Final Year Induction - Re-engagement and Re-motivation

This paper considers design education in practice and reports on a new experience undertaken at ?? University (?U) with final year BA/BSc Product Design students. Increasingly, students returning to the final year of the programme have struggled in recent years to both develop credible final year project proposals and also re-engage with academic life and meet the expectations held of them at Honours level. Therefore, the final year project team took the decision to implement a new strategy for the start of the final year in September 2011. The students returned to University a week early and undertook an intensive, week long, programme that was specifically designed to: a) Engage them fully with a return to academic life and set expectations of final year b) Expose them to a wide range of opportunities to seek meaningful problems that would benefit from a product based solution. This paper expands upon the structure of the week and the activities that were undertaken by students and also provides feedback on the experience from the perspective of both academic staff and students. The paper concludes with a detailed evaluation of the experience and what has been learnt. However, the experience has been deemed to be a success by both staff and students and planning for a similar experience next year has already begun, along with a plan to roll out the principles to all design courses within the Framework

Microfluidic technologies for immunotherapy studies on solid tumours

Immunotherapy is a powerful and targeted cancer treatment that exploits the body's immune system to attack and eliminate cancerous cells. This form of therapy presents the possibility of long-term control and prevention of recurrence due to the memory capabilities of the immune system. Various immunotherapies are successful in treating haematological malignancies and have dramatically improved outcomes in melanoma. However, tackling other solid tumours is more challenging, mostly because of the immunosuppressive tumour microenvironment (TME). Current in vitro models based on traditional 2D cell monolayers and animal models, such as patient-derived xenografts, have limitations in their ability to mimic the complexity of the human TME. As a result, they have inadequate translational value and can be poorly predictive of clinical outcome. Thus, there is a need for robust in vitro preclinical tools that more faithfully recapitulate human solid tumours to test novel immunotherapies. Microfluidics and lab-on-a-chip technologies offer opportunities, especially when performing mechanistic studies, to understand the role of the TME in immunotherapy, and to expand the experimental throughput when using patient-derived tissue through its miniaturization capabilities. This review first introduces the basic concepts of immunotherapy, presents the current preclinical approaches used in immuno-oncology for solid tumours and then discusses the underlying challenges. We provide a rationale for using microfluidic-based approaches, highlighting the most recent microfluidic technologies and methodologies that have been used for studying cancer–immune cell interactions and testing the efficacy of immunotherapies in solid tumours. Ultimately, we discuss achievements and limitations of the technology, commenting on potential directions for incorporating microfluidic technologies in future immunotherapy studies

Molecular and clinical predictors of improvement in progression-free survival with maintenance PARP inhibitor therapy in women with platinum-sensitive, recurrent ovarian cancer: A meta-analysis

BACKGROUND: The authors performed a meta‐analysis to better quantify the benefit of maintenance poly(ADP‐ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum‐sensitive, recurrent, high‐grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild‐type BRCA but homologous recombinant‐deficient (HRD), homologous recombinant‐proficient (HRP), and baseline clinical prognostic characteristics. METHODS: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression‐free survival were pooled across trials using the inverse variance weighted method. RESULTS: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23‐0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17‐0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12‐0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild‐type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31‐0.56); and, in those who had wild‐type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49‐0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab. CONCLUSIONS: In platinum‐sensitive, recurrent, high‐grade ovarian cancer, maintenance PARPi improves progression‐free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy

Investigating the Impact of Ultra-Radical Surgery on Survival in Advanced Ovarian Cancer Using Population-Based Data in a Multicentre UK Study

We investigated URS and impact on survival in whole patient cohorts with AOC treated within gynaecological cancer centres that participated in the previously presented SOCQER 2 study. National cancer registry datasets were used to identify FIGO Stage 3,4 and unknown stage patients from 11 cancer centres that had previously participated in the SOCQER2 study. Patient outcomes’ association with surgical ethos were evaluated using logistic regression and Cox proportional hazards. Centres were classified into three groups based on their surgical complexity scores (SCS); those practicing mainly low complexity, (5/11 centres with >70% low SCS procedures, 759 patients), mainly intermediate (3/11, 35–50% low SCS, 356 patients), or mainly high complexity surgery (3/11, >35% high SCS, 356 patients). Surgery rates were 43.2% vs. 58.4% vs. 60.9%. across mainly low, intermediate and high SCS centres, respectively, p < 0.001. Combined surgery and chemotherapy rates were 39.2% vs. 51.8% vs. 38.3% p < 0.000 across mainly low, intermediate and high complexity groups, respectively. Median survival was 23.1 (95% CI 19.0 to 27.2) vs. 22.0 (95% CI 17.6 to 26.3) vs. 17.9 months (95% CI 15.7 to 20.1), p = 0.043 in mainly high SCS, intermediate, and low SCS centres, respectively. In an age and deprivation adjusted model, compared to patients in the high SCS centres, patients in the low SCS group had an HR of 1.21 (95% CI 1.03 to 1.40) for death. Mainly high/intermediate SCS centres have significantly higher surgery rates and better survival at a population level. Centres that practice mainly low complexity surgery should change practice. This study provides support for the utilization of URS for patients with advanced OC

Quality of life from cytoreductive surgery in advanced ovarian cancer: Investigating the association between disease burden and surgical complexity in the international, prospective, SOCQER-2 cohort study

