From conventional to microphotochemistry: A study of phthalimide and phthalonitrile derivatives

This research explores the application of synthetic organic photochemistry for the preparation of new phthalimide and phthalonitrile derivatives. Photodecarboxylative (PDC) additions of carboxylates to phthalimides were explored, this work included addition reactions using phenyl acetates, α-keto carboxylates and protected amino acids. Once these photo-additions were optimised using a Rayonet reactor, interest was turned to the conversion of this chemistry to a micro-flow platform with a view to improving the results obtained using the large-scale Rayonet reactor. It was successfully demonstrated that the microreactor delivered comparable if not superior results. The possibility of using the PDC addition products as precursors for the synthesis of aristolactams was investigated. Optimisation of a method for the preparation of several compounds related to the aristolactam family was attempted, with the successful preparation of two compounds achieved. Also described is the photochemical synthesis of new phosphorescent phthalonitrile derivatives and their respective phthalocyanines. Two of the phthalonitrile derivatives were successfully converted to water soluble derivatives by selective sulfonation and one such derivative was screened as a potential cell-imaging agent

Microflow photochemistry—photodecarboxylations in microformats

This article summarizes selected examples of intra- and intermolecular photodecarboxylations involving phthalimides in a commercially available dwell device. Compared to batch conditions in a larger chamber reactor, the investigated transformations in the microreactor furnished higher conversions and yields after significantly shorter reaction times. The product qualities were commonly higher under flow conditions thus avoiding the need for further purifications

Radiation mitigating properties of the lignan component in flaxseed

BACKGROUND: Wholegrain flaxseed (FS), and its lignan component (FLC) consisting mainly of secoisolariciresinol diglucoside (SDG), have potent lung radioprotective properties while not abrogating the efficacy of radiotherapy. However, while the whole grain was recently shown to also have potent mitigating properties in a thoracic radiation pneumonopathy model, the bioactive component in the grain responsible for the mitigation of lung damage was never identified. Lungs may be exposed to radiation therapeutically for thoracic malignancies or incidentally following detonation of a radiological dispersion device. This could potentially lead to pulmonary inflammation, oxidative tissue injury, and fibrosis. This study aimed to evaluate the radiation mitigating effects of FLC in a mouse model of radiation pneumonopathy. METHODS: We evaluated FLC-supplemented diets containing SDG lignan levels comparable to those in 10% and 20% whole grain diets. 10% or 20% FLC diets as compared to an isocaloric control diet (0% FLC) were given to mice (C57/BL6) (n=15-30 mice/group) at 24, 48, or 72-hours after single-dose (13.5 Gy) thoracic x-ray treatment (XRT). Mice were evaluated 4 months post-XRT for blood oxygenation, lung inflammation, fibrosis, cytokine and oxidative damage levels, and survival. RESULTS: FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0% FLC demonstrated 36.7% survival 4 months post-XRT compared to 60–73.3% survival in mice fed 10%-20% FLC initiated 24–72 hours post-XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10% FLC initiated 24-hours post-XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TGF-beta1 levels detected immunohistochemically were also decreased. Additionally, 10-20% FLC initiated at any time point post radiation exposure, mitigated radiation-induced lung injury evidenced by decreased bronchoalveolar lavage (BAL) protein and inflammatory cytokine/chemokine release at 16 weeks post-XRT. Importantly, neutrophilic and overall inflammatory cell infiltrate in airways and levels of nitrotyrosine and malondialdehyde (protein and lipid oxidation, respectively) were also mitigated by the lignan diet. CONCLUSIONS: Dietary FLC given early post-XRT mitigated radiation effects by decreasing inflammation, lung injury and eventual fibrosis while improving survival. FLC may be a useful agent, mitigating adverse effects of radiation in individuals exposed to incidental radiation, inhaled radioisotopes or even after the initiation of radiation therapy to treat malignancy

Occurrence of liver cirrhosis in England, a cohort study, 1998-2009: a comparison with cancer

OBJECTIVES: There is no routine registration of the occurrence of newly diagnosed cases of cirrhosis in the United Kingdom. This study seeks to determine precise estimates and trends of the incidence of cirrhosis in England, and directly compare these figures with those for the 20 most commonly diagnosed cancers in the United Kingdom. METHODS: We used the Clinical Practice Research Datalink and linked English Hospital Episode Statistics to perform a population-based cohort study. Adult incident cases with a diagnosis of cirrhosis between January 1998 and December 2009 were identified. We described trends in incidence by sex and etiology. We performed a direct standardization to estimate the number of people being newly diagnosed with cirrhosis in 2009, and calculated the change in incidence between 1998 and 2009. RESULTS: A total of 5,118 incident cases of cirrhosis were identified, 57.9% were male. Over the 12-year period, crude incidence increased by 50.6%. Incidence increased for both men and women and all etiology types. We estimated approximately 17,000 people were newly diagnosed with cirrhosis in 2009 in the United Kingdom, greater than that of the fifth most common cancer non-Hodgkin's lymphoma. The percentage change in incidence of cirrhosis between 1998 and 2009 for both men (52.4%) and women (38.3%) was greater than that seen for the top four most commonly diagnosed cancers in the United Kingdom (breast, lung, bowel, and prostate). CONCLUSIONS: The occurrence of cirrhosis increased more than that of the top four cancers during 1998 to 2009 in England. Strategies to monitor and reduce the incidence of this disease are urgently needed

Pleasure and meaningful discourse: an overview of research issues

The concept of pleasure has emerged as a multi-faceted social and cultural phenomenon in studies of media audiences since the 1980s. In these studies different forms of pleasure have been identified as explaining audience activity and commitment. In the diverse studies pleasure has emerged as a multi-faceted social and cultural concept that needs to be contextualized carefully. Genre and genre variations, class, gender, (sub-)cultural identity and generation all seem to be instrumental in determining the kind and variety of pleasures experienced in the act of viewing. This body of research has undoubtedly contributed to a better understanding of the complexity of audience activities, but it is exactly the diversity of the concept that is puzzling and poses a challenge to its further use. If pleasure is maintained as a key concept in audience analysis that holds much explanatory power, it needs a stronger theoretical foundation. The article maps the ways in which the concept of pleasure has been used by cultural theorists, who have paved the way for its application in reception analysis, and it goes on to explore the ways in which the concept has been used in empirical studies. Central to our discussion is the division between the ‘public knowledge’ and the ‘popular culture’ projects in reception analysis which, we argue, have major implications for the way in which pleasure has come to be understood as divorced from politics, power and ideology. Finally, we suggest ways of bridging the gap between these two projects in an effort to link pleasure to the concepts of hegemony and ideology

Phase II Study of Biweekly Plitidepsin as Second-Line Therapy for Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium

The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m2) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting ≥ 6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting

Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR

Metastasis is respoMetastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors