160 research outputs found
Impact of mitochondrial alterations on prostate cancer progression
No full textPh. D. Thesis.Cancer metabolism is characterised by a ‘Warburg shift’ to aerobic glycolysis with decreased
mitochondrial oxidative phosphorylation (OXPHOS), feasibly mediated by alterations in
mitochondrial DNA (mtDNA). However, despite recent advances in our understanding of
nuclear genomic alterations in prostate cancer, there remains a paucity of data evaluating the
impact of mitochondrial alterations in prostate cancer progression.
Therefore, using publicly available genomic datasets, the mitochondrial molecular landscape
of aggressive prostate cancer was characterized. This revealed a spectrum of mtDNA
mutations under clonal selection pressures, reduced mtDNA copy number, and a
transcriptomic profile composed of reduced mitochondrial and increased nuclear OXPHOS
gene expression.
In order to assess the downstream impact of these alterations and aid clinical translation, I
developed an automated assay to evaluate proteomic OXPHOS defects in archived prostate
cancer tissue microarrays at the single cell level. Upon unpicking widespread multi-faceted
heterogeneity in OXPHOS protein expression, patients with low complex I abundance and
increased mitochondrial mass appeared to be at increased risk of all-cause mortality at 20-
year follow-up.
The prognostic value of both mitochondrial molecular alterations and proteomic OXPHOS
defects was enriched in patients with PTEN-loss and TMPRSS2:ERG fusion. Given that
mitochondrial alterations and prostate cancer risk features are also associated with advancing
age, transgenic models were generated to elucidate the impact of age-related systemic
mitochondrial dysfunction on PTEN-deficient prostate cancer progression. Despite early
mortality due to accelerated age-related phenotypes, attenuated tumour progression was
observed, suggesting a tumour suppressive effect of systemic mitochondrial dysfunction.
In conclusion, mitochondrial alterations exert diverse systemic and local effects on prostate
cancer progression. Leveraging mitochondrial tissue biomarkers and mitochondrial-targeted
systemic therapies may provide a novel approach for identifying aggressive prostate cancer
and suppressing progression to lethal disease
Impact of mitochondrial alterations on prostrate cancer progression
No full textPhD ThesisCancer metabolism is characterised by a ‘Warburg shift’ to aerobic glycolysis with decreased
mitochondrial oxidative phosphorylation (OXPHOS), feasibly mediated by alterations in
mitochondrial DNA (mtDNA). However, despite recent advances in our understanding of
nuclear genomic alterations in prostate cancer, there remains a paucity of data evaluating the
impact of mitochondrial alterations in prostate cancer progression.
Therefore, using publicly available genomic datasets, the mitochondrial molecular landscape
of aggressive prostate cancer was characterized. This revealed a spectrum of mtDNA
mutations under clonal selection pressures, reduced mtDNA copy number, and a
transcriptomic profile composed of reduced mitochondrial and increased nuclear OXPHOS
gene expression.
In order to assess the downstream impact of these alterations and aid clinical translation, I
developed an automated assay to evaluate proteomic OXPHOS defects in archived prostate
cancer tissue microarrays at the single cell level. Upon unpicking widespread multi-faceted
heterogeneity in OXPHOS protein expression, patients with low complex I abundance and
increased mitochondrial mass appeared to be at increased risk of all-cause mortality at 20-
year follow-up.
The prognostic value of both mitochondrial molecular alterations and proteomic OXPHOS
defects was enriched in patients with PTEN-loss and TMPRSS2:ERG fusion. Given that
mitochondrial alterations and prostate cancer risk features are also associated with advancing
age, transgenic models were generated to elucidate the impact of age-related systemic
mitochondrial dysfunction on PTEN-deficient prostate cancer progression. Despite early
mortality due to accelerated age-related phenotypes, attenuated tumour progression was
observed, suggesting a tumour suppressive effect of systemic mitochondrial dysfunction.
In conclusion, mitochondrial alterations exert diverse systemic and local effects on prostate
cancer progression. Leveraging mitochondrial tissue biomarkers and mitochondrial-targeted
systemic therapies may provide a novel approach for identifying aggressive prostate cancer
and suppressing progression to lethal disease
SDH-deficient renal cell carcinoma: a clinicopathological analysis highlighting the role of genetic counselling.
No full textSuccinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) accounts for 0.05-2% of all RCCs. The majority of patients have germline mutations, most frequently in the SDHB gene. People with these mutations are predisposed to developing paragangliomas, phaeochromocytomas and gastrointestinal stromal tumours. Patients should be referred to genetic services for further workup and close surveillance imaging due to the risk of development of further tumours. We present a woman with SDH-deficient RCC and review the literature associated with this uncommon entity
Metal Organic Frameworks for Gas-phase Capacitive Sensing
No full textOLD ChemE/Organic Materials and Interface
Non-steroidal anti-inflammatory drugs for treating symptomatic uncomplicated urinary tract infections in non-pregnant adult women
No full textBACKGROUND: Almost half of all women will have at least one symptomatic urinary tract infection (UTI) in their lifetime. Although usually self-remitting, 74% of women contacting a health professional are prescribed an antibiotic, and in rare instances, they may progress to more severe infections. Therefore, the standard of care for the treatment of symptomatic uncomplicated UTIs is oral antibiotic therapy, which aims to achieve symptom resolution and prevent the development of complications such as pyelonephritis. Given that a number of UTIs are self-remitting, non-antibiotic treatments that may help reduce the severity or duration of symptoms or reduce the need for antibiotics may be of benefit.OBJECTIVES: This review aims to investigate the benefits and risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of symptomatic uncomplicated UTIs in non-pregnant adult women.SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 18 November 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs looking at the effectiveness of NSAIDs in the treatment of symptomatic uncomplicated UTIs in non-pregnant adult women. The outcomes of interest were: 1) short-term resolution of symptoms (days 1 to 4); 2) medium-term resolution of symptoms (days 5 to 10); and 3) incidence of adverse events (including progression to sepsis or complicated UTI, hospitalisation or need for intravenous antibiotics, gastrointestinal complications, or death) up to 30 days from randomisation.DATA COLLECTION AND ANALYSIS: Screening, abstract selection, and data extraction were carried out independently by two authors, and any disagreements were resolved by discussion with a third author. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.MAIN RESULTS: Six studies (1646 randomised women) published between 2010 and 2019 met our inclusion criteria. The mean age ranged from 28 to 50 years; previous UTIs were reported in 7.2% to 77% of participants. There were five multicentre studies, and studies were carried out in Denmark, Germany, Korea, Norway, Sweden, Switzerland, and the UK. Overall, the risk of bias was low or unclear. Compared to antibiotics, NSAIDs probably result in less short-term resolution of symptoms (4 studies, 1144 participants: RR 0.67, 95% CI 0.49 to 0.91; I 2 = 75%; moderate certainty) and may also result in less medium-term resolution of symptoms (4 studies, 1140 participants: RR 0.84, 95% CI 0.71 to 1.01; I 2 = 78%; low certainty). NSAIDs probably make little or no difference to the number of adverse events by day 30 (4 studies, 1165 participants: RR 1.08, 95% CI 0.88 to 1.33; I 2 = 64%; moderate certainty). NSAIDs may result in longer duration of symptoms (2 studies, 553 participants: MD 1.00 day, 95% CI 0.61 to 1.39; I 2 = 0%; low certainty). NSAIDs may result in a lower proportion of women experiencing microbiological resolution by day 10 compared to antibiotics (2 studies, 322 participants: RR 0.76, 95% CI 0.68 to 0.85; I 2 = 0%; low certainty) and probably result in more women using rescue antibiotic treatment by day 30 (4 studies, 1165 participants: RR 3.14, 95% CI 2.23 to 4.42; I 2 = 49%; moderate certainty). Compared to placebo, NSAIDs may reduce the use of rescue antibiotic treatment (1 study, 183 participants: RR 0.56, 95% CI 0.36 to 0.87; low certainty evidence) but may make little or no difference to adverse events at day 30. Compared to the herbal product Uva-Ursi, NSAIDs may make little or no difference to adverse events by day 30. AUTHORS' CONCLUSIONS: The use of NSAIDs for symptomatic management of uncomplicated UTIs probably results in less short-term resolution of symptoms and greater use of rescue antibiotics by day 30 compared to primary antibiotic treatment. Future studies should consider the various confounders such as degree of symptoms, microbiology, type and resistance patterns of bacteria involved and number of UTI episodes in the months prior to commencement of treatment.</p
Agricultural trade liberalization in the Uruguay Round : one step forward, one step back?
No full textAfter evaluating the Uruguay Round's impact on agriculture and border protection in the next decade, the author concludes that while there was significant reform of the rules - particularly the conversion of nontariff barriers into tariffs and the reduction and binding of all tariffs - in practice, trade will probably be liberalized less than expected. The objective of the Round was to reverse protectionism and remove trade distortions. This may not be achieved in practice, at least not until further reductions are carried out in future rounds of negotiations. The major exception to this conclusion is in high-income Asian countries, where protection for major commodities will be significantly reduced. The tariffication and binding of all tariffs on agricultural products represents a significant step forward. Liberalization is implicit because countries are prohhibited from arbitrarily raising tariffs to new higher levels. But many of the newly established tariffs are so high in many countries as to effectively prohibit trade. Patterns of liberalization vary considerably by commodity and by country. Generally, the extent of liberalization was diminished by binding tariffs to the base period of 1986-88, when border protection was at a high point. In most OECD countries, this was worsened by"dirty tariffication:"the new base tariffs offered even greater protection than the nontariff barriers they replaced. Even after the commitments to tariff reductions in the Round, the ad valorem measure of the final binding tariffs will remain higher than the average rate of protection in 1982-93. A number of developing countries in East Asia, Latin America, and the Middle East chose to lock in prior liberalization efforts on some products. But for most commodities, there will be little actual liberalization, since most developing countries chose to bind their tariffs at a maximum level. Even when countries reduced already-bound rates, bound tariffs remained significantly higher than current applied rates, giving countries the flexibility to raise tariffs later. The high level of bound tariffs may allow countries to apply variable tariffs below the bound level, thus failing to stabilize tariffs and improve market access. Moreover, the Round did not touch many of the worst distortions in developing countries, such as import subsidies, export taxes, state-trading monopolies, and domestic policies that implicitly tax agriculture.Trade Policy,Environmental Economics&Policies,Economic Theory&Research,Export Competitiveness,Rules of Origin,Trade Policy,Rules of Origin,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Environmental Economics&Policies,Economic Theory&Research
Design of Low-Threshold Comparator for Improved Timing-Resolution Analog/Digital SiPM
No full textCoincidence time resolution (CTR) in time-of-flight (TOF) positron emission tomography (PET) determines the signal-to-noise ratio (SNR) in iterative image reconstruction algorithms. In PET detectors, the photodetector's single-photon timing resolution (SPTR) influences the CTR by adding uncertainty to the single photoelectron time-of-arrivals. This effect can be modelled as the convolution of the scintillation pulse shape function and the total photodetector jitter at single-photon level, before following an order statistics process. Particularly in Cherenkov-based PET detectors, SPTR has a direct impacton the CTR due to the low number of detected photons. In this thesis, the research is focussed on the design of low thresh-old comparators for two specific purposes in PET. Firstly, the design of in-pixel (SPAD-cell) low-threshold comparator that improves SPAD jitter at the pixel level, since it allows the detection of photo-electron triggered avalanche at the earliest possible time, thus minimizing statistical fluctuations. The design is targeted for Cherenkov-based PET, where improvement in SPTR directly results in improvement of CTR. Secondly, for the integration of analog silicon photomultiplier (A-SiPM) on-chip. Such integration helps in realizing a high Photon Detection Effciency (PDE) and low Dark Count Rate (DCR) A-SiPM with integrated readout electronics. A high speed comparator with a direct connection to the fast terminal of A-SiPM has been realized.Electrical Engineering | Microelectronic
Sachdeva’s Ark: The imminent deluge of space crimes
No full textDeviation from accepted social standards of living has been a concern since the inception of society. Society, through its laws, has set a threshold of deviations, the crossing of which, whatsoever be the motivation for such imprudence, becomes behaviour that warrant attention and correction. G S Sachdeva, the author of the book under review, echoes this social truth about human nature, in the same vein and grandeur as David Hume, at the outset of his exposition, ‘Humans are after all human and wherever they go (…) And under stress or provocation, these [their human instincts] may burst open, criminally’ (p. vii). Does Sachdeva maintain this Humeanist elegance and eloquence that he displays at the start of his discourse through the rest of the book? In fact, Sachdeva, of everything he is and he is not, is thoroughly philosophical in his approach to things, which manifests as an irresistible desire to explore meanings and to provide explanations for the same. That perhaps qualifies him as a Humeanist
Effect of the optimisation time interval on the performance of mobile networks
No full textThis thesis project researches the effect of the optimisation time interval on the performance of a self-optimised mobile network. The goal of the thesis is to ascertain if there exists an optimal time interval for the self-optimisation of the KPN network, and what that interval is. In order to research this question, the project uses data from the KPN network as input, and sets up a simulation study in MATLAB. Two areas in the Netherlands are considered in this study – Friesland and Purmerend. The self-optimisation of the network is carried out through the modification of three optimisation parameters – antenna tilt, RS power, and Cell Individual Offset. The scope of the study is limited to LTE in the downlink, for the 800 MHz band. The bandwidth used in this study is 10 MHz. The performance of the mobile network has been studied using KPIs such as 10th throughput percentile, coverage failure rate, call drop rate, and load. In the end, the study analyses the results for each area, for the self-optimisation carried out by modifying the three parameters over several different optimisation time intervals, and discusses their impact on the performance of the network. A comparison has also been drawn between the performance of a self-optimised network and an un-optimised network, to highlight the gains achieved with SON. Finally, recommendations are made regarding a suitable time interval, and a relative comparison between suitability of the three optimisation parameters has been drawn. The study finds that a suitable time interval for optimisation does exist, and is 240 minutes, for both the simulation areas. The study finds RS power to be the most suitable parameter for self-optimisation, in both the areas. However, the research runs into some unexpected results with respect to the optimisations using tilt angle, and has been discussed in detail in the report. Significant gains are observed with SON, as compared to the case of ‘No SON’ or an un-optimised network. Electrical Engineering | Network Architectures and Service
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