PGC-1 Coactivators Regulate MITF and the Tanning Response

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Highlights? PGC-1 induces pigment formation in melanocytes ? PGC-1s activate expression of MITF ? α-MSH induces PGC-1s, which are required for induction of melanogenic genes ? eQTLs in human PGC-1β are associated with tanning ability and melanoma protection     

The immunogenicity to the first anti-TNF therapy determines the outcome of switching to a second anti-TNF therapy in spondyloarthritis patients

Introduction

Anti-TNF drugs have proven to be effective against spondyloarthritis (SpA), although 30% of patients fail to respond or experience adverse events leading to treatment discontinuation. In rheumatoid arthritis, the presence of anti-drug antibodies (ADA) against the first TNF inhibitor influences the outcome after switching. Our aim was to assess whether the response to a second anti-TNF drug is related to the previous development of ADA to the first anti-TNF drug SpA patients.

Methods

Forty-two SpA patients began a second anti-TNF drug after failing to respond to the first anti-TNF therapy. Clinical activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline (at the beginning of the first and second anti-TNF therapy) and at 6 months after switching. The drug and ADA levels were measured by ELISA before each administration.

Results

All patients were treated with anti-TNF drugs and mainly due to inefficacy were switched to a second anti-TNF drug. Eleven of 42 (26.2%) developed ADA during the first biologic treatment. At baseline, no differences in ASDAS were found in patients with or without ADA to the first anti-TNF drug (3.52 ± 1.03 without ADA vs. 3.14 ± 0.95 with ADA, p = 0.399) and to the second anti-TNF drug (3.36 ± 0.94 without ADA vs. 3.09 ± 0.91 with ADA, p = 0.466). At 6 months after switching, patients with previous ADA had lower disease activity (1.62 ± 0.93 with ADA vs. 2.79 ± 1.01 without ADA, p = 0.002) and most patients without ADA had high disease activity state by the ASDAS (25 out of 31 (80.6%) without ADA vs. 3 out of 11 (27.3%) with ADA, p = 0.002).

Conclusions

In SpA the failure to respond to the first anti-TNF drug due to the presence of ADA predicts a better clinical response to a second anti-TNF drug.     

Poor knowledge of methotrexate associated with older age and limited English-language proficiency in a diverse rheumatoid arthritis cohort

Introduction

Our objective was to determine rheumatoid arthritis (RA) patients’ understanding of methotrexate and assess whether knowledge varies by age, education, English language proficiency, or other disease-related factors.

Methods

Adults with RA (n = 135) who were enrollees of an observational cohort completed a structured telephone interview in their preferred language between August 2007 and July 2009. All subjects who reported taking methotrexate were asked 11 questions about the medication in addition to demographics, education level, and language proficiency. Primary outcome was a total score below the 50^th percentile (considered inadequate methotrexate knowledge). Bivariable and multivariable logistic regressions were performed. Covariates included demographics, language proficiency, education, and disease characteristics.

Results

Of 135 subjects, 83% were female, with a mean age of 55 ± 14 years. The majority spoke English (64%), followed by 22% Spanish and 14% Cantonese or Mandarin. Limited English language proficiency (LEP) was reported in 42%. Mean methotrexate knowledge score was 5.4 ± 2.6 (range, 0 to 10); 73 (54%) had a score lower than 5 (of 10). Age older than 55, less than high school education, LEP, better function, and biologic use were independently associated with poor knowledge.

Conclusions

In a diverse RA cohort, overall methotrexate knowledge was poor. Older age and limited proficiency in English were significant correlates of poor knowledge. Identification of language barriers and improved clinician-patient communication around methotrexate dosing and side effects may lead to improved safety and enhanced benefits of this commonly used RA medication.     

Microvesicles as promising biological tools for diagnosis and therapy

ABSTRACT

Introduction: Shed by most cells, in response to a myriad of stimuli, extracellular vesicles (EVs) carry proteins, lipids, and various nucleic acids. EVs encompass diverse subpopulations differing for biogenesis and content. Among these, microvesicles (MVs) derived from plasma membrane, are key regulators of physiopathological cellular processes including cancer, inflammation and infection. This review is unique in that it focuses specifically on the MVs as a mediator of information transfer. In fact, few proteomic studies have rigorously distinguished MVs from exosomes.

Areas covered: Aim of this review is to discuss the proteomic analyses of the MVs. Many studies have examined mixed populations containing both exosomes and MVs. We discuss MVs’ role in cell-specific interactions. We also show their emerging roles in therapy and diagnosis.

Expert commentary: We see MVs as therapeutic tools for potential use in precision medicine. They may also have potential for allowing the identification of new biomarkers. MVs represent an invaluable tool for studying the cell of origin, which they closely represent, but it is critical to build a repository with data from MVs to deepen our understanding of their molecular repertoire and biological functions.     

Oligonucleotide Conjugates: Alteration of the Pharmacokinetic Properties of Antisense Agents

Abstract

Cholic acid, cholesterol, several polyamines and polyethylene glycols were conjugated to antisense oligonucleotides targeted to human or murine intercellular adhesion molecule-1 (ICAM-1) mRNA to study their effects on cellular absorption.     

Phylogeny and morphology of Hirsutella tunicata sp. nov. (Ophiocordycipitaceae), a novel mite parasite from Peru

A new species of Hirsutella was isolated from unidentified mites on Petri plates inoculated with soil and root fragments collected from asparagus rhizosphere at Virú, Northern Peru. The fungus differs from other Hirsutella species by an envelope surrounding the conidium, conidia dimension and DNA sequences. In PDA cultures, the mycelium produced aerial hyphae with conidiogenous cells mainly at right angles, occasionally showing a secondary conidiophore. The solitary conidia are cymbiform, slightly apiculate, 5.0–6.0 × 3.0–4.0 μm. Phylogenetic analyses with partial rRNA and β-tubulin gene sequences confirmed the fungus as an Hirsutella (Ophiocordycipitaceae). Closest species shown by maximum likelihood and neighbor-joining trees were H. nodulosa and H. aphidis, from which the new species differs for conidium or conidiogenous cells dimensions, lack of synnemata and host type. A recombination event was also detected in the rRNA of the holotype strain, involving Ophiocordyceps sinensis as major parent and O. cochlidiicola as minor parent. A complement, inverted insertion was also found in its rRNA, involving part of the ITS2 and 5.8S regions, flanked by two short nucleotide arrays. Due to conidia dimension and phylogenetic position, the fungus is described as Hirsutella tunicata sp. nov. A review of mononematous Hirsutella species is provided.     

Maintenance of temporal synchrony between syrphid flies and floral resources despite differential phenological responses to climate

Variation in species’ responses to abiotic phenological cues under climate change may cause changes in temporal overlap among interacting taxa, with potential demographic consequences. Here, we examine associations between the abiotic environment and plant–pollinator phenological synchrony using a long‐term syrphid fly–flowering phenology dataset (1992–2011). Degree‐days above freezing, precipitation, and timing of snow melt were investigated as predictors of phenology. Syrphids generally emerge after flowering onset and end their activity before the end of flowering. Neither flowering nor syrphid phenology has changed significantly over our 20‐year record, consistent with a lack of directional change in climate variables over the same time frame. Instead we document interannual variability in the abiotic environment and phenology. Timing of snow melt was the best predictor of flowering onset and syrphid emergence. Snow melt and degree‐days were the best predictors of the end of flowering, whereas degree‐days and precipitation best predicted the end of the syrphid period. Flowering advanced at a faster rate than syrphids in response to both advancing snow melt and increasing temperature. Different rates of phenological advancements resulted in more days of temporal overlap between the flower–syrphid community in years of early snow melt because of extended activity periods. Phenological synchrony at the community level is therefore likely to be maintained for some time, even under advancing snow melt conditions that are evident over longer term records at our site. These results show that interacting taxa may respond to different phenological cues and to the same cues at different rates but still maintain phenological synchrony over a range of abiotic conditions. However, our results also indicate that some individual plant species may overlap with the syrphid community for fewer days under continued climate change. This highlights the role of interannual variation in these flower–syrphid interactions and shows that species‐level responses can differ from community‐level responses in nonintuitive ways.     

Capsaicin as an inducer of damage-associated molecular patterns (DAMPs) of immunogenic cell death (ICD) in human bladder cancer cells

Few conventional cytotoxic anticancer therapeutics induce immunogenic cell death (ICD). This means that they induce tumor cells to undergo apoptosis while eliciting the emission of a spatiotemporal-defined combination of damage-associated molecular patterns (DAMPs) decoded by the immune system to activate antitumor immunity effective for long-term therapeutic success. The neurotoxin capsaicin (CPS) can induce both cancer cell apoptosis and immune-mediated tumor regression. In the present study, we investigated whether CPS is capable of eliciting the emission of ICD hallmarks in human bladder cancer cell lines undergoing apoptosis. We demonstrated that CPS induces pre- and early apoptotic cell surface exposure of calreticulin (CRT), HSP90, and HSP70 as well as ATP release. Moreover, CRT exposure was prevented by inhibition of endoplasmic reticulum–Golgi traffic by brefeldin A. Furthermore, high-mobility group box 1, HSP90, and HSP70 were passively released at late apoptotic stages. We provide the first evidence that CPS is an inducer of ICD hallmarks, suggesting CPS as a novel potential immunogenic cytotoxic agent.     

Prothymosin alpha protects cardiomyocytes against ischemia-induced apoptosis via preservation of Akt activation

The human prothymosin alpha (PTα) gene encodes a 12.5 kDa highly acidic nuclear protein that is widely expressed in mammalian tissues including the heart and importantly, is detectable also in blood serum. During apoptosis or necrosis, PTα changes its nuclear localization and is able to exert an important cytoprotective effect. Since the role of PTα in the heart has never been evaluated, the aim of the present study was to investigate the effects of PTα on cardiomyocytes during ischemic injury. Our data show that seven after myocardial infarction (MI), PTα expression levels are significantly increased both in blood serum and in cardiac tissue, and notably we observe that PTα translocates from the nuclei to cytoplasm and plasma membrane of cardiomyocytes following MI. Furthermore, in vitro experiments in cardiomyocytes, confirm that after 6 h of simulated ischemia (SI), PTα protein levels are upregulated compared to normoxic cells. Importantly, treatment of cardiomyocytes with a recombinant PTα (rPTα), during SI results in a significant decrease in the apoptotic response and in a robust increase in cell survival. Moreover, these effects are accompanied to a significant preservation of the activated levels of the anti-apoptotic serine-threonine kinase Akt. Consistent with our in vitro observation, rPTα-treated MI mice exhibit a strong reduction in infarct size at 24 h, compared to the MI control group and at the molecular level, PTα treatment induces activation of Akt. The present study provides for the first time the demonstration that PTα offers cardioprotection against ischemic injury by an Akt-dependent mechanism.