Echocardiography combined with cardiopulmonary exercise testing for the prediction of outcome in idiopathic pulmonary arterial hypertension

BACKGROUND: Right ventricular (RV) function is a major determinant of exercise intolerance and outcome in idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to evaluate the incremental prognostic value of echocardiography of the RV and cardiopulmonary exercise testing (CPET) on long-term prognosis in these patients. METHODS: One hundred-thirty treatment-naïve IPAH patients were enrolled and prospectively followed. Clinical worsening (CW) was defined by a reduction in 6-minute walk distance plus an increase in functional class, or non elective hospitalization for PAH, or death. Baseline evaluation included clinical, hemodynamic, echocardiographic and CPET variables. Cox regression modeling with c-statistic and bootstrapping validation methods were done. RESULTS: During a mean period of 528 ± 304 days, 54 patients experienced CW (53%). Among demographic, clinical and hemodynamic variables at catheterization, functional class and cardiac index were independent predictors of CW (Model-1). With addition of echocardiographic and CPET variables (Model-2), peak O2 pulse (peak VO2/heart rate) and RV fractional area change (RVFAC) independently improved the power of the prognostic model (AUC: 0.81 vs 0.66, respectively; p=0.005). Patients with low RVFAC and low O2 pulse (low RVFAC + low O2 pulse) and high RVFAC+low O2 pulse showed 99.8 and 29.4 increase in the hazard ratio, respectively (relative risk -RR- of 41.1 and 25.3, respectively), compared with high RVFAC+high O2 pulse (p=0.0001). CONCLUSIONS: Echocardiography combined with CPET provides relevant clinical and prognostic information. A combination of low RVFAC and low O2 pulse identifies patients at a particularly high risk of clinical deterioration

Human RNASET2: A Highly Pleiotropic and Evolutionary Conserved Tumor Suppressor Gene Involved in the Control of Ovarian Cancer Pathogenesis

Ovarian cancer represents one of the most malignant gynecological cancers worldwide, with an overall 5-year survival rate, being locked in the 25–30% range in the last decade. Cancer immunotherapy is currently one of the most intensively investigated and promising therapeutic strat- egy and as such, is expected to provide in the incoming years significant benefits for ovarian cancer treatment as well. Here, we provide a detailed survey on the highly pleiotropic oncosuppressive roles played by the human RNASET2 gene, whose protein product has been consistently reported to estab- lish a functional crosstalk between ovarian cancer cells and key cellular effectors of the innate immune system (the monocyte/macrophages lineage), which is in turn able to promote the recruitment to the cancer tissue of M1-polarized, antitumoral macrophages. This feature, coupled with the ability of T2 ribonucleases to negatively affect several cancer-related parameters in a cell-autonomous manner on a wide range of ovarian cancer experimental models, makes human RNASET2 a very promising candidate to develop a “multitasking” therapeutic approach for innovative future applications for ovarian cancer treatment

Novel recurrent chromosome anomalies in Shwachman Diamond syndrome

Clonal chromosome anomalies are frequently acquired in the bone marrow (BM) of patients with Shwachman-Diamond syndrome (SDS), and two are the most frequent: an isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q). Patients with SDS have a risk of developing myelodysplasia (MDS) and/or acute myeloid leukaemia (AML), and the presence of chromosome changes was studied in relation with this risk. Starting in 1999 we have monitored the cytogenetic picture of a cohort of 92 Italian patients with SDS by all suitable cytogenetic and molecular methods. Clonal anomalies in BM were present in 41/92 patients. The i(7)(q10) was observed in 16 patients, and the del(20)(q) in 15, both these changes in four, but in independent clones. So, the most frequent clonal anomalies were found in 35 patients. Other, different, clonal anomalies were found in the BM of 13 patients, in eight cases in the absence of i(7)(q10) or del(20)(q), in five cases in association with one of these changes. In these less common clonal anomalies, the distribution of the chromosomes involved was markedly disparate, and some of them were novel and recurrent: - structural rearrangements of chromosome 7, mainly unbalanced (deletions, inversions or translocations), were present in five of our 13 patients, three of whom developed MDS/AML. - a further complex rearrangement of the more common del(20)(q), leading to duplicated and deleted portions, was identical in two patients, with almost identical a-CGH profiles, neither developed MDS/AML. - an unbalanced translocation t(3;6), with partial trisomy of the long arm of chromosome 3 and partial monosomy of the long arm of chromosome 6, was not identical but very similar in two patients, one of whom developed MDS/AML

Comparative genomic hybridization on microarray (a-CGH) in constitutional and acquired mosaicism may detect as low as 8% abnormal cells

<p>Abstract</p> <p>Background</p> <p>The results of cytogenetic investigations on unbalanced chromosome anomalies, both constitutional and acquired, were largely improved by comparative genomic hybridization on microarray (a-CGH), but in mosaicism the ability of a-CGH to reliably detect imbalances is not yet well established. This problem of sensitivity is even more relevant in acquired mosaicism in neoplastic diseases, where cells carrying acquired imbalances coexist with normal cells, in particular when the proportion of abnormal cells may be low.</p> <p>We constructed a synthetic mosaicism by mixing the DNA of three patients carrying altogether seven chromosome imbalances with normal sex-matched DNA. Dilutions were prepared mimicking 5%, 6%, 7%, 8%, 10% and 15% levels of mosaicism. Oligomer-based a-CGH (244 K whole-genome system) was applied on the patients' DNA and customized slides designed around the regions of imbalance were used for the synthetic mosaics.</p> <p>Results and conclusions</p> <p>The a-CGH on the synthetic mosaics proved to be able to detect as low as 8% abnormal cells in the tissue examined. Although in our experiment some regions of imbalances escaped to be revealed at this level, and were detected only at 10-15% level, it should be remarked that these ones were the smallest analyzed, and that the imbalances recurrent as clonal anomalies in cancer and leukaemia are similar in size to those revealed at 8% level.</p

Saharan dust impact in central Italy: An overview on three years elemental data records

In southern European countries, Saharan dust may episodically produce significant increases of PM10, which may also cause the exceedance of the PM10 daily limit value established by the European Directive (2008/50/EC). The detection with very high sensitivity of all the elements that constitute mineral dust makes PIXE technique a very effective tool to assess the actual impact of these episodes. In this work, a review of long-term series of elemental concentrations obtained by PIXE has been accomplished with the aim of identifying the occurrence of Saharan dust transport episodes over long periods in Tuscany and characterising them in terms of composition and impact on PM concentration, tracing back their contribution to the exceedances of the PM10 limit value. The impact of the different Saharan intrusions on PM10 showed a very high variability. During the most intense episodes (which occurred with a frequency of few times per year) the calculated soil dust concentration reached values as high as 25\u201330 \u3bcg m 123, to be compared with background values of the order of 5 \u3bcg m 123. The Saharan dust contribution was decisive to cause the exceedance of the PM10 daily limit value in the 1\u20132% of the days considered in the present work

Chiral recognition by supramolecular porphyrin-hemicucurbit[8]uril-functionalized gravimetric sensors

Enantiorecognition of a chiral analyte usually requiresthe abilityto respond with high specificity to one of the two enantiomers ofa chiral compound. However, in most cases, chiral sensors have chemicalsensitivity toward both enantiomers, showing differences only in theintensity of responses. Furthermore, specific chiral receptors areobtained with high synthetic efforts and have limited structural versatility.These facts hinder the implementation of chiral sensors in many potentialapplications. Here, we utilize the presence of both enantiomers ofeach receptor to introduce a novel normalization that allows the enantio-recognitionof compounds even when single sensors are not specific for one enantiomerof a target analyte. For this purpose, a novel protocol that permitsthe fabrication of a large set of enantiomeric receptor pairs withlow synthetic efforts by combining metalloporphyrins with (R,R)- and (S,S)-cyclohexanohemicucurbit[8]uril is developed. The potentialitiesof this approach are investigated by an array of four pairs of enantiomericsensors fabricated using quartz microbalances since gravimetric sensorsare intrinsically non-selective toward the mechanism of interactionof analytes and receptors. Albeit the weak enantioselectivity of singlesensors toward limonene and 1-phenylethylamine, the normalizationallows the correct identification of these enantiomers in the vaporphase indifferent to their concentration. Remarkably, the achiralmetalloporphyrin choice influences the enantioselective properties,opening the way to easily obtain a large library of chiral receptorsthat can be implemented in actual sensor arrays. These enantioselectiveelectronic noses and tongues may have a potential striking impactin many medical, agrochemical, and environmental fields

