RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response

Chromosomal region 1p22 is deleted in 6520% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to bortezomib and; both in newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the role of these genes in promoting MM progression remains to be determined, we identify RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients

Continuum of vasodilator stress from rest to contrast medium to adenosine hyperemia for fractional flow reserve assessment

Objectives: This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). Background: FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. Methods: We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. Results: A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. Conclusions: cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement

A Screen for Genes Expressed in the Olfactory Organs of Drosophila melanogaster Identifies Genes Involved in Olfactory Behaviour

BACKGROUND: For insects the sense of smell and associated olfactory-driven behaviours are essential for survival. Insects detect odorants with families of olfactory receptor proteins that are very different to those of mammals, and there are likely to be other unique genes and genetic pathways involved in the function and development of the insect olfactory system. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a genetic screen of a set of 505 Drosophila melanogaster gene trap insertion lines to identify novel genes expressed in the adult olfactory organs. We identified 16 lines with expression in the olfactory organs, many of which exhibited expression of the trapped genes in olfactory receptor neurons. Phenotypic analysis showed that six of the lines have decreased olfactory responses in a behavioural assay, and for one of these we showed that precise excision of the P element reverts the phenotype to wild type, confirming a role for the trapped gene in olfaction. To confirm the identity of the genes trapped in the lines we performed molecular analysis of some of the insertion sites. While for many lines the reported insertion sites were correct, we also demonstrated that for a number of lines the reported location of the element was incorrect, and in three lines there were in fact two pGT element insertions. CONCLUSIONS/SIGNIFICANCE: We identified 16 new genes expressed in the Drosophila olfactory organs, the majority in neurons, and for several of the gene trap lines demonstrated a defect in olfactory-driven behaviour. Further characterisation of these genes and their roles in olfactory system function and development will increase our understanding of how the insect olfactory system has evolved to perform the same essential function to that of mammals, but using very different molecular genetic mechanisms

Rationale and design of the precise percutaneous coronary intervention plan (P3) study. Prospective evaluation of a virtual computed tomography-based percutaneous intervention planner

Introduction: Fractional flow reserve (FFR) measured after percutaneous coronary intervention (PCI) has been identified as a surrogate marker for vessel related adverse events. FFR can be derived from standard coronary computed tomography angiography (CTA). Moreover, the FFR derived from coronary CTA (FFRCT) Planner is a tool that simulates PCI providing modeled FFRCT values after stenosis opening. Aim: To validate the accuracy of the FFRCT Planner in predicting FFR after PCI with invasive FFR as a reference standard. Methods: Prospective, international and multicenter study of patients with chronic coronary syndromes undergoing PCI. Patients will undergo coronary CTA with FFRCT prior to PCI. Combined morphological and functional evaluations with motorized FFR hyperemic pullbacks, and optical coherence tomography (OCT) will be performed before and after PCI. The FFRCT Planner will be applied by an independent core laboratory blinded to invasive data, replicating the invasive procedure. The primary objective is to assess the agreement between the predicted FFRCT post-PCI derived from the Planner and invasive FFR. A total of 127 patients will be included in the study. Results: Patient enrollment started in February 2019. Until December 2020, 100 patients have been included. Mean age was 64.1 ± 9.03, 76% were males and 24% diabetics. The target vessels for PCI were LAD 83%, LCX 6%, and RCA 11%. The final results are expected in 2021. Conclusion: This study will determine the accuracy and precision of the FFRCT Planner to predict post-PCI FFR in patients with chronic coronary syndromes undergoing percutaneous revascularization

A Family of Chemoreceptors in Tribolium castaneum (Tenebrionidae: Coleoptera)

Chemoperception in invertebrates is mediated by a family of G-protein-coupled receptors (GPCR). To date nothing is known about the molecular mechanisms of chemoperception in coleopteran species. Recently the genome of Tribolium castaneum was sequenced for use as a model species for the Coleoptera. Using blast searches analyses of the T. castaneum genome with previously predicted amino acid sequences of insect chemoreceptor genes, a putative chemoreceptor family consisting of 62 gustatory receptors (Grs) and 26 olfactory receptors (Ors) was identified. The receptors have seven transmembrane domains (7TMs) and all belong to the GPCR receptor family. The expression of the T. castaneum chemoreceptor genes was investigated using quantification real- time RT-PCR and in situ whole mount RT-PCR analysis in the antennae, mouth parts, and prolegs of the adults and larvae. All of the predicted TcasGrs were expressed in the labium, maxillae, and prolegs of the adults but TcasGr13, 19, 28, 47, 62, 98, and 61 were not expressed in the prolegs. The TcasOrs were localized only in the antennae and not in any of the beetles gustatory organs with one exception; the TcasOr16 (like DmelOr83b), which was localized in the antennae, labium, and prolegs of the beetles. A group of six TcasGrs that presents a lineage with the sugar receptors subfamily in Drosophila melanogaster were localized in the lacinia of the Tribolium larvae. TcasGr1, 3, and 39, presented an ortholog to CO2 receptors in D. melanogaster and Anopheles gambiae was recorded. Low expression of almost all of the predicted chemoreceptor genes was observed in the head tissues that contain the brains and suboesophageal ganglion (SOG). These findings demonstrate the identification of a chemoreceptor family in Tribolium, which is evolutionarily related to other insect species

Residual plaque burden in patients with acute coronary syndromes after successful percutaneous coronary intervention

