Clinical Evaluation of the ButterfLife Device for Simultaneous Multiparameter Telemonitoring in Hospital and Home Settings.

We conducted a two-phase study to test the reliability and usability of an all-in-one artificial intelligence-based device (ButterfLife), which allows simultaneous monitoring of five vital signs. The first phase of the study aimed to test the agreement between measurements performed with ButterfLife vs. standard of care (SoC) in 42 hospitalized patients affected by acute respiratory failure. In this setting, the greatest discordance between ButterfLife and SoC was in respiratory rate (mean difference -4.69 bpm). Significantly close correlations were observed for all parameters except diastolic blood pressure and oxygen saturation (Spearman's Rho -0.18 mmHg; p = 0.33 and 0.20%; p = 0.24, respectively). The second phase of the study was conducted on eight poly-comorbid patients using ButterfLife at home, to evaluate the number of clinical conditions detected, as well as the patients' compliance and satisfaction. The average proportion of performed tests compared with the scheduled number was 67.4%, and no patients reported difficulties with use. Seven conditions requiring medical attention were identified, with a sensitivity of 100% and specificity of 88.9%. The median patient satisfaction was 9.5/10. In conclusion, ButterfLife proved to be a reliable and easy-to-use device, capable of simultaneously assessing five vital signs in both hospital and home settings.

Conformational Propensity and Biological Studies of Proline Mutated LR Peptides Inhibiting Human Thymidylate Synthase and Ovarian Cancer Cell Growth.

LR and [d-Gln4]LR peptides bind the monomer-monomer interface of human thymidylate synthase and inhibit cancer cell growth. Here, proline-mutated LR peptides were synthesized. Molecular dynamics calculations and circular dichroism spectra have provided a consistent picture of the conformational propensities of the [Pro n]-peptides. [Pro3]LR and [Pro4]LR show improved cell growth inhibition and similar intracellular protein modulation compared with LR. These represent a step forward to the identification of more rigid and metabolically stable peptides.

Proteomic and Bioinformatic Studies for the Characterization of Response to Pemetrexed in Platinum Drug Resistant Ovarian Cancer.

Proteomics and bioinformatics are a useful combined technology for the characterization of protein expression level and modulation associated with the response to a drug and with its mechanism of action. The folate pathway represents an important target in the anticancer drugs therapy. In the present study, a discovery proteomics approach was applied to tissue samples collected from ovarian cancer patients who relapsed after the first-line carboplatin-based chemotherapy and were treated with pemetrexed (PMX), a known folate pathway targeting drug. The aim of the work is to identify the proteomic profile that can be associated to the response to the PMX treatment in pre-treatement tissue. Statistical metrics of the experimental Mass Spectrometry (MS) data were combined with a knowledge-based approach that included bioinformatics and a literature review through ProteinQuest™ tool, to design a protein set of reference (PSR). The PSR provides feedback for the consistency of MS proteomic data because it includes known validated proteins. A panel of 24 proteins with levels that were significantly different in pre-treatment samples of patients who responded to the therapy vs. the non-responder ones, was identified. The differences of the identified proteins were explained for the patients with different outcomes and the known PMX targets were further validated. The protein panel herein identified is ready for further validation in retrospective clinical trials using a targeted proteomic approach. This study may have a general relevant impact on biomarker application for cancer patients therapy selection.

Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers.

Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM), an array-based analysis. Promoter regions of 41 genes were analyzed in 102 ovarian tumors and 17 normal ovarian samples. An average of 29% of hypermethylated promoter genes was observed in normal ovarian tissues. This percentage increased slightly in serous, endometrioid, and mucinous carcinomas (32%, 34%, and 45%, respectively), but decreased in germ cell tumors (20%). Ovarian tumors had methylation profiles that were more heterogeneous than other epithelial cancers. Unsupervised hierarchical clustering identified four groups that are very close to the histological subtypes of ovarian tumors. Aberrant methylation of three genes (BRCA1, MGMT, and MLH1), playing important roles in the different DNA repair mechanisms, were dependent on the tumor subtype and represent powerful biomarkers for precision therapy. Furthermore, a promising relationship between hypermethylation of MGMT, OSMR, ESR1, and FOXL2 and overall survival was observed. Our study of DNA methylation profiling indicates that the different histotypes of ovarian cancer should be treated as separate diseases both clinically and in research for the development of targeted therapies.

