To determine the prevalence of nightmares, sleep terrors and vivid dreams in patients with advanced cancer (and the factors associated with them in this group of patients).
The study was a ...multicentre, prospective observational study. Participants were patients with locally advanced/metastatic cancer, who were under the care of a specialist palliative care team. Data were collected on demographics, cancer diagnosis, cancer treatment, current medication, performance status, sleep quality (Pittsburgh Sleep Quality Index), dreams and nightmares, and physical and psychological symptoms (Memorial Symptom Assessment Scale-Short Form).
174 patients completed the study. Sleep quality was poor in 70.5% participants and was worse in younger patients and in inpatients (hospital, hospice). 18% of patients reported nightmares, 8% sleep terrors and 34% vivid dreams. Nightmares were associated with poor sleep quality and greater sleep disturbance; nightmares were also associated with greater physical and psychological burden. Nightmares (and vivid dreams) were not associated with the use of opioid analgesics.
Nightmares do not seem to be especially common in patients with advanced cancer, and when they do occur, there is often an association with sleep disturbance, and/or physical and psychological burden.
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Site-selective protein modification strategies can be used to insert non-natural functional groups into protein structures. Herein, we report on the use of the bis-electrophile ...3-bromo-2-bromomethyl-1-propene as a reagent to introduce an electrophilic handle at cysteine residues under mild conditions. This method is demonstrated on a variety of proteins containing a solvent-exposed cysteine residue, including an anti-HER2 nanobody. Chemically distinct protein conjugates are then efficiently formed through further reaction of the electrophilic site with various nucleophiles, including thiols and amines. The resulting chemically-defined conjugates are highly stable in the presence of glutathione or human plasma and retain both the structure and function of the native protein.
The prevalence of deep venous thrombosis in patients with advanced cancer is unconfirmed and it is unknown whether current international thromboprophylaxis guidance is applicable to this population. ...We aimed to determine prevalence and predictors of femoral deep vein thrombosis in patients admitted to specialist palliative care units (SPCUs).
We did this prospective longitudinal observational study in five SPCUs in England, Wales, and Northern Ireland (four hospices and one palliative care unit). Consecutive adults with cancer underwent bilateral femoral vein ultrasonography on admission and weekly until death or discharge for a maximum of 3 weeks. Data were collected on performance status, attributable symptoms, and variables known to be associated with venous thromboembolism. Patients with a short estimated prognosis (<5 days) were ineligible. The primary endpoint of the study was the prevalence of femoral deep vein thrombosis within 48 h of SPCU admission, analysed by intention to treat. This study is registered with the ISRCTN registry, number ISRCTN97567719.
Between June 20, 2016, and Oct 16, 2017, 343 participants were enrolled (mean age 68·2 years SD 12·8; range 25–102; 179 52% male; mean Australian-modified Karnofsky performance status 49 SD 16·6; range 20–90). Of 273 patients with evaluable scans, 92 (34%, 95% CI 28–40) had femoral deep vein thrombosis. Four participants with a scan showing no deep vein thrombosis on admission developed a deep vein thrombosis on repeat scanning over 21 days. Previous venous thromboembolism (p=0·014), being bedbound in the past 12 weeks for any reason (p=0·003), and lower limb oedema (p=0·009) independently predicted deep vein thrombosis. Serum albumin concentration (p=0·43), thromboprophylaxis (p=0·17), and survival (p=0·45) were unrelated to deep vein thrombosis.
About a third of patients with advanced cancer admitted to SPCUs had a femoral deep vein thrombosis. Deep vein thrombosis was not associated with thromboprophylaxis, survival, or symptoms other than leg oedema. These findings are consistent with venous thromboembolism being a manifestation of advanced disease rather than a cause of premature death. Thromboprophylaxis for SPCU inpatients with poor performance status seems to be of little benefit.
National Institute for Health Research (Research for Patient Benefit programme).
