Isolation and synthesis of N-(2-methyl-3-oxodec-8-enoyl)-2-pyrroline and 2-(hept-5-enyl)-3-methyl-4-oxo-6,7,8,8a-tetrahydro-4H-pyrrolo(2,1-b)-3-oxazine, two new fungal metabolites with in vivo antijuvenile hormone and insecticidal activity

[EN] Two new natural products, N-(2-methyl-3-oxodec-8-enoyl)-2-pyrroline (2) and 2-(hept-5-enyl)-3-methyl-4-oxo-6,7,8,8a-tetrahydro-4H-pyrrolo[2,1-b]-1,3-oxazine (3), have been isolated from Penicillium brevicompactum Dierckx. Compound 2 has shown an important in vivo anti-juvenile-hormone (anti-JH) activity while compound 3 has exhibited insecticidal activity against Oncopeltus fasciatus Dallas. Both products have been synthesized starting from 1,4-hexadiene, by means of a sequence of reactions which includes the preparation of 6-octenoic acid and its transformation into the corresponding acid chloride, in order to acylate Meldrum's acid. Subsequent aminolysis with pyrrolidine, followed by methylation at the activated position of the ß-oxo amide with iodomethane, introduction of a methoxy group at the pyrrolidine ring by anodic oxidation and final elimination of methanol on SiO2 led to 2 and 3. The fact that both metabolites can be prepared by the same sequence indicates that they must be biogenetically related. Based on structural similarities, compounds 2 and 3 are also closely related to the recently discovered brevioximeCantin Sanz, A.; Moya Sanz, MDP.; Castillo López, MÁ.; Primo Millo, J.; Miranda Alonso, MÁ.; Primo Yufera, E. (1999). Isolation and synthesis of N-(2-methyl-3-oxodec-8-enoyl)-2-pyrroline and 2-(hept-5-enyl)-3-methyl-4-oxo-6,7,8,8a-tetrahydro-4H-pyrrolo(2,1-b)-3-oxazine, two new fungal metabolites with in vivo antijuvenile hormone and insecticidal activity. European Journal of Organic Chemistry. 1:221-226. doi:10.1002/(SICI)1099-0690(199901)1999:13.0.CO;2-YS221226

Therapeutic Approaches to Stroke: Prevention and Acute Treatment

The work submitted for examination concerns several aspects of stroke patient management. Chapter one is a general overview of the relevant literature concerning prevention of stroke both primary and secondary. The rationale for acute therapy, pathophysiology and specific treatments such as thrombolysis, anti-platelet agents, anticoagulation and novel neuroprotective agents are discussed within the introduction. In Chapter two I examined the effects of the ACE inhibitor perindopril on blood pressure and total cerebral blood flow in hypertensive patients with recent ischaemic stroke. At present it is unclear at what stage it is safe to initiate anti-hypertensive therapy but in most cases this is delayed at least 72 hours. Patients admitted to the Acute Stroke Unit of the Western Infirmary are generally discharged either to the care of their general practitioners or to a further in-patient facility within 5 to 7 days of admission. It is therefore important to devise a risk factor intervention plan prior to discharge. Deferring decisions can result in unacceptable delays or even failure in the initiation of antihypertensive treatment. A total of 28 patients were recruited to the study with 24 completing the protocol. With a sample size of 24 patients we would expect to detect a difference in cerebral blood flow of 16% with 80% power. I hypothesised that the ACE inhibitor perindopril could be instituted within 3-7 days of ischaemic stroke onset, and this treatment would be effective and safe. 1 used transcranial and carotid duplex Doppler ultrasound to assess any effect on cerebral blood flow. Blood pressure was effectively reduced, but there was no drug associated neurological deterioration and cerebral blood flow was unaltered. Patients were screened for underlying hypertension and following informed written consent allocated either perindopril 4 mg or placebo for a period of 2 weeks within a double-blind, randomised, placebo-controlled study. Blood flow was calculated from bilateral internal carotid artery Doppler ultrasound coupled to a wall tracker device. Arterial flow was calculated equal to pi x diameter2. Doppler recordings were undertaken pre-treatment and at 2, 4, 8 and 24 hours and again at 2 weeks. In chapter three I examined the relationship between cholesterol and outcome following stroke with surprising results. All patients admitted through the Acute Stroke Unit of the Western Infirmary had total serum cholesterol measured routinely. 1,165 patients were included in the analysis. The results of the study suggested a clear dose dependent effect of elevated cholesterol on survival following stroke. The results were, however, counterintuitive with those patients with a significantly higher cholesterol having a better chance of survival. As the data linking cerebrovascular disease and elevated cholesterol is not wholly convincing appropriate placebo controlled intervention studies in patients with cerebrovascular disease are indicated before elderly patients should be routinely prescribed lipid lowering agents. I am currently involved in setting up such a placebo controlled study. In chapter four I assessed the relationship between poor stroke outcome and hyperglycaemia. A number of studies have suggested a relationship between poor functional outcome and hyperglycaemia. 811 patients with computed tomography confirmed acute stroke and plasma glucose data were included in the study. The analysis was carried out retrospectively and represent consecutive admissions for which CT and immediate blood glucose data were available. Our results were consistent with the hypothesis that hyperglycaemia exerts a direct and independent effect predisposing to poor stroke outcome. These results have been confirmed by other investigators and there are a number of postulated mechanisms which have been put forward to explain this trial of insulin therapy to correct hyperglycaemia versus standard observation in patients with acute stroke. Chapters five, six and seven were phase II placebo controlled trials of novel neuroprotective compounds currently being evaluated as treatment for acute stroke. The studies were not powered to demonstrate efficacy but rather to evaluate tolerability, safety and clinical pharmacology prior to phase III studies. In chapter five we evaluated the safety and tolerability of GV150526 (a glycine receptor antagonist) in patients with acute stroke. This drug was found to be extremely well tolerated when compared with other neuroprotective agents and the results suggest that putative neuroprotective concentrations can be achieved in patients with good tolerability. We observed a hitherto unrecognised effect on liver function. These observations lead to further toxicology studies. The results of the study and pharmacokinetic analysis have been utilised in the design of a phase III clinical efficacy study. (Abstract shortened by ProQuest.)

Economic Feasibility, General Economic Impact and Implications of a Free Trade Agreement Between the European Union and Armenia

This study of the feasibility, costs and benefits of a free trade agreement between the EU and Armenia was conducted from July 2007 to April 2008 under contract with the European Commission. The first meeting in Brussels in September 2007 with Staff members of Directorates-General for Trade, External Relations, Economic and Financial Affairs, Internal Market and Services, Competition, Enterprise and Industry proved indispensable in our work on this report. During mission to Yerevan in October 2007 the consultations were held with a number of ministries, research institutes and business organizations. We greatly benefited from consultations with the representatives of the Ministry of Energy, Customs State Committee, Ministry of Trade and Economic Development, Chamber of Commerce and Industry, Union of Manufacturers and Businessmen (Employers) of Armenia, National Institute of Standards, Wine Producers Union, Ministry of Finance and Economy AEPLAC Ministry of Foreign Affairs, Armenian Development Agency UNDP, IMF and the World Bank. The European Commission Delegation to Armenia provided us with extensive information, consultation on key policy issues and organizational support, for chich we are very grateful. Several authors contributed to this study. David Dyker is the author of the introductory section (chapter 2) and the analysis of services sectors (chapter 7). Michael Emerson is the author of section on regional integration scenarios (chapter 3) and he also provided very valuable comments on all chapters in this study. Sveta Taran, Peter Holmes and Michael Gasiorek are the authors of chapter 4 employing the Sussex Framework to study the impact of FTA. Michael Gasiorek and Peter Holmes also provided valuable comments on the CGE modelling section. Evgeny Polyakov, Andrei Roudoi as well as Gevorg Torosyan contributed to the chapter on the institutional and regulatory harmonization (chapter 5). The team from the Global Insight including Andre Jungmittag, Vicki Korchagin, Evgeny Polyakov and Andrei Roudoi supervised the implementation of the survey and completed the analysis of the survey results (chapter 6). Also the same team from Global Insight contributed chapter 10 on sensitive sectors. The implementation of the survey of NTBs was conducted by AVAG Solutions under the supervision of Vardan Baghdasaryan and Melik Gasparyan. The analysis of FDI flows and their likely trends following an FTA was prepared by Malgorzata Jakubiak, while the estimation of the potential FDI flows was completed by Alina Kudina (section 8.4). The CGE analysis (chapter 9) was prepared by Maryla Maliszewska, who also acted as the project manager and the editor of the study. Finally, conclusions are a collective work of all the authors. Sierz Naurodski and Elena Kozarzewska provided an excellent administrative support. I would like to take his opportunity to thank them all for their cooperation, valuable contributions and comments.European Neighborhood Policy, free trade agreement, institutional harmonization, EU, Armenia

Economic Feasibility, General Economic Impact and Implications of a Free Trade Agreement Between the European Union and Georgia

This study of the feasibility, costs and benefits of a free trade agreement between the EU and Georgia was conducted from July 2007 to April 2008 under contrach with the European Commission. The first meeting in Brussels in September 2007 with staff members of Directorates-General for Trade, External Relations, Economic and Financial Affairs, Internal Market and Services, Competition, Enterprise and Industry proved indispensable in our work on this report. During mission to Tbilisi in October 2007 the consultations were held with a number of ministries, research institutes and business organizations. We greatly benefited from consultations with the Ministry of Economic Development, Standardization Office, UN Team Leader for Economic Development, State Minister for Reforms Coordination, Ministry of Energy, Office of Deputy State Minister for European and Euro Atlantic Integration, American Chamber of Commerce, Georgian Chamber of Commerce, IMF, World Bank, EBRD, GEPLAC – Georgian European Policy Legal Advice Centre, Wine Producers Association, Federation of Georgian Businessman. The European Commission Delegation to Georgia provided us with extensive information, consultation on key policy issues and organizational support, for which we are very grateful. Several authors contributed to this study. David Dyker is the author of the introductory section (chapter 2) and the analysis of services sectors (chapter 7). Michael Emerson is the author of section on regional integration scenarios (charter 3) and he also provided very valuable comments on all chapters in this study. Sveta Taran, Peter Holmes and Michael Gasiorek are the authors of chapter 4 employing the Sussex Framework to study the impact of a free trade agreement. Michael Gasiorek and Peter Holmes also provided valuable comments on the CGE modelling section. Evgeny Polyakov, Andrei Roudoi as well as Nino Chokheli and Giorgi Pertaia contributed to the chapter on the institutional and regulatory harmonization (chapter 5). The team from the Global Insight including Andre Jungmittag, Vicki Korchagin, Evgeny Polyakov and Andrei Roudoi supervised the implementation of the survey and completed the analysis of the survey results (chapter 6). Also the same team from Global Insight contributed chapter 10 on sensitive sectors. The implementation of the survey of NTBs was conducted by CASE-Transcaucasus under the supervision of Tamaz Asatiani. The analysis of FDI flows and their likely trends following an FTA was prepared by Malgorzata Jakubiak, while the estimation of the potential FDI flows was conducted by Alina Kudina (section 8.4). The CGE analysis (chapter 9) was written by Maryla Maliszewska, who also acted as the project manager and the editor of the study. Finally, conclusions are a collective work of all the authors. Sierz Naurodski and Elena Kozarzewska provided an excellent administrative support. I would like to take this opportunity to thank them all for their cooperation, valuable contributions and comments.European Neighborhood Policy, free trade agreement, institutional harmonization, EU, Georgia.

1-Benzyl-3-(1,2-diphenyl­ethen­yl)-1H-indole

In the title compound, C29H23N, the planar [maximum deviation from the least squares plane = 0.056 (1) Å] indole ring makes dihedral angles of 83.4 (4), 69.9 (1) and 59.9 (1)°, with the least-squares planes of three benzene rings. The mol­ecular packing is stabilized by weak inter­molecular C—H⋯π inter­actions

Post-treatment FDG PET-CT in head and neck carcinoma: comparative analysis of 4 qualitative interpretative criteria in a large patient cohort