Promoter methylation and downregulated expression of the TBX15 gene in ovarian carcinoma.

TBX15 is a gene involved in the development of mesodermal derivatives. As the ovaries and the female reproductive system are of mesodermal origin, the aim of the present study was to determine the methylation status of the TBX15 gene promoter and the expression levels of TBX15 in ovarian carcinoma, which is the most lethal and aggressive type of gynecological tumor, in order to determine the role of TBX15 in the pathogenesis of ovarian carcinoma. This alteration could be used to predict tumor development, progression, recurrence and therapeutic effects. The study was conducted on 80 epithelial ovarian carcinoma and 17 control cases (normal ovarian and tubal tissues). TBX15 promoter methylation was first determined by pyrosequencing following bisulfite modification, then by cloning and sequencing, in order to obtain information about the epigenetic haplotype. Immunohistochemical analysis was performed to evaluate the correlation between the methylation and protein expression levels. Data revealed a statistically significant increase of the TBX15 promoter region methylation in 82% of the tumor samples and in various histological subtypes. Immunohistochemistry showed an inverse correlation between methylation levels and the expression of the TBX15 protein. Furthermore, numerous tumor samples displayed varying degrees of intratumor heterogeneity. Thus, the present study determined that ovarian carcinoma typically expresses low levels of TBX15 protein, predominantly due to an epigenetic mechanism. This may have a role in the pathogenesis of ovarian carcinoma independent of the histological subtype.

DNA methylation profiling of esophageal adenocarcinoma using Methylation Ligation-dependent Macroarray (MLM).

Most types of cancer cells are characterized by aberrant methylation of promoter genes. In this study, we described a rapid, reproducible, and relatively inexpensive approach allowing the detection of multiple human methylated promoter genes from many tissue samples, without the need of bisulfite conversion. The Methylation Ligation-dependent Macroarray (MLM), an array-based analysis, was designed in order to measure methylation levels of 58 genes previously described as putative biomarkers of cancer. The performance of the design was proven by screening the methylation profile of DNA from esophageal cell lines, as well as microdissected formalin-fixed and paraffin-embedded (FFPE) tissues from esophageal adenocarcinoma (EAC). Using the MLM approach, we identified 32 (55%) hypermethylated promoters in EAC, and not or rarely methylated in normal tissues. Among them, 21promoters were found aberrantly methylated in more than half of tumors. Moreover, seven of them (ADAMTS18, APC, DKK2, FOXL2, GPX3, TIMP3 and WIF1) were found aberrantly methylated in all or almost all the tumor samples, suggesting an important role for these genes in EAC. In addition, dysregulation of the Wnt pathway with hypermethylation of several Wnt antagonist genes was frequently observed. MLM revealed a homogeneous pattern of methylation for a majority of tumors which were associated with an advanced stage at presentation and a poor prognosis. Interestingly, the few tumors presenting less methylation changes had a lower pathological stage. In conclusion, this study demonstrated the feasibility and accuracy of MLM for DNA methylation profiling of FFPE tissue samples.

Predictive mechanisms in idiom comprehension.

Prediction is pervasive in human cognition and plays a central role in language comprehension. At an electrophysiological level, this cognitive function contributes substantially in determining the amplitude of the N400. In fact, the amplitude of the N400 to words within a sentence has been shown to depend on how predictable those words are: The more predictable a word, the smaller the N400 elicited. However, predictive processing can be based on different sources of information that allow anticipation of upcoming constituents and integration in context. In this study, we investigated the ERPs elicited during the comprehension of idioms, that is, prefabricated multiword strings stored in semantic memory. When a reader recognizes a string of words as an idiom before the idiom ends, she or he can develop expectations concerning the incoming idiomatic constituents. We hypothesized that the expectations driven by the activation of an idiom might differ from those driven by discourse-based constraints. To this aim, we compared the ERP waveforms elicited by idioms and two literal control conditions. The results showed that, in both cases, the literal conditions exhibited a more negative potential than the idiomatic condition. Our analyses suggest that before idiom recognition the effect is due to modulation of the N400 amplitude, whereas after idiom recognition a P300 for the idiomatic sentence has a fundamental role in the composition of the effect. These results suggest that two distinct predictive mechanisms are at work during language comprehension, based respectively on probabilistic information and on categorical template matching.

The commissural transfer of the horizontal optokinetic signal in the rat: a c-Fos study.

We applied the Fos method in rats subjected to horizontal optokinetic stimulation (OKS) to study whether optokinetic information is transferred through the commissural pretectal fibres from one optic tract nucleus (NOT) to the opposite. In binocular as well as in monocular nasalward OKS, the highest Fos immunoreactivity was found in the NOT contralateral to the nasalward stimulation, as expression of the activation either of direction-selective cells and of commissural neurons. Even the opposite NOT showed many Fos-positive cells activated by the opposite nucleus throughout the commissural pretectal pathway. They might be the GABA positive cells, which are thought to allow the activation in one nucleus to be transformed into inhibition of the opposite side. In monocular temporalward OKS, the inhibition on direction-selective cells and the consequent silencing of commissural neurons caused the faint immunoreactivity in the NOT contralateral to eye stimulated. In the opposite nucleus the few Fos-positive cells emerged as a consequence of the lack of the normal tonic commissurally mediated inhibition.

Cloze probability does not only affect N400 amplitude: the case of complex prepositions.

Cloze-probability levels are inversely correlated with N400 amplitude, indicating an easier integration for expected words in semantic-pragmatic contexts. Here we exploited the prespecified standard order of complex prepositions and measured the ERPs time-locked to the last preposition in sentences in which complex prepositions were presented in their standard form or with the last preposition changed. The expected preposition elicited an N280 followed by an N400-700, two ERP components previously associated to the processing of closed-class words. The unexpected preposition elicited only an N280, and the N400-700 was reduced. These results reflect the specificity of the contextual constraints linked to the complex preposition word sequence.

Optical and electrical recording of neural activity evoked by graded contrast visual stimulus.

BACKGROUND: Brain activity has been investigated by several methods with different principles, notably optical ones. Each method may offer information on distinct physiological or pathological aspects of brain function. The ideal instrument to measure brain activity should include complementary techniques and integrate the resultant information. As a "low cost" approach towards this objective, we combined the well-grounded electroencephalography technique with the newer near infrared spectroscopy methods to investigate human visual function. METHODS: The article describes an embedded instrumentation combining a continuous-wave near-infrared spectroscopy system and an electroencephalography system to simultaneously monitor functional hemodynamics and electrical activity. Near infrared spectroscopy (NIRS) signal depends on the light absorption spectra of haemoglobin and measures the blood volume and blood oxygenation regulation supporting the neural activity. The NIRS and visual evoked potential (VEP) are concurrently acquired during steady state visual stimulation, at 8 Hz, with a b/w "windmill" pattern, in nine human subjects. The pattern contrast is varied (1%, 10%, 100%) according to a stimulation protocol. RESULTS: In this study, we present the measuring system; the results consist in concurrent recordings of hemodynamic changes and evoked potential responses emerging from different contrast levels of a patterned stimulus. The concentration of [HbO2] increases and [HHb] decreases after the onset of the stimulus. Their variation shows a clear relationship with the contrast value: large contrast produce huge difference in concentration, while low contrast provokes small concentration difference. This behaviour is similar to the already known relationship between VEP response amplitude and contrast. CONCLUSION: The simultaneous recording and analysis of NIRS and VEP signals in humans during visual stimulation with a b/w pattern at variable contrast, demonstrates a strong linear correlation between hemodynamic changes and evoked potential amplitude. Furthermore both responses present a logarithmic profile with stimulus contrast.