Despite several advances in medicine, ischaemic heart disease remains a major cause of morbidity and mortality. The unravelling of molecular mechanisms underlying disease pathophysiology has revealed ...targets for pharmacological interventions. However, transfer of these pharmcological possibilities to clinical use has been disappointing. Considering the complexity of ischaemic disease at the cellular and molecular levels, an equally multifaceted treatment approach may be envisioned. The pharmacological principle of ‘one target, one key’ may fall short in such contexts, and optimal treatment may involve one or many agents directed against complementary targets. Here, we introduce a ‘multi‐target approach to cardioprotection’ and propose heat shock protein 90 (HSP90) as a target of interest. We report on a member of a distinct class of HSP90 inhibitor possessing pleiotropic activity, which we found to exhibit potent infarct‐sparing effects.
The aim of the study was to evaluate the interest of quantitative bone SPECT-CT in the preoperative assessment of knee osteoarthritis (OA) before unicompartmental knee arthroplasty (UKA).Patients ...eligible for UKA were prospectively included in 2 centers and underwent a preoperative SPECT-CT. Images were reconstructed with an OSEM, an OSCGM (allowing SUV quantification) and an enhanced OSCGM (containing uptakes to bones) algorithms. Visual analysis and quantification (SUVmax) were performed for each compartment (medial compartment MC, lateral compartment LC, and patellofemoral compartment PFC). Clinical data were preoperatively assessed. The gold standard was the per-operative OA staging (International Cartilage Repair Society ICRS scale). Spearman's correlation coefficient was used for correlations. Sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and accuracy of SPECT-CT were assessed.One hundred three patients (50 women, 53 men, mean age = 64.5 ± 10.3 y/o, 120 preoperative knees) were analyzed. There was no correlation between SUVmax and clinical data. There was a correlation between ICRS staging and SUVmax with both OSCGM (MC rs = 0.25, LC rs = 0.51, and PFC rs = 0.27), and enhanced OSCGM, except in the PFC (MC rs = 0.22, LC rs = 0.62, and PFC rs = 0.03). The Se, Sp, PPV, NPV, and accuracy of SPECT-CT were, respectively, 0.99, 0.67, 0.98, 0.80, 0.97 for the MC; 0.50, 0.85, 0.42, 0.89, 0.79 for the LC; and 0.23, 0.86, 0.50, 0.64, 0.62 for the PFC.Bone SPECT-CT SUVmax is correlated with per-operative OA staging. Despite the low sensitivity of SPECT-CT in the LC, its high specificity in the LC should prompt the surgeon to be vigilant before UKA surgery.
BACKGROUND:Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and ...atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined.
METHODS:Adcy9-inactivated (Adcy9) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtgAdcy9 and CETPtgAdcy9), were submitted to an atherogenic protocol (injection of an AAV8 adeno-associated virus serotype 8 expressing a PCSK9 proprotein convertase subtilisin/kexin type 9 gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated.
RESULTS:Adcy9 mice had a 65% reduction in aortic atherosclerosis compared to WT (P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9 mice compared to WT animals (P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9 mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9 (P<0.01 for all). Aortic endothelium from Adcy9 mice allowed significantly less adhesion of splenocytes compared to WT (P<0.05). Adcy9 mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume (P<0.01 for both). Feed efficiency was increased in Adcy9 compared to WT mice (P<0.01), which was accompanied by prolonged cardiac RR interval (P<0.05) and improved nocturnal heart rate variability (P=0.0572). Adcy9 inactivation–induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtgAdcy9 mice (P>0.05 versus CETPtgAdcy9).
CONCLUSIONS:Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.
