Biomarker-Drug and Liquid Biopsy Co-development for Disease Staging and Targeted Therapy: Cornerstones for Alzheimer's Precision Medicine and Pharmacology.

Systems biology studies have demonstrated that different (epi)genetic and pathophysiological alterations may be mapped onto a single tumor's clinical phenotype thereby revealing commonalities shared by cancers with divergent phenotypes. The success of this approach in cancer based on analyses of traditional and emerging body fluid-based biomarkers has given rise to the concept of liquid biopsy enabling a non-invasive and widely accessible precision medicine approach and a significant paradigm shift in the management of cancer. Serial liquid biopsies offer clues about the evolution of cancer in individual patients across disease stages enabling the application of individualized genetically and biologically guided therapies. Moreover, liquid biopsy is contributing to the transformation of drug research and development strategies as well as supporting clinical practice allowing identification of subsets of patients who may enter pathway-based targeted therapies not dictated by clinical phenotypes alone. A similar liquid biopsy concept is emerging for Alzheimer's disease, in which blood-based biomarkers adaptable to each patient and stage of disease, may be used for positive and negative patient selection to facilitate establishment of high-value drug targets and counter-measures for drug resistance. Going beyond the "one marker, one drug" model, integrated applications of genomics, transcriptomics, proteomics, receptor expression and receptor cell biology and conformational status assessments during biomarker-drug co-development may lead to a new successful era for Alzheimer's disease therapeutics. We argue that the time is now for implementing a liquid biopsy-guided strategy for the development of drugs that precisely target Alzheimer's disease pathophysiology in individual patients

The Application of Article 101 of the Treaty of Lisbon to forms of horizontal collaboration in the Financial Services Sector

PhDSince the dawn of the European Union, insurance and banking undertakings claimed to be subject to a special status vis-à-vis the application of EU competition law, due to the quasi social nature of the services they provide. Within the financial services industry, anti-trust concerns do arise in relation to mergers and acquisitions, possible abuses of dominant position and state aid; however Art. 101 TFEU and the regulation of forms of co-operation arguably represent the paramount and most intricate aspects of the application of the EU competition rules to the financial services sector. This is due to the fact that the insurance and banking industries historically have been characterised by intense forms of horizontal co-operation between undertakings deemed necessary for the correct functioning of the financial services industry. On a general level, any agreement establishing a homogeneous pricing structure vis-à-vis consumers represents a blatant violation of Art. 101 TFEU giving rise to serious anti-trust concerns. Nevertheless, as will be explored in this thesis, in the financial services sector the Commission has often allowed what the doctrine has correctly defined as “forms of horizontal agreements concerning a relevant cost element making up the final price vis-à-vis customers”1 through its decisions relating 1 See Faull & Nikpay, “The EC Law of Competition” OUP 2007, p. 636.to interbank fees in payment systems and through the enactment of a block exemption for the insurance industry. Art. 101 thus seems to manifest a common element for these two industries, presenting interesting and intricate teleological quandaries. This thesis endeavours to break the impasse down into questions to which an answer may be provided: Ought Art. 101 to apply to the financial services sector at all? If so, to what extent? Is there any justification for a block exemption in the insurance sector? Indeed, should the banking sector too benefit from a block exemption? This thesis endeavours to answer the above questions and thereby to contribute to the identification of an ideal regulatory framework for forms of horizontal co-operation in the financial services sector

Biomarker-Drug and Liquid Biopsy Co-development for Disease Staging and Targeted Therapy: Cornerstones for Alzheimer’s Precision Medicine and Pharmacology

Systems biology studies have demonstrated that different (epi)genetic and pathophysiological alterations may be mapped onto a single tumor’s clinical phenotype thereby revealing commonalities shared by cancers with divergent phenotypes. The success of this approach in cancer based on analyses of traditional and emerging body fluid-based biomarkers has given rise to the concept of liquid biopsy enabling a non-invasive and widely accessible precision medicine approach and a significant paradigm shift in the management of cancer. Serial liquid biopsies offer clues about the evolution of cancer in individual patients across disease stages enabling the application of individualized genetically and biologically guided therapies. Moreover, liquid biopsy is contributing to the transformation of drug research and development strategies as well as supporting clinical practice allowing identification of subsets of patients who may enter pathway-based targeted therapies not dictated by clinical phenotypes alone. A similar liquid biopsy concept is emerging for Alzheimer’s disease, in which blood-based biomarkers adaptable to each patient and stage of disease, may be used for positive and negative patient selection to facilitate establishment of high-value drug targets and counter-measures for drug resistance. Going beyond the “one marker, one drug” model, integrated applications of genomics, transcriptomics, proteomics, receptor expression and receptor cell biology and conformational status assessments during biomarker-drug co-development may lead to a new successful era for Alzheimer’s disease therapeutics. We argue that the time is now for implementing a liquid biopsy-guided strategy for the development of drugs that precisely target Alzheimer’s disease pathophysiology in individual patients

