Quantitative peritumoral magnetic resonance imaging fingerprinting improves machine learning-based prediction of overall survival in colorectal cancer

Aim: To investigate magnetic resonance imaging (MRI)-based peritumoral texture features as prognostic indicators of survival in patients with colorectal liver metastasis (CRLM). Methods: From 2007–2015, forty-eight patients who underwent MRI within 3 months prior to initiating treatment for CRLM were identified. Clinicobiological prognostic variables were obtained from electronic medical records. Ninety-four metastatic hepatic lesions were identified on T1-weighted post-contrast images and volumetrically segmented. A total of 112 radiomic features (shape, first-order, texture) were derived from a 10 mm region surrounding each segmented tumor. A random forest model was applied, and performance was tested by receiver operating characteristic (ROC). Kaplan-Meier analysis was utilized to generate the survival curves. Results: Forty-eight patients (male:female = 23:25, age 55.3 years ± 18 years) were included in the study. The median lesion size was 25.73 mm (range 8.5–103.8 mm). Microsatellite instability was low in 40.4% (38/94) of tumors, with Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation detected in 68 out of 94 (72%) tumors. The mean survival was 35 months ± 21 months, and local disease progression was observed in 35.5% of patients. Univariate regression analysis identified 42 texture features [8 first order, 5 gray level dependence matrix (GLDM), 5 gray level run time length matrix (GLRLM), 5 gray level size zone matrix (GLSZM), 2 neighboring gray tone difference matrix (NGTDM), and 17 gray level co-occurrence matrix (GLCM)] independently associated with metastatic disease progression (P < 0.03). The random forest model achieved an area under the curve (AUC) of 0.88. Conclusions: MRI-based peritumoral heterogeneity features may serve as predictive biomarkers for metastatic disease progression and patient survival in CRLM

In-depth phenotyping for clinical stratification of Gaucher disease

Abstract: Background: The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5–87 years with Gaucher disease in the United Kingdom—an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study. Results: At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease—indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery. Conclusion: Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability

Monitoring protein aggregation and toxicity in Alzheimer's disease mouse models using in vivo imaging

Aggregation of amyloid beta peptide into senile plaques and hyperphosphorylated tau protein into neurofibrillary tangles in the brain are the pathological hallmarks of Alzheimer’s disease. Despite over a century of research into these lesions, the exact relationship between pathology and neurotoxicity has yet to be fully elucidated. In order to study the formation of plaques and tangles and their effects on the brain, we have applied multiphoton in vivo imaging of transgenic mouse models of Alzheimer’s disease. This technique allows longitudinal imaging of pathological aggregation of proteins and the subsequent changes in surrounding neuropil neurodegeneration and recovery after therapeutic interventions

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Impacts of the invasive cane toad on aquatic reptiles in a highly modified ecosystem:The importance of replicating impact studies

Invasive species can have dramatic and detrimental effects on native species, and the magnitude of these effects can be mediated by a plethora of factors. One way to identify mediating factors is by comparing attributes of natural systems in species with heterogeneity of responses to the invasive species. This method first requires quantifying impacts in different habitats, ecosystems or geographic locations. We used a long-term, before-and-after study to quantify the impacts of the invasive and toxic cane toad (Rhinella marina) on two predators in a highly modified ecosystem: an irrigation channel in an agricultural landscape. Survey counts spanning 8 years indicated a severe population-level decline of 84 % in Merten's Water Monitor (Varanus mertensi) that was coincident with the arrival of cane toads. The impact of cane toads on V. mertensi was similar to that found in other studies in other habitats, suggesting that cane toads severely impact V. mertensi populations, regardless of habitat type or geographic location. In contrast, a decline was not detected in the Freshwater Crocodile (Crocodylus johnstoni). There is now clear evidence that some C. johnstoni populations are vulnerable to cane toads, while others are not. Our results reinforce the need for the replication of impact studies within and among species; predicting impacts based on single studies could lead to overgeneralizations and potential mismanagement

Machine Learning-Based Radiomic Features on Pre-Ablation MRI as Predictors of Pathologic Response in Patients with Hepatocellular Carcinoma Who Underwent Hepatic Transplant

Background: The aim was to investigate the role of pre-ablation tumor radiomics in predicting pathologic treatment response in patients with early-stage hepatocellular carcinoma (HCC) who underwent liver transplant. Methods: Using data collected from 2005–2015, we included adult patients who (1) had a contrast-enhanced MRI within 3 months prior to ablation therapy and (2) underwent liver transplantation. Demographics were obtained for each patient. The treated hepatic tumor volume was manually segmented on the arterial phase T1 MRI images. A vector with 112 radiomic features (shape, first-order, and texture) was extracted from each tumor. Feature selection was employed through minimum redundancy and maximum relevance using a training set. A random forest model was developed based on top radiomic and demographic features. Model performance was evaluated by ROC analysis. SHAP plots were constructed in order to visualize feature importance in model predictions. Results: Ninety-seven patients (117 tumors, 31 (32%) microwave ablation, 66 (68%) radiofrequency ablation) were included. The mean model for end-stage liver disease (MELD) score was 10.5 ± 3. The mean follow-up time was 336.2 ± 179 days. Complete response on pathology review was achieved in 62% of patients at the time of transplant. Incomplete pathologic response was associated with four features: two first-order and two GLRM features using univariate logistic regression analysis (p < 0.05). The random forest model included two radiomic features (diagnostics maximum and first-order maximum) and four clinical features (pre-procedure creatinine, pre-procedure albumin, age, and gender) achieving an AUC of 0.83, a sensitivity of 82%, a specificity of 67%, a PPV of 69%, and an NPV of 80%. Conclusions: Pre-ablation MRI radiomics could act as a valuable imaging biomarker for the prediction of tumor pathologic response in patients with HCC

Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice

Neuritic plaques are a defining feature of Alzheimer disease (AD) pathology. These structures are composed of extracellular accumulations of amyloid-β peptide (Aβ) and other plaque-associated proteins, surrounded by large, swollen axons and dendrites (dystrophic neurites) and activated glia. Dystrophic neurites are thought to disrupt neuronal function, but whether this damage is static, dynamic, or reversible is unknown. To address this, we monitored neuritic plaques in the brains of living PDAPP;Thy-1:YFP transgenic mice, a model that develops AD-like pathology and also stably expresses yellow fluorescent protein (YFP) in a subset of neurons in the brain. Using multiphoton microscopy, we observed and monitored amyloid through cranial windows in PDAPP;Thy-1:YFP double-transgenic mice using the in vivo amyloid-imaging fluorophore methoxy-X04, and individual YFP-labeled dystrophic neurites by their inherent fluorescence. In vivo studies using this system suggest that amyloid-associated dystrophic neurites are relatively stable structures in PDAPP;Thy-1:YFP transgenic mice over several days. However, a significant reduction in the number and size of dystrophic neurites was seen 3 days after Aβ deposits were cleared by anti-Aβ antibody treatment. This analysis suggests that ongoing axonal and dendritic damage is secondary to Aβ and is, in part, rapidly reversible

Epoxyeicosanoids promote organ and tissue regeneration

Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis

Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements

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