Domain 5 (D5) of cleaved high molecular weight kininogen (HKa) inhibits angiogenesis in vivo and endothelial cell migration in vitro, but the cell signaling pathways involved in HKa and D5 inhibition of endothelial cell migration are incompletely delineated. This study examines the mechanism of HKa and D5 inhibition of two potent stimulators of endothelial cell migration, sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF), that act through the P13-kinase-Akt signaling pathway. HKa and D5 inhibit bovine pulmonary artery endothelial cell (BPAE) or human umbilical vein endothelial cell chemotaxis in the modified-Boyden chamber in response toVEGF or S1P. The inhibition of migration by HKa is reversed by antibodies to urokinase-type plasminogen activator receptor. Both HKa and D5 decrease the speed of BPAE cell migration and alter the morphology in live, time-lapse microscopy after stimulation with S1P or VEGF. HKa and D5 reduce the localization of paxillin to the focal adhesions after S1P and VEGF stimulation. To better understand the intracellular signaling pathways, we examined the effect of HKa on the phosphorylation of Akt and its downstream effector, GSK-3alpha HKa and D5 inhibit phosphorylation of Akt and GSK-3alpha after stimulation withVEGF and S1P. Inhibitors of Akt and P13-kinase, the upstream activator of Akt, block endothelial cell migration and disrupt paxillin localization to the focal adhesions after stimulation with VEGF and S1P.Therefore we suggest that HKa through its D5 domain alters P13-kinase-Akt signaling to inhibit endothelial cell migration through alterations in the focal adhesions. 相似文献
BACKGROUND: The effectiveness of acaricides in homes is controversial. OBJECTIVE: To determine whether disodium octaborate tetrahydrate (DOT) combined with vacuuming lowers dust mite numbers and their allergens in carpets and sofas. METHODS: A 6-month study was carried out with 93 homes, which were randomized into three groups: (i). active, received DOT; (ii). placebo, received water; and (iii). control, received no application. Active and placebo homes were vacuumed weekly. Dust was collected from carpets and sofas at the start of the study and every 2 months thereafter and quantified for live, total mites, and mite allergen levels. RESULTS: At 2 months, live mite numbers in active carpets were 3 +/- 1, in placebo carpets 129 +/- 48, and in control carpets 177 +/- 39 mites/g. The corresponding numbers in sofas were 3 +/- 2, 81 +/- 31, and 134 +/- 45 mites/g, respectively (P < 0.001 active vs placebo and vs. control). Live mites in carpets and sofas remained lower in the active group at 6 months (P < 0.001). Total mites in active carpets decreased from 555 +/- 69 at baseline to 223 +/- 32 mites/g at 6 months (P < 0.001) and mite allergen levels from 1.36 +/- 0.13 to 0.85 +/- 0.16 microg/g (P < 0.001). Total mites in active sofas remained unchanged, but mite allergen levels decreased from 1.48 +/- 0.25 at baseline to 0.7 +/- 0.15 microg/g at month 6 (P < 0.05). CONCLUSION: DOT kills mites in carpets and sofas, and, combined with vacuuming, effectively reduces total mites in carpets and mite allergen levels in carpets and sofas. 相似文献
The purpose of the present study was to investigate the influence of a polyhydroxy base, N-acetyl glucamine (also know as Meglumine), as a ternary component on the complexation of DRF-4367, a poorly water-soluble and weakly acidic anti-inflammatory molecule, with 2-hydroxypropyl-β-cyclodextrin (HPβCD). The molecular inclusion of DRF-4367 with HPβCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate-limited oral bioavailability. The solid complexes of DRF-4367 and HPβCD with or without meglumine (binary and ternary systems, respectively) were prepared as coevaporated product in different stoichiometric ratios and compared against physical mixture. The formation of inclusion complexes was confirmed by using classical instrumental techniques. Phase solubility studies suggested that meglumine was responsible for solubility improvement via multiple factors rather than just providing a favorable pH. Mechanisms and factors governing solubility enhancement were investigated by using phase solubility and thermodynamic parameters. The complexation of DRF-4367 with HPβCD is thermodynamically favored because the Gibbs free energies of transfer of the drug to the cyclodextrin cavity are negative. The solubilization efficiency and stability were further improved while retaining the favorable Gibbs free energies of transfer with the addition of meglumine. Inclusion ternary complex of DRF-4367 with HPβCD and meglumine showed significant improvement in dissolution compared with uncomplexed drug and binary system. Moreover, the phenomena of reprecipitation observed with binary system during dissolution could be avoided with meglumine as an enabling ternary component. This improved physicochemical behavior of ternary complex with the novel inclusion of a polyhydroxy base translated into an enhanced oral bioavailability of DRF-4367 compared with either uncomplexed drug or nanosuspension. 相似文献
Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia. 相似文献
Surgical repair of acquired tracheo-esophageal fistula may result in tracheal stenosis or esophageal stricture. We used fistula with esophageal cuff as flap to repair the tracheal defect. Esophageal repair was performed by rotating ends through 90° in opposite direction. This technique offers excellent repair in a single stage. 相似文献
