Biodegradative mechanism of the brown rot basidiomycete Gloeophyllum trabeum: evidence for an extracellular hydroquinone-driven fenton reaction

AbstractWe have identified key components of the extracellular oxidative system that the brown rot fungus Gloeophyllum trabeum uses to degrade a recalcitrant polymer, polyethylene glycol, via hydrogen abstraction reactions. G. trabeum produced an extracellular metabolite, 2,5-dimethoxy-1,4-benzoquinone, and reduced it to 2,5-dimethoxyhydroquinone. In the presence of 2,5-dimethoxy-1,4-benzoquinone, the fungus also reduced extracellular Fe3+ to Fe2+ and produced extracellular H2O2. Fe3+ reduction and H2O2 formation both resulted from a direct, non-enzymatic reaction between 2,5-dimethoxyhydroquinone and Fe3+. polyethylene glycol depolymerization by G. trabeum required both 2,5-dimethoxy-1,4-benzoquinone and Fe3+ and was completely inhibited by catalase. These results provide evidence that G. trabeum uses a hydroquinone-driven Fenton reaction to cleave polyethylene glycol. We propose that similar reactions account for the ability of G. trabeum to attack lignocellulose

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

Background: Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. Methods: A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. Results: Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. Conclusions: Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here

ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer.

Background Docetaxel and prednisolone chemotherapy (DP) extends survival in metastatic castration resistant prostate cancer (mCRPC). However, emergent clinical resistance is almost inevitable. AKT pathway activation is highly prevalent in mCRPC contributing to disease progression and DP resistance. AZD5363 is a potent oral pan-AKT inhibitor with pre-clinical data indicating activity in mCRPC and synergy with docetaxel. Methods This phase I trial was to determine an AZD5363 recommended phase II dose (RP2D) for combination with DP. Eligibility criteria included chemotherapy naive mCRPC, PSA or radiographic disease progression and ECOG performance status 0 or 1. Treatment comprised DP (75 mg/m2, IV, day 1 and 5 mg BID, PO, day 1-21 respectively for ten cycles) and AZD5363 to disease progression for all patients. We utilised a 3 + 3 dose escalation design to determine a maximum tolerated dose according to defined dose limiting toxicity criteria assessed using CTCAE version 4.03. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from day 2 of each cycle. Results 10 patients were treated. Dose limiting toxicities affected 2 patients (grade 3 rash ≥5 days; grade 3 diarrhoea) in DL2. The commonest grade 3 or 4, AZD5363 related, symptomatic adverse events were rash and diarrhoea. Hyperglycaemia affected all patients but was self-limiting. PSA reduction to <50% at 12 weeks occurred in 7 patients. Conclusions The RP2D for AZD5363 is 320 mg BID, 4 days on/3 days off, in combination with full dose DP for mCRPC

Migraine and psychiatric comorbidity: a review of clinical findings

Migraine is an extremely common disorder. The underlying mechanisms of this chronic illness interspersed with acute symptoms appear to be increasingly complex. An important aspect of migraine heterogeneity is comorbidity with other neurological diseases, cardiovascular disorders, and psychiatric illnesses. Depressive disorders are among the leading causes of disability worldwide according to WHO estimation. In this review, we have mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988). Though not easily comparable due to differences in methodology to reach diagnosis, general population studies generally indicate an increased risk of affective and anxiety disorders in patients with migraine, compared to non-migrainous subjects. There would also be a trend towards an association of migraine with bipolar disorder, but not with substance abuse/dependence. With respect to migraine subtypes, comorbidity mainly involves migraine with aura. Patients suffering from migraine, however, show a decreased risk of developing affective and anxiety disorders compared to patients with daily chronic headache. It would also appear that psychiatric disorders prevail in patients with chronic headache and substance use than in patients with simple migraine. The mechanisms underlying migraine psychiatric comorbidity are presently poorly understood, but this topic remains a priority for future research. Psychiatric comorbidity indeed affects migraine evolution, may lead to chronic substance use, and may change treatment strategies, eventually modifying the outcome of this important disorder

The Spin Structure of the Nucleon

We present an overview of recent experimental and theoretical advances in our understanding of the spin structure of protons and neutrons.Comment: 84 pages, 29 figure

Transportations of space, time and self: the role of reading groups in managing mental distress in the community

Background: The practice of reading and discussing literature in groups is long established, stretching back into classical antiquity. Although benefits of therapeutic reading groups have been highlighted, research into participants’ perceptions of these groups has been limited. Aims: To explore the experiences of those attending therapeutic reading groups, considering the role of both the group, and the literature itself, in participants’ ongoing experiences of distress. Method: Eleven participants were recruited from two reading groups in the South-East of England. One focus group was run, and eight individuals self-selected for individual interviews. The data were analysed together using a thematic analysis drawing on dialogical theories. Results: Participants described the group as an anchor, which enabled them to use fiction to facilitate the discussion of difficult emotional topics, without referring directly to personal experience. Two aspects of this process are explored in detail: the use of narratives as transportation, helping to mitigate the intensity of distress; and using fiction to explore possibilities, alternative selves and lives. Conclusions: For those who are interested and able, reading groups offer a relatively de-stigmatised route to exploring and mediating experiences of distress. Implications in the present UK funding environment are discussed