Lab on a chip genotyping for Brucella spp. based on 15-loci multi locus VNTR analysis

<p>Abstract</p> <p>Background</p> <p>Brucellosis is an important zoonosis caused by the genus <it>Brucella</it>. In addition <it>Brucella </it>represents potential biological warfare agents due to the high contagious rates for humans and animals. Therefore, the strain typing epidemiological tool may be crucial for tracing back source of infection in outbreaks and discriminating naturally occurring outbreaks versus bioterroristic event. A Multiple Locus Variable-number tandem repeats (VNTR) Analysis (MLVA) assay based on 15 polymorphic markers was previously described. The obtained MLVA band profiles may be resolved by techniques ranging from low cost manual agarose gels to the more expensive capillary electrophoresis sequencing. In this paper a rapid, accurate and reproducible system, based on the Lab on a chip technology was set up for <it>Brucella </it>spp. genotyping.</p> <p>Results</p> <p>Seventeen DNA samples of <it>Brucella </it>strains isolated in Sicily, previously genotyped, and twelve DNA samples, provided by MLVA <it>Brucella </it>VNTR ring trial, were analyzed by MLVA-15 on Agilent 2100. The DNA fragment sizes produced by Agilent, compared with those expected, showed discrepancies; therefore, in order to assign the correct alleles to the Agilent DNA fragment sizes, a conversion table was produced. In order to validate the system twelve unknown DNA samples were analyzed by this method obtaining a full concordance with the VNTR ring trial results.</p> <p>Conclusion</p> <p>In this paper we described a rapid and specific detection method for the characterization of <it>Brucella </it>isolates. The comparison of the MLVA typing data produced by Agilent system with the data obtained by standard sequencing or ethidium bromide slab gel electrophoresis showed a general concordance of the results. Therefore this platform represents a fair compromise among costs, speed and specificity compared to any conventional molecular typing technique.</p

High throughput MLVA-16 typing for Brucella based on the microfluidics technology

<p>Abstract</p> <p>Background</p> <p>Brucellosis, a zoonosis caused by the genus <it>Brucella</it>, has been eradicated in Northern Europe, Australia, the USA and Canada, but remains endemic in most areas of the world. The strain and biovar typing of <it>Brucella </it>field samples isolated in outbreaks is useful for tracing back source of infection and may be crucial for discriminating naturally occurring outbreaks versus bioterrorist events, being <it>Brucella </it>a potential biological warfare agent. In the last years MLVA-16 has been described for <it>Brucella </it>spp. genotyping. The MLVA band profiles may be resolved by different techniques i.e. the manual agarose gels, the capillary electrophoresis sequencing systems or the microfluidic Lab-on-Chip electrophoresis. In this paper we described a high throughput system of MLVA-16 typing for <it>Brucella </it>spp. by using of the microfluidics technology.</p> <p>Results</p> <p>The Caliper LabChip 90 equipment was evaluated for MLVA-16 typing of sixty-three <it>Brucella </it>samples. Furthermore, in order to validate the system, DNA samples previously resolved by sequencing system and Agilent technology, were <it>de novo </it>genotyped. The comparison of the MLVA typing data obtained by the Caliper equipment and those previously obtained by the other analysis methods showed a good correlation. However the outputs were not accurate as the Caliper DNA fragment sizes showed discrepancies compared with real data and a conversion table from observed to expected data was created.</p> <p>Conclusion</p> <p>In this paper we described the MLVA-16 using a rapid, sophisticated microfluidics technology for detection of amplification product sizes. The comparison of the MLVA typing data produced by Caliper LabChip 90 system with the data obtained by different techniques showed a general concordance of the results. Furthermore this platform represents a significant improvement in terms of handling, data acquiring, computational efficiency and rapidity, allowing to perform the strain genotyping in a time equal to one sixth respect to other microfluidics systems as e.g. the Agilent 2100 bioanalyzer.</p> <p>Finally, this platform can be considered a valid alternative to standard genotyping techniques, particularly useful dealing with a large number of samples in short time. These data confirmed that this technology represents a significative advancement in high-throughput accurate <it>Brucella </it>genotyping.</p

Menopause hormone therapy significantly alters pathophysiological biomarkers of Alzheimer's disease

INTRODUCTION: This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysiological dynamics in de-novo diagnosed menopausal women. METHODS: We analyzed baseline and longitudinal differences between MHT-taking and -not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid-β (Aβ) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration. RESULTS: We report a prominent and significant treatment response at the Aβ pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment. DISCUSSION: To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause