Combining olfactory test and motion analysis sensors in Parkinson's disease preclinical diagnosis: A pilot study

Objectives: Preclinical diagnosis of Parkinson's disease (PD) is nowadays a topic of interest as the neuropathological process could begin years before the appearance of motor symptoms. Several symptoms, among them hyposmia, could precede motor features in PD. In the preclinical phase of PD, a subclinical reduction in motor skills is highly likely. In this pilot study, we investigate a step-by-step method to achieve preclinical PD diagnosis. Material and methods: We used the IOIT (Italian Olfactory Identification Test) to screen a population of healthy subjects. We identified 20 subjects with idiopathic hyposmia. Hyposmic subjects underwent an evaluation of motor skills, at baseline and after 1 year, using motion analysis sensors previously created by us. Results: One subject showed significant worsening in motor measurements. In this subject, we further conducted a dopaminergic challenge test monitored with the same sensors and, finally, he underwent [123I]-FP/CIT (DaTscan) SPECT brain imaging. The results show that he is probably affected by preclinical PD. Conclusions: Our pilot study suggests that the combined use of an olfactory test and motor sensors for motion analysis could be useful for a screening of healthy subjects to identify those at a high risk of developing PD

Antiproliferative and pro-apoptotic effects afforded by novel Src-kinase inhibitors in human neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Neuroblastoma (NB) is the second most common solid malignancy of childhood that usually undergoes rapid progression with a poor prognosis upon metastasis. The Src-family tyrosine kinases (SFKs) are a group of proteins involved in cancer development and invasiveness that seem to play an important role in the NB carcinogenesis.</p> <p>Methods</p> <p>To determine cell proliferation, the growth rate was evaluated by both MTT test and cells counted. Analysis of DNA content was performed for the evaluation of the cell cycle and apoptosis. To characterize the mechanisms underlying the antiproliferative effects induced by SI 34, a novel pyrazolo-pyrimidine derivative provided with Src inhibitory activity, the involvement of some cellular pathways that are important for cell proliferation and survival was investigated by western blot assays. In particular, the contribution of cyclins, Src and ERK were examined. Finally, experiments of cell adhesion and invasiveness were performed.</p> <p>Results</p> <p>Treatment of SH-SY5Y human NB cells and CHP100 human neuroepithelioma (NE) cultures with three novel pyrazolo[3,4-<it>d</it>]pyrimidine derivatives, namely SI 34, SI 35 and SI 83, inhibits the cell proliferation in a time and concentration-dependent manner. The maximal effect was obtained after 72 hours incubation with SI 34 10 μM. Fluorescence microscopy experiments, flow cytometry analysis and determination of caspase-3 activity by fluorimetric assays showed that SI 34 induced SH-SY5Y apoptosis. Moreover, SI 34 determined cell cycle arrest at the G0/G1 phase, paralleled by a decreased expression of cyclin D1. Furthermore, our data indicate that SI 34 reduces the SH-SY5Y cells adhesion and invasiveness. Evidence that SI 34 inhibits the Src and the ERK-phosphorylation, suggests the mechanism through which it exerts its effects in SH-SY5Y cells.</p> <p>Conclusions</p> <p>Our study shows the ability of this pyrazolo-pyrimidine Src inhibitor in reducing the growth and the invasiveness of human NB cells, suggesting a promising role as novel drug in the treatment of neuroblastoma.</p

Requirement for pectin methyl esterase and preference for fragmented over native pectins for wall-associated kinase-activated, EDS1/PAD4-dependent stress response in arabidopsis

Background: The wall-associated kinases (WAKs) serve as pectin receptors. Results: A pectin methyl esterase and two transcription factor mutants suppress a dominant WAK allele. Conclusion: De-esterification of pectin is required for WAK activation though EDS1 and PAD4. Significance: The results provide a mechanism for the state of pectins to activate two different pathways. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio

A Wide Database for a Multicenter Study on Pneumocystis jirovecii Pneumonia in Intensive Care Units

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that may affect patients with immunosuppression. In order to improve the diagnosis accuracy for PJP, facilitating the collection of data across Europe to reliably assess the performance of diagnostic tests for PJP is essential to improve the care of critically ill patients developing this severe condition. Such large data can be collected thanks to the contribution of several European hospitals in the compilation of a dedicated electronic Case Report Form (eCRF). The main focus of this work is to create an interface with high ergonomics both in the compilation and in the subsequent validation of the records

hTERT Transduction Extends the Lifespan of Primary Pediatric Low-Grade Glioma Cells While Preserving the Biological Response to NGF

The neurotrophin nerve growth factor (NGF) modulates the growth of human gliomas and is able to induce cell differentiation through the engagement of tropomyosin receptor kinase A (TrkA) receptor, although the role played in controlling glioma survival has proved controversial. Unfortunately, the slow growth rate of low-grade gliomas (LGG) has made it difficult to investigate NGF effects on these tumors in preclinical models. In fact, patient-derived low-grade human astrocytoma cells duplicate only a limited number of times in culture before undergoing senescence. Nevertheless, replicative senescence can be counteracted by overexpression of hTERT, the catalytic subunit of telomerase, which potentially increases the proliferative potential of human cells without inducing cancer-associated changes. We have extended, by hTERT transduction, the proliferative in vitro potential of a human LGG cell line derived from a pediatric pilocytic astrocytoma (PA) surgical sample. Remarkably, the hTERT-transduced LGG cells showed a behavior similar to that of the parental line in terms of biological responses to NGF treatment, including molecular events associated with induction of NGF-related differentiation. Therefore, transduction of LGG cells with hTERT can provide a valid approach to increase the in vitro life-span of patient-derived astrocytoma primary cultures, characterized by a finite proliferative potential

Crilin: A CRystal calorImeter with Longitudinal InformatioN for a future Muon Collider

The measurement of physics processes at new energy frontier experiments requires excellent spatial, time, and energy resolutions to resolve the structure of collimated high-energy jets. In a future Muon Collider, the beam-induced backgrounds (BIB) represent the main challenge in the design of the detectors and of the event reconstruction algorithms. The technology and the design of the calorimeters should be chosen to reduce the effect of the BIB, while keeping good physics performance. Several requirements can be inferred: i) high granularity to reduce the overlap of BIB particles in the same calorimeter cell; ii) excellent timing (of the order of 100 ps) to reduce the out-of-time component of the BIB; iii) longitudinal segmentation to distinguish the signal showers from the fake showers produced by the BIB; iv) good energy resolution (less than 10%/sqrt(E)) to obtain good physics performance, as has been already demonstrated for conceptual particle flow calorimeters. Our proposal consists of a semi-homogeneous electromagnetic calorimeter based on Lead Fluoride Crystals (PbF2) readout by surface-mount UV-extended Silicon Photomultipliers (SiPMs): the Crilin calorimeter. In this paper, the performances of the Crilin calorimeter in the Muon Collider framework for hadron jets reconstruction have been analyzed. We report the single components characterizations together with the development of a small-scale prototype, consisting of 2 layers of 3x3 crystals each

Crilin: A Semi-Homogeneous Calorimeter for a Future Muon Collider

Calorimeters, as other detectors, have to face the increasing performance demands of the new energy frontier experiments. For a future Muon Collider the main challenge is given by the Beam Induced Background that may pose limitations to the physics performance. However, it is possible to reduce the BIB impact by exploiting some of its characteristics by ensuring high granularity, excellent timing, longitudinal segmentation and good energy resolution. The proposed design, the Crilin calorimeter, is an alternative semi-homogeneous ECAL barrel for the Muon Collider based on Lead Fluoride Crystals (PbF (Formula presented.)) with a surface-mount UV-extended Silicon Photomultipliers (SiPMs) readout with an optimized design for a future Muon Collider

The CRILIN calorimeter: gamma radiation resistance of crystals and SiPMs

The Crilin calorimeter is a semi-homogeneous calorimetric system based on Lead Fluoride (PbF2) crystals with UV-extended Silicon Photomultipliers (SiPMs) proposed for the Muon Collider. This study investigates the radiation resistance of crystals and SiPMs, subjected to 10 kGy gamma irradiation, equivalent to a 10-year service life in the Muon Collider. Our findings indicate that while PbF2 crystals exhibit a decrease in transmittance post-irradiation with partial recovery over time, the alternative PbWO4-Ultra Fast (PWO-UF) demonstrates exceptional radiation hardness, maintaining stable transmittance. SiPMs showed an increase in dark current and breakdown voltage post-irradiation, with less degradation observed in the SiPM biased during the exposure to radiation compared to the unbiased component. These results underscore the viability of PbF2 for radiation-tolerant calorimeters, though improvements in production homogeneity are needed. The superior performance of PWO-UF crystals suggests they are a promising alternative for high-radiation applications, but their higher cost must be carefully considered

Protein kinase C and cardiac dysfunction: a review

Heart failure (HF) is a physiological state in which cardiac output is insufficient to meet the needs of the body. It is a clinical syndrome characterized by impaired ability of the left ventricle to either fill or eject blood efficiently. HF is a disease of multiple aetiologies leading to progressive cardiac dysfunction and it is the leading cause of deaths in both developed and developing countries. HF is responsible for about 73,000 deaths in the UK each year. In the USA, HF affects 5.8 million people and 550,000 new cases are diagnosed annually. Cardiac remodelling (CD), which plays an important role in pathogenesis of HF, is viewed as stress response to an index event such as myocardial ischaemia or imposition of mechanical load leading to a series of structural and functional changes in the viable myocardium. Protein kinase C (PKC) isozymes are a family of serine/threonine kinases. PKC is a central enzyme in the regulation of growth, hypertrophy, and mediators of signal transduction pathways. In response to circulating hormones, activation of PKC triggers a multitude of intracellular events influencing multiple physiological processes in the heart, including heart rate, contraction, and relaxation. Recent research implicates PKC activation in the pathophysiology of a number of cardiovascular disease states. Few reports are available that examine PKC in normal and diseased human hearts. This review describes the structure, functions, and distribution of PKCs in the healthy and diseased heart with emphasis on the human heart and, also importantly, their regulation in heart failure