Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver ...diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through ‘activation’, and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the ‘ductular reaction’ as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.
The abrupt outbreak of the novel coronavirus disease 2019 and its rapid spread over many healthcare systems throughout the world has led to a shortage in personal protective equipment (PPE), which ...cannot be solved by reducing their use or by increasing production. It is thus necessary to promote PPE rational use, highlighting possible differences in terms of efficacy and promoting an effective technique to reuse them.
A literature search was performed on PubMed, Scopus, Cochrane database, and Google Scholar, and from the 25 top cited articles, 15 were selected for relevance and impact.
Most studies on previous respiratory virus epidemics to date suggest surgical masks are not inferior compared with N95 respirators in terms of protective efficacy among healthcare workers. Therefore, the use of N95 respirators should be limited to high-risk situations. Concerning respirator reuse, highly energetic, short-wave, ultraviolet germicidal irradiation (UVGI) at 254 nm was determined to decontaminate N95 respirators from viral respiratory agents, but UVGI requires careful consideration of the type of respirator and of the biologic target.
Rational use and successful reuse of respirators can help in the shortage of PPE during a pandemic. Further studies testing UVGI and other decontamination techniques are an unmet need. The definitive answer to pandemic issues can be found in artificial intelligence and deep learning. These groundbreaking modalities could help in identifying high-risk patients and in suggesting appropriate types and use of PPE.
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Risk stratification (characterization) of tumors from radiology images can be more accurate and faster with computer-aided diagnosis (CAD) tools. Tumor characterization through such tools can also ...enable non-invasive cancer staging, prognosis, and foster personalized treatment planning as a part of precision medicine. In this paper, we propose both supervised and unsupervised machine learning strategies to improve tumor characterization. Our first approach is based on supervised learning for which we demonstrate significant gains with deep learning algorithms, particularly by utilizing a 3D convolutional neural network and transfer learning. Motivated by the radiologists' interpretations of the scans, we then show how to incorporate task-dependent feature representations into a CAD system via a graph-regularized sparse multi-task learning framework. In the second approach, we explore an unsupervised learning algorithm to address the limited availability of labeled training data, a common problem in medical imaging applications. Inspired by learning from label proportion approaches in computer vision, we propose to use proportion-support vector machine for characterizing tumors. We also seek the answer to the fundamental question about the goodness of "deep features" for unsupervised tumor classification. We evaluate our proposed supervised and unsupervised learning algorithms on two different tumor diagnosis challenges: lung and pancreas with 1018 CT and 171 MRI scans, respectively, and obtain the state-of-the-art sensitivity and specificity results in both problems.
Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons ...in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)—all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS.
•Glutamatergic Ube3a loss decreases tonic inhibition onto L2/3 pyramidal neurons•GABAergic Ube3a loss does not compromise inhibition onto L2/3 pyramidal neurons•GABAergic, not glutamatergic, Ube3a loss causes EEG abnormalities and seizures•L2/3 GABAergic defects in AS mice neither cause, nor are caused by, seizures
Judson and colleagues use neuron-type-specific manipulations of maternal Ube3a expression to demonstrate that GABAergic Ube3a loss is sufficient to yield Angelman syndrome-like EEG abnormalities, enhancements in seizure susceptibility, and atypical clathrin-coated vesicle accumulations within presynaptic terminals.
Colorectal cancer Dekker, Evelien; Tanis, Pieter J; Vleugels, Jasper L A ...
The Lancet (British edition),
10/2019, Letnik:
394, Številka:
10207
Journal Article
Recenzirano
Several decades ago, colorectal cancer was infrequently diagnosed. Nowadays, it is the world's fourth most deadly cancer with almost 900 000 deaths annually. Besides an ageing population and dietary ...habits of high-income countries, unfavourable risk factors such as obesity, lack of physical exercise, and smoking increase the risk of colorectal cancer. Advancements in pathophysiological understanding have increased the array of treatment options for local and advanced disease leading to individual treatment plans. Treatments include endoscopic and surgical local excision, downstaging preoperative radiotherapy and systemic therapy, extensive surgery for locoregional and metastatic disease, local ablative therapies for metastases, and palliative chemotherapy, targeted therapy, and immunotherapy. Although these new treatment options have doubled overall survival for advanced disease to 3 years, survival is still best for those with non-metastasised disease. As the disease only becomes symptomatic at an advanced stage, worldwide organised screening programmes are being implemented, which aim to increase early detection and reduce morbidity and mortality from colorectal cancer.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A. AS model mice, which carry a maternal Ube3a null mutation (Ube3am−/p+), ...recapitulate major features of AS in humans, including enhanced seizure susceptibility. Excitatory neurotransmission onto neocortical pyramidal neurons is diminished in Ube3am−/p+ mice, seemingly at odds with enhanced seizure susceptibility. We show here that inhibitory drive onto neocortical pyramidal neurons is more severely decreased in Ube3am−/p+ mice. This inhibitory deficit follows the loss of excitatory inputs and appears to arise from defective presynaptic vesicle cycling in multiple interneuron populations. In contrast, excitatory and inhibitory synaptic inputs onto inhibitory interneurons are largely normal. Our results indicate that there are neuron type-specific synaptic deficits in Ube3am−/p+ mice despite the presence of Ube3a in all neurons. These deficits result in excitatory/inhibitory imbalance at cellular and circuit levels and may contribute to seizure susceptibility in AS.
► Inhibitory neurotransmission is reduced in adult Ube3am−/p+ mice ► Inhibition is decreased onto excitatory, but not FS-inhibitory interneurons ► Decreased inhibition arises from multiple inhibitory interneuron classes ► Synaptic vesicle cycling defect may impair inhibitory neurotransmission
Wallace et al. describe a novel defect in vesicular cycling at inhibitory axon terminals in a mouse model of Angelman syndrome. These deficits result in an excitatory/inhibitory imbalance that may contribute to cognitive deficits and seizure susceptibility in AS.
...miss rate by a human endoscopist has been strictly associated with one or more of these factors.1 As only one every two lesions was rated as adenomatous by centralised pathology in the original ...study3 (see online supplementary data), AI may result in the useless removal of hyperplastic polyps. ...a leave in situ strategy at least for distal non-adenomatous lesions is critical for AI not to increase false-positive rate at colonoscopy. Despite the general enthusiasm, prospective series are affected by ineludible operator-related bias, as the endoscopist cannot be blinded in most of the cases to the innovative technique. ...retrospective reassessment of whole colonoscopy videos, such as those in our series, owns the unique advantage of eliminating all of these subjective biases, objectively exposing independent videos to the new technologies. ...a possible bias that we could not eliminate is the fact that AI had in each video clip a relatively long interval between a few seconds before polyp appearance and the use of snare or another device. ...we could not exclude in principle that AI was somewhat facilitated by the fact that the polyp is usually put in a better and close position to the endoscope before resection. ...AI cannot compensate for lesions missed for a suboptimal exploration of colorectal mucosa. ...an adequate level of cleansing, a longer than 6 min withdrawal time and a good withdrawal technique remain prerequisites to maximise the performance of AI.6 We limited our study to white-light high definition colonoscopy.
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