Introduction: Gastrin Releasing peptide receptors (GRPRs) are potential molecular imaging targets in a variety of tumors. Recently, a ⁶⁸Ga-labelled antagonist to GRPRs, NeoBOMB1, was developed for PET. We report on the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) within the EU-FP7 project Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with Metastatic Gastrointestinal Stromal Tumours (‘MITIGATE’) (grant agreement number 602306) in patients with oligometastatic gastrointestinal stromal tumors (GIST). Materials and Methods: The main objectives were evaluation of safety, biodistribution, dosimetry and preliminary tumor targeting of ⁶⁸Ga-NeoBOMB1 in patients with advanced TKI-treated GIST using PET/CT. Six patients with histologically confirmed GIST and unresectable primary or metastases undergoing an extended protocol for detailed pharmacokinetic analysis were included. ⁶⁸Ga-NeoBOMB1 was prepared using a kit procedure with a licensed ⁶⁸Ge/⁶⁸Ga generator. 3 MBq/kg body-weight were injected intravenously and safety parameters were assessed. PET/CT included dynamic imaging at 5 min, 11 min and 19 min as well as static imaging at 1, 2 and 3-4 h p.i. for dosimetry calculations. Venous blood samples and urine were collected for pharmacokinetics. Tumor targeting was assessed on a per-lesion and per-patient basis. Results: ⁶⁸Ga-NeoBOMB1 (50 µg) was prepared with high radiochemical purity (yield >97%). Patients received 174 ± 28 MBq of the radiotracer, which was well tolerated in all patients over a follow-up period of 4 weeks. Dosimetry calculations revealed a mean adsorbed effective dose of 0.029 ± 0.06 mSv/MBq with highest organ dose to the pancreas (0.274 ± 0.099 mSv/MBq). Mean plasma half-life was 27.3 min with primarily renal clearance (mean 25.7 ± 5.4% of injected dose 4h p.i.). Plasma metabolite analyses revealed high stability, metabolites were only detected in the urine. In three patients a significant uptake with increasing maximum standard uptake values (SUV_max at 2h p.i.: 4.3 to 25.9) over time was found in tumor lesions. Conclusion: This Phase I/IIa study provides safety data for ⁶⁸Ga-NeoBOMB1, a promising radiopharmaceutical for targeting GRPR-expressing tumors. Safety profiles and pharmacokinetics are suitable for PET imaging and absorbed dose estimates are comparable to other ⁶⁸Ga-labelled radiopharmaceuticals used in clinical routine.

The cyclic GMP-AMP synthase (cGAS) protein is a pattern-recognition receptor of the mammalian innate immune system that is recognized as a main cytosolic sensor of pathogenic or damaged DNA. cGAS DNA binding initiates catalytic production of the second messenger, cyclic GMP-AMP, which activates the STING-TBK1-IRF3 signaling axis to induce cytokine expression. Post-translational modification (PTM) has started to be recognized as a critical component of cGAS regulation, yet the extent of these modifications remains unclear. Here, we report the identification and functional analysis of cGAS phosphorylations and acetylations in several cell types under basal and immune-stimulated conditions. cGAS was enriched by immunoaffinity purification from human primary fibroblasts prior to and after infection with herpes simplex virus type 1 (HSV-1), as well as from immune-stimulated STING-HEK293T cells. Six phosphorylations and eight acetylations were detected, of which eight PTMs were not previously documented. PTMs were validated by parallel reaction monitoring (PRM) mass spectrometry in fibroblasts, HEK293T cells, and THP-1 macrophage-like cells. Primary sequence and structural analysis of cGAS highlighted a subset of PTM sites with elevated surface accessibility and high evolutionary sequence conservation. To assess the functional relevance of each PTM, we generated a series of single-point cGAS mutations. Stable cell lines were constructed to express cGAS with amino acid substitutions that prevented phosphorylation (Ser-to-Ala) and acetylation (Lys-to-Arg) or that mimicked the modification state (Ser-to-Asp and Lys-to-Gln). cGAS-dependent apoptotic and immune signaling activities were then assessed for each mutation. Our results show that acetyl-mimic mutations at Lys384 and Lys414 inhibit the ability of cGAS to induce apoptosis. In contrast, the Lys198 acetyl-mimic mutation increased cGAS-dependent interferon signaling when compared to the unmodified charge-mimic. Moreover, targeted PRM quantification showed that Lys198 acetylation is decreased upon infections with two herpesviruses—HSV-1 and human cytomegalovirus (HCMV), highlighting this residue as a regulatory point during virus infection.

Juli Bai
Jun 1, 2019; 68:1099-1108
Perspectives in Diabetes

Smogasbord, and so Health, A dashboard of delights. Supine could be; Relaxed on a hospital bed, Goose down, Luxurious but bad for your back, Foam, Sometimes current but initially, Uncomfortable, A sister healed, A discussion beyond Mum, Silver hair framing, Ice-blue eyes, Wrinkles round a mouth; Ripe fruit is determined by smell, and A mango, […]

Research Event

Event participants

Charles Wanguhu, Coordinator, Kenya CSO Platform on Oil and Gas
Ndanga Kamau, Oil and Gas Policy Adviser, Oxfam Kenya
John Ochola, Chairman, Kenya CSO Platform on Oil and Gas / EcoNews Africa
Simon Thompson, Chairman, Tullow Oil
Chair: Alex Vines, Research Director, Area Studies and International Law; Head, Africa Programme, Chatham House 

13 July 2016

The updated Guidelines focus on eight key objectives for the petroleum sector in emerging producing countries and include policy-oriented recommendations for each objective.

THE ACQUISITION of Epping resulted in Total Jamaica controlling nearly a third of the retail gasolene market, but that’s not enough to lessen competition, the Fair Trading Commission, FTC, has found. “The acquisition is unlikely to have either the...

Invitation Only Research Event

Event participants

Professor Keun-Wook Paik, Associate Fellow, Energy, Environment and Resources Department, Chatham House
Chair: John Lough, Associate Fellow, Russia and Eurasia Programme, Chatham House

Ricardo V. Cohen
Jul 1, 2012; 35:1420-1428
Diabetes Care Symposium

At least eight people died and hundreds were hospitalized after toxic gas leaked from a chemical factory in southern India early Thursday, officials said.

OBJECTIVE

We examined detailed renal and cardiovascular (CV) outcomes after gastric bypass (GBP) surgery in people with obesity and type 2 diabetes mellitus (T2DM), across several renal function categories, in a nationwide cohort study.

Amid the rich, luxuriously sexual hotbed of Las Vegas hides secrets, lies, mystery, and murder.Tahlia Johnston is on the run from a horror she barely remembers, and a stalker chasing her in her dreams and in real life. Then, at a gas station in the middle of nowhere, the most incredible looking man walks into her life. Vegas is an oozing package of masculine sexuality who's rough around the edges and ready for anything. Especially sexual. He has a past he'll be damned if he reveals and a list of secrets to hide, and his list of problems soon grows longer -- From the Internet.

"A special challenge of hard rock exploration is to identify targets of interest within complex geological settings. Interpretation of the geology can be made from direct geological observations and knowledge of the area, and from 2D or 3D seismic surveys. These interpretations can be developed into 3D geological models that provide the basis for predictions as to likely targets for drilling and/or mining. To verify these predictions we need to simulate 3D seismic wave propagation in the proposed geological models and compare the simulation results to seismic survey data. To achieve this we convert geological surfaces created in an interpretation software package into discretised block models representing the different lithostratigraphic units, and segment these into discrete volumes to which appropriate density and seismic velocity values are assigned. This approach allows us to scale models appropriately for desired wave propagation parameters and to go from local to global geological models and vice versa. Then we use these digital models with forward modelling codes to undertake numerous 3D acoustic wave simulations. Simulations are performed with single shot and with exploding reflector (located on extracted geological surface) configurations" -- Summary.

United Kingdom, c.1935.

United Kingdom, c.1935.

England, 1935.

Philadelphia : Barrington and Haswell, 1850.

Paris : Asselin et Houzeau, 1893.

Paris : Germer Bailliere, 1878.

[Place of publication not identified] : [publisher not identified], 1889.

[Dresden?], [1754?]

São Paulo : Governo do Estado de Sao Paulo, Secretaria da Segurança Pública, 1975.

São Paulo : Serviço Grafíco da Secretaria da Segurança Pública, 1976.

Prices on P.E.I. for gas, heating oil and diesel all took a big jump upwards Friday.

Madagascar is putting its self-proclaimed, plant-based "cure" for COVID-19 on sale and several countries in Africa have already put in orders for purchase, despite warnings from the World Health Organization that its efficacy is unproven.