Abstract only Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib on cardiovascular events, ...atherosclerosis imaging and body weight variation. The underlying mechanisms responsible for the interactions between ADCY9 and CETP have not yet been determined. Adcy9 -inactivated ( Adcy9 Gt/Gt ) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETP Gt and CETP WT ), were submitted to an atherogenic protocol (injection of an AAV8 expressing a PCSK9 gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, cell adhesion, vasorelaxation, telemetry and adipose tissue MRI were evaluated. Adcy9 Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P <0.01). CD68-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9 Gt/Gt mice compared to WT animals ( P <0.05 for both). Adcy9 inactivation did not change counts of blood monocytes and their subsets. Splenocytes showed reduced adhesion to native aortic endothelium from Adcy9 Gt/Gt mice ( P <0.05 vs WT). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9 Gt/Gt mice (versus WT, P <0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase and endothelial-dependent hyperpolarization pathways all contributed to the improvement of vasodilatation in Adcy9 Gt/Gt versus WT ( P <0.01 for all). Adcy9 Gt/Gt mice gained more weight than WT with the atherogenic diet, and this was associated with an increase in whole body adipose tissue volume ( P <0.05 for both). Feed efficiency was increased in Adcy9 Gt/Gt compared to WT mice ( P <0.05), which was accompanied by improved nocturnal heart rate variability ( P =0.0572) and prolonged cardiac RR interval ( P <0.05). Adcy9 inactivation-induced effects on atherosclerosis, endothelium-dependent vasodilation, weight gain and feed efficiency were lost in CETP Gt mice ( P >0.05 vs CETP WT ). Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, improved endothelial function and autonomic tone.
Single nucleotide polymorphisms located in the adenylate cyclase type 9 (ADCY9) gene determine cardiovascular outcomes of patients treated with dalcetrapib, a cholesteryl ester transfer protein ...inhibitor (Tardif et al, Circ Cardiovasc Genetics 2015). The roles of the different subtypes of adenylate cyclases responsible for vasodilatation (VD) are ill-defined. We aimed at evaluating the role of Adcy9 expression in the control of vascular tone by using isolated vessels from Adcy9-inactivated (Adcy9Gt) and wild-type (WT) mice. Vasomotor tone was studied by recording the isometric tension developed by aorta rings and the diameter of pressurized isolated femoral arteries from mice aged 8 to 13 weeks. We studied VD in response to adenylate cyclase activators, isoproterenol (Iso), a β-adrenergic receptor (β-AR) agonist and iloprost, a prostaglandin I2 receptor agonist, as well as endothelial-dependent vasodilatation (EDV) in response to acetylcholine (Ach). EDV and β-AR-induced VD in the aorta were similar in WT and Adcy9Gt mice. In femoral arteries, Adcy9 inactivation decreased Iso-induced VD (Emax, WT48.3+/-4.7%, n=7; Adcy9Gt24.1+/-4.7%, n=11; P<0.01). In contrast, Iloprost-induced VD was not modified by Adcy9 inactivation (Emax, WT35.1+/-6.6%, n=7; Adcy9Gt39.5+/-5.6%, n=8). Surprisingly, Ach-induced VD was potentiated by Adcy9 inactivation in femoral arteries (Emax, WT57.3+/-8.0%, n=11; Adcy9Gt84.7+/-4.2%, n=14, P<0.01). This potentiation was specific to endothelial function as endothelial-independent VD with nitroprusside was similar in WT (Emax, 70.5+/-5.7%, n=4) and Adcy9Gt (Emax, 88.2+/-5.9%, n=6) mice. Our results demonstrate that Adcy9 expression mediates the control of vascular tone in mouse femoral arteries. Adcy9 function is specific to the vascular bed studied and its expression inhibits endothelial-dependent vasodilatation and mediates that induced by β-adrenergic agonism. These findings suggest that Adcy9 function might be involved in the genotype-dependent effects of dalcetrapib on cardiovascular outcomes.
Objective Robotic mitral valve repair is the least invasive approach to mitral valve repair, yet there are few data comparing its outcomes with those of conventional approaches. Therefore, we ...compared outcomes of robotic mitral valve repair with those of complete sternotomy, partial sternotomy, and right mini-anterolateral thoracotomy. Methods From January 2006 to January 2009, 759 patients with degenerative mitral valve disease and posterior leaflet prolapse underwent primary isolated mitral valve surgery by complete sternotomy (n = 114), partial sternotomy (n = 270), right mini-anterolateral thoracotomy (n = 114), or a robotic approach (n = 261). Outcomes were compared on an intent-to-treat basis using propensity-score matching. Results Mitral valve repair was achieved in all patients except 1 patient in the complete sternotomy group. In matched groups, median cardiopulmonary bypass time was 42 minutes longer for robotic than complete sternotomy, 39 minutes longer than partial sternotomy, and 11 minutes longer than right mini-anterolateral thoracotomy ( P < . 0001); median myocardial ischemic time was 26 minutes longer than complete sternotomy and partial sternotomy, and 16 minutes longer than right mini-anterolateral thoracotomy ( P < . 0001). Quality of mitral valve repair was similar among matched groups ( P = .6, .2, and .1, respectively). There were no in-hospital deaths. Neurologic, pulmonary, and renal complications were similar among groups ( P > .1). The robotic group had the lowest occurrences of atrial fibrillation and pleural effusion, contributing to the shortest hospital stay (median 4.2 days), 1.0, 1.6, and 0.9 days shorter than for complete sternotomy, partial sternotomy, and right mini-anterolateral thoracotomy (all P < .001), respectively. Conclusions Robotic repair of posterior mitral valve leaflet prolapse is as safe and effective as conventional approaches. Technical complexity and longer operative times for robotic repair are compensated for by lesser invasiveness and shorter hospital stay.
