Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma.

BACKGROUND: Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC). METHODS: Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months. RESULTS: Median pretherapeutic serum GGT level was 25 U l(-1). Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l(-1) was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l(-1)), normal high (17.5 to <34.5 U l(-1)), elevated (34.5 to <181.5 U l(-1)), and highly elevated (⩾181.5 U l(-1)). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit. CONCLUSIONS: Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design

RNA from LPS-stirnulated macrophages induces the release of tumour necrosis factor-α and interleukin-1 by resident macrophages

The effect of exogenous RNA on many cellular functions has been studied in a variety of eukaryotic cells but there are few reports on macrophages. In the present study, it is demonstrated that cytoplasmatic RNA extracted from rat macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L-RNA, induced the release of TNF-α and IL-1 from monolayers of peritoneal resident macrophages. The activity of L-RNA was not altered by polymyxin B but was abolished by ribonuclease (RNase) pretreatment, indicating the absence of LPS contamination and that the integrity of the polynucleotide chain is essential for this activity. Both the poly A(−) and poly A(+) fractions obtained from L-RNA applied to oligo(dT)–cellulose chromatography induced TNF-α and IL-1 release. The L-RNA-induced cytokine release was inhibited by dexamethasone and seemed to be dependent on protein synthesis since this effect was abolished by cycloheximide or actinomycin-D. The LPS-stimulated macrophages, when pre-incubated with [5-3H]-uridine, secreted a trichloroacetic acid (TCA) precipitable material which was sensitive to RNase and KOH hydrolysis, suggesting that the material is RNA. This substance was also released from macrophage monolayers stimulated with IL-1β but not with TNF-α, IL-6 or IL-8. The substance secreted (3H-RNA) sediments in the 4–5S region of a 5–20% sucrose gradient. These results show that L-RNA induces cytokine secretion by macrophage monolayers and support the idea that, during inflammation, stimulated macrophages could release RNA which may further induce the release of cytokines by the resident cell population

Metal-catalyzed asymmetric aldol reactions

The aldol reaction is one of the most powerful and versatile methods for the construction of C-C bonds. Traditionally, this reaction was developed in a stoichiometric version; however, great efforts in the development of chiral catalysts for aldol reactions were performed in recent years. Thus, in this review article, the development of metal-mediated chiral catalysts in Mukaiyama-type aldol reaction, reductive aldol reaction and direct aldol reaction are discussed. Moreover, the application of these catalysts in the total synthesis of complex molecules is discussed.A reação aldólica é uma das ferramentas mais poderosas e versáteis para a construção de ligações C-C. Tradicionalmente, esta reação foi desenvolvida em sua versão estequiométrica, no entanto, grandes esforços no desenvolvimento de catalisadores quirais para reações aldólicas foram realizados nos últimos anos. Desta forma, neste artigo de revisão, é discutido o desenvolvimento de catalisadores metálicos em reação aldólica do tipo Mukaiyama, reação aldólica redutiva e reação aldólica direta. Além disto, a aplicação destes catalisadores na síntese total de moléculas complexas será abordada.21372158Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Associations Between Presenting Symptoms, Clinicopathological Parameters, and Prognosis in a Contemporary Series of Patients With Renal Cell Carcinoma

PURPOSE: To evaluate the impact of presenting symptoms on survival in a contemporary series of patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: We prospectively recorded data on the presenting symptoms, pathology, and RCC-specific survival of 633 consecutive RCC patients who underwent surgery between 2003 and 2012. RESULTS: Four hundred thirty-three RCCs (68%) were incidental, 111 (18%) were associated with local symptoms, and 89 (14%) were associated with systemic symptoms. Among those with incidental RCC, 317 patients (73%) were completely asymptomatic and 116 patients (27%) presented with symptoms not related to the tumor. During a median follow-up interval of 40 months (interquartile range: 39 to 69 months), 77 patients died from RCC. In univariate analyses, symptom classification was significantly associated with RCC-specific survival (p<0.001). Patients with incidental RCC and unrelated symptoms tended to have worse prognosis than did patients who were completely asymptomatic, although this difference was not statistically significant (p=0.057). The symptom classification was associated with advanced TNM stages (p<0.001) and grade (p<0.001). CONCLUSIONS: This study confirms that presenting symptoms are associated with tumor characteristics and survival. The majority of RCCs are diagnosed incidentally in patients without any symptoms or with symptoms not related to RCC. Patients in the latter group tend to have a worse prognosis than do patients who are completely asymptomatic. With the increasing number of incidentally diagnosed RCCs, substratification of patients with incidental tumors may be prognostically relevant

