DNA damage is frequently utilized as the basis for cancer therapies; however, resistance to DNA damage remains one of the biggest challenges for successful treatment outcomes. Critically, the ...molecular drivers behind resistance are poorly understood. To address this question, we created an isogenic model of prostate cancer exhibiting more aggressive characteristics to better understand the molecular signatures associated with resistance and metastasis. 22Rv1 cells were repeatedly exposed to DNA damage daily for 6 weeks, similar to patient treatment regimes. Using Illumina Methylation EPIC arrays and RNA-seq, we compared DNA methylation and transcriptional profiles between the parental 22Rv1 cell line and the lineage exposed to prolonged DNA damage. Here we show that repeated DNA damage drives the molecular evolution of cancer cells to a more aggressive phenotype and identify molecular candidates behind this process. Total DNA methylation was increased while RNA-seq demonstrated these cells had dysregulated expression of genes involved in metabolism and the unfolded protein response (UPR) with Asparagine synthetase (ASNS) identified as central to this process. Despite the limited overlap between RNA-seq and DNA methylation, oxoglutarate dehydrogenase-like (OGDHL) was identified as altered in both data sets. Utilising a second approach we profiled the proteome in 22Rv1 cells following a single dose of radiotherapy. This analysis also highlighted the UPR in response to DNA damage. Together, these analyses identified dysregulation of metabolism and the UPR and identified ASNS and OGDHL as candidates for resistance to DNA damage. This work provides critical insight into molecular changes which underpin treatment resistance and metastasis.
Background
The Griffiths Mental Development Scales (GMDS) are used in many countries to assess the development of children from birth to 8 years. There is a need for accurate and culturally ...appropriate developmental assessment tools for Chinese children. Here, we adapted the GMDS for use in Chinese children and compare the developmental trajectories between Chinese and British children.
Methods
Children with typical development were recruited from 7 urban cities in China between 2009 and 2013. The Griffiths Mental Development Scales‐Chinese (GDS‐C) were adapted and used to assess the development of urban Chinese children. Developmental curves were computed for 6 subscales using learning management system methods and compare against the British curves from the Griffiths Mental Development Scales‐Extended Revised (GMDS‐ER).
Results
The GDS‐C were used to assess the developmental status of 815 Chinese children. Plots of the 1st, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 99th percentiles, and full percentile tables were obtained, which showed similar trends to data from the British GMDS‐ER.
Conclusions
The Chinese developmental curves obtained from the GDS‐C showed similarities and differences to the developmental curves from the British GMDS‐ER. The development of urban Chinese children should be assessed with the culturally appropriate GDS‐C.
This paper reports on the relationships between facets of integrated manufacturing - consisting of total quality management, just in time and advanced manufacturing technology - various ...organizational improvement initiatives (such as in leadership, teams, human resource management and benchmarking), and employee and manufacturing performance. Results from a survey of 1024 Australian and New Zealand manufacturing sites indicate that the integrated manufacturing facets of total quality management and just in time are significantly associated with organizational and human resource practices, while advanced manufacturing technology is weakly associated with a narrower range of practices. Organizational and human resource practices also explain significant additional variance in both employee and manufacturing performance, above that explained by integrated manufacturing facets. Further, by partitioning the large data set into three sections using manufacturing performance as a cutting variable, it was found that high-performing firms place considerably more emphasis on 'soft' human resource management practices and relied on total quality management principles half as much as low-performing firms. The implications of these findings for managers are then discussed.
Abstract Background Laser therapy is now a well recognised treatment for twin-to-twin transfusion syndrome (TTTS). We investigated the early childhood neurodevelopmental outcome of children post ...laser treatment for TTTS in our centre. Methods Children of women who had laser therapy for TTTS between March 2006 and June 2008 were assessed at 30–69 months of age with WPPSI-III and a general health questionnaire. Major neurodevelopmental impairment (NDI) was reported as IQ < 70 or cerebral palsy (CP). Borderline cognitive impairment was defined by IQ 70–79. Results Amongst the 37 pregnancies treated, 62 infants were discharged home and the overall foetal survival rate was 84%. A total of 50 children (84%) from 31 pregnancies were assessed. Average age at assessment was 47 months. Two children with late treatment of congenital hypothyroidism were excluded. The majority of pregnancies were Quintero Stage III (74%). There was a significant trend for worse outcome with higher Quintero stage. The average gestational age at birth was 32 weeks. The majority (39, 78%) of children were found to be neurodevelopmentally normal; 9 (18%) had borderline cognitive development; and 2 (4%) had a major NDI, including one with cerebral palsy (2%). Conclusions There was a modest level of neurocognitive impairment post laser therapy for TTTS, mainly borderline cognitive development, lesser so major NDI. There was a low incidence of cerebral palsy. Routine developmental and neurological follow-up of these children is recommended.
Objectives: To examine whether the mix of community and institutional long-term care (ILTC) for people with dementia (PwD) in Europe could be improved; assess the economic consequences of providing ...alternative services for particular groups of ILTC entrants and explore the transnational application of the 'Balance of Care' (BoC) approach.
Method: A BoC study was undertaken in Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden, and the UK as part of the RightTimePlaceCare project. Drawing on information about 2014 PwD on the margins of ILTC admission, this strategic planning framework identified people whose needs could be met in more than one setting, and compared the relative costs of the possible alternatives.
Results: The findings suggest a noteworthy minority of ILTC entrants could be more appropriately supported in the community if enhanced services were available. This would not necessarily require innovative services, but more standard care (including personal and day care), assuming quality was ensured. Potential cost savings were identified in all countries, but community care was not always cheaper than ILTC and the ability to release resources varied between nations.
Conclusions: This is believed to be the first transnational application of the BoC approach, and demonstrates its potential to provide a consistent approach to planning across different health and social care systems. Better comparative information is needed on the number of ILTC entrants with dementia, unit costs and outcomes. Nevertheless, the findings offer important evidence on the appropriateness of current provision, and the opportunity to learn from different countries' experience.
Abstract This work studies the influence of radio frequency (RF) waves in the ion cyclotron resonance heating (ICRH) range of frequencies on fusion alphas during the recent JET D-T campaign. Fusion ...alphas from D-T reactions are created with energies of about 3.5 MeV and therefore have significant Doppler shifts enabling synergistic interactions between them and RF waves at a broad range of frequencies, including the ones foreseen for future fusion machines in ITER (Schneider et al 2021 Nucl. Fusion 61 126058) and SPARC (Creely et al 2020 J. Plasma Phys. 86 865860502). Resonant interactions between RF waves and alphas, also called synergistic effects, will modify the alpha distribution and ultimately will have an impact on alpha orbit losses and heating. Data from JET 3.43 T/2.3 MA pulses based on the hybrid scenario (Hobirk et al 2023 Nucl. Fusion ; Hobirk et al 29th IAEA FEC23 Conf. ( 16–21 October 2023 ); Challis et al 48th EPS Conf. on Plasma Physics ( 27 June–1 July 2022 ) during the DTE2 campaign (Maggi et al 2023 Nucl. Fusion )) were used for the analysis in this study. The impact of synergistic effects on alpha orbit losses and alpha heating are assessed. The conclusions are based on the analysis of experimental data for fast alpha losses, i.e. measurements from neutral particle analyser (NPA), fast ion losses scintillator detector, Faraday cups (FCs), and TRANSP (Hawryluk et al 1980 Physics of Plasmas Close to Thermonuclear Conditions vol 1 (CEC) pp 19–46) simulations. Experimental data and TRANSP analysis indicates that there are indeed changes in the alpha distribution function (DF) due to interaction with RF waves. Data from the NPA show increased 4 He flux in the range from a few hundred keV up to 800 keV for pulses with RF power, while TRANSP clearly shows modifications in the fast alpha DF for these energies. Data from the scintillator detector and the FCs were compared for pulses with and without ICRH power and versus cases with enhanced alpha losses due to MHD activity. The trends from these diagnostics consistently show no additional alpha losses due to interaction with RF waves. TRANSP predictions for the impact of ynergistic effects on alpha heating show up to a 42% increase in alpha electron heating and up to a 25% increase in alpha ion heating. These effects, however, become negligibly small, less than 1%, when alpha heating is compared to the total auxiliary heating power in the investigated JET pulses.
Objective: To audit the outcome for laser photocoagulation for twin–twin transfusion syndrome (TTTS) as managed by the New South Wales Fetal Therapy Centre (NSW FTC).
Methods: A retrospective ...cohort study. Outcome data were reviewed for referrals between June 2003 and June 2008.The outcome measures included the severity of TTTS at presentation, delivery details (gestational age at delivery, birth weight and Apgar score at 5 min) and perinatal outcome (spontaneous miscarriage, premature rupture of membranes, intrauterine death, placental abruption and neonatal death).
Results: Seventy‐nine patients were treated with laser therapy for stage I–IV TTTS (median stage III). Median gestational age at treatment was 20 weeks (range 16–25). Median gestational age at delivery was 32 weeks (range 24–40). Survival of at least one baby in this study was 90.7% (88.9% for anterior and 92.1% for posterior placenta), and of both babies was 60.0%. Median birth weight was 1788 g (range 490–3695). Median Apgar score was nine at 5 min. Three women required repeat laser treatment for persistent TTTS.
Conclusions: Selective laser photocoagulation of communicating vessels remains the treatment of choice for TTTS. Referrals to the NSW FTC have increased from five cases in the last half of 2003, to 18 cases in the first half of 2008. Local outcome figures at least equal any in the published international literature and support a continued policy of centralised care in Australia. A two‐year follow‐up study on neonatal outcome for survivors is underway.
The belief that most older people, including those with complex needs, can, and would prefer to be, cared for in their own homes underpins community care policy in many developed nations. There is ...thus a common desire to avoid the unnecessary or inappropriate placement of older people in care homes or in hospital by shifting the balance of provision. This paper demonstrates the utility of a 'balance of care' approach to address these issues in the context of commissioners' intention to reconfigure services for older people with mental health problems in a defined geographical area of the North West of England. The findings suggest that, if enhanced community services were available, a number of people currently admitted to residential or hospital beds could be more appropriately supported in their own homes at a cost that is no greater than local agencies currently incur.
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