Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

The intrinsic apoptotic pathway lies upstream of reactive species production in cortical neurons and age-related oxidative stress in the brain.

A BAX- and mitochondria-dependent production of reactive oxygen species (ROS) and reactive species (reactive nitrogen species, RNS) lying downstream of these ROS occurs in apoptotic and nonapoptotic mouse sympathetic neurons and cerebellar granule cells in cell culture. These ROS have been shown to lie downstream of caspase 3 in mouse sympathetic neurons. Here we show that BAX is necessary for similar ROS production in apoptotic and nonapoptotic mouse cortical neurons in cell culture and that it also positively regulates oxidative stress in the brains of mice of different ages. Brains from mice with genetically reduced levels of mitochondrial superoxide dismutase 2 (SOD2) exhibited elevated levels of DNA strand breaks consistent with oxidative damage. Lipid peroxides were also elevated at some ages in comparison to the brains of wild type animals. BAX deletion in these mice reduced both brain DNA strand breaks and lipid peroxide levels to well below those of wild type animals. Deletion of caspase 3 greatly reduced age-augmented levels of brain oxidative stress markers including lipid peroxides, oxidized DNA, and nitrosylated proteins. These findings indicate that BAX contributes to ROS production in mouse cortical neurons, to oxidative stress their brains, and that this effect is likely mediated via caspase 3 activity.

Outcomes of National Survey of the Practice of Hepatocellular Carcinoma Surveillance.

Background & Aim: HCC has significantly improved outcomes when detected early. Guidelines recommend biannual surveillance with ultrasound (US) and/or AFP in at-risk individuals. This survey aimed to describe HCC surveillance adherence/practices amongst the NHS hospitals in the UK. Methods: An electronic survey was sent to 79 NHS hospitals via the British Association for the Study of the Liver distribution list. The responses were captured from July 2021 to January 2022. Centres were divided into hepato-pancreato-biliary (HPB) and non-HPB centres, depending on whether the hospital undertakes major liver surgeries. Results: A total of 39 (49.3%) centres responded: 15 HPB and 24 non-HPB centres from across the UK. HCC surveillance eligibility criteria were universally applied, but heterogeneous approaches occur outside these criteria. Eighty per cent of patients undergoing surveillance were estimated to have cirrhosis. Eighty-five per cent of centres do 6-monthly US and AFP requested by clinicians and liver clinical nurse specialists. Compliance was estimated at 80% but not routinely audited. In most centres, general sonographers and/or radiologists perform surveillance US scans without a standard reporting template, although structured reporting was viewed as desirable by the majority. Poor views on US are approached heterogeneously, with patients variably offered ongoing US, CT, or MRI with different protocols. Conclusion: Most responding NHS hospitals follow 6-monthly HCC surveillance guidance. Data recording is variable, with limited routine data collection regarding compliance, yield, and quality. Surveillance US is mostly performed by non-HPB specialists without standardised reporting. There is an inconsistent approach to poor views with US surveillance. Even in a universal healthcare system such as NHS, which is free at the point of care, delivery of HCC surveillance has not improved over the last decade and remains variable.

A Hippocratic Oath for Mathematicians? Mapping the Landscape of Ethics in Mathematics.

While the consequences of mathematically-based software, algorithms and strategies have become ever wider and better appreciated, ethical reflection on mathematics has remained primitive. We review the somewhat disconnected suggestions of commentators in recent decades with a view to piecing together a coherent approach to ethics in mathematics. Calls for a Hippocratic Oath for mathematicians are examined and it is concluded that while lessons can be learned from the medical profession, the relation of mathematicians to those affected by their work is significantly different. There is something to be learned also from the codes of conduct of cognate but professionalised quantitative disciplines such as engineering and accountancy, as well as from legal principles bearing on professional work. We conclude with recommendations that professional societies in mathematics should sponsor an (international) code of ethics, institutional mission statements for mathematicians and syllabuses of ethics courses for incorporation into mathematics degrees.