Differential expression of microRNAs in mouse pain models

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are short non-coding RNAs that inhibit translation of target genes by binding to their mRNAs. The expression of numerous brain-specific miRNAs with a high degree of temporal and spatial specificity suggests that miRNAs play an important role in gene regulation in health and disease. Here we investigate the time course gene expression profile of miR-1, -16, and -206 in mouse dorsal root ganglion (DRG), and spinal cord dorsal horn under inflammatory and neuropathic pain conditions as well as following acute noxious stimulation.</p> <p>Results</p> <p>Quantitative real-time polymerase chain reaction analyses showed that the mature form of miR-1, -16 and -206, is expressed in DRG and the dorsal horn of the spinal cord. Moreover, CFA-induced inflammation significantly reduced miRs-1 and -16 expression in DRG whereas miR-206 was downregulated in a time dependent manner. Conversely, in the spinal dorsal horn all three miRNAs monitored were upregulated. After sciatic nerve partial ligation, miR-1 and -206 were downregulated in DRG with no change in the spinal dorsal horn. On the other hand, axotomy increases the relative expression of miR-1, -16, and 206 in a time-dependent fashion while in the dorsal horn there was a significant downregulation of miR-1. Acute noxious stimulation with capsaicin also increased the expression of miR-1 and -16 in DRG cells but, on the other hand, in the spinal dorsal horn only a high dose of capsaicin was able to downregulate miR-206 expression.</p> <p>Conclusions</p> <p>Our results indicate that miRNAs may participate in the regulatory mechanisms of genes associated with the pathophysiology of chronic pain as well as the nociceptive processing following acute noxious stimulation. We found substantial evidence that miRNAs are differentially regulated in DRG and the dorsal horn of the spinal cord under different pain states. Therefore, miRNA expression in the nociceptive system shows not only temporal and spatial specificity but is also stimulus-dependent.</p

Expression and cellular localization of microRNA-29b and RAX, an activator of the RNA-dependent protein kinase (PKR), in the retina of streptozotocin-induced diabetic rats

Purpose: The apoptosis of retinal neurons plays a critical role in the pathogenesis of diabetic retinopathy (DR), but the molecular mechanisms underlying this phenomenon remain unclear. The purpose of this study was to investigate the cellular localization and the expression of microRNA-29b (miR-29b) and its potential target PKR associated protein X (RAX), an activator of the pro-apoptotic RNA-dependent protein kinase (PKR) signaling pathway, in the retina of normal and diabetic rats. Methods: Retinas were obtained from normal and diabetic rats within 35 days after streptozotocin (STZ) injection. In silico analysis indicated that RAX is a potential target of miR-29b. The cellular localization of miR-29b and RAX was assessed by in situ hybridization and immunofluorescence, respectively. The expression levels of miR-29b and RAX mRNA were evaluated by quantitative reverse transcription PCR (qRT-PCR), and the expression of RAX protein was evaluated by western blot. A luciferase reporter assay and inhibition of endogenous RAX were performed to confirm whether RAX is a direct target of miR-29b as predicted by the in silico analysis. Results: We found that miR-29b and RAX are localized in the retinal ganglion cells (RGCs) and the cells of the inner nuclear layer (INL) of the retinas from normal and diabetic rats. Thus, the expression of miR-29b and RAX, as assessed in the retina by quantitative RT-PCR, reflects their expression in the RGCs and the cells of the INL. We also revealed that RAX protein is upregulated (more than twofold) at 3, 6, 16, and 22 days and downregulated (70%) at 35 days, whereas miR-29b is upregulated (more than threefold) at 28 and 35 days after STZ injection. We did not confirm the computational prediction that RAX is a direct target of miR-29b. Conclusions: Our results suggest that RAX expression may be indirectly regulated by miR-29b, and the upregulation of this miRNA at the early stage of STZ-induced diabetes may have a protective effect against the apoptosis of RGCs and cells of the INL by the pro-apoptotic RNA-dependent protein kinase (PKR) signaling pathway.FAPESP[08/58325-4]FAPESP[08/50294-2]Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Resilience, Cardiological Outcome, and Their Correlations With Anxious-Depressive Symptoms and Quality of Life in Patients With an Implantable Cardioverter Defibrillator

