We recently identified 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, as a potential therapeutic target of the head and neck squamous ...cell carcinomas (HNSCC) and cervical carcinomas (CC). The products of this complex biochemical pathway, including de novo cholesterol, are vital for a variety of key cellular functions affecting membrane integrity, cell signaling, protein synthesis, and cell cycle progression. Lovastatin, a specific inhibitor of HMG-CoA reductase, induces a pronounced apoptotic response in a specific subset of tumor types, including HNSCC and CC. The mediators of this response are not well established. Identification of differentially expressed genes represents a feasible approach to delineate these mediators as lovastatin has the potential to modulate transcription indirectly by perturbing levels of sterols and other mevalonate metabolites. Expression analysis following treatment of the HNSCC cell lines SCC9 or SCC25 with 10 μM lovastatin for 1 day showed that less than 2% (9 cDNAs) of the 588 cDNAs on this microarray were affected in both cell lines. These included diazepam-binding inhibitor/acyl-CoA-binding protein, the activated transcription factor 4 and rhoA. Because the biosynthesis of mevalonate leads to its incorporation into more than a dozen classes of end products, their role in lovastatin-induced apoptosis was also evaluated. Addition of the metabolites of all the major branches of the mevalonate pathway indicated that only the nonsterol moiety, geranylgeranyl pyrophosphate (GGPP), significantly inhibited the apoptotic effects of lovastatin in HNSCC and CC cells. Because rhoA requires GGPP for its function, this links the microarray and biochemical data and identifies rhoA as a potential mediator of the anticancer properties of lovastatin. Our data suggest that the depletion of nonsterol mevalonate metabolites, particularly GGPP, can be potential mediators of lovastatin-induced apoptosis of HNSCC and CC cells.
The citizen Continental-America Telescopic Eclipse (CATE) Experiment was a new type of citizen science experiment designed to capture a time sequence of white-light coronal observations during ...totality from 17:16 to 18:48 UT on 2017 August 21. Using identical instruments the CATE group imaged the inner corona from 1 to 2.1 RSun with 1″.43 pixels at a cadence of 2.1 s. A slow coronal mass ejection (CME) started on the SW limb of the Sun before the total eclipse began. An analysis of CATE data from 17:22 to 17:39 UT maps the spatial distribution of coronal flow velocities from about 1.2 to 2.1 RSun, and shows the CME material accelerates from about 0 to 200 km s−1 across this part of the corona. This CME is observed by LASCO C2 at 3.1–13 RSun with a constant speed of 254 km s−1. The CATE and LASCO observations are not fit by either constant acceleration nor spatially uniform velocity change, and so the CME acceleration mechanism must produce variable acceleration in this region of the corona.
The fish fauna of the Southern Ocean is dominated by species of the perciform suborder Notothenioidei, which constitute 46% of fish species and 90% of biomass. Notothenioids have undergone rapid ...morphological and ecological diversification and developed physiological adaptations to a cold, highly oxygenated environment. Microbes inhabiting animal intestines include those that perform essential nutritional functions, but notothenioid gut microbial communities have not been investigated using cultivation-independent approaches. We analyzed bacterial 16S rRNA gene sequences obtained from the intestinal tract of Notothenia coriiceps and Chaenocephalus aceratus, which differ in their pelagic distribution and feeding strategies. Both samples showed dominance of Gammaproteobacteria (mostly Vibrionaceae), as has been reported for temperate teleost species. Both samples showed low diversity relative to that reported for other fish microbiota studies, with C. aceratus containing fewer OTUs than N. coriiceps. Despite the small sample size of this preliminary study, our findings suggest that Antarctic notothenioids carry a gut microbiota similar in composition to that of temperate fish, but exhibiting lower species-level diversity. The omnivorous N. coriiceps individual exhibited greater diversity than the exclusively carnivorous C. aceratus individual, which may indicate that increasing herbivory in fish leads to gut microbe diversification, as found in mammals. Lastly, we detected members of taxa containing known microbial pathogens, which have not been previously reported in Antarctic notothenioid fish.
As part of a safety and tolerability study, a 65‐year‐old man with Parkinson's disease (PD) received monthly intracerebroventricular injections of glial‐derived neurotrophic factor (GDNF). His ...parkinsonism continued to worsen following intracerebroventricular GDNF treatment. Side effects included nausea, loss of appetite, tingling, L'hermitte's sign, intermittent hallucinations, depression, and inappropriate sexual conduct. There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions. Alternative GDNF delivery systems should be explored.
PurposeArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine ...the prevalence of disease thus ascertained.MethodsIndividuals (n = 30,716) underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes.ResultsEighteen subjects had pLOF variants; none of these had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram, one had a minor diagnostic criterion; the rest were normal. A total of 184 subjects had VUS, none of whom had an ARVC diagnosis. The proportion of subjects with VUS with major (4%) or minor (13%) electrocardiogram diagnostic criteria did not differ from that of variant-negative controls. ICD-9 codes showed no difference in defibrillator use, electrophysiologic abnormalities or nonischemic cardiomyopathies in patients with pLOF or VUSs compared with controls.ConclusionpLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.
Enteric
Campylobacter species cause gastrointestinal diseases in humans. Like almost all organisms, campylobacters have an absolute requirement for iron, but are faced with variable availability of ...iron in the environment and host tissues. Campylobacters have developed mechanisms to scavenge sufficient iron for metabolism and growth. However, iron also participates in the formation of reactive oxygen species, and this forces pathogens to maintain intracellular iron homeostasis and to cope with oxidative stresses. The presence of two separate, but possibly overlapping iron-responsive regulatory systems, which regulate iron acquisition and oxidative stress defense, and the presence of genes encoding multiple iron acquisition and detoxification systems in
Campylobacter indicate the central role that iron plays in
Campylobacter gene regulation and virulence.
To assess predictors of outcome following endovascular treatment of small ruptured intracranial aneurysms (SRA).
Between 2004 and 2011, 91 patients with SRA (≤3 mm) were treated at our institution. ...Multivariate analysis was carried out to assess predictors of endovascular-related complications, aneurysm obliteration (>95%), recanalization and favorable outcome (Glasgow Outcome Scale 3-5).
Endovascular treatment was aborted in nine of 91 patients (9.9%). Procedure-related complications occurred in eight of 82 patients (9.8%) of which five were transient and three were permanent. Three patients (3.7%) undergoing endovascular treatment experienced an intraprocedural aneurysm rupture. Three of nine patients (33.3%) treated with stent- or balloon-assisted coiling experienced periprocedural complications compared with five of 73 patients (6.8%) receiving only coils or Onyx (p=0.039). There were no procedural deaths or rehemorrhages. Rates of recanalization and retreatment were 18.2% and 12.7%, respectively. No factors predicted initial occlusion or recanalization. In multivariate analysis, pretreatment factors predictive of a favorable outcome included younger age (OR 0.94; 95% CI 0.91 to 0.99, p=0.017), larger aneurysm size (OR 3.4; 95% CI 1.02 to 11.11, p=0.045), Hunt and Hess grade (OR 0.38; 95% CI 0.19 to 0.75, p=0.005) and location (OR 5.12; 95% CI 1.29 to 20.25, p=0.02). When assessing treatment and post-treatment variables, vasospasm was the only additional covariate predictive of a poor outcome (OR 5.90; 95% CI 1.34 to 25.93,p=0.019).
Most patients with SRA can be treated with endovascular therapy and have limited complications. Overall predictors of outcome for patients undergoing endovascular treatment of SRA include age, aneurysm size, Hunt and Hess grade, location and post-treatment vasospasm.
Distinguishing migraine from stroke is a challenge due to many common signs and symptoms. It is important to consider the cost of hospitalization and the time spent by neurologists and stroke nurses ...to visit, diagnose, and assign appropriate care to the patients; therefore, devising new ways to distinguish stroke, migraine and other types of mimics can help in saving time and cost, and improve decision-making. In this study, we utilized text and data mining methods to extract the most important predictors from clinical reports in order to establish a migraine detection model and distinguish migraine patients from stroke or other types of mimic (non-stroke) cases. The available data for this study was a heterogeneous mix of free-text fields, such as triage main-complaints and specialist final-impressions, as well as numeric data about patients, such as age, blood-pressure, and so on. After a careful combination of these sources, we obtained a highly imbalanced dataset where the migraine cases were only about 6 % of the dataset. Our main challenge was tackling this data imbalance. Using the dataset in its original form to build classifiers led to a learning bias towards the majority class and against the minority (migraine) class. We used a sampling method to address the imbalance problem. First, different sources of data were preprocessed and balanced datasets were generated; second, attribute selection algorithms were used to reduce the dimensionality of the data; third, a novel combination of data mining algorithms was employed in order to effectively distinguish migraine from other cases. We achieved a sensitivity and specificity of about 80 and 75 %, respectively, which is in contrast to a sensitivity and specificity of 15.7 and 97 % when using the original imbalanced data for building classifiers.
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