Polyps seen but not removed during index colonoscopy: an underestimated inefficiency in endoscopy practice.

BACKGROUND AND AIMS: In the United Kingdom endoscopists are certified for independent practice once competent in the removal of polyps up to 20 mm in size. Where polyps are detected but not removed during the index colonoscopy, a repeat procedure is required. The aim of this study was to identify the proportion of polyps <20 mm that were not removed at the time of diagnosis. METHODS: Polyps identified at colonoscopy during a 12-month period in a single institution were included in this study. All polyps were categorized according to the reported size and complexity per the size, morphology, site, access (SMSA) classification. In cases where polyps ≤20 mm were not removed, patient records and endoscopy reports were interrogated to ascertain the reasons for this. RESULTS: Across 1444 patients, 2442 polyps <20 mm in size were diagnosed. Removal at the time of the index procedure occurred in 1158 patients (80.2%). Nonremoval for a predefined acceptable reason, such as concomitant anticoagulation therapy, accounted for 174 cases (12.0%). Nonremoval without contraindication was noted in 112 cases (7.8%). The mean polypectomy complexity as determined by the SMSA score of these polyps was lower than level 2, denoting low complexity. The requirement for unnecessary repeat procedures equated to 9.3 days of endoscopy capacity per year. CONCLUSIONS: This study demonstrates that a small but significant proportion of small colorectal polyps are not removed at the time of diagnosis. This practice has implications for both patients and service provision.

Comprehensive Imaging Characterization of Colorectal Liver Metastases.

Colorectal liver metastases (CRLM) have heterogenous histopathological and immunohistochemical phenotypes, which are associated with variable responses to treatment and outcomes. However, this information is usually only available after resection, and therefore of limited value in treatment planning. Improved techniques for in vivo disease assessment, which can characterise the variable tumour biology, would support further personalization of management strategies. Advanced imaging of CRLM including multiparametric MRI and functional imaging techniques have the potential to provide clinically-actionable phenotypic characterisation. This includes assessment of the tumour-liver interface, internal tumour components and treatment response. Advanced analysis techniques, including radiomics and machine learning now have a growing role in assessment of imaging, providing high-dimensional imaging feature extraction which can be linked to clinical relevant tumour phenotypes, such as a the Consensus Molecular Subtypes (CMS). In this review, we outline how imaging techniques could reproducibly characterize the histopathological features of CRLM, with several matched imaging and histology examples to illustrate these features, and discuss the oncological relevance of these features. Finally, we discuss the future challenges and opportunities of CRLM imaging, with a focus on the potential value of advanced analytics including radiomics and artificial intelligence, to help inform future research in this rapidly moving field.

Long-term nitrogen addition does not sustain host tree stem radial growth but doubles the abundance of high-biomass ectomycorrhizal fungi.

Global change has altered nitrogen availability in boreal forest soils. As ectomycorrhizal fungi play critical ecological functions, shifts in their abundance and community composition must be considered in the response of forests to changes in nitrogen availability. Furthermore, ectomycorrhizas are symbiotic, so the response of ectomycorrhizal fungi to nitrogen cannot be understood in isolation of their plant partners. Most previous studies, however, neglect to measure the response of host trees to nitrogen addition simultaneously with that of fungal communities. In addition to being one-sided, most of these studies have also been conducted in coniferous forests. Deciduous and "dual-mycorrhizal" tree species, namely those that form ecto- and arbuscular mycorrhizas, have received little attention despite being widespread in the boreal forest. We applied nitrogen (30 kg ha-1  year-1 ) for 13 years to stands dominated by aspen (Populus tremuloides Michx.) and hypothesized that tree stem radial growth would increase, ectomycorrhizal fungal biomass would decrease, ectomycorrhizal fungal community composition would shift, and the abundance of arbuscular mycorrhizal (AM) fungi would increase. Nitrogen addition initially increased stem radial growth of aspen, but it was not sustained at the time we characterized their mycorrhizas. After 13 years, the abundance of fungi possessing extramatrical hyphae, or "high-biomass" ectomycorrhizas, doubled. No changes occurred in ectomycorrhizal and AM fungal community composition, or in ecto- and AM abundance measured as root colonization. This dual-mycorrhizal tree species did not shift away from ectomycorrhizal fungal dominance with long-term nitrogen input. The unexpected increase in high-biomass ectomycorrhizal fungi with nitrogen addition may be due to increased carbon allocation to their fungal partners by growth-limited trees. Given the focus on conifers in past studies, reconciling results of plant-mycorrhizal fungal relationships in stands of deciduous trees may demand a broader view on the impacts of nitrogen addition on the structure and function of boreal forests.

Assessing the dual-mycorrhizal status of a widespread tree species as a model for studies on stand biogeochemistry.

Viewing plant species by their mycorrhizal type has explained a range of ecosystem processes. However, mycorrhizal type is confounded with plant phylogeny and the environments in which mycorrhizal partners occur. To circumvent these confounding effects, "dual-mycorrhizal" plant species may be potential models for testing the influence of mycorrhizal type on stand biogeochemistry. To assess their use as models, duality in mycorrhizas within a single host species must be confirmed and factors underlying their variation understood. We surveyed roots, soils, and leaves of mature aspen (Populus tremuloides) across 27 stands in western Canada spanning two biomes: boreal forest and parklands. Aspen roots were mostly ectomycorrhizal with sporadic and rare occurrences of arbuscular mycorrhizas. We further tested whether a climate moisture index predicted abundance of ectomycorrhizal roots (number of ectomycorrhizal root tips m-1 root length) surveyed at two depths (0-20 cm and 20-40 cm) and found that ectomycorrhizal root abundance in subsoils (20-40 cm) was positively related to the index. We subsequently examined the relationships between ectomycorrhizal root abundance, leaf traits, and slow and fast pools of soil organic carbon and nitrogen. The ratio of leaf lignin:N, but not its components, increased along with ectomycorrhizal root abundance in subsoils. Soil carbon and nitrogen pools were independent of ectomycorrhizal root abundance. Our results suggest that (1) categorizing aspen as dual-mycorrhizal may overstate the functional importance of arbuscular mycorrhizas in this species and life stage, (2) water availability influences ectomycorrhizal root abundance, and (3) ectomycorrhizal root abundance coincides with leaf quality.

Membrane Depolarization Inhibits BIMEL Upregulation but Prevents Neuronal Apoptosis Primarily by Increasing Cellular GSH Levels.

Sympathetic neurons deprived of nerve growth factor (NGF) die by apoptosis. Chronic depolarization with elevated concentrations of extracellular potassium ([K+]E) supports long-term survival of these and other types of neurons in culture. While depolarization has long been used to support neuronal cultures, little is known about the mechanism. We explored how chronic depolarization of NGF-deprived mouse sympathetic neurons in culture blocks apoptotic death. First, we determined the effects of elevated [K+]E on proapoptotic BH3-only proteins reported to be upregulated in sympathetic neurons after NGF withdrawal. Upregulation of BIMEL was blocked by depolarization while upregulation of PUMA was not. BMF levels did not increase after NGF withdrawal, and elevated [K+]E had no effect on its expression. dp5/HRK was not detectable. A large increase in production of mitochondria-derived reactive species (RS), including reactive oxygen species (ROS), occurs in NGF-deprived sympathetic neurons. Suppressing these RS prevents cytochrome c release from mitochondria and apoptosis. The addition of high [K+]E to cultures rapidly blocked increased RS and cytochrome c release. Elevated [K+]E caused an increase of the cellular antioxidant glutathione (GSH). Preventing this increase prevented the elevated [K+]E from blocking cytochrome c release and death. While suppression of BIMEL upregulation by elevated [K+]E may contribute to high [K+]E pro-survival effects, we conclude that elevated [K+]E prevents apoptotic death of NGF-deprived sympathetic neurons primarily via an antioxidant mechanism.