Arc lavas display elevated Fe3+/ΣFe ratios relative to MORB. One mechanism to explain this is the mobilization and transfer of oxidized or oxidizing components from the subducting slab to the mantle ...wedge. Here we use iron and zinc isotopes, which are fractionated upon complexation by sulfide, chloride, and carbonate ligands, to remark on the chemistry and oxidation state of fluids released during prograde metamorphism of subducted oceanic crust. We present data for metagabbros and metabasalts from the Chenaillet massif, Queyras complex, and the Zermatt‐Saas ophiolite (Western European Alps), which have been metamorphosed at typical subduction zone P‐T conditions and preserve their prograde metamorphic history. There is no systematic, detectable fractionation of either Fe or Zn isotopes across metamorphic facies, rather the isotope composition of the eclogites overlaps with published data for MORB. The lack of resolvable Fe isotope fractionation with increasing prograde metamorphism likely reflects the mass balance of the system, and in this scenario Fe mobility is not traceable with Fe isotopes. Given that Zn isotopes are fractionated by S‐bearing and C‐bearing fluids, this suggests that relatively small amounts of Zn are mobilized from the mafic lithologies in within these types of dehydration fluids. Conversely, metagabbros from the Queyras that are in proximity to metasediments display a significant Fe isotope fractionation. The covariation of δ56Fe of these samples with selected fluid mobile elements suggests the infiltration of sediment derived fluids with an isotopically light signature during subduction.
Key Points
Iron and zinc stable isotope and elemental data are presented for a prograde suite of metabasalts and metagabbros from Western Alpine ophiolite complexes
Bulk rock δ56Fe and δ66Zn do not vary across metamorphic facies and the eclogitic samples show a MORB‐like isotope composition
Blueschist facies metagabbros preserve evidence for infiltration of sediment derived fluids that impart a light δ56Fe isotope composition to the gabbro
IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the ...evolutionary history of CA-CRC using multiregion sequencing.
Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC.
10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated 'catastrophic' CNA increase.
Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and ...invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.
Levamisole-sensitive acetylcholine receptors (L-AChRs) are ligand-gated ion channels that mediate excitatory neurotransmission at the neuromuscular junctions of nematodes. They constitute a major ...drug target for anthelminthic treatments because they can be activated by nematode-specific cholinergic agonists such as levamisole. Genetic screens conducted in Caenorhabditis elegans for resistance to levamisole toxicity identified genes that are indispensable for the biosynthesis of L-AChRs. These include 5 genes encoding distinct AChR subunits and 3 genes coding for ancillary proteins involved in assembly and trafficking of the receptors. Despite extensive analysis of L-AChRs in vivo, pharmacological and biophysical characterization of these receptors has been greatly hampered by the absence of a heterologous expression system. Using Xenopus laevis oocytes, we were able to reconstitute functional L-AChRs by coexpressing the 5 distinct receptor subunits and the 3 ancillary proteins. Strikingly, this system recapitulates the genetic requirements for receptor expression in vivo because omission of any of these 8 genes dramatically impairs L-AChR expression. We demonstrate that 3 α- and 2 non-α-subunits assemble into the same receptor. Pharmacological analysis reveals that the prototypical cholinergic agonist nicotine is unable to activate L-AChRs but rather acts as a potent allosteric inhibitor. These results emphasize the role of ancillary proteins for efficient expression of recombinant neurotransmitter receptors and open the way for in vitro screening of novel anthelminthic agents.
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