Supramolecular amplification of amyloid self-assembly by iodination

Amyloid supramolecular assemblies have found widespread exploitation as ordered nanomaterials in a range of applications from materials science to biotechnology. New strategies are, however, required for understanding and promoting mature fibril formation from simple monomer motifs through easy and scalable processes. Noncovalent interactions are key to forming and holding the amyloid structure together. On the other hand, the halogen bond has never been used purposefully to achieve control over amyloid self-assembly. Here we show that single atom replacement of hydrogen with iodine, a halogen-bond donor, in the human calcitonin-derived amyloidogenic fragment DFNKF results in a super-gelator peptide, which forms a strong and shape-persistent hydrogel at 30-fold lower concentration than the wild-type pentapeptide. This is remarkable for such a modest perturbation in structure. Iodination of aromatic amino acids may thus develop as a general strategy for the design of new hydrogels from unprotected peptides and without using organic solvents

OTX Genes in Adult Tissues

OTX homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. reactivation of OTX genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the "toolbox" to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets

Comparative small angle neutron scattering (SANS) study of Eurofer97 steel neutron irradiated in mixed (HFR) and fast spectra (BOR60) reactors

AbstractThis contribution presents a comparative microstructural investigation, carried out by Small-Angle Neutron Scattering (SANS), of ferritic/martensitic steel Eurofer97 (0.12 C, 9 Cr, 0.2V, 1.08Wwt%) neutron irradiated at two different neutron sources, the HFR-Petten (SPICE experiment) and the BOR60 reactor (ARBOR experiment). The investigated “SPICE” sample had been irradiated to 16dpa at 250°C, the investigated “ARBOR” one had been irradiated to 32dpa at 330°C. The SANS measurements were carried under a 1 T magnetic field to separate nuclear and magnetic SANS components; a reference, un-irradiated Eurofer sample was also measured to evaluate as accurately as possible the genuine effect of the irradiation on the microstructure. The detected increase in the respective SANS cross-sections of these two samples under irradiation is attributed primarily to the presence of micro-voids, for neutron contrast reasons; it is quite similar in the two samples, despite the higher irradiation dose and temperature of the “ARBOR” sample with respect to the “SPICE” one. This is tentatively correlated with the higher helium content produced under HFR irradiation, playing an important role to stabilize the micro-voids under irradiation. In fact, the size distributions obtained by transformation of the SANS data yield a micro-void volume fraction of 1.3% for the “SPICE” sample and of 0.6% for the “ARBOR” one

Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects

14noopenShwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.openFrattini, Annalisa; Bolamperti, Simona; Valli, Roberto; Cipolli, Marco; Pinto, Rita Maria; Bergami, Elena; Frau, Maria Rita; Cesaro, Simone; Signo, Michela; Bezzerri, Valentino; Porta, Giovanni; Khan, Abdul Waheed; Rubinacci, Alessandro; Villa, IsabellaFrattini, Annalisa; Bolamperti, Simona; Valli, Roberto; Cipolli, Marco; Pinto, Rita Maria; Bergami, Elena; Frau, Maria Rita; Cesaro, Simone; Signo, Michela; Bezzerri, Valentino; Porta, Giovanni; Khan, Abdul Waheed; Rubinacci, Alessandro; Villa, Isabell