Impact of the COVID-19 pandemic on radiography practice: findings from a UK radiography workforce survey.

OBJECTIVES: Radiographers are key patient-facing healthcare professionals involved in many aspects of patient care. The working patterns and professional practice of the radiography workforce (RW) has been altered during the COVID-19 pandemic. This survey aimed to assess the impact of the pandemic on radiography practice in the United Kingdom (UK). METHODS: An online cross-sectional survey of the UK RW was performed (March 25th to April 26th, 2020). The survey sought information regarding 1. Demographics 2. Impact of the pandemic on professional practice 3. Infection prevention/control and 4. COVID-19 related stress. Data collected was analysed using the Statistical Package for Social Sciences (v.26). RESULTS: A total of 522 responses were received, comprising n = 412 (78.9%) diagnostic and n = 110 (21.1%) therapeutic RW categories from across the UK. 12.5% (65/522) of the respondents were redeployed. Redeployment did not appear to contribute (p = 0.31) to work-related stress. However, fear of contracting the infection and perceived inadequate personal protective equipment (PPE) were identified as key contributors to stress during the study period. Compared to the therapeutic RW, a significantly higher proportion of the diagnostic RW identified fear of being infected as a major stressor (166/412 (40.3%) vs 30/110 (27.3%), p = 0.01). CONCLUSION: This survey has demonstrated changes to clinical practice, in particular to working patterns, service delivery and infection prevention and control were key contributors to workplace-related stress during the pandemic. ADVANCES IN KNOWLEDGE: Timely and adequate staff training and availability of PPE as well as psychosocial support during future pandemics would enhance quality patient and staff safety.

Population-level variation in host plant response to multiple microbial mutualists.

PREMISE: Multipartite mutualisms are widespread in nature, but population-level variation in these interactions is rarely quantified. In the model multipartite mutualism between legumes, arbuscular mycorrhizal (AM) fungi and rhizobia bacteria, host responses to microbial partners are expected to be synergistic because the nutrients provided by each microbe colimit plant growth, but tests of this prediction have not been done in multiple host populations. METHODS: To test whether plant response to associations with AM fungi and rhizobia varies among host populations and whether synergistic responses to microbial mutualists are common, we grew 34 Medicago truncatula populations in a factorial experiment that manipulated the presence or absence of each mutualist. RESULTS: Plant growth increased in response to each mutualist, but there were no synergistic effects. Instead, plant response to inoculation with AM fungi was an order of magnitude higher than with rhizobia. Plant response to AM fungi varied among populations, whereas responses to rhizobia were relatively uniform. There was a positive correlation between plant host response to each mutualist but no correlation between AM fungal colonization and rhizobia nodulation of plant roots. CONCLUSIONS: The greater population divergence in host response to AM fungi relative to rhizobia, weak correlation in host response to each microbial mutualist, and the absence of a correlation between measures of AM fungal and rhizobia performance suggests that each plant-microbe mutualism evolved independently among M. truncatula populations.

Baseline use of angiotensin-converting enzyme inhibitor/AT1 blocker and outcomes in hospitalized coronavirus disease 2019 African-American patients.

