Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

The Holocene humid period in the Nefud Desert: Hunters and herders in the Jebel Oraf palaeolake basin, Saudi Arabia

Archaeological surveys and excavations in the Jebel Oraf palaeolake basin, north-western Saudi Arabia, have identified a well-preserved early- to mid-Holocene landscape. Two types of occupation site can be distinguished: nine small and ephemeral scatters from single occupation phases on the slopes of sand dunes and three hearth sites indicative of repeated occupation on palaeolake shorelines. In addition, 245 rock art panels, 81 cairns, and 15 stone structures were recorded. This diverse dataset provides an opportunity to reconstruct occupation patterns and changes in landscape use. A particularly important site, Jebel Oraf 2, documents two episodes of lake high stands at ca. 6500 BC and 5300 BC, flooding parts of the locality. Neolithic pastoralists likely occupied the site after the end of the wet season, when the terrain was dry. Earlier sites are located in dune embayments some 7–14 m above the shore of the palaeolake. These locations are consistent with hunting strategies identifiable in the rock art that suggest wildlife was ambushed at watering places. Later rock art at Jebel Oraf also documents the hunting of wild camel in the Iron Age. The lithic industries documented in the Jebel Oraf basin support arguments of repeated contact with Levantine populations

Exploring the psychological health of emergency dispatch centre operatives: a systematic review and narrative synthesis

Background. The study objective was to investigate and synthesize available evidence relating to the psychological health of Emergency Dispatch Centre (EDC) operatives, and to identify key stressors experienced by EDC operatives. Methods. Eight electronic databases (Embase, PubMed, Medline, CINAHL, PsycInfo, PsycArticles, The Psychology and Behavioural Sciences Collection, and Google Scholar) were searched. All study designs were included, and no date limits were set. Studies were included if they were published in English, and explored the psychological health of any EDC operatives, across fire, police, and emergency medical services. Studies were excluded if they related solely to other emergency workers, such as police officers or paramedics. Methodological quality of included studies was assessed using checklists adapted from the Critical Appraisal Skills Programme. A narrative synthesis was conducted, using thematic analysis. Results. A total of 16 articles were included in the review. Two overarching themes were identified during the narrative synthesis: `Organisational and Operational Factors' and `Interactions with Others'. Stressors identified included being exposed to traumatic calls, lacking control over high workload, and working in under-resourced and pres- sured environments. Lack of support from management and providing an emotionally demanding service were additional sources of stress. Peer support and social support from friends and family were helpful in managing work-related stress. Discussion. EDC operatives experience stress as a result of their work, which appears to be related to negative psychological health outcomes. Future research should explore the long-term effects of this stress, and the potential for workplace interventions to alleviate the negative impacts on psychological health.</p

Randomized evaluation of cognitive-behavioral therapy and graded exercise therapy for post-cancer fatigue

Context Cancer-related fatigue is prevalent and disabling. When persistent and unexplained, it is termed post-cancer fatigue (PCF). Cognitive behavioral therapy (CBT) and graded exercise therapy (GET) may improve symptoms and functional outcomes. Objectives To evaluate the outcomes of a randomized controlled trial, which assigned patients with post-cancer fatigue to education, or 12 weeks of integrated cognitive-behavioral therapy (CBT) and graded exercise therapy (GET). Methods Three months after treatment for breast or colon cancer, eligible patients had clinically significant fatigue, no comorbid medical or psychiatric conditions that explained the fatigue, and no evidence of recurrence. The CBT/GET arm included individually tailored consultations at approximately two weekly intervals. The education arm included a single visit with clinicians describing the principles of CBT/GET and a booklet. The primary outcome was clinically significant improvement in self-reported fatigue (Somatic and Psychological HEalth REport 0–12), designated a priori as greater than one SD of improvement in fatigue score. The secondary outcome was associated improvement in function (role limitation due to physical health problems—36-Item Short Form Health Survey 0–100) comparing baseline, end treatment (12 weeks), and follow-up (24 weeks). Results There were 46 patients enrolled, including 43 women (94%), with a mean age of 51 years. Fatigue severity improved in all subjects from a mean of 5.2 (±3.1) at baseline to 3.9 (±2.8) at 12 weeks, suggesting a natural history of improvement. Clinically significant improvement was observed in 7 of 22 subjects in the intervention group compared with 2 of 24 in the education group (P < 0.05, χ). These subjects also had improvement in functional status compared with nonresponders (P < 0.01, t-test). Conclusion Combined CBT/GET improves fatigue and functional outcomes for a subset of patients with post-cancer fatigue. Further studies to improve the response rate and the magnitude of the benefit are warranted