Liver disease is an important clinical problem, impacting over 30million Americans and over 600million people worldwide. It is the 12th leading cause of death in the United States and the 16th ...worldwide. Due to a paucity of donor organs, several thousand Americans die yearly while waiting for liver transplantation. Unfortunately, alternative tissue sources such as fetal hepatocytes and hepatic cell lines are unreliable, difficult to reproduce, and do not fully recapitulate hepatocyte phenotype and functions. As a consequence, alternative cell sources that do not have these limitations have been sought. Human embryonic stem (hES) cell- and induced pluripotent stem (iPS) cell-derived hepatocyte-like cells may enable cell based therapeutics, the study of the mechanisms of human disease and human development, and provide a platform for screening the efficacy and toxicity of pharmaceuticals. iPS cells can be differentiated in a step-wise fashion with high efficiency and reproducibility into hepatocyte-like cells that exhibit morphologic and phenotypic characteristics of hepatocytes. In addition, iPS-derived hepatocyte-like cells (iHLCs) possess some functional hepatic activity as they secrete urea, alpha-1-antitrypsin, and albumin. However, the combined phenotypic and functional traits exhibited by iHLCs resemble a relatively immature hepatic phenotype that more closely resembles that of fetal hepatocytes rather than adult hepatocytes. Specifically, iHLCs express fetal markers such as alpha-fetoprotein and lack key mature hepatocyte functions, as reflected by drastically reduced activity (~0.1%) of important detoxification enzymes (i.e. CYP2A6, CYP3A4). These key differences between iHLCs and primary adult human hepatocytes have limited the use of stem cells as a renewable source of functional adult hepatocytes for in vitro and in vivo applications. Unfortunately, the developmental pathways that control hepatocyte maturation from a fetal into an adult hepatocyte are poorly understood, which has hampered the field in its efforts to induce further maturation of iPS-derived hepatic lineage cells. This review analyzes recent developments in the derivation of hepatocyte-like cells, and proposes important points to consider and assays to perform during their characterization. In the future, we envision that iHLCs will be used as in vitro models of human disease, and in the longer term, provide an alternative cell source for drug testing and clinical therapy.
Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population worldwide and may confer increased cardiometabolic risk with consequent adverse cardiovascular outcomes independent ...of traditional cardiovascular risk factors and the metabolic syndrome. It is characterized almost universally by insulin resistance and is strongly associated with type 2 diabetes and obesity. Non-alcoholic fatty liver disease is a marker of pathological ectopic fat accumulation combined with a low-grade chronic inflammatory state. This results in several deleterious pathophysiological processes including abnormal glucose, fatty acid and lipoprotein metabolism, increased oxidative stress, deranged adipokine profile, hypercoaguability, endothelial dysfunction, and accelerated progression of atherosclerosis. This ultimately leads to a dysfunctional cardiometabolic phenotype with cardiovascular mortality representing the main mode of premature death in NAFLD. This review is aimed at introducing NAFLD to the clinical cardiologist by discussing in-depth the evidence to date linking NAFLD with cardiovascular disease, reviewing the likely mechanisms underlying this association, as well as summarizing from a cardiologist's perspective, current and potential future treatment options for this increasingly prevalent disease.
Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals ...deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.
Objective
To evaluate real-time shear wave ultrasound elastography (SWE) for characterizing focal thyroid lesions in routine clinical practice.
Methods
Seventy-four patients with 81 focal thyroid ...lesions undergoing conventional US with needle cytology also underwent SWE. Absolute and relative SWE stiffness measurements on colour-coded elastograms were correlated with cytology and their discriminatory performances assessed.
Results
Seventeen nodules were malignant (13 papillary, 4 other cancers), 45 benign (43 hyperplastic nodules, 2 focal thyroiditis), 5 indeterminate (“follicular lesions”), and 5 had inadequate cytology. SWE results were higher in malignant than benign nodules (
P
values 0.02–0.05) although their discriminatory performances were mediocre (AUCs 0.58–0.74). The most accurate SWE cut-off, 34.5 kPa for a 2-mm region of interest, achieved 76.9 % sensitivity and 71.1 % specificity for discriminating papillary cancer from benign nodules. No thresholds produced high sensitivity without lowering specificity appreciably, and vice versa. Nodule size correlated with SWE for benign nodules (
P
< 0.01). Intranodular cystic change or calcification did not influence SWE. Qualitatively, elastographic artefacts and foci lacking colour elasticity signal occurred in some solid nodules.
Conclusion
Although malignant nodules are generally stiffer than benign nodules, the precision results do not suggest a definitive role for SWE, at present, in identifying or excluding thyroid malignancy.
Key Points
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Shear wave ultrasound elastography (SWE) offers new insight into thyroid disease
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Papillary cancers have higher SWE indices (equating to higher stiffness) than benign nodules
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SWE appears limited in terms of identifying or excluding thyroid malignancy accurately
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Vertically aligned elastographic artefacts can occur in thyroid SWE
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Areas lacking SWE colour signal can occur in some solid thyroid nodules
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Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) ...and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.
Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.
OS data were available for 912 patients. The median PFS was 3.3months (95% CI 2.9–3.6) and 6-month PFS rate was 27% (95% CI 24–30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3cm versus <3cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2months (95% CI 9.5–11.0) and 1year OS was 43% (95% CI 40–47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.
Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
Coumarins as antioxidants Kostova, I; Bhatia, S; Grigorov, P ...
Current medicinal chemistry,
09/2011, Letnik:
18, Številka:
25
Journal Article
Recenzirano
Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of ...compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design.
Biodiesel has high potential as a new and renewable energy source in the future, as a substitution fuel for petroleum-derived diesel and can be used in existing diesel engine without modification. ...Currently, more than 95% of the world biodiesel is produced from edible oil which is easily available on large scale from the agricultural industry. However, continuous and large-scale production of biodiesel from edible oil without proper planning may cause negative impact to the world, such as depletion of food supply leading to economic imbalance. A possible solution to overcome this problem is to use non-edible oil or waste edible oil (WEO). In this context, the next question that comes in mind would be if the use of non-edible oil overcomes the short-comings of using edible oil. Apart from that, if WEO were to be used, is it sufficient to meet the demand of biodiesel. All these issues will be addressed in this paper by discussing the advantages and disadvantages of using edible oil vs. non-edible vs. WEO as feedstock for biodiesel production. The discussion will cover various aspects ranging from oil composition, oil yield, economics, cultivation requirements, land availability and also the resources availability. Finally, a proposed solution will be presented.
Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through ...defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.
Tight-fitting respirators are a critical component of respiratory protection against airborne diseases for health workers. However, they are not recommended for health workers with facial hair. Some ...health workers are unable to shave for religious or medical reasons. Under-mask beard covers have been proposed as a solution to allow health workers with facial hair to wear tight-fitting respirators. However, studies to date have been limited by their predominant reliance on qualitative rather than quantitative fit testing techniques.
To assess the efficacy of under-mask beard covers in achieving an adequate seal with tight-fitting disposable P2/N95 respirators using quantitative fit testing.
Bearded adult males underwent quantitative fit testing with an under-mask beard cover using either a TSI PortaCount Respirator Fit Tester 8038 or an AccuFit 9000 PRO fit testing device on up to five disposable P2/N95 respirators (3M 1860, 3M 1870+, BYD N95 Healthcare Particulate Respirator, BSN Medical ProShield N-95 Medium and Trident RTCFFP2). The primary outcome was the proportion of subjects that passed or failed quantitative fit testing with an under-mask beard cover.
Thirty subjects were assessed; of these, 24 (80%) passed quantitative fit testing with at least one tight-fitting P2/N95 disposable respirator. Among these subjects, the median best-achieved fit factor was 200 (interquartile range 178–200). None of the subjects had an adverse reaction to the under-mask beard cover.
The under-mask beard cover technique may be used to achieve a satisfactory seal with tight-fitting P2/N95 respirators in health workers with facial hair who cannot shave.
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