OBJECTIVES: The primary objective of this study is to determine the effect of baseline use of angiotensin-converting enzyme inhibitor (ACE-i)/AT1 blocker (ARB) on mortality in hospitalized coronavirus disease 2019 (Covid-19) African-American patients. The secondary objectives are, to determine the effect of baseline use of ACE-i/ARB on the need for mechanical ventilation, new dialysis, ICU care, and on composite of above-mentioned outcomes in the same cohort. METHODS: In this retrospective study, we analyzed data using electronic medical records from all hospitalized Covid-19 African-American patients, who either died in the hospital or survived to discharge between 2 March and 22 May 2020. Patients were divided into two groups, those on ACE-i/ARB at baseline and those not on them. We used Pearson chi-square test for categorical variables, and Student's t test for continuous variables. We performed multiple logistic regression to test the primary and secondary objectives using SAS 9.4. RESULTS: Out of 531 patients included in the analysis, 207 (39%) were on ACE-i/ARB at baseline. Patients in ACE-i/ARB group were older (64 vs. 57 years, P < 0.001), and had higher prevalence of hypertension (96.6 vs. 69.4%, P < 0.001) and diabetes mellitus (55.6 vs. 34.9%, P < 0.001). There was no difference in sex, BMI, other comorbidities, and presenting illness severity among the groups. After adjustment of multiple covariates, there was no difference in outcomes between the two groups including mortality, need for mechanical ventilation, new dialysis, ICU care, as well as composite outcomes. CONCLUSION: Baseline use of ACE-i/ARB does not worsen outcomes in hospitalized Covid-19 African-American patients.

Demographics, comorbidities and outcomes in hospitalized Covid-19 patients in rural southwest Georgia.

BACKGROUND: There is limited data on outcomes in patients with coronavirus disease 2019 (Covid-19) in rural United States (US). This study aimed to describe the demographics, and outcomes of hospitalized Covid-19 patients in rural Southwest Georgia. METHODS: Using electronic medical records, we analyzed data from all hospitalized Covid-19 patients who either died or survived to discharge between 2 March 2020 and 6 May 2020. RESULTS: Of the 522 patients, 92 died in hospital (17.6%). Median age was 63 years, 58% were females, and 87% African-Americans. Hypertension (79.7%), obesity (66.5%) and diabetes mellitus (42.3%) were the most common comorbidities. Males had higher overall mortality compared to females (23 v 13.8%). Immunosuppression [odds ratio (OR) 3.6; (confidence interval (CI): 1.52-8.47, p=.003)], hypertension (OR 3.36; CI:1.3-8.6, p=.01), age ≥65 years (OR 3.1; CI:1.7-5.6, p<.001) and morbid obesity (OR 2.29; CI:1.11-4.69, p=.02), were independent predictors of in-hospital mortality. Female gender was an independent predictor of decreased in-hospital mortality. Mortality in intubated patients was 67%. Mortality was 8.9% in <50 years, compared to 20% in ≥50 years. CONCLUSIONS: Immunosuppression, hypertension, age ≥ 65 years and morbid obesity were independent predictors of mortality, whereas female gender was protective for mortality in hospitalized Covid-19 patients in rural Southwest Georgia. KEY MESSAGES Patients hospitalized with Covid-19 in rural US have higher comorbidity burden. Immunosuppression, hypertension, age ≥ 65 years and morbid obesity are independent predictors of increased mortality. Female gender is an independent predictor of reduced mortality.

The intrinsic apoptotic pathway lies upstream of oxidative stress in multiple organs.

Oxidative stress increases with age in multiple organ systems and is implicated in the development of age-related pathologies in them. Studies from our laboratory show that the intrinsic pathway proapoptotic proteins BAX and caspase-3 (CASP3) lie upstream of mitochondrial production of oxidative stress-inducing reactive species (RS) such as reactive oxygen and reactive nitrogen species (ROS and RNS) in apoptotic and nonapoptotic neurons in cell culture. Our objective in this study was to determine if these findings could be generalized to the development of oxidative stress in nonneuronal tissues in vivo. We first investigated the effect of genetic deletion of Bax on DNA damage in the liver, heart and kidneys of female mice of increasing ages (5, 14, 22 months). The organs of the aged mice showed increased oxidative DNA strand breaks compared to young animals (5 month). Ablation of Bax greatly reduced this damage. We next assessed lipid peroxidation, DNA oxidation, and protein tyrosine nitration to determine whether Casp3 deletion reduces oxidative stress in the hearts, livers, and kidneys of 12-month-old female mice. Lipid peroxides and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were much lower in organs from mice with depleted Casp3 than in those of wild type animals. Nitration of protein tyrosine residues, caused by RNS, was also significantly suppressed in the tissues of Casp3 null mice compared to those in wild type mice. Our findings indicate that BAX and CASP3 have a vital role in the generation of oxidative stress in organs of aged mice.

