Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic ...triggers. Sustained, aberrant activation of cytotoxic CD8+ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.
Applications of tumor chip technology Hachey, Stephanie J; Hughes, Christopher C. W
Lab on a chip,
09/2018, Letnik:
18, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Over the past six decades the inflation-adjusted cost to bring a new drug to market has been increasing constantly and doubles every 9 years - now reaching in excess of $2.5 billion. Overall, the ...likelihood of FDA approval for a drug (any disease indication) that has entered phase I clinical trials is a mere 9.6%, with the approval rate for oncology far below average at only 5.1%. Lack of efficacy or toxicity is often not revealed until the later stages of clinical trials, despite promising preclinical data. This indicates that the current
in vitro
systems for drug screening need to be improved for better predictability of
in vivo
outcomes. Microphysiological systems (MPS), or bioengineered 3D microfluidic tissue and organ constructs that mimic physiological and pathological processes
in vitro
, can be leveraged across preclinical research and clinical trial stages to transform drug development and clinical management for a range of diseases. Here we review the current state-of-the-art in 3D tissue-engineering models developed for cancer research, with a focus on tumor-on-a-chip, or tumor chip, models. From our viewpoint, tumor chip systems can advance innovative medicine to ameliorate the high failure rates in anti-cancer drug development and clinical treatment.
By surpassing the predictive accuracy of conventional 2D cell culture models, tumor chips can reduce reliance on animal models in line with the 3Rs initiative and eliminate false positive selection of ineffective or toxic drugs earlier in the drug development pipeline, saving time and resources. Most importantly, better predictability of human drug response will reduce human risk and improve patient outcomes.
Covering: Up to 2020.
It is widely accepted that small molecule natural products (NPs) evolved to carry out a particular ecological function and that these finely-tuned molecules can sometimes be ...appropriated for the treatment of disease in humans. Unfortunately, for the natural products chemist, NPs did not evolve to possess favorable physicochemical properties needed for HPLC-MS analysis. The process known as derivatization, whereby an NP in a complex mixture is decorated with a nonnatural moiety using a derivatizing agent (DA), arose from this sad state of affairs. Here, NPs are freed from the limitations of natural functionality and endowed, usually with some degree of chemoselectivity, with additional structural features that make HPLC-MS analysis more informative. DAs that selectively label amines, carboxylic acids, alcohols, phenols, thiols, ketones, and aldehydes, terminal alkynes, electrophiles, conjugated alkenes, and isocyanides have been developed and will be discussed here in detail. Although usually employed for targeted metabolomics, chemical labeling strategies have been effectively applied to uncharacterized NP extracts and may play an increasing role in the detection and isolation of certain classes of NPs in the future.
Chemical labeling enhances the analysis of complex mixtures
via
HPLC-MS in both targeted and untargeted metabolomics workflows.
The evolution of past global ice sheets is highly uncertain. One example is the missing ice problem during the Last Glacial Maximum (LGM, 26 000-19 000 years before present) - an apparent 8-28 m ...discrepancy between far-field sea level indicators and modelled sea level from ice sheet reconstructions. In the absence of ice sheet reconstructions, researchers often use marine δ
O proxy records to infer ice volume prior to the LGM. We present a global ice sheet reconstruction for the past 80 000 years, called PaleoMIST 1.0, constructed independently of far-field sea level and δ
O proxy records. Our reconstruction is compatible with LGM far-field sea-level records without requiring extra ice volume, thus solving the missing ice problem. However, for Marine Isotope Stage 3 (57 000-29 000 years before present) - a pre-LGM period - our reconstruction does not match proxy-based sea level reconstructions, indicating the relationship between marine δ
O and sea level may be more complex than assumed.
Background
Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of ...neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010.
Objectives
To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain.
Search methods
On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain.
Selection criteria
We selected all randomised or quasi‐randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration.
Main results
We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose‐dependent effect. Most adverse effects were minor, but 12.6% of participants stopped the drug due to adverse effects. Serious adverse events were rare.
Authors' conclusions
There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy.
Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare.
Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.
We present a new time‐slice reconstruction of the Eurasian ice sheets (British–Irish, Svalbard–Barents–Kara Seas and Scandinavian) documenting the spatial evolution of these interconnected ice sheets ...every 1000 years from 25 to 10 ka, and at four selected time periods back to 40 ka. The time‐slice maps of ice‐sheet extent are based on a new Geographical Information System (GIS) database, where we have collected published numerical dates constraining the timing of ice‐sheet advance and retreat, and additionally geomorphological and geological evidence contained within the existing literature. We integrate all uncertainty estimates into three ice‐margin lines for each time‐slice; a most‐credible line, derived from our assessment of all available evidence, with bounding maximum and minimum limits allowed by existing data. This approach was motivated by the demands of glaciological, isostatic and climate modelling and to clearly display limitations in knowledge. The timing of advance and retreat were both remarkably spatially variable across the ice‐sheet area. According to our compilation the westernmost limit along the British–Irish and Norwegian continental shelf was reached up to 7000 years earlier (at c. 27–26 ka) than the eastern limit on the Russian Plain (at c. 20–19 ka). The Eurasian ice sheet complex as a whole attained its maximum extent (5.5 Mkm2) and volume (~24 m Sea Level Equivalent) at c. 21 ka. Our continental‐scale approach highlights instances of conflicting evidence and gaps in the ice‐sheet chronology where uncertainties remain large and should be a focus for future research. Largest uncertainties coincide with locations presently below sea level and where contradicting evidence exists. This first version of the database and time‐slices (DATED‐1) has a census date of 1 January 2013 and both are available to download via the Bjerknes Climate Data Centre and PANGAEA (www.bcdc.no; http://doi.pangaea.de/10.1594/PANGAEA.848117).
Abstract
Wildlife trade is a key driver of the biodiversity crisis. Unregulated, or under-regulated wildlife trade can lead to unsustainable exploitation of wild populations. International efforts to ...regulate wildlife mostly miss ‘lower-value’ species, such as those imported as pets, resulting in limited knowledge of trade in groups like reptiles. Here we generate a dataset on web-based private commercial trade of reptiles to highlight the scope of the global reptile trade. We find that over 35% of reptile species are traded online. Three quarters of this trade is in species that are not covered by international trade regulation. These species include numerous endangered or range-restricted species, especially hotspots within Asia. Approximately 90% of traded reptile species and half of traded individuals are captured from the wild. Exploitation can occur immediately after scientific description, leaving new endemic species especially vulnerable. Pronounced gaps in regulation imply trade is having unknown impacts on numerous threatened species. Gaps in monitoring demand a reconsideration of international reptile trade regulations. We suggest reversing the status-quo, requiring proof of sustainability before trade is permitted.
The unprecedented pandemic of pneumonia caused by a novel coronavirus, SARS-CoV-2, in China and beyond has had major public health impacts on a global scale 1, 2. Although bats are regarded as the ...most likely natural hosts for SARS-CoV-2 3, the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomic analysis of samples from 227 bats collected from Yunnan Province in China between May and October 2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-2 at the scale of the complete virus genome and 97.2% identity in the 1ab gene, in which it is the closest relative of SARS-CoV-2 reported to date. In contrast, RmYN02 showed low sequence identity (61.3%) to SARS-CoV-2 in the receptor-binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, and in a similar manner to SARS-CoV-2, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 subunits of the spike (S) protein. This provides strong evidence that such insertion events can occur naturally in animal betacoronaviruses.
•Metagenomic analysis identified a novel coronavirus, RmYN02, from R. malayanus•RmYN02 was the closest relative of SARS-CoV-2 in most of the virus genome•Two loop deletions in RBD may reduce the binding of RmYN02 with ACE2•RmYN02 contains an insertion at the S1/S2 cleavage site in the spike protein
Zhou et al. report a bat-derived coronavirus, RmYN02, which is the closest relative of SARS-CoV-2 in most of the virus genome reported to date. RmYN02 contains an insertion at the S1/S2 cleavage site in the spike protein in a similar manner to SARS-CoV-2. This suggests that such insertion events can occur naturally in animal betacoronaviruses.
Ecosystems services (ES) assessment is a significant scientific topic recognized for its potential to address sustainability issues. However, there is an absence of science-policy frameworks in land ...use planning that lead to the ES science being used in policy. China's Ecological Redline Policy (ERP) is one of the first national policies utilizing multiple ES, but there is no standardized approach for working across the science-policy interface. We propose a transdisciplinary framework to determine ecological redline areas (ERAs) in Shanghai using: ES, biodiversity and ecologically fragile hotspots, landscape structure, and stakeholder opinions. We determine the five criteria to identify ERAs for Shanghai using multi-temporal, high resolution images (0.5 m) and biophysical models. We examine ERP effectiveness by comparing land use scenarios for 2040. Compared to alternative land uses, ES increase significantly under the ERP. The inclusion of ES in spatial planning led stakeholders to increase terrestrial habitat protection by 174% in Shanghai. Our analysis suggests that strategic planning for ES could reduce tradeoffs between environmental quality and development.
Southeast Asia (SE Asia) is a known global hotspot of biodiversity and endemism, yet the region is also one of the most biotically threatened. Ecosystems across the region are threatened by an array ...of drivers, each of which increases the probability of extinction of species in a variety of ecosystems. These issues are symptomatic of the issues that face the global tropics; however, with around 4 billion people in the wider region and the associated pressures on biodiversity, this region may be under some of the greatest levels of biotic threat. Deforestation rates in SE Asia are some of the highest globally, additionally it has the highest rate of mining in the tropics, around the greatest number of hydropower dams under construction, and a consumption of species for traditional medicines which is a threat to biodiversity globally. In this review, the greatest threats to regional biodiversity in the SE Asian region are discussed. Tree‐plantations and deforestation represent one of the most imminent threats, and some countries have already lost over half their original forest cover (i.e., the Philippines, parts of Indonesia), with projections of as much as 98% loss for some regions in the coming decade. Hunting and trade represent a significant threat as demand stems not only for food, but also for medicine, for ornamentation, and as a status symbol. Mining represents a frequently overlooked threat, as the Asian region is one of the greatest exporters of limestone and various minerals globally, and the cost of this to biodiversity is not only through the direct loss of areas for mines, but also through the development of roads that further fragment the landscape, the leakage of heavy metals, and the destruction of limestone karsts, which represent global endemicity hotspots. Reservoir construction, wetland drainage, fires, pollution, invasive species, disease, and finally climate change are also considered. Once each issue has been discussed, the overall prognosis of regional biodiversity and priority actions to protect SE Asian biodiversity in the future is discussed.
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