Our aim in the present investigation was to develop a nanoparticulate carrier of amphotericin B (AmB) for controlled delivery as well as reduced toxicity. Nanoparticles of different gelatins (GNPs) (type A or B) were prepared by two-step desolvation method and optimized for temperature, pH, amount of cross-linker, and theoretical drug loading. AmB-loaded GNPs were characterized for size, polydispersity index (PI), shape, morphology, surface charge, drug release, and hemolysis. The developed GNPs (GNP(A300)) were found to be of nanometric size (213 +/- 10 nm), having low PI (0.092 +/- 0.015) and good entrapment efficiency (49.0 +/- 2.9%). All GNPs showed biphasic release characterized by an initial burst followed by controlled release. The in vivo hematological toxicity results suggest nonsignificant reduction (P > .05) in hemoglobin concentration and hematocrit. Nephrotoxicity results showed that there was a nonsignificant (P > .05) increase in blood urea nitrogen and serum creatinine levels. The results confirm that developed GNPs could optimize AmB delivery in terms of cost and safety, and type A gelatin with bloom number 300 was found suitable for such preparation. 相似文献
Dopamine is linked to gastrointestinal functions. However, its exact nature in stress-induced gastric pathology is still not clear. In the present study, an attempt has been made to identify the effects of dopamine in stress-induced gastric ulcers, and concurrent alterations in various ulcer-influencing factors such as plasma corticosterone levels, gastric mucosal PGE2 content and proton pump activity. The dopamine D1 receptor agonist (A 68930) and antagonist (SCH 23390), and D2 receptor agonist (quinpirole) and antagonist (sulpiride) were used to evaluate their effects on acute stress (single immobilization for 150 min) and chronic unpredictable stress (two different types of stressors for 7 days) induced gastric ulcers in rats. Acute and chronic unpredictable stress significantly increased the gastric ulcer severity, adrenal hypertrophy and corticosterone levels, while gastric mucosal dopamine levels were decreased. Pretreatment of sulpiride (60 mg/kg) significantly reverted the acute stress-induced alterations, while A 68930 (0.25 mg/kg) significantly restored the acute and chronic unpredictable stress-induced alterations. In contrast, administration of SCH 23390 (0.1-0.5 mg/kg) and quinpirole (0.1-0.5 mg/kg) failed to alter acute stress-induced alterations. Further, A 68930 and sulpiride showed different response on proton pump inhibition under in-vitro condition. A 68930 (10-50 μg/ml) inhibited the gastric H+ K+-ATPase activity comparable to positive control omeprazole, while sulpiride (10-50 μg/ml) had no effect. A 68930 also normalized the decreased gastric PGE2 content observed during chronic unpredictable stress. The histopathological evaluation of gastric mucosal tissue supported the observations regarding the gastroprotective effect of sulpiride during acute stress and of A 68930 during both acute and chronic unpredictable stress conditions. Our results provide important insights into the mechanism of dopamine-regulated pathways, which cause an overall pathophysiology of gastric stress ulcers and implicating the importance of D1 agonist in ulcer protection. Thus, current study highlights the need to evaluate anti-stress and anti-ulcer agents in terms of their ability to modulate dopaminergic transmissions. 相似文献
Recent developments in isolation and characterization of tumor stem cells (TSCs) have opened new possibilities for developing TSC-targeted therapies. Extensive efforts have been made to ascertain markers of TSCs, including cell surface, enzymatic, gene expression profile, and functional markers. These markers and the technologies used to identify and isolate TSCs are discussed in this review. TSC characteristics, such as quiescence, multidrug resistance, enhanced DNA repair ability, and anti-apoptotic mechanisms, and various features of the in vivo niche, which may make them resistant to conventional therapy, are also discussed here. The increasing understanding of aberrantly expressed molecules and signaling pathways in TSCs may provide the foundation for design of therapeutic strategies for TSC ablation. ( Cancer Sci 2009) 相似文献
Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored.
Objective
To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity.
Design, setting, and participants
Multicenter single arm phase 2 study enrolling 36 chemotherapy-naïve patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients.
Intervention
Two cycles of GC followed by four cycles of GC plus ipilimumab.
Outcome measurements and statistical analysis
The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival.
Results and limitations
Grade ≥3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity = 47.6%, specificity = 100%, positive predictive value = 100%, and negative predictive value = 38.9%). Limitations are related to the sample size and single-arm design.
Conclusions
GC + ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers. Trial registration: ClinicalTrials.gov NCT01524991.
Patient summary
Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit. 相似文献
Introduction: Substance use among elderly is an emerging mental health problem and requires modification in management approaches. Systematic literature on natural opiates especially among elderly in India has been rather limited.
Materials and methods: This retrospective chart review included 24 elderly subjects (aged 60 and above) seeking outpatient treatment at a tertiary care de-addiction center in North India. Information pertaining to socio-demographic profile, clinical characteristics, and treatment seeking was extracted from the records.
Results: All the subjects were male with a mean age of 64.3 (±5.0) years. Most common substance used was doda (poppy husk) with a mean duration of dependence of 33.1 (±11.8) years. Six subjects (25.0%) had used other forms apart from natural forms of opiates. Most common reason for initiation of opiate use was to increase work efficiency (n = 9, 37.5%). Dependence on another substance (apart from opiate and tobacco) was present in seven subjects (29.2%). Majority of patients never sought any treatment previously despite using the substance for long duration.
Conclusion: Natural opioid use among elderly has a distinct profile, especially in Indian setting where its use has sociocultural sanction. There is a need for research on management of elderly natural opioid users which may pose an important clinical challenge in the future. 相似文献