There is no consensus regarding optimal interpretative criteria (IC) for Fluorine-18 fluorodeoxyglucose (FDG) Positron Emission Tomography – Computed Tomography (PET-CT) response assessment following (chemo)radiotherapy (CRT) for head and neck squamous cell carcinoma (HNSCC). The aim was to compare accuracy of IC (NI-RADS, Porceddu, Hopkins, Deauville) for predicting loco-regional control and progression free survival (PFS). All patients with histologically confirmed HNSCC treated at a specialist cancer centre with curative-intent non-surgical treatment who underwent baseline and response assessment FDG PET-CT between August 2008 and May 2017 were included. Metabolic response was assessed using 4 different IC harmonised into 4-point scales (complete response, indeterminate, partial response, progressive disease). IC performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy) were compared. Kaplan-Meier and Cox proportional hazards regression analyses were performed for survival analysis. 562 patients were included (397 oropharynx, 53 hypopharynx, 48 larynx, 64 other/unknown primary). 420 patients (75%) received CRT and 142 (25%) had radiotherapy alone. Median follow-up was 26 months (range 3–148). 156 patients (28%) progressed during follow-up. All IC were accurate for prediction of primary tumour (mean NPV 85.0% (84.6–85.3), PPV 85.0% (82.5–92.3), accuracy 84.9% (84.2–86.0)) and nodal outcome (mean NPV 85.6% (84.1–86.6), PPV 94.7% (93.8–95.1), accuracy 86.8% (85.6–88.0)). Number of indeterminate scores for NI-RADS, Porceddu, Deauville and Hopkins were 91, 25, 20, 13 and 55, 70, 18 and 3 for primary tumour and nodes respectively. PPV was significantly reduced for indeterminate uptake across all IC (mean PPV primary tumour 36%, nodes 48%). Survival analyses showed significant differences in PFS between response categories classified by each of the four IC (p <0.001). All four IC have similar diagnostic performance characteristics although Porceddu and Deauville scores offered the best trade off of minimising indeterminate outcomes whilst maintaining a high NPV

Retropharyngeal Lymph Node Involvement in Oropharyngeal Carcinoma: Impact upon Risk of Distant Metastases and Survival Outcomes

The influence of retropharyngeal lymph node (RPLN) involvement on prognosis in oropharyngeal carcinoma remains poorly defined. The aim of this study was to assess the impact of RPLN involvement upon outcomes. A single-centre retrospective analysis of 402 patients with oropharyngeal carcinoma treated nonsurgically between 2010 and 2017 was performed. All had a baseline 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) PET-CT and contrast-enhanced MRI and/or CT. RPLN status was determined by radiology review of cases with reported abnormal RPLN. Multivariate backwards logistic regression was used to examine impact on outcomes of factors. Abnormal RPLNs were identified in 40/402 (10%) of patients. Median follow up was 42.9 months. RPLN involvement was associated with inferior 3 year outcomes for overall survival (OS) (67.1% vs. 79.1%, p = 0.006) and distant metastases-free survival (DMFS) (73.9% versus 88.0%, p = 0.011), with no significant difference in local control (81.6% vs. 87.7%, p = 0.154) or regional control (80.7% vs. 85.4%, p = 0.252). On multivariate analysis abnormal RPLN, no concurrent chemotherapy and ongoing smoking were associated with inferior DMFS and OS, while advanced T stage was also associated with inferior OS. In summary, RPLN involvement, present in 10% of patients, was an independent prognostic factor for the development of distant disease failure translating into inferior OS. These findings need confirmation in future studies

rac-7,7′,9,9′-Tetra­phenyl-9a,9a′-bi(7,8,9,9a-tetra­hydro-6aH-penta­leno[1,2,3-ij]naphthalen-8-one)

The racemic title compound, C54H38O2, consists of two C-linked penta­leno[1,2,3-ij]naphthalenone moieties, the crowded aryl ring substitution on the cyclo­pentane rings forcing the two segments to assume a conformation which has pseudo-twofold rotational symmetry, with a dihedral angle between the naphthalene substituent groups of 55.30 (8)°. In each segment, the two phenyl rings have different conformational orientations, with inter-ring dihedral angles of 34.7 (2) and 49.63 (16)°. Each cyclo­pentane ring has the same relative configuration in its four chiral centres and together with the fused naphthalene ring assumes an overall chair-like conformation

A single centre experience with sequential and concomitant chemoradiotherapy in locally advanced stage IV tonsillar cancer

<p>Abstract</p> <p>Background</p> <p>Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil.</p> <p>Methods</p> <p>A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone.</p> <p>Results</p> <p>Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively.</p> <p>Conclusion</p> <p>Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer.</p