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Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. ClinicalTrials.gov NCT01310855.

Ira Levin’s works Rosemary’s Baby and The Stepford Wives have been cultural touchstones since their releases in 1967 and 1972, respectively, with their legacy as iconic American horror stories cemented by successful film adaptations. At the surface level, these stories can be read as tales about unfortunate housewives that face unusual horrors. Rosemary Woodhouse finds herself trapped in a gothic New York City apartment building, the Bramford, where her husband and neighbors collude to force her to carry and birth Satan’s son, like a perverse Virgin Mary. Joanna Ebert is similarly stuck in suburban Stepford, Connecticut where she discovers the town’s men conspire to turn their wives from thinking, feeling human women into robotic “hausfraus” (Levin TSW 22). Though these works function as gothic and gothic-futuristic narratives, truly understanding these novels requires thorough analysis of how Levin strategically employs these literary aesthetics for the purpose of satire. In both Rosemary’s Baby and The Stepford Wives, he uses conventions of horror to craft allegories which astutely critique the social and political landscape of the United States in the late 1960s and early 1970s. Because these novels primarily focus on women’s experiences and feminist issues, reading them together illuminates the transformative influence of the second wave feminist movement that erupted in the five years between their publishing. While both texts offer commentary on marriage, gender roles, and domesticity, The Stepford Wives’ more direct engagement with feminist ideas reflects the raised consciousness of both Levin and his audience.

BackgroundNeurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype–phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown.MethodsWe evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan–Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2.ResultsThe study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6–15 had lower mortality than patients with splice-site mutations in exons 1–5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier.ConclusionsContinuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.

Sets out a range of complementary and alternative medicines (CAM) whose efficacy the authors assert is either not biologically plausible and/or not supported by research evidence : colloidal silver, deer velvet, rescue remedy, arnica, megadoses of vitamin C, propolis, magnets, shark cartilage, and lemon detox diet. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.

I'm now playing a waiting game to see if my exam results will be regraded.

Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved in thermo- and osmosensation, has a large N-terminal IDR of approximately 150 amino acids. With an integrated structural biology approach, we analyze the structural ensemble of the TRPV4 IDR and the network of antagonistic regulatory elements it encodes. These modulate channel activity in a hierarchical lipid-dependent manner through transient long-range interactions. A highly conserved autoinhibitory patch acts as a master regulator by competing with PIP 2 binding to attenuate channel activity. Molecular dynamics simulations show that loss of the interaction between the PIP 2 -binding site and the membrane reduces the force exerted by the IDR on the structured core of TRPV4. This work demonstrates that IDR structural dynamics are coupled to TRPV4 activity and highlights the importance of IDRs for TRP channel function and regulation. An integrated structural biology approach uncovers the structural complexity of the intrinsically disordered region (IDR) within the TRPV4 ion channel. Multiple stimulatory and inhibitory elements were identified within the IDR that modulate channel activity in a lipid-dependent manner.