Villagers placed the bodies of three victims of a deadly gas leak from an LG Polymers plant in southern India at the gates of the site on Saturday and demanded the factory be shut down immediately and its top management arrested.

The OM Madagascar team mobilises the Malagasy church for prayer through radio programmes and SMS messages.

The vision of OM Madagascar is to partner with the Malagasy Church in every ministry. This vision is being realised in Manakara.

Madagascar’s ongoing crisis continues to defy definition. Some call Andry Rajoelina’s taking power in March 2009 a popular uprising. Others say this was a military-supported coup, pure and simple. The legitimacy of the new regime remains in question both internally and externally, and peace agreements mediated by the international community lie in tatters.

While the reality and extent of the coup announced yesterday by military officers is still uncertain, the latest events demonstrate the fragility of the situation in Madagascar and the urgent need for a new international strategy to end the long crisis. Negotiations should now focus on international support to the electoral process based on strict conditions.

A l’approche de la décision de la SADC, il est important qu’elle porte toute son attention sur les mesures qui permettent de garantir l’équité de traitement entre les protagonistes. Sans modifier le texte de la feuille de route, les autorités ont la possibilité de prouver leur volonté de garantir la neutralité du processus, afin que l’opposition soit libre de faire le choix d’entrer ou non dans cette transition sur une base équilibrée. Le rejet des autorités de ces mesures exposerait leur absence de volonté de voir se dérouler une transition et des élections crédibles. Il démontrerait également leur choix de plonger le pays dans l’instabilité plutôt que d’accepter des mesures qui renforcent la transition. Le refus de l’opposition d’adhérer au processus ne pourrait plus être justifié par un déséquilibre de la solution proposée.

During the last few months, new options for resolving the Madagascar crisis have emerged in the form of the most recent roadmap proposed by the mediation team of the Southern African Development Community (SADC). Accepted by the authorities and rejected by elements of the opposition, the roadmap remains the subject of debate and there is still no agreement on how to achieve a peaceful transition. In a few weeks from now, the SADC is due to make a statement on the document and accept, reject or amend it. There are other options for changing the course of events without changing the roadmap and these should be explored as quickly as possible.

Madagascar, one of the world’s poorest countries, has been mired in political crisis, since 2009, when 34-year-old former radio disc jockey Andry Rajoelina toppled President Marc Ravalomanana in a military coup d’état.

Madagascar’s recent elections marked an ostensible return to democracy, but unless the new government works hard to implement meaningful political, economic and social reforms, the prospect of further crisis is just a matter of time.

Zinfandel Gastro Bar

Jill Gascoine, actress and novelist

Approximately 27% of children with rotavirus in the hospital acquire it while hospitalized for another condition. Pediatric rotavirus vaccination greatly decreased the number of children hospitalized with rotavirus from 2007 to 2008.

Routine community-based rotavirus infant vaccination protects hospitalized children from acquiring rotavirus. Thus, community-based vaccination efforts should be encouraged as a strategy to decrease hospital-acquired rotavirus. (Read the full article)

Although gastroenteritis guidelines describe the need to perform oral rehydration, it remains underused, resulting in excessive use of intravenous rehydration. Other interventions, such as antiemetic administration, vary according to location, often resulting in differences in cost and outcomes.

In this nationwide cohort, intravenous rehydration use varied dramatically. Use was associated with the institution providing care and an increase in the need for future health care provider visits. Use of ondansetron also varied significantly across Canada. (Read the full article)

Dimenhydrinate, an antihistaminic agent, is a widely used drug in Canada and Europe. It limits stimulation of the vomiting center via the vestibular system. Multiple studies have shown its effectiveness in the treatment of vertigo and postoperative nausea and vomiting.

Dimenhydrinate, when given orally, did not significantly decrease the frequency of vomiting in children with acute gastroenteritis compared with placebo. The reported adverse effect proportions were similar for the dimenhydrinate and placebo groups. (Read the full article)

Rotavirus is a major cause of acute gastroenteritis among children worldwide. Vaccines targeting rotavirus have been demonstrated to be highly efficacious against severe disease in clinical trials and postlicensure studies. Vaccine impact on mild gastroenteritis has not been well studied.

We used a novel surveillance platform consisting of telephone triage data to capture mild gastroenteritis not detected in other surveillance systems. Since rotavirus vaccine licensure, gastroenteritis-related call proportions have declined, and peak gastroenteritis-related calls are correlated with community norovirus circulation. (Read the full article)