprotective effect of baicalin on focal cerebral ischemia in rats.

Baicalin, a flavonoid compound from the root of the herb Scutellaria baicalensis Georgi, has been widely used to treat patients with inflammatory disease. The aim of this study was to assess the efficacy of baicalin in a rat model of focal cerebral ischemia. Adult male Sprague-Dawley rat models of cerebral artery occlusion were established and then randomly and equally divided into three groups: ischemia (cerebral ischemia and reperfusion), valproic acid (cerebral ischemia and reperfusion + three intraperitoneal injections of valproic acid; positive control), and baicalin (cerebral ischemia and reperfusion + intraperitoneal injection of baicalin for 21 days). Neurological deficits were assessed using the postural reflex test and forelimb placing test at 3, 7, 14, and 21 days after ischemia. Rat cerebral infarct volume was measured using 2,3,5-triphenyltetrazolium chloride (TTC) staining method. Pathological change of ischemic brain tissue was assessed using hematoxylin-eosin staining. In the baicalin group, rat neurological function was obviously improved, cerebral infarct volume was obviously reduced, and the pathological impairment of ischemic brain tissue was obviously alleviated compared to the ischemia group. Cerebral infarct volume was similar in the valproic acid and baicalin groups. These findings suggest that baicalin has a neuroprotective effect on cerebral ischemia.

Effects of AQP5 gene silencing on proliferation, migration and apoptosis of human glioma cells through regulating EGFR/ERK/ p38 MAPK signaling pathway.

We investigated the effects of aquaporin 5 (AQP5) gene silencing on the proliferation, migration and apoptosis of human glioma cells through regulating the EGFR/ERK/p38MAPK signaling pathway. qRT-PCR was applied to examine the mRNA expressions of AQP5 in five human glioma cell lines. U87-MG, U251 and LN229 cells were selected and assigned into blank, vector, AQP5 siRNA and FlagAQP5 groups. MTT assay was used to measure cell proliferation. Flow cytometry (FCM) with AnnexinV-FITC/PI double staining and PI staining were employed to analyze cell apoptosis and cell cycle respectively. Scratch test was used to detect cell migration. Western blotting was performed to determine the EGFR/ERK/p38 MAPK signaling pathway-related proteins. Results showed that the positive expression of AQP5 in primary glioblastoma was associated with the tumor size and whether complete excision was performed. The mRNA expressions of AQP5 in cell lines of U87-MG, U251 and LN229 were significantly higher than in U373 and T98G. The proliferation rates of U87-MG, U251 and LN229 cells in the AQP5 siRNA group were lower than in the vector and blank groups. The apoptosis rate increased in the AQP5 siRNA group compared with the vector group. Scratch test demonstrated that AQP5 gene silencing could suppress cell migration. Compared with the vector and blank groups, the AQP5 siRNA group showed decreased expressions of the ERK1/2, p38 MAPK, p-ERK1/2 and p-p38 MAPK proteins. AQP5 gene silencing could inhibit the cell proliferation, reduce cell migration and promote the cell apoptosis of U87-MG, U251 and LN229 by suppressing EGFR/ERK/p38 MAPK signaling pathway.

Genetic Variants of VEGF (rs201963 and rs3025039) and KDR (rs7667298, rs2305948, and rs1870377) Are Associated with Glioma Risk in a Han Chinese Population: a Case-Control Study.

