A Logistic Model Tree Solution

Beretta, S., Castelli, M., Gonçalves, I., Kel, I., Giansanti, V., & Merelli, I. (2018). Improving eQTL Analysis Using a Machine Learning Approach for Data Integration: A Logistic Model Tree Solution. Journal of Computational Biology, 25(10), 1091-1105. DOI: 10.1089/cmb.2017.0167Expression quantitative trait loci (eQTL) analysis is an emerging method for establishing the impact of genetic variations (such as single nucleotide polymorphisms) on the expression levels of genes. Although different methods for evaluating the impact of these variations are proposed in the literature, the results obtained are mostly in disagreement, entailing a considerable number of false-positive predictions. For this reason, we propose an approach based on Logistic Model Trees that integrates the predictions of different eQTL mapping tools to produce more reliable results. More precisely, we employ a machine learning-based method using logistic functions to perform a linear regression able to classify the predictions of three eQTL analysis tools (namely, R/qtl, MatrixEQTL, and mRMR). Given the lack of a reference dataset and that computational predictions are not so easy to test experimentally, the performance of our approach is assessed using data from the DREAM5 challenge. The results show the quality of the aggregated prediction is better than that obtained by each single tool in terms of both precision and recall. We also performed a test on real data, employing genotypes and microRNA expression profiles from Caenorhabditis elegans, which proved that we were able to correctly classify all the experimentally validated eQTLs. These good results come both from the integration of the different predictions, and from the ability of this machine learning algorithm to find the best cutoff thresholds for each tool. This combination makes our integration approach suitable for improving eQTL predictions for testing in a laboratory, reducing the number of false-positive results.authorsversionpublishe

Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates

Abstract Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues

Integration of Machine Learning Methods to Dissect Genetically Imputed Transcriptomic Profiles in Alzheimer's Disease.

The genetic component of many common traits is associated with the gene expression and several variants act as expression quantitative loci, regulating the gene expression in a tissue specific manner. In this work, we applied tissue-specific cis-eQTL gene expression prediction models on the genotype of 808 samples including controls, subjects with mild cognitive impairment, and patients with Alzheimer's Disease. We then dissected the imputed transcriptomic profiles by means of different unsupervised and supervised machine learning approaches to identify potential biological associations. Our analysis suggests that unsupervised and supervised methods can provide complementary information, which can be integrated for a better characterization of the underlying biological system. In particular, a variational autoencoder representation of the transcriptomic profiles, followed by a support vector machine classification, has been used for tissue-specific gene prioritizations. Interestingly, the achieved gene prioritizations can be efficiently integrated as a feature selection step for improving the accuracy of deep learning classifier networks. The identified gene-tissue information suggests a potential role for inflammatory and regulatory processes in gut-brain axis related tissues. In line with the expected low heritability that can be apportioned to eQTL variants, we were able to achieve only relatively low prediction capability with deep learning classification models. However, our analysis revealed that the classification power strongly depends on the network structure, with recurrent neural networks being the best performing network class. Interestingly, cross-tissue analysis suggests a potentially greater role of models trained in brain tissues also by considering dementia-related endophenotypes. Overall, the present analysis suggests that the combination of supervised and unsupervised machine learning techniques can be used for the evaluation of high dimensional omics data.Includes EPSRC

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Attività antivirale delle proteine del siero di latte

Le proteine del siero di latte sia nella loro forma nativa che chimicamente modificata e i loro derivati peptidici hanno incontrato già da diversi anni molto interesse frai ricercatori del settore nutraceutico e farmaceutico per le loro numerose proprietà tra cui quelle antimicrobiche, immunomodulanti e antitumorali, tali da rendere il latte e le sue proteine utilizzabili in un ampio spettro di trattamenti sanitari e di prevenzione. Recentemente è stata riscontrata una importante attività antivirale di queste molecole e bisogna sottolineare come lo studio di molecole antivirali con bassa o nulla tossicità, come quelle derivate dagli alimenti, sia attualmente considerato cruciale come trattamento aggiuntivo alle terapie convenzionali per contrastare le infezioni virali già note e quelle più recenti e meno conosciute come il COVID-19. Nella presente rassegna vengono riportate le recenti pubblicazioni riguardanti le proprietà antivirali elle proteine del siero di latte e le loro potenziali applicazioni nel campo della protezione della salute umana

Antiviral properties of whey proteins and their activity against SARS-CoV-2 infection

Native and chemically modified whey proteins and their peptide derivatives are encountering the interest of nutraceutical and pharmaceutical industries, due to the numerous properties, ranging from antimicrobial to immunological and antitumorigenic, that result in the possibility to employ milk and its protein components in a wide range of treatment and prevention strategies. Importantly, whey proteins were found to exert antiviral actions against different enveloped and non-enveloped viruses. Recently, the scientific community is focusing on these proteins, especially lactoferrin, since in vitro studies have demonstrated that they exert an important antiviral activity also against SARS-CoV-2. Up-to date, several studies are investigating the efficacy of lactoferrin and other whey proteins in vivo. Aim of this review is to shed light on the most relevant findings concerning the antiviral properties of whey proteins and their potential applications in human health, focussing on their application in prevention and treatment of SARS-CoV-2 infection

