Differential gene expression in cells with different p53 mutations identifies genome-wide p53 targets and shows distinct modulation of cellular pathways in response to DNA damage

© 2024 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License (CC BY-NC), https://creativecommons.org/licenses/by-nc/4.0/The fundamental transcription factor p53 regulates cellular processes and integrates signals of cellular stress, triggering a coordinated response to ensure survival of cells restored to healthy function and programmed death of those that couldn’t be repaired. Unsurprisingly, this is one of the most mutated genes in human cancers, with most changes occurring in the DNA-binding domain of the protein. In this work, we take a genome-wide approach and use available resources to identify high confidence p53-target genes, that we examine in three breast cancer cell lines with different p53 status, wild type (MCF-7) and different mutations in the DNA-binding domain (MDA-MB231, T47D). Comparison of p53-targets expression in response to DNA damage by RNAseq and cellular assays reveals that MDA-MB231 have a severely impaired p53-dependent pathway functionality while T47D are much less affected. MDA-MB231 are more resistant to DNA damage yet unable to repair and able to override cell cycle arrest leading to survival while T47D are sensitive only to high dose and exposure to genotoxic agents. This data shows the variability of effects of different p53 mutations and highlight the importance of understanding the mechanisms of p53 in the context of genotoxicity-based treatment

Do red deer stags (Cervus elaphus) use roar fundamental frequency (F0) to assess rivals?

It is well established that in humans, male voices are disproportionately lower pitched than female voices, and recent studies suggest that this dimorphism in fundamental frequency (F0) results from both intrasexual (male competition) and intersexual (female mate choice) selection for lower pitched voices in men. However, comparative investigations indicate that sexual dimorphism in F0 is not universal in terrestrial mammals. In the highly polygynous and sexually dimorphic Scottish red deer Cervus elaphus scoticus, more successful males give sexually-selected calls (roars) with higher minimum F0s, suggesting that high, rather than low F0s advertise quality in this subspecies. While playback experiments demonstrated that oestrous females prefer higher pitched roars, the potential role of roar F0 in male competition remains untested. Here we examined the response of rutting red deer stags to playbacks of re-synthesized male roars with different median F0s. Our results show that stags’ responses (latencies and durations of attention, vocal and approach responses) were not affected by the F0 of the roar. This suggests that intrasexual selection is unlikely to strongly influence the evolution of roar F0 in Scottish red deer stags, and illustrates how the F0 of terrestrial mammal vocal sexual signals may be subject to different selection pressures across species. Further investigations on species characterized by different F0 profiles are needed to provide a comparative background for evolutionary interpretations of sex differences in mammalian vocalizations

Human helminth therapy to treat inflammatory disorders - where do we stand?

Parasitic helminths have evolved together with the mammalian immune system over many millennia and as such they have become remarkably efficient modulators in order to promote their own survival. Their ability to alter and/or suppress immune responses could be beneficial to the host by helping control excessive inflammatory responses and animal models and pre-clinical trials have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, MS, asthma and atopy. Thus, helminth therapy has been suggested as a possible treatment method for autoimmune and other inflammatory disorders in humans

Review of mobile applications for optimizing the follow-up care of patients with diabetes

© 2018, The Author(s). Background: Several smartphone applications aim at facilitating communication between patients and healthcare providers. In this review, we evaluate and compare the most promising applications in the field of diabetes mellitus (DM) and obesity. Most applications monitor body weight, fasting or postprandial blood glucose, glycosylated hemoglobin (Hgb) A1c (HgbA1c), and units and types of insulin used. Methods: Nine clinically tested applications and two Web platforms were grouped into three categories that were evaluated and compared. Group 1 included seven applications focusing mainly on monitoring DM, fitness and weight, blood glucose levels, and HbA1c. Group 2 included two applications that focus on insulin dosage calculators and glucose self-monitoring tests. Group 3 included two web-platforms that interact with patients via SMS (short message service) messaging. Results: A common feature of the applications examined was the limited number of clinical parameters tested, the small number of subjects taking part in the evaluation, and the fact that the controls were not randomized. Furthermore, the interfaces of the applications varied and were not standardized. Finally, another common characteristic across applications was the lack of standardization of the interface and the overall structure due to language barriers, the devices usually having been designed around a specific language. Lastly, most applications lacked a critical mass of evaluators and were thus not worthy of being considered of serious clinical relevance. Conclusions: The current smartphone applications for DM are characterized by a limited number of participants, a small number of parameters, and a lack of standardization.Published versio

Characterisation of a Peripheral Neuropathic Component of the Rat Monoiodoacetate Model of Osteoarthritis

Joint degeneration observed in the rat monoiodoacetate (MIA) model of osteoarthritis shares many histological features with the clinical condition. The accompanying pain phenotype has seen the model widely used to investigate the pathophysiology of osteoarthritis pain, and for preclinical screening of analgesic compounds. We have investigated the pathophysiological sequellae of MIA used at low (1 mg) or high (2 mg) dose. Intra-articular 2 mg MIA induced expression of ATF-3, a sensitive marker for peripheral neuron stress/injury, in small and large diameter DRG cell profiles principally at levels L4 and 5 (levels predominated by neurones innervating the hindpaw) rather than L3. At the 7 day timepoint, ATF-3 signal was significantly smaller in 1 mg MIA treated animals than in the 2 mg treated group. 2 mg, but not 1 mg, intra-articular MIA was also associated with a significant reduction in intra-epidermal nerve fibre density in plantar hindpaw skin, and produced spinal cord dorsal and ventral horn microgliosis. The 2 mg treatment evoked mechanical pain-related hypersensitivity of the hindpaw that was significantly greater than the 1 mg treatment. MIA treatment produced weight bearing asymmetry and cold hypersensitivity which was similar at both doses. Additionally, while pregabalin significantly reduced deep dorsal horn evoked neuronal responses in animals treated with 2 mg MIA, this effect was much reduced or absent in the 1 mg or sham treated groups. These data demonstrate that intra-articular 2 mg MIA not only produces joint degeneration, but also evokes significant axonal injury to DRG cells including those innervating targets outside of the knee joint such as hindpaw skin. This significant neuropathic component needs to be taken into account when interpreting studies using this model, particularly at doses greater than 1 mg MIA

Improving identification & management of familial hypercholesterolaemia in primary care: pre- and post-intervention study

Background and Aims: Familial hypercholesterolaemia (FH) is a major cause of premature heart disease but remains unrecognised in most patients. This study investigated if a systematic primary care-based approach to identify and manage possible FH improves recommended best clinical practice. Methods: Pre- and post-intervention study in six UK general practices (population 45,033) which invited patients with total cholesterol >7.5 mmol/L to be assessed for possible FH. Compliance with national guideline recommendations to identify and manage possible FH (repeat cholesterol; assess family history of heart disease; identify secondary causes and clinical features; reduce total & LDL-cholesterol; statin prescribing; lifestyle advice) was assessed by calculating the absolute difference in measures of care pre- and six months post-intervention. Results: The intervention improved best clinical practice in 118 patients consenting to assessment (of 831 eligible patients): repeat cholesterol test (+75.4%, 95% CI 66.9-82.3); family history of heart disease assessed (+35.6%, 95% CI 27.0-44.2); diagnosis of secondary causes (+7.7%, 95% CI 4.1-13.9), examining clinical features (+6.0%, 95% CI 2.9-11.7). For 32 patients diagnosed with possible FH using Simon-Broome criteria, statin prescribing significantly improved (18.8%, 95% CI 8.9-35.3) with non-significant mean reductions in cholesterol post-intervention (total: -0.16 mmol/L, 95% CI -0.78-0.46; LDL: -0.12 mmol/L, 95% CI -0.81-0.57). Conclusions: Within six months, this simple primary care intervention improved both identification and management of patients with possible FH, in line with national evidence-based guidelines. Replicating and sustaining this approach across the country could lead to substantial improvement in health outcomes for these individuals with very high cardiovascular risk

Pneumonia in adults - Quality standard QS110

IntroductionThis quality standard covers adults (18 years and older) with a suspected or confirmed diagnosis of community acquired pneumonia. For more information see the pneumonia topic overview.Why this quality standard is neededPneumonia is an infection of the lung tissue. When a person has pneumonia the air sacs in their lungs become filled with microorganisms, fluid and inflammatory cells and their lungs are not able to work properly. Diagnosis of pneumonia is based on symptoms and signs of an acute lower respiratory tract infection, and can be confirmed by a chest X-ray showing new shadowing that is not due to any other cause (such as pulmonary oedema or infarction). The NICE guideline on pneumonia classifies pneumonia depending on the source of the infection as community acquired or hospital-acquired, which need different management strategies. Every year between 0.5% and 1% of adults in the UK will have community-acquired pneumonia. It is diagnosed in 5–12% of adults who present to GPs with symptoms of lower respiratory tract infection, and 22–42% of these are admitted to hospital, where the mortality rate is between 5% and 14%. Between 1.2% and 10% of adults admitted to hospital with community acquired pneumonia are managed in an intensive care unit, and for these patients the risk of dying is over 30%. More than half of pneumonia-related deaths occur in people older than 84 years.At any time, 1.5% of hospital patients in England have a hospital-acquired respiratory infection, more than half of which are hospital-acquired pneumonia and are not associated with intubation. Hospital-acquired pneumonia is estimated to increase a hospital stay by about 8 days and has a reported mortality rate ranging from 30–70%. There are variations in clinical management and outcomes across the UK

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40