Objective: To investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach. Design: Prospective multicentre observational study. Setting: Gynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia. Sample: Patients undergoing surgical resection (with low, intermediate or high surgical complexity score, SCS) for late-stage ovarian cancer. Main Outcome Measures: Primary: change in global score on the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30). Secondary: EORTC ovarian cancer module (OV28), progression-free survival. Results: Patients’ preoperative disease burden and SCS varied between centres, confirming differences in surgical ethos. QoL response rates were 90% up to 18 months. Mean change from the pre-surgical baseline in the EORTC QLQ-C30 was 3.4 (SD 1.8, n = 88) in the low, 4.0 (SD 2.1, n = 55) in the intermediate and 4.3 (SD 2.1, n = 52) in the high-SCS group after 6 weeks (p = 0.048), and 4.3 (SD 2.1, n = 51), 5.1 (SD 2.2, n = 41) and 5.1 (SD 2.2, n = 35), respectively, after 12 months (p = 0.133). In a repeated-measures model, there were no clinically or statistically meaningful differences in EORTC QLQ-C30 global scores between the three SCS groups (p = 0.840), but there was a small statistically significant improvement in all groups over time (p < 0.001). The high-SCS group experienced small to moderate decreases in physical (p = 0.004), role (p = 0.016) and emotional (p = 0.001) function at 6 weeks post-surgery, which resolved by 6–12 months. Conclusions: The global QoL of patients undergoing low-, intermediate- and high-SCS surgery improved at 12 months after surgery and was no worse in patients undergoing extensive surgery

Earliest land plants created modern levels of atmospheric oxygen

The progressive oxygenation of the Earth’s atmosphere was pivotal to the evolution of life, but the puzzle of when and how atmospheric oxygen (O2) first approached modern levels (~21%) remains unresolved. Redox proxy data indicate the deep oceans were oxygenated during 435-392 Ma, and the appearance of fossil charcoal indicates O2>15-17% by 420-400 Ma. However, existing models have failed to predict oxygenation at this time. Here we show that the earliest plants, which colonized the land surface from ~470 Ma onwards, were responsible for this mid- Paleozoic oxygenation event, through greatly increasing global organic carbon burial – the net long-term source of O2. We use a trait-based ecophysiological model to predict that cryptogamic vegetation cover could have achieved ~30% of today’s global terrestrial net primary productivity by~445 Ma. Data from modern bryophytes suggests this plentiful early plant material had a much higher molar C:P ratio (~2000) than marine biomass (~100), such that a given weathering flux of phosphorus could support more organic carbon burial. Furthermore, recent experiments suggest that early plants selectively increased the flux of phosphorus (relative to alkalinity) weathered from rocks. Combining these effects in a model of long-term biogeochemical cycling, we reproduce a sustained +2‰ increase in the carbonate carbon isotope (δ13C) record by ~445 Ma, and predict a corresponding rise in O2 to present levels by 420-400 Ma, consistent with geochemical data. This oxygen rise represents a permanent shift in regulatory regime to one where fire-mediated negative feedbacks on organic carbon burial stabilise high O2 levels

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo

Histone deacetylation and DNA methylation have a central role in the control of gene expression in tumours, including transcriptional repression of tumour suppressor genes and genes involved in sensitivity to chemotherapy. Treatment of cisplatin-resistant cell lines with an inhibitor of DNA methyltransferases, 2-deoxy-5′azacytidine (decitabine), results in partial reversal of DNA methylation, re-expression of epigenetically silenced genes including hMLH1 and sensitisation to cisplatin both in vitro and in vivo. We have investigated whether the combination of decitabine and a clinically relevant inhibitor of histone deacetylase activity (belinostat, PXD101) can further increase the re-expression of genes epigenetically silenced by DNA methylation and enhance chemo-sensitisation in vivo at well-tolerated doses. The cisplatin-resistant human ovarian cell line A2780/cp70 has the hMLH1 gene methylated and is resistant to cisplatin both in vitro and when grown as a xenograft in mice. Treatment of A2780/cp70 with decitabine and belinostat results in a marked increase in expression of epigenetically silenced MLH1 and MAGE-A1 both in vitro and in vivo when compared with decitabine alone. The combination greatly enhanced the effects of decitabine alone on the cisplatin sensitivity of xenografts. As the dose of decitabine that can be given to patients and hence the maximum pharmacodynamic effect as a demethylating agent is limited by toxicity and eventual re-methylation of genes, we suggest that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumours that have acquired drug resistance due to DNA methylation and gene silencing

Palynological constraints on the provenance and stratigraphic range of a Lopingian (Late Permian) inter-extinction floral lagerstätte from the Xuanwei Formation, Guizhou Province, China

Late Permian (Lopingian) volcanoclastic lithologies from the Huopu Mine near Fuyuan, Guzihou Province, SW China have yielded konservat lagerstatte-grade plant macrofossils. These fossils derive from a stratigraphic interval bounded by the mid-Capitanian extinction below and the end Permian extinction above and globally, few anatomically preserved floras are known from this age. Due to practical constraints of active mining at the site, to date this konservat lagerstatte is only known from ex situ mine spoil. However, through the use of combined petrographic and palynologic analyses it has been possible to constrain the stratigraphic position, provenance and taphonomic history of these fossils, such that they are now known to have been deposited in in a shallow marine setting as part of the lower member of the Xuanwei Formation during the Wuchiapingian. The palynological assemblage is of low abundance and diversity and is dominated by fern spores with less common lycopsid and sphenopsid spores and gymnosperm pollen, and rare marine acritarchs and is suggestive of an ecologically pioneering rather than established flora. Given the Wuchiapingian age of the lagerstatte this flora has broader potential significance in that affords insights into pre-adaption and resilience to the profound environmental perturbations associated with the mid-Capitanian and end-Permian extinctions, which were key to long term survival into the Triassic. (C) 2016 Elsevier B.V. All rights reserved