A glioma is the most common type of brain tumor that accounts for nearly 80 % of brain cancers. Vascular endothelial growth factor (VEGF) and its receptor, the kinase insert domain receptor (KDR), are involved in the angiogenesis of cancers. In this study, we investigate whether the polymorphisms of VEGF and KDR are associated with a glioma risk. Blood samples were collected from 477 glioma patients and 477 healthy controls. Five tag-single nucleotide polymorphisms (SNPs) of KDR were obtained from the HapMap database, and eight tag-SNPs of VEGF were selected based on previous studies. After extraction of genomic DNAs by a Qiagen DNA blood kit, the SNPs of VEGF and KDR were genotyped with a Sequenom MassArray iPLEX platform and further analyzed with matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. The odds ratios and their 95% confidence interval (95% CI) were used to assess the association between VEGF, KDR polymorphisms, and glioma risks with the aid of SPSS 13.0 software. The haplotype analysis demonstrated that two SNPs of VEGF [rs3025039 (C>T), rs2010963 (G>C)] could elevate the susceptibility to a glioma in the homozygous model [odds ratio (OR) = 3.13 (95% confidence interval (CI) 1.30-7.49, P = 0.007) and OR = 1.58 (95% CI 1.07-2.34, P = 0.022), respectively], dominant model [OR = 1.38 (95% CI 1.04-1.84, P = 0.025) and OR = 1.32 (95% CI 1.01-1.72, P = 0.043), respectively], and allelic model [OR = 1.43 (95% CI 1.11-1.84, P = 0.005) and OR = 1.24 (95% CI 1.04-1.50, P = 0.019), respectively]. Furthermore, three SNPs of KDR [rs7667298 (A>G), rs2305948 (C>T), rs1870377 (T>A)] were also assumed to be associated with an increased risk of a glioma in the homozygous [OR = 1.93 (95% CI 1.30-2.86, P = 0.001), OR = 2.56 (95% CI 1.28-5.11, P = 0.006), and OR = 1.52 (95% CI 1.00-2.31, P = 0.049), respectively], dominant [OR = 1.52 (95% CI 1.16-1.98, P = 0.002), OR = 1.41 (95% CI 1.05-1.87, P = 0.020), and OR = 1.48 (95% CI 1.13-1.93, P = 0.004), respectively], and allele models [OR = 1.39 (95% CI 1.15-1.67, P = 0.001), OR = 1.47 (95% CI 1.14-1.89, P = 0.002), and OR = 1.27 (95% CI 1.05-1.52, P = 0.013), respectively]. The genetic polymorphisms of VEGF [rs3025039 (C>T), rs2010963 (G>C)] and KDR [rs7667298 (A>G), rs2305948 (C>T), rs1870377 (T>A)] increased glioma susceptibility in a Chinese population, suggesting the possibility of VEGF and KDR as genetic markers for glioma. Additional functional and association studies with different ethnic groups included are needed to further confirm our results.

PDGFR-ß-activated ACK1-AKT signaling promotes glioma tumorigenesis.

Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-ß activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-ß and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-ß phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR-ß. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR-ß-induced AKT activation, the subsequent nuclear translocation of ß-catenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-ß activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF-PDGFR-induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment.

The diagnosis and surgical treatment of central brain herniations caused by traumatic bifrontal contusions.

The objective of this study was to investigate the diagnosis and surgical treatment of central brain herniations caused by traumatic bifrontal contusions. A total of 63 patients (45 men and 18 women; mean age of 43 years with a range from 20 to 72 years) who suffered from traumatic bifrontal contusions between January 2007 and December 2012 were inspected. The clinical and imaging results were studied for all patients, and we found that swelling of the mesencephalon and a downward shift of the bilateral red nucleus were significant signs of central brain herniation in the image of magnetic resonance imaging. All patients were given a simultaneous bilateral craniotomy for balanced decompressive surgery. The Glasgow Outcome Scale was used to monitor the patients during the follow-up period, which lasted from 6 to 52 months with a mean of 22 months. At the termination of the follow-up period, the following Glasgow Outcome Scale scores were obtained: 14 patients scored 5 points, 22 patients scored 4 points, 7 patients scored 3 points, 13 patients scored 2 points, and 7 patients scored 1 point. Therefore, our study suggested that an early magnetic resonance imaging scan could result in a more timely diagnosis of central brain herniation, and simultaneous bilateral craniotomy was found to be one of the best treatments for central brain herniation to improve patient outcomes.

Migration of neural stem cells to ischemic brain regions in ischemic stroke in rats.

An established rat model of ischemic stroke, produced by temporary middle cerebral artery occlusion and reperfusion (MCAO/R), was used in the evaluation of organ migration of intra-arterial (IA) transplantation of neural stem cells (NSCs). Immediately after transplantation, ischemic rats (n=8) transplanted with either NSCs (MCAO/R+NSC group) or NSC growth medium (MCAO/R+medium group) exhibited neurological dysfunction but rats in a sham+NSCs group (n=5) did not. During the post-operative period, neurological function improved to a similar extent in both MCAO/R groups. At 10 and 14 days post-transplantation, neurological function in the MCAO/R+NSC group was superior to that in the MCAO/R+medium group (p<0.001). Hematoxylin-eosin staining showed neuronal degeneration and necrosis in ischemic rats. Immunofluorescence staining revealed that NSCs had migrated to the frontal and parietal lobes, caudate, and putamen. Some cells had begun differentiating into neurons and astrocytes. Rat NSCs can migrate into the ischemic region, survive, and differentiate into astrocytes and neurons, and thereby potentially improve neurologic function after cerebral ischemia.

Activations of GABAergic signaling, HSP70 and MAPK cascades are involved in baicalin's neuroprotection against gerbil global ischemia/reperfusion injury.

