Coronary stent healing in cancer patients: an optical coherence tomography perspective

Objective: This study assessed stent healing patterns and cardiovascular outcomes by optical coherence tomography (OCT) in cancer patients after drug-eluting stent (DES) placement.Background: Cancer treatment, owing to its cytotoxic and antiproliferative effects, could delay stent healing and increase stent thrombosis risk, especially when dual antiplatelet therapy (DAPT) is discontinued early for oncological treatment. OCT can assess stent endothelialization and other healing parameters, which may provide clinical guidance in these challenging scenarios.Methods: This single-center retrospective study enrolled all cancer patients who underwent OCT for assessment of vascular healing patterns after prior DES placement from November 2009 to November 2018. Primary study endpoints were stent healing parameters, including stent coverage, apposition, degree of expansion, neointimal hyperplasia heterogeneity, in-stent restenosis, stent thrombosis, and overall survival (OS).Results: A total of 67 patients were included in this study. Mean time between DES placement and OCT evaluation was 154 +/- 82 days. Stent healing matched published values for DES in non-cancer patients (P >= 0.063). At 1 year, the OS was 86% (95% confidence interval [CI]: 78-96%) with 0% incidence of acute coronary syndrome. Advanced cancers and active chemotherapies were associated with inferior OS (P = 0.024, hazard ratio [HR]: 3.50, 95% CI: 1.18-10.42 and P = 0.026, HR: 2.65, 95% CI: 1.13-6.22, respectively), while stent healing parameters were unassociated with OS. Forty-one patients (61%) had DAPT duration <= 6 months.Conclusions: Stent healing of contemporary DES appears similar in cancer and non-cancer patients. Cardiovascular risk of cancer patients after DES placement can be managed to facilitate timely cancer therapies, as the underlying malignancy and active chemotherapy ultimately determine survival.Cardiovascular Aspects of Radiolog

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Randomized Clinical Trial on Ivermectin versus Thiabendazole for the Treatment of Strongyloidiasis

Strongyloidiasis is the infection caused by the worm Strongyloides stercoralis. Due to its peculiar life cycle Strongyloides may remain indefinitely in the host, if not effectively cured. Although the disease is usually mild, in case of weakening of the host's immune defenses the worm may invade virtually all organs and tissues (disseminated strongyloidiasis, almost invariably fatal). The treatment must then reach the goal of the complete elimination of the parasite. Small size clinical trials showed similar, high efficacy of the two drugs ivermectin (used as a single dose) and thiabendazole (used twice daily for two consecutive days). All trials used as the criterion for cure the absence of larvae in stool exams. The latter however may easily miss the infection, falsely suggesting that the infection has been cured. This trial, using a test detecting specific Strongyloides antibodies as an additional and more sensitive diagnostic tool, confirms previous reports: the two drugs have similar efficacy but ivermectin is better tolerated and is therefore the first choice. However the cure rate was lower than 70% for the standard, single dose. The authors then conclude that a larger, multi center trial is needed to find the optimal dose schedule of ivermectin

Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation

yesInflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes. AMPK activation inhibited IL-1β-stimulated CXCL10 secretion, associated with reduced interleukin-1 receptor associated kinase-4 (IRAK4) phosphorylation and downregulated MKK4/JNK and IKK/IκB/NFκB signalling. AMPK activation inhibited TNF-α-stimulated IKK/IκB/NFκB signalling but had no effect on JNK phosphorylation. The JAK/STAT3 pathway was also suppressed by AMPK after IL-6 stimulation and during adipogenesis. Adipose tissue from AMPKα1−/− mice exhibited increased JNK and STAT3 phosphorylation, supporting suppression of these distinct proinflammatory pathways by AMPK in vivo. The inhibition of multiple pro-inflammatory signalling pathways by AMPK may underlie the reported beneficial effects of AMPK activation in adipose tissue.British Heart Foundatio

Structure-based functional inference of hypothetical proteins from Mycoplasma hyopneumoniae