Objectives: The aim of this study was to characterize and evaluate the clinical impact of untreated atherosclerotic disease after percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS). Background: Residual atherosclerotic disease after successful PCI may predispose future major adverse cardiovascular events (MACE). Compared with intravascular ultrasound (IVUS), angiography underestimates the presence and severity of coronary artery disease. Methods: Following successful PCI of all clinically significant lesions in 697 patients with ACS, 3-vessel grayscale and radiofrequency IVUS was performed. Lesions were prospectively characterized, and patients were followed for a median of 3.4 years. A total of 3,229 untreated lesions (4.89 ± 1.98 lesions/patient) were identified by IVUS, with mean plaque burden (PB) of 49.6 ± 4.2%. Results: By angiography these nonculprit lesions were mild, with mean diameter stenosis of 38.9 ± 15.3%. At least 1 lesion with a PB <70% (PB70 lesion) was found in 220 (33%) patients. By multivariable analysis, a history of prior PCI and angiographic 3-vessel disease were independent predictors of PB70 lesions. Patients with PB70 lesions had greater total percent plaque volume, normalized PB, fibroatheromas, thin-cap fibroatheromas, and normalized volumes of necrotic core and dense calcium. Patients with PB70 lesions had greater 3-year rates of MACE due to untreated nonculprit lesions (20.8% vs. 7.7%, p < 0.0001). Among imaged nonculprit lesions, the proportion of PB70 lesions causing MACE was significantly greater than non-PB70 lesions (8.7% vs. 1.0%, p < 0.0001). Conclusions: After successful PCI of all angiographically significant lesions, overall untreated atherosclerotic burden remains high, and PB70 lesions are frequently present in the proximal and mid-coronary tree. Patients with PB70 lesions have greater atherosclerosis throughout the coronary tree, have more thin-cap fibroatheromas, and are at increased risk for future cardiovascular events. (PROSPECT: An Imaging Study in Patients With Unstable Atherosclerotic Lesions; NCT00180466

Renal artery stenosis-when to screen, what to stent?

Renal artery stensosis (RAS) continues to be a problem for clinicians, with no clear consensus on how to investigate and assess the clinical significance of stenotic lesions and manage the findings. RAS caused by fibromuscular dysplasia is probably commoner than previously appreciated, should be actively looked for in younger hypertensive patients and can be managed successfully with angioplasty. Atheromatous RAS is associated with increased incidence of cardiovascular events and increased cardiovascular mortality, and is likely to be seen with increasing frequency. Evidence from large clinical trials has led clinicians away from recommending interventional revascularisation towards aggressive medical management. There is now interest in looking more closely at patient selection for intervention, with focus on intervening only in patients with the highest-risk presentations such as flash pulmonary oedema, rapidly declining renal function and severe resistant hypertension. The potential benefits in terms of improving hard cardiovascular outcomes may outweigh the risks of intervention in this group, and further research is needed

Hedonic Taste in Drosophila Revealed by Olfactory Receptors Expressed in Taste Neurons

Taste and olfaction are each tuned to a unique set of chemicals in the outside world, and their corresponding sensory spaces are mapped in different areas in the brain. This dichotomy matches categories of receptors detecting molecules either in the gaseous or in the liquid phase in terrestrial animals. However, in Drosophila olfactory and gustatory neurons express receptors which belong to the same family of 7-transmembrane domain proteins. Striking overlaps exist in their sequence structure and in their expression pattern, suggesting that there might be some functional commonalities between them. In this work, we tested the assumption that Drosophila olfactory receptor proteins are compatible with taste neurons by ectopically expressing an olfactory receptor (OR22a and OR83b) for which ligands are known. Using electrophysiological recordings, we show that the transformed taste neurons are excited by odor ligands as by their cognate tastants. The wiring of these neurons to the brain seems unchanged and no additional connections to the antennal lobe were detected. The odor ligands detected by the olfactory receptor acquire a new hedonic value, inducing appetitive or aversive behaviors depending on the categories of taste neurons in which they are expressed i.e. sugar- or bitter-sensing cells expressing either Gr5a or Gr66a receptors. Taste neurons expressing ectopic olfactory receptors can sense odors at close range either in the aerial phase or by contact, in a lipophilic phase. The responses of the transformed taste neurons to the odorant are similar to those obtained with tastants. The hedonic value attributed to tastants is directly linked to the taste neurons in which their receptors are expressed

The scope of language contact as a constraint factor in language change: The periphrasis haber de plus infinitive in a corpus of language immediacy in modern Spanish

In this work an empirical study grounded in the principles and methods of the comparative variationist framework is conducted to measure the scope of language contact as a factor constraining some potentially diverging uses of a Spanish verbal periphrasis that has undergone a sharp decline over the last century (haber de plus infinitive). The analysis is based on three independent samples of text that correspond to three dialectal areas of peninsular Spanish (monolingual zones, Catalan-speaking linguistic territories and the north-western linguistic area). These samples, extracted from a corpus made up of texts of communicative immediacy from the 19th and the first half of the 20th centuries, confirm the existence of a certain linguistic convergence in the expressive habits of the speakers in the bilingual communities. In each region, however, the outcomes are different, due to parallel differences in the structural position of the periphrasis in each language. However, a thorough analysis of the variable context that surrounds the periphrasis shows that the observed differences do not affect the essence of the underlying grammar of this variant, whose decline (which favours tener que plus infinitive and becomes faster as the 20th century advances) is constrained by identical linguistic and extralinguistic conditioning factors in all the dialectal areas

Prognostic value of fractional flow reserve: Linking physiologic severity to clinical outcomes

BACKGROUND: Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear.OBJECTIVES: The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization.METHODS: Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold.RESULTS: A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief.CONCLUSIONS: FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy