Increased contractile responses to 5-hydroxytryptamine and Angiotensin II in high fat diet fed rat thoracic aorta

BACKGROUND: Feeding normal rats with high dietary levels of saturated fat leads to pathological conditions, which are quite similar to syndrome X in humans. These conditions such as hypertriglyceridemia, hypercholesterolemia, obesity, and hyperglycemia might induce hypertension through various mechanisms. Metabolic syndrome and the resulting NIDDM represent a major clinical challenge because implementation of treatment strategies is difficult. Vascular abnormalities probably contribute to the etiology of many diabetic complications including nephropathy, neuropathy, retinopathy, and cardiomyopathy. It has been shown that in Streptozotocin induced diabetic animals there is an increase in maximal responses to 5-Hydroxytryptamine and Angiotensin II. The purpose of this study was to evaluate High fat diet fed rats for the development of hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperglycemia and to assess their vascular responses to 5-Hydroxytryptamine and Angiotensin II. METHODS: Male Sprague Dawley rats were used for this study and were divided into two equal groups. One of the groups was fed with normal pellet diet and they served as the control group, whereas the other group was on a high fat diet for 4 weeks. Body weight, plasma triglycerides, plasma cholesterol, and plasma glucose were measured every week. Intraperitoneal glucose tolerance test was performed after 4 weeks of feeding. At the end of fourth week of high fat diet feeding, thoracic aortae were removed, and cut into helical strips for vascular reactivity studies. Dose-response curves of 5-Hydroxytryptamine and Angiotensin II were obtained. RESULTS: There was no significant difference in pD(2), with 5-Hydroxytryptamine and Angiotensin II in both groups but E(max )was increased. CONCLUSIONS: These results suggest that hypertension in high fat diet rats is associated with increased in vitro vascular reactivity to 5-HT and Ang II

Integrating Clinical Trial Imaging Data Resources Using Service-Oriented Architecture and Grid Computing

Clinical trials which use imaging typically require data management and workflow integration across several parties. We identify opportunities for all parties involved to realize benefits with a modular interoperability model based on service-oriented architecture and grid computing principles. We discuss middleware products for implementation of this model, and propose caGrid as an ideal candidate due to its healthcare focus; free, open source license; and mature developer tools and support

β3-adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived nitric oxide and vascular relaxation in small arteries

BACKGROUND AND PURPOSE In response to norepinephrine healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arterial tissue. Organ bath solution transfer experiments have demonstrated the release of PVAT-derived relaxing factors that mediate this function. The present studies were designed to investigate the mechanism responsible for the norepinephrine-induced PVAT anticontractile effect. EXPERIMENTAL APPROACH In vitro rat small arterial contractile function was assessed using wire myography in the presence and absence of PVAT and the effects of sympathomimetic stimulation on the PVAT environment explored using Western blotting and assays of organ bath buffer. KEY RESULTS PVAT elicited an anticontractile effect in response to norepinephrine but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the β3-adrenoceptor agonist, CL-316,243 reduced the vasoconstrictor effect of phenylephrine but not norepinephrine. Kv7 channel inhibition using XE 991 reversed the norepinephrine-induced anticontractile effect in exogenously applied PVAT studies. Adrenergic stimulation of PVAT with norepinephrine and CL-316,243, but not phenylephrine was associated with increased adipocyte-derived nitric oxide production and the contractile response to norepinephrine was augmented following incubation of exogenous PVAT with L-NMMA. PVAT from eNOS-/- mice had no anticontractile effect. Assays of adipocyte cAMP demonstrated an increase with norepinephrine stimulation implicating Gαs signalling in this process. CONCLUSIONS AND IMPLICATIONS We have shown that adipocyte-located β3-adrenoceptor stimulation leads to activation of Gαs signaling pathways with increased cAMP and the release of adipocyte-derived nitric oxide. This process is dependent upon Kv7 channel function. We conclude that adipocyte-derived nitric oxide plays a central role in anticontractile activity when rodent PVAT is stimulated by norepinephrine

Baifuzi reduces transient ischemic brain damage through an interaction with the STREX domain of BKCa channels

Stroke is a long-term disability and one of the leading causes of death. However, no successful therapeutic intervention is available for the majority of stroke patients. In this study, we explored a traditional Chinese medicine Baifuzi (Typhonium giganteum Engl.). We show, at first, that the ethanol extract of Baifuzi exerts neuroprotective effects against brain damage induced by transient global or focal cerebral ischemia in rats and mice. Second, the extract activated large-conductance Ca2+-activated K+ channel (BKCa) channels, and BKCa channel blockade suppressed the neuroprotection of the extract, suggesting that the BKCa is the molecular target of Baifuzi. Third, Baifuzi cerebroside (Baifuzi-CB), purified from its ethanol extract, activated BKCa channels in a manner similar to that of the extract. Fourth, the stress axis hormone-regulated exon (STREX) domain of the BKCa channel directly interacted with Baifuzi-CB, and its deletion suppressed channel activation by Baifuzi-CB. These results indicate that Baifuzi-CB activated the BKCa channel through its direct interaction with the STREX domain of the channel and suggests that Baifuzi-CB merits exploration as a potential therapeutic agent for treating brain ischemia

A Whole-Genome SNP Association Study of NCI60 Cell Line Panel Indicates a Role of Ca2+ Signaling in Selenium Resistance