Baicalin, a flavonoid compound isolated from the plant Scutellaria baicalensis Georgi, is known as a protective agent against delayed neuronal cell death after ischemia/reperfusion. To investigate the neuroprotective mechanism of baicalin, the present study was conducted to explore whether the alterations of GABAergic signaling, heat shock protein 70 (HSP70) and mitogen-activated protein kinases (MAPKs) were involved in its neuroprotection on gerbils global ischemia. The bilateral carotid arteries were occluded by 5 min and baicalin at the dose of 200 mg/kg was intraperitoneally injected into the gerbils immediately after cerebral ischemia. Seven days after reperfusion, neurological deficit was scored and changes in hippocampal neuronal cell death were assessed by Nissl staining as well as NeuN immunohistochemistry. The mRNA and protein expressions of GABAergic signal molecules (GABA(A)R α1, GABA(A)R γ2, KCC2 and NKCC1) were determined in ischemic hippocampus by real-time RT-PCR and Western blot, respectively. In addition, HSP70 and MAPKs cascades (ERK, JNK and p38) were also detected using western blot assay. Our results illustrated that baicalin treatment significantly facilitated neurological function, suppressed the ischemia-induced neuronal damage. Besides, administration of baicalin also caused a striking increase of GABA(A)R α1, GABA(A)R γ2 and KCC2 together with the decrease of NKCC1 at mRNA and protein levels in gerbils hippocampus following an ischemic insult. Furthermore, the protein expressions of HSP70 and phosphorylated ERK (p-ERK) were evidently augmented while the phosphorylated JNK (p-JNK) and phosphorylated p38 (p-p38) were strikingly diminished in ischemic gerbils with baicalin treatment. These findings suggest that baicalin activates GABAergic signaling, HSP70 and MAPKs cascades in global ischemia, which may be a mechanism underlying the baicalin's neuroprotection.

Notch1 promotes glioma cell migration and invasion by stimulating ß-catenin and NF-κB signaling via AKT activation.

The Notch signaling pathway has been implicated in both developmental processes and tumorigenesis. Aberrant Notch signaling has been repeatedly demonstrated to facilitate the proliferation and survival of glioma cells by regulating downstream effectors or other signaling pathways. In glioblastoma multiforme specimens from 59 patients, Notch1 was highly expressed in tumor tissues compared with normal brain tissues, and this expression was correlated with elevated AKT phosphorylation and Snail expression. Increased nuclear localization of ß-catenin and p50 as well as enhanced IKKα/AKT interaction were also observed in glioma tissues. In U87MG cells, the activation of Notch1 by DLL4 stimulation or by the overexpression of Notch intracellular domain (NICD) resulted in AKT activation and thereby promoted ß-catenin activity and NF-κB signaling. Inhibition of EGFR partially blocked the ß-catenin and NF-κB signaling stimulated by Notch1 activation. Furthermore, NICD overexpression in U87MG cells led to the upregulated expression of several metastasis-associated molecules, which could be abrogated by the knockdown of either ß-catenin or p50. In U87MG and U251 cells, DLL4-induced cellular migration and invasion could be inhibited by either ß-catenin or a p50 inhibitor. Collectively, these results indicate that Notch activation could stimulate ß-catenin and NF-κB signaling through AKT activation in glioma cells. Thus, Notch activation-stimulated ß-catenin and NF-κB signaling synergistically promote the migratory and invasive properties of glioma cells.

The mechanism of pathological changes of intraventricular hemorrhage in dogs.

BACKGROUND: Intraventricular hemorrhage (IVH) is an independent risk factor for both morbidity and mortality in patients with intracerebral hemorrhage and subarchnoid hemorrhage. The pathophysiological mechanisms by which blood within the ventricles causes brain damage are still poorly understood. SETTINGS AND DESIGN: We developed a canine (dog) model with long-term survival. AIMS: To study the mechanisms of pathological changes associated with IVH. MATERIALS AND METHODS: The neurological status, cranial computed tomographic findings, and the pathological changes were studied in the dogs with IVH and also in the control dogs, intraventiricular saline injection. RESULTS: In all the dogs in the control group there were no abnormalities in all the three parameters studied. The dogs in the IVH group developed neurological deficits after the blood injection. There was linear relationship between the ventricular volume and blood clot volume in the first week. After the first week, there was progressive enlargement of the ventricular volume, while the clots continued to shrink. There was complete lysis of the clots within 4 weeks. Pathological studies showed distruction of the ependymal lining of the ventricular system, subependymal gliosis and ischemia of the neurons in the subependymal areas, prominently around the aqueduct. CONCLUSION: Ventricular dilation was the prominent feature following intraventricular injection of the blood. The other pathological features included disruption of ependymal lining, subependymal gliosis, and ischemic necrosis of neurons in the periventricular tissue of the third ventricle, aqueduct, and the fourth ventricle. These pathological may have some role in the ventricular dilatation following IVH.