Target validation remains a challenge in drug discovery, which leads to a high attrition rate in the drug discovery process, particularly in Phase II clinical trials. Consequently, new approaches to ...enhance target validation are valuable tools to improve the drug discovery process. Here, we report the combination of site-directed mutagenesis and electrophilic fragments to enable the rapid identification of small molecules that selectively inhibit the mutant protein. Using the bromodomain-containing protein BRD4 as an example, we employed a structure-based approach to identify the L94C mutation in the first bromodomain of BRD4 BRD4(1) as having a minimal effect on BRD4(1) function. We then screened a focused, KAc mimic-containing fragment set and a diverse fragment library against the mutant and wild-type proteins and identified a series of fragments that showed high selectivity for the mutant protein. These compounds were elaborated to include an alkyne click tag to enable the attachment of a fluorescent dye. These clickable compounds were then assessed in HEK293T cells, transiently expressing BRD4(1)WT or BRD4(1)L94C, to determine their selectivity for BRD4(1)L94C over other possible cellular targets. One compound was identified that shows very high selectivity for BRD4(1)L94C over all other proteins. This work provides a proof-of-concept that the combination of site-directed mutagenesis and electrophilic fragments, in a mutate and conjugate approach, can enable rapid identification of small molecule inhibitors for an appropriately mutated protein of interest. This technology can be used to assess the cellular phenotype of inhibiting the protein of interest, and the electrophilic ligand provides a starting point for noncovalent ligand development.
TRIM33 is a member of the tripartite motif (TRIM) family of proteins, some of which possess E3 ligase activity and are involved in the ubiquitin-dependent degradation of proteins. Four of the TRIM ...family proteins, TRIM24 (TIF1α), TRIM28 (TIF1β), TRIM33 (TIF1γ) and TRIM66, contain C-terminal plant homeodomain (PHD) and bromodomain (BRD) modules, which bind to methylated lysine (KMe n ) and acetylated lysine (KAc), respectively. Here we investigate the differences between the two isoforms of TRIM33, TRIM33α and TRIM33β, using structural and biophysical approaches. We show that the N1039 residue, which is equivalent to N140 in BRD4(1) and which is conserved in most BRDs, has a different orientation in each isoform. In TRIM33β, this residue coordinates KAc, but this is not the case in TRIM33α. Despite these differences, both isoforms show similar affinities for H31–27K18Ac, and bind preferentially to H31–27K9Me3K18Ac. We used this information to develop an AlphaScreen assay, with which we have identified four new ligands for the TRIM33 PHD-BRD cassette. These findings provide fundamental new information regarding which histone marks are recognized by both isoforms of TRIM33 and suggest starting points for the development of chemical probes to investigate the cellular function of TRIM33.
This study approached the problem of obscurity in the Sonnets using historical analysis considering the sonnets' placement within the religious persecution, torture, and martyrdom of significant ...persons known to Shakespeare. The plausibility of Shakespeare's recusancy as a Catholic or Catholic sympathizer is examined with historical as well as current and ongoing scholarship including that of Peter Milward, Joseph Pearce and Claire Asquith who are writing from a studied assumption of Shakespeare as a Catholic. These scholars have filtered Shakespeare's dramatic works for associations with Elizabethan politics and my work extends their moderate inquiry into the Sonnets with further analysis. From an historical look at familial relationships and associations, my study considers Shakespeare's proximity to the Spiritual Exercises of St. Ignatius. The Spiritual Exercises were promulgated by Jesuit missionaries who confessed under torture to being houseguests of Shakespeare's relatives only ten miles north of Stratford in 1580 when Shakespeare was sixteen years old, and could easily have traveled with his father, John Shakespeare to meet the distinguished priests. For in the Sonnets, my study reveals some evidence of poems written to the specific meditations called for in the Spiritual Exercises. My study also considers Ovidian influences in Shakespeare's Sonnets taken from Book X of Ovid's Metamorphosis. This historical study sustains the possibility of a secondary spiritual cast to the Sonnets that can unwind problem obscurities in some of the poems with a latent spirituality which responds to specific moments in Elizabethan society, such as the destruction of sacred objects and defacing of medieval church art, sacraments and symbols, even artifacts made criminal by law.
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