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis

Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer

Purpose: Tissue factor (TF) is a potential target in cervical cancer as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase 1/2 study (NCT02001623). Experimental Design: Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity. Results: Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab+doublet chemotherapy. 51% of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% (95% confidence interval [CI]: 13%−37%). Median duration of response (DOR) was 4.2 months (range: 1.0+−9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%−43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%−35%), median DOR of 6.0 months (range: 1.0+−9.7), and 6-month PFS rate of 40% (95% CI: 24%−55%). TF expression was confirmed in most patients; no significant association with response was observed. Conclusions: Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer

Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial

Background Tisotumab vedotin is a first-in-human antibody–drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor. Methods InnovaTV 201 is a phase 1–2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0–1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing. Findings Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2–22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment. Interpretations Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours

Author response

International audienc

Implementation of IEC61850, in a conventional substation control system

Examensarbete i Elektronik och datorteknik utfördes på teknikavdelningen vid ABB Substations, Västerås.  Syftet med arbetet är att teoretiskt illustrera skillnaden mellan konventionella och numeriska kontrollsystem för substationer. Kontrollsystemen är vitala delar i substationer som styr, övervakar och skyddar anläggningens kopplingsutrustning och skyddar mot skador på egendom och människor. Konventionella kontrollsystem kräver mycket material och konsumerar onödigt på jordens naturresurser. I konventionella kontrollsystem sker allt signalutbyte och kommunikation mellan utrustningar i anläggningarna via kopparkablar. Alla manöversignaler skickas via koppartråd mellan manövertavlor och apparater. Kopparkablar isolerat med olika isolationsmaterial, förläggs i kabalkanaler och kabelstegar. Kontrollutrustning byggs i apparatskåp. Man kan minska miljöpåverkan genom att används IEC61850-teknik och fiberoptiska kablar för kommunikation och signalutbyte. Det reducerar konsumtionen av naturens tillgångar och miljöpåverkan. IEC61850 är ett standardprotokoll för automationsystem i anläggningar och är kompatibelt för produkter mellan de flesta tillverkarna av kontrollutrustning. Numeriska kontrollsystem har enkelt åtkomst till stationsdata och kan upprätta statistik för att analysera och förstå systemet karaktär och därmed underlätta planering av underhåll och uppgradering av systemet.This bachelor thesis in Electronic and computer engineering is performed at ABB Substations Engineering department. Purpose of the thesis is to illustrate theoretically differences between conventional and numerical control systems for substation. Control system is vital part of substation which control, monitor and protect substations equipment hence protect against damage to property and human beings. Conventional control system consume lots of material and have huge impact on environment and has more risk for fire, toxic gases, and explosions. All operations and signal exchange in conventional control system is through copper cables which are isolated with different isolation materials and to be laid in cable trenches, on cable ladders. It needs metal case cubicles to install and manage different components. Manufacturing and transportation of all material consume resources from nature. The footprints can be reduced dramatically by implementing IEC61850 to conventional control system and using fiber optics cables for communication and signal exchange. This reduces the consumption of natural resources. It can even decrease or eliminate the dependency of particular manufacturer of control equipment or components. IEC61850 is a standard protocol which is compatible with all major control equipment, manufactured by different companies and have high interoperability. Numerical control systems have easy access to data and statistics which help to understand nature of system hence planning maintenance and upgrading of system

Implementation of IEC61850, in a conventional substation control system

Examensarbete i Elektronik och datorteknik utfördes på teknikavdelningen vid ABB Substations, Västerås.  Syftet med arbetet är att teoretiskt illustrera skillnaden mellan konventionella och numeriska kontrollsystem för substationer. Kontrollsystemen är vitala delar i substationer som styr, övervakar och skyddar anläggningens kopplingsutrustning och skyddar mot skador på egendom och människor. Konventionella kontrollsystem kräver mycket material och konsumerar onödigt på jordens naturresurser. I konventionella kontrollsystem sker allt signalutbyte och kommunikation mellan utrustningar i anläggningarna via kopparkablar. Alla manöversignaler skickas via koppartråd mellan manövertavlor och apparater. Kopparkablar isolerat med olika isolationsmaterial, förläggs i kabalkanaler och kabelstegar. Kontrollutrustning byggs i apparatskåp. Man kan minska miljöpåverkan genom att används IEC61850-teknik och fiberoptiska kablar för kommunikation och signalutbyte. Det reducerar konsumtionen av naturens tillgångar och miljöpåverkan. IEC61850 är ett standardprotokoll för automationsystem i anläggningar och är kompatibelt för produkter mellan de flesta tillverkarna av kontrollutrustning. Numeriska kontrollsystem har enkelt åtkomst till stationsdata och kan upprätta statistik för att analysera och förstå systemet karaktär och därmed underlätta planering av underhåll och uppgradering av systemet.This bachelor thesis in Electronic and computer engineering is performed at ABB Substations Engineering department. Purpose of the thesis is to illustrate theoretically differences between conventional and numerical control systems for substation. Control system is vital part of substation which control, monitor and protect substations equipment hence protect against damage to property and human beings. Conventional control system consume lots of material and have huge impact on environment and has more risk for fire, toxic gases, and explosions. All operations and signal exchange in conventional control system is through copper cables which are isolated with different isolation materials and to be laid in cable trenches, on cable ladders. It needs metal case cubicles to install and manage different components. Manufacturing and transportation of all material consume resources from nature. The footprints can be reduced dramatically by implementing IEC61850 to conventional control system and using fiber optics cables for communication and signal exchange. This reduces the consumption of natural resources. It can even decrease or eliminate the dependency of particular manufacturer of control equipment or components. IEC61850 is a standard protocol which is compatible with all major control equipment, manufactured by different companies and have high interoperability. Numerical control systems have easy access to data and statistics which help to understand nature of system hence planning maintenance and upgrading of system