Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt

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.     

Disodium octaborate tetrahydrate (DOT) application and vacuum cleaning,a combined strategy to control house dust mites

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.     

Differential response of A 68930 and sulpiride in stress-induced gastric ulcers in rats

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.     

Potential for therapeutic targeting of tumor stem cells

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)     

Phase 2 Trial of Gemcitabine,Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes

Background

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.

Natural opioid use in elderly in India: a case series

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.     

Staging Systems for Newly Diagnosed Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation: The Revised International Staging System Shows the Most Differentiation between Groups

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N?=?628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.     

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome

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.     

Spontaneous Rupture of a Giant Hepatic Hemangioma �C Sequential Management with Transcatheter Arterial Embolization and Resection

Hemangioma is the most common benign tumor of liver and is often asymptomatic. Spontaneous rupture is rare but has a catastrophic outcome if not promptly managed. Emergent hepatic resection has been the treatment of choice but has high operative mortality. Preoperative transcatheter arterial embolization (TAE) can significantly improve outcome in such patients. We report a case of spontaneous rupture of giant hepatic hemangioma that presented with abdominal pain and shock due to hemoperitoneum. Patient was successfully managed by TAE, followed by tumor resection. TAE is an effective procedure in symptomatic hemangiomas, and should be considered in such high risk patients prior to surgery.     

Formulation and Characterization of Polyester/Polycarbonate Nanoparticles for Delivery of a Novel Microtubule Destabilizing Agent

Purpose

Since our newly synthesized potent 5-indolyl derivative, (2-(1?H-Indol-5-yl) thiazol-4-yl) 3, 4, 5-trimethoxyphenyl methanone (LY293), to treat resistant melanoma was hydrophobic, our objective was to synthesize a biodegradable copolymer for formulating this drug into nanoparticles and to determine its anticancer activity and mechanism of action.

Methods

Methoxy poly (ethylene glycol)-b-poly (carbonate-co-lactide) [mPEG-b-P (CB-co-LA)] was synthesized for formulating LY293 into nanoparticles by o/w emulsification and stabilization by solvent evaporation. Particle size, drug release profile, in vitro efficacy in multiple melanoma cells, and mechanism of action of drug-loaded nanoparticles were determined.

Results

LY293-loaded nanoparticles with 170 nm mean size and 2.2 and 4.16% drug loading efficiently inhibited proliferation of A375 and B16F10 cells with IC₅₀ of 12.5 nM and 25 nM, respectively. LY293 circumvented multidrug resistance and inhibited proliferation of Pgp overexpressing MDA-MB435/LCC6 MDR1 melanoma cells. Upon treatment with LY293-loaded nanoparticles, A375 cells underwent cell cycle arrest in G2/M phase and apoptotic cell death. Immunofluorescence images showed inhibition of tubulin polymerization after treatment with LY293.

Conclusion

LY293-loaded mPEG-b-P (CB-co-LA) nanoparticles showed excellent efficacy and induced apoptosis in melanoma cells. These polyester/polycarbonate-based nanoparticles provided an excellent platform to deliver different poorly soluble drugs to melanoma.