Background: Resilience is proven as a protective factor against the development of psychiatric disorders, and it has gained clinical relevance in the development and progression of cardiovascular pathology. The authors performed a longitudinal study on patients with implantable cardioverter defibrillator (ICD) with the primary aim to highlight the possible existence of a correlation between individual resilience capacity, depressive and anxiety symptoms, and quality of life in terms of outcomes. The secondary aim was to analyze the differences between patients with major cardiac events in the follow-up and patients without cardiac events with respect to the previous variables. Materials and Methods: A total of 80 patients enrolled in the Cardiology Unit were evaluated at T0 and during the follow-up through the following scales: the 14-item Resilience Scale (RS-14), the Hospital Anxiety and Depression Scale (HADS), and the World Health Organization Quality of Life-Brief Version (WHOQOL-Bref). Results: A significant linear correlation between resilience and all the areas of quality of life at T0, T1, and T2 emerged. A negative correlation between resilience and anxiety and depressive symptoms emerged, as well as between depression and anxiety and quality of life. Patients with cardiac events during the follow up have shown a worse quality of life and the onset of anxiety-depressive symptoms over time, without changes to the resilience scores. Patients without cardiac events showed an increasing trend in resilience scores. Discussion: Given the speed and simplicity of use of the RS-14 scale, it seems promising to further investigate the real clinical usefulness of this instrument in the cardiology field

Permittivity-asymmetric quasi-bound states in the continuum

Broken symmetries lie at the heart of nontrivial physical phenomena. Breaking the in-plane geometrical symmetry of optical systems allows to access a set of electromagnetic states termed symmetry-protected quasi-bound states in the continuum (qBICs). Here we demonstrate, theoretically, numerically and experimentally, that such optical states can also be accessed in metasurfaces by breaking the in-plane symmetry in the permittivity of the comprising materials, showing a remarkable equivalence to their geometrically-asymmetric counterparts. However, while the physical size of atoms imposes a limit on the lowest achievable geometrical asymmetry, weak permittivity modulations due to carrier doping and electro-optical Pockels and Kerr effects, usually considered insignificant, open up the possibility of infinitesimal permittivity asymmetries for on-demand, and dynamically tuneable optical resonances of extremely high quality factors. We probe the excitation of permittivity-asymmetric qBICs (${\varepsilon}$-qBICs) using a prototype Si/TiO$_{2}$ metasurface, in which the asymmetry in the unit cell is provided by the refractive index contrast of the dissimilar materials, surpassing any unwanted asymmetries from nanofabrication defects or angular deviations of light from normal incidence. ${\varepsilon}$-qBICs can also be excited in 1D gratings, where quality-factor enhancement and tailored interference phenomena via the interplay of geometrical and permittivity asymmetries are numerically demonstrated. The emergence of ${\varepsilon}$-qBICs in systems with broken symmetries in their permittivity may enable to test time-energy uncertainties in quantum mechanics, and lead to a whole new class of low-footprint optical and optoelectronic devices, from arbitrarily narrow filters and topological sources, biosensing and ultrastrong light-matter interaction platforms, to tuneable optical switches.Comment: Manuscript and Supplementary Information, 27 pages, 4 Figures manuscript + 4 Supplementary Figure