Recent advances in understanding and preventing oesophageal cancer.

Oesophageal cancer is a common cancer that continues to have a poor survival. This is largely in part due to its late diagnosis and early metastatic spread. Currently, screening is limited to patients with multiple risk factors via a relatively invasive technique. However, there is a large proportion of patients diagnosed with oesophageal cancer who have not been screened. This has warranted the development of new screening techniques that could be implemented more widely and lead to earlier identification and subsequently improvements in survival rates. This article also explores progress in the surveillance of Barrett's oesophagus, a pre-malignant condition for the development of oesophageal adenocarcinoma. In recent years, advances in early endoscopic intervention have meant that more patients are considered at an earlier stage for potentially curative treatment.

Tumour subregion analysis of colorectal liver metastases using semi-automated clustering based on DCE-MRI: Comparison with histological subregions and impact on pharmacokinetic parameter analysis.

PURPOSE: To use a novel segmentation methodology based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to define tumour subregions of liver metastases from colorectal cancer (CRC), to compare these with histology, and to use these to compare extracted pharmacokinetic (PK) parameters between tumour subregions. MATERIALS AND METHODS: This ethically-approved prospective study recruited patients with CRC and ≥1 hepatic metastases scheduled for hepatic resection. Patients underwent DCE-MRI pre-metastasectomy. Histological sections of resection specimens were spatially matched to DCE-MRI acquisitions and used to define histological subregions of viable and non-viable tumour. A semi-automated voxel-wise image segmentation algorithm based on the DCE-MRI contrast-uptake curves was used to define imaging subregions of viable and non-viable tumour. Overlap of histologically-defined and imaging subregions was compared using the Dice similarity coefficient (DSC). DCE-MRI PK parameters were compared for the whole tumour and histology-defined and imaging-derived subregions. RESULTS: Fourteen patients were included in the analysis. Direct histological comparison with imaging was possible in nine patients. Mean DSC for viable tumour subregions defined by imaging and histology was 0.738 (range 0.540-0.930). There were significant differences between Ktrans and kep for viable and non-viable subregions (p < 0.001) and between whole lesions and viable subregions (p < 0.001). CONCLUSION: We demonstrate good concordance of viable tumour segmentation based on pre-operative DCE-MRI with a post-operative histological gold-standard. This can be used to extract viable tumour-specific values from quantitative image analysis, and could improve treatment response assessment in clinical practice.

The mitochondria-targeted antioxidant MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg-AD mice.

Oxidative stress, likely stemming from dysfunctional mitochondria, occurs before major cognitive deficits and neuropathologies become apparent in Alzheimer's disease (AD) patients and in mouse models of the disease. We previously reported that treating 2- to 7-month-old 3xTg-AD mice with the mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl](triphenyl)phosphonium methanesulfonate), a period when AD-like pathologies first manifest in them, prevents AD-like symptoms from developing. To elucidate further a role for mitochondria-derived oxidative stress in AD progression, we examined the ability of MitoQ to inhibit AD-like pathologies in these mice at an age in which cognitive and neuropathological symptoms have fully developed. 3xTg-AD female mice received MitoQ in their drinking water for five months beginning at twelve months after birth. Untreated 18-month-old 3xTg-AD mice exhibited significant learning deficits and extensive AD-like neuropathologies. MitoQ-treated mice showed improved memory retention compared to untreated 3xTg-AD mice as well as reduced brain oxidative stress, synapse loss, astrogliosis, microglial cell proliferation, Aß accumulation, caspase activation, and tau hyperphosphorylation. Additionally, MitoQ treatment significantly increased the abbreviated lifespan of the 3xTg-AD mice. These findings support a role for the involvement of mitochondria-derived oxidative stress in the etiology of AD and suggest that mitochondria-targeted antioxidants may lessen symptoms in AD patients.

An Argument Against Drug Testing Welfare Recipients.

Programs of drug testing welfare recipients are increasingly common in US states and have been considered elsewhere. Though often intensely debated, such programs are complicated to evaluate because their aims are ambiguous-aims like saving money may be in tension with aims like referring people to treatment. We assess such programs using a proportionality approach, which requires that for ethical acceptability a practice must be reasonably likely to meet its aims, sufficiently important in purpose as to outweigh harms incurred, and lower in costs than feasible alternatives. In the light of empirical findings, we argue that the programs fail the three requirements. Pursuing recreational drug users is not important in the light of costs incurred, while dependent users who may require referral are usually identifiable without testing and typically need a broader approach than one focussing on drugs. Drug testing of welfare recipients is therefore not ethically acceptable policy.

GIFTed Demons: deformable image registration with local structure-preserving regularization using supervoxels for liver applications.

Deformable image registration, a key component of motion correction in medical imaging, needs to be efficient and provides plausible spatial transformations that reliably approximate biological aspects of complex human organ motion. Standard approaches, such as Demons registration, mostly use Gaussian regularization for organ motion, which, though computationally efficient, rule out their application to intrinsically more complex organ motions, such as sliding interfaces. We propose regularization of motion based on supervoxels, which provides an integrated discontinuity preserving prior for motions, such as sliding. More precisely, we replace Gaussian smoothing by fast, structure-preserving, guided filtering to provide efficient, locally adaptive regularization of the estimated displacement field. We illustrate the approach by applying it to estimate sliding motions at lung and liver interfaces on challenging four-dimensional computed tomography (CT) and dynamic contrast-enhanced magnetic resonance imaging datasets. The results show that guided filter-based regularization improves the accuracy of lung and liver motion correction as compared to Gaussian smoothing. Furthermore, our framework achieves state-of-the-art results on a publicly available CT liver dataset.

Dissociation of JNK Activation from Elevated Levels of Reactive Oxygen Species, Cytochrome c Release, and Cell Death in NGF-Deprived Sympathetic Neurons.

Withdrawal of nerve growth factor (NGF) from sympathetic neurons causes their apoptotic death. Activation of c-Jun NH2-terminal kinase (JNK) may contribute to this death by the induction and phosphorylation of pro-apoptotic Bcl-2 proteins, such as Bax, that are involved in cytochrome c release from mitochondria and reactive oxygen species (ROS) production. Induction of either JNK or ROS may stimulate the other, and both may regulate release of apoptogenic factors from the mitochondria. In order to discern the relationship between JNK and ROS in apoptosis, we treated NGF-deprived, mouse sympathetic neurons with a JNK inhibitor and examined the effect on several important apoptotic events. Block of JNK activation prevented induction of c-Jun expression and resulted in a dose-dependent, yet surprisingly modest, increase in cell survival after 48 h of NGF deprivation. JNK suppression was also not sufficient to prevent the elevation in ROS or the release of cytochrome c from the mitochondria in NGF-deprived sympathetic neurons. Bax deletion prevents apoptotic death of NGF-deprived neurons by preventing release of cytochrome c from their mitochondria. It also prevents increased ROS on NGF deprivation. However, we found that induction of c-Jun in cells lacking Bax was equivalent to that in wild-type neurons. Our results suggest that while JNK activation plays an important role in many forms of apoptosis, it may not be a crucial regulator of Bax-dependent events involved in the apoptotic death of mouse sympathetic neurons deprived of NGF and that ROS is not involved in its activation in these cells.