The impact of osteotomy technique for corticotomy-assisted orthodontic treatment (CAOT) on oral health-related quality of life

BACKGROUND: Corticotomy in accelerating orthodontic tooth movement, also defined as corticotomy-assisted orthodontic treatment (CAOT), is a promising technique that recently had many applications in orthodontics. AIM: The purpose of this study was to compare the use of piezoelectric surgery and conventional rotatory osteotomy technique for CAOT, determining the duration of surgery and oral health-related quality of life (OHRQoL). PATIENTS AND METHODS: CAOT was performed in a sample of subjects, randomly choosing piezoelectric: surgery (PS Group) or conventional rotary osteotomy technique (RT Group). The duration of surgery was recorded and the oral health-related quality of life evaluated using the short form Oral Health Impact Profile (OHIP-14) preoperatively, 3 and 7 days after surgery. t-test and Cronbach's alpha were used for statistical analysis. RESULTS: 12 patients (mean age 14; range: 13-17) were enrolled. The time needed to complete the osteotomy cuts was greater (p = 0.1) for the piezoelectric surgery group (mean 34.3 minutes; range 35.3-32.6) than for the rotator group(mean 28.2 minutes; range 27.1-29.2). Oral health-related quality of life deteriorated from baseline (OHIP-14 mean: 6.33) to first follow-up, 3 day after surgery, in both groups (PS Group: 22.67 OHIP-14; RT Group: 21.33 OHIP-14). At 7 days follow-up there was a nearly complete recovery of the original OHIP-14 values, even faster with the conventional rotary osteotomy technique; however, no statistically significant differences were recorded between the two methods (p = 0.35). Cronbach's alpha values indicated an excellent internal consistency reliability. CONCLUSIONS: In clinical decision-making regarding the use of corticotomy-assisted orthodontic treatment, it should be aware of the expected decrease in oral health-related quality of life both using piezoelectric surgery or rotary osteotomy technique. In addition, the piezoelectric osteotomy requires a longer surgical time

Importance of ultrasound elastography prior to testicular surgery: clinical evidence

The elastosonographic study is a comparative study of the density of the lesions investigated in comparison with the surrounding of the body that uoy are looking at. We used this technique of investigation to assess the nature of a testicular lesion in a patient affected by Carney Complex Syndrom

Existence of hybrid structures in cationic liposome/DNA complexes revealed by their interaction with plasma proteins

The self-assembling of cationic liposomes (CLs) and DNA can give rise to a variety of nanostructures and morphologies. Multilamellar complexes are made of DNA intercalated between opposing lipid bilayers, while clusters formed by intact vesicles may exist as 'beads-on-a-string' (i.e. CLs attached to a string of DNA). Precise knowledge of the structure and morphology of complexes is relevant in many biological important processes such as gene delivery. Here dynamic light scattering, zeta potential, synchrotron small angle X-ray scattering and one-dimensional polyacrylamide gel electrophoresis were performed to investigate the equilibrium structure, morphology and interactions with plasma proteins of lipoplexes made of the cationic lipid (3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl])-cholesterol (DC-Chol), the zwitterionic lipid dioleoylphosphatidylethanolamine (DOPE) and DNA. Results show that DC-Chol-DOPE/DNA complexes are multilamellar systems with DNA protected by cationic lipids. On the other hand, the 'protein corona' associated to lipoplexes after interaction with human plasma was found to be much richer in basic immunoglobulins gamma proteins (Ig-Gs) than that of pure lipid vesicles in the absence of DNA. According to the most recent evidences reported in the literature, this finding would suggest the existence of hybrid structures made of multilamellar complexes either stuck together by DNA or coexisting with DNA-loaded intact vesicles. Because surface properties of lipoplexes may determine their interaction with cells and tissues, these results may be important for predicting biological responses in vivo. © 2010 Elsevier B.V

MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression

The MDM2 oncoprotein antagonizes the tumor suppressor p53 by physical interaction and ubiquitination. However, it also sustains the progression of DNA replication forks, even in the absence of functional p53. Here, we show that MDM2 binds, inhibits, ubiquitinates, and destabilizes poly(ADP-ribose) polymerase 1 (PARP1). When cellular MDM2 levels are increased, this leads to accelerated progression of DNA replication forks, much like pharmacological inhibition of PARP1. Conversely, overexpressed PARP1 restores normal fork progression despite elevated MDM2. Strikingly, MDM2 profoundly reduces the frequency of fork reversal, revealed as four-way junctions through electron microscopy. Depletion of RECQ1 or the primase/polymerase (PRIMPOL) reverses the MDM2-mediated acceleration of the nascent DNA elongation rate. MDM2 also increases the occurrence of micronuclei, and it exacerbates camptothecin-induced cell death. In conclusion, high MDM2 levels phenocopy PARP inhibition in modulation of fork restart, representing a potential vulnerability of cancer cells.publishe