Enzootic pneumonia caused by Mycoplasma hyopneumoniae is a major constraint to efficient pork production throughout the world. This pathogen has a small genome with 716 coding sequences, of which 418 are homologous to proteins with known functions. However, almost 42% of the 716 coding sequences are annotated as hypothetical proteins. Alternative methodologies such as threading and comparative modeling can be used to predict structures and functions of such hypothetical proteins. Often, these alternative methods can answer questions about the properties of a model system faster than experiments. In this study, we predicted the structures of seven proteins annotated as hypothetical in M. hyopneumoniae, using the structure-based approaches mentioned above. Three proteins were predicted to be involved in metabolic processes, two proteins in transcription and two proteins where no function could be assigned. However, the modeled structures of the last two proteins suggested experimental designs to identify their functions. Our findings are important in diminishing the gap between the lack of annotation of important metabolic pathways and the great number of hypothetical proteins in the M. hyopneumoniae genome

Maximal Wall Thickness Measurement in Hypertrophic Cardiomyopathy: Biomarker Variability and its Impact on Clinical Care

OBJECTIVES: The aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Left ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD). METHODS: A 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death. RESULTS: MWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years' experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range -59% to 117% [SD ±20%] and -61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk). CONCLUSIONS: Using the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM

A transcriptomic analysis of Echinococcus granulosus larval stages:implications for parasite biology and host adaptation

The cestode Echinococcus granulosus--the agent of cystic echinococcosis, a zoonosis affecting humans and domestic animals worldwide--is an excellent model for the study of host-parasite cross-talk that interfaces with two mammalian hosts. To develop the molecular analysis of these interactions, we carried out an EST survey of E. granulosus larval stages. We report the salient features of this study with a focus on genes reflecting physiological adaptations of different parasite stages.We generated ~10,000 ESTs from two sets of full-length enriched libraries (derived from oligo-capped and trans-spliced cDNAs) prepared with three parasite materials: hydatid cyst wall, larval worms (protoscoleces), and pepsin/H(+)-activated protoscoleces. The ESTs were clustered into 2700 distinct gene products. In the context of the biology of E. granulosus, our analyses reveal: (i) a diverse group of abundant long non-protein coding transcripts showing homology to a middle repetitive element (EgBRep) that could either be active molecular species or represent precursors of small RNAs (like piRNAs); (ii) an up-regulation of fermentative pathways in the tissue of the cyst wall; (iii) highly expressed thiol- and selenol-dependent antioxidant enzyme targets of thioredoxin glutathione reductase, the functional hub of redox metabolism in parasitic flatworms; (iv) candidate apomucins for the external layer of the tissue-dwelling hydatid cyst, a mucin-rich structure that is critical for survival in the intermediate host; (v) a set of tetraspanins, a protein family that appears to have expanded in the cestode lineage; and (vi) a set of platyhelminth-specific gene products that may offer targets for novel pan-platyhelminth drug development.This survey has greatly increased the quality and the quantity of the molecular information on E. granulosus and constitutes a valuable resource for gene prediction on the parasite genome and for further genomic and proteomic analyses focused on cestodes and platyhelminths

Echinococcus granulosus Antigen B Structure: Subunit Composition and Oligomeric States

Antigen B (AgB) is the major secretory protein of the Echinococcus granulosus hydatid cyst, the causative agent of cystic hydatid disease. Structurally, AgB is a multisubunit protein formed by 8-kDa subunits, but it is not known which subunits are secreted by a single parasite (cyst) and how they interact in the formation of distinct AgB oligomeric states. Here, we investigated AgB subunit composition and oligomeric states in individual samples from bovine and human cysts. We identified AgB8/1, AgB8/2, AgB8/3 and AgB8/4 subunits in AgB oligomers of all samples analyzed. Quantitative and qualitative differences in the expression of AgB subunits were observed within and between samples. Using recombinant subunits as models, we showed that AgB subunits form distinct oligomeric states, with a rAgB8/3>rAgB8/2>rAgB8/1 maximum size relation. We also demonstrated by different experimental approaches that rAgB8/3 oligomers are more similar, both in size and morphology, to those observed for E. granulosus AgB. Overall, we provided experimental evidences that AgB is composed of different subunits within a single cyst, and that subunits have different abundances and oligomerization properties. These issues are important for the understanding of AgB expression and structure variations, and their impact for the host-parasite cross-talk

Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress