Reports 2017/18

College hosted a number of PhD students and medical trainees during the 2017/18 academic year and several of them are actively engaged in College life, including College Committees.   Brief accounts of their research or trainning are offered in this page.

Monah Abou Allez.  Computational Approach Towards Genomic Characterization of Human Long Non-coding RNAs
CNR Institute of Molecular Genetics (supervisor: Silvia Bione)

M PhD project is based at the Unit of Computational Biology of the Institute of Molecular Genetics of the National Research Council (CNR). Recent developments in deep sequencing approaches have greatly increased the resolution and facilitated the understanding of the transcriptome. The more recent understanding that the genome is pervasively transcribed stimulated the discovery of a new prevalent class of long non-coding RNAs (lncRNAs), and consequently, there has been continuous discovery of a significantly large number of novel lncRNA gene loci in the genomes. HoIver, while these are relatively less abundant and conserved than other classes of functional RNAs, identifying and determining the function of individual lncRNAs, still remains a challenge. In my current research during the academic year of 2017/2018, I applied an integrative bioinformatics approach to systematically characterize the different properties that distinguish lncRNAs genes, as a class and as individuals, apart from protein coding genes. By utilizing different computational and statistical tools and examining lncRNAs genes annotated in GENCODE compendium for human genome annotations, I established a panorama of lncRNA genes general properties including gene and transcript structure, gene length, GC-content, genome coverage, combinatorial and spatial patterns of chromatin marks and states, cellular localization and levels of expression. I also elucidated the difference of these general properties between the different lncRNA biotypes annotated by GENCODE. Moreover, I determined a sex-specific expression pattern of lncRNA genes in comparison to protein-coding ones by performing transcriptome sequence analysis and differentialgene expression in blood tissues. In particular, I focused my analysis on lncRNA splicing features and alternative splicing events that showed unique peculiarities distinguishing them from protein coding genes. Our analysis suggested a considerable difference between splice site strength, introns length, introns GC-content and the enrichment of binding sites for regulatory RNA binding proteins between lncRNA and protein-coding transcripts.

Sultan S Alteeg. 
The Relationship between Organization Culture and Innovation in Saudi Nonprofit Organisations
Department of Economics and Business Studies (supervisor: Stefano De Nicolai)

In 2017/18 I carried out extensive survey and analysis of the literature underlying my research project. I presented my first chapter to the PhD degree committee of the Department and I will start the relevant data collection in January 2019. I have also been working in parallele on two manuscripts on Emotional Intelligence: Definitions, History and Models, and Projects Evaluation in the Third Sector: What, Why and How ? which I intend to submit for publication before the end of 2018 in one of the business management journals.

Valentina Astesana. [Pt(O,O'-acac)(γ-acac)(DMS)]: another platinum (II) compound to overcome Cisplatin resistance and toxicity

Department of Biology and Biotechnology (supervisors: M Biggiogera and MG Bottone)

Cisplatin is one of the most effective chemotherapeutic agents used in the treatment of many type of tumours including non-small cell lung cancer, ovarian, testicular, glioblastoma, neuroblastoma and others. Cisplatin is able to form bonds with the N7 atom on guanine and adenine bases and when this damage is not repaired, DNA replication and transcription were stopped, inducing death of the cells. Despite the clinical benefit provided by Cisplatin many patients undergo phenomena of resistance and toxicity (especially ototoxicity, nephrotoxicity and neurotoxicity). To overcome Cisplatin resistance and toxicity, some strategies include the use of alternative platinum compounds, such as [Pt(O,O'-acac)(γ-acac)(DMS)], synthetized by the team of Prof. Fanizzi (University of Salento, Lecce), considering its activity and mechanism of action respect to Cisplatin. For this purpose, we used human glioblastoma T98G cell line. Our results suggest that PtAcacDMS is able to induce apoptosis and necrosis with a concentration five-fold lower respect to Cisplatin (10µM respect to 40µM). Furthermore, ultrastructural analysis of TEM revealed an intense process of autophagy takes place in the cells, confirmed by the analysis of autophagic markers. Different cell death can be regulated by calcium and by oxidative stress. We find that PtAcacDMS induce an acute increases in [Ca2+]i respect to CDDP that was likely to be due to extracellular Ca2+ entry and enhanced both cytosolic and endoplasmic reticulum Ca2+ concentration after 48h of treatment. Increase of oxidative stress, especially the expression of ROS, can also represents a mechanism of cell death of PtAcacDMS and can modulate the modifications of chromatin and thus gene expression.

R Cacciatore.  Plasma levels of soluble HLA-G, genomic polymorphism HLA-E and HLA- DRB1 as factors involved in the pathogenesis of autoimmune diseases in pregnancy
Immunogenetic Laboratory of the S. Matteo Hospital of Pavia (supervisors: Annamaria Pasi and Fausta Beneventi)

In 2017/18 I continued my research on the above project. Specifically, I determined the f HLA-DRB1 polymorphism in 96 pregnant women with pre-existing rheumatic diseases (undifferentiated connective tissue, fibromyalgia, systemic lupus erythematosus (SLE), systemic sclerosis, antiphospholipid antibody syndrome, Sjögren's syndrome, spondyloarthritis) and in 188 women who have gone through physiological pregnancies. All blood samples were received at the Immunematology Laboratory of the Immunohaematology and Transfusion Medicine Service, the registry of both the controls and each patient with the related cord blood samples was recorded and included in the Daisy management software. The latter represents an informatics archive that allows the laboratory to encode each subject in a univocal way through the use of a numerical code. As a first step, each sample was processed by centrifugation at 1500 rpm for 15 minutes, in this way we obtained plasma and buffy coat aliquots. DNA was extracted from each aliquot of buffy coat. DNA extraction, necessary for the determination of HLA-DRB1 polymorphism, was performed using an automatic extractor that uses magnetic particles that act as a solid phase around which the nucleic acid precipitates under suitable conditions. Plasma was used for the determination of plasma levels of soluble HLA-G. Therefore, going forward with the aims of the research itself and considering the crucial role of HLA-DR molecules in susceptibility to rheumatic diseases we proceeded to analyze controls and patients for the polymorphisms of the HLA-DRB1 gene. As a result, 188 controls and 96 patients were typed by PCR-SSO methods, applied to xMap Luminex technology, and PCR-SSP. From the analysis of the data it was observed that the frequency of the HLA-DRB1 * 03 allele, among the HLA alleles most frequently associated with SLE, was higher and statistically significant in patients compared to controls (11% vs 6.12% p = 0.04 , OR = 1.88), as well as the frequency of the allele DRB1 * 15 (8% vs 4% p = 0.077 OR 1.91) described in the literature as also associated with Sjögren's syndrome and multiple sclerosis. Intriguing and statistically significant, the HLA-DRB1 * 07 allele also showed a somewhat higher and statistically significant frequency in patients than controls (14.58% vs 9.04% p = 0.04, OR = 1.72). Among the HLA alleles known to be most associated with rheumatoid arthritis, the DRB1 * 04: 05 allele presents a higher frequency in patients than healthy controls (2.08% vs 1.06% p = 0.32, OR = 1.98), instead the frequency of HLA-DRB1 alleles (HLA-DRB1 * 01: 01, * 01: 02, * 04: 01, * 04: 04, * 04: 05, * 04: 08), which taken together represent the amino acid sequence defined " shared epitope "(SE), was slightly lower among patients compared to controls (9% vs 10%). The data obtained confirm substantially those obtained during the last year and we can see an increase in significance for the HLA-DRB1 * 03 allele. The high frequency of HLA-DRB1 * 03, but also of HLA-DRB1 * 07, both in linkage disequilibrium with the HLA-DQB1 * 02 allele, in sick pregnancies could suggest a silent celiac disease, therefore not manifesting but that could flash in the future in subjects at risk. The data could be useful to the clinician in order to suggest the execution of analyzes such as the research of anti-tranglutaminase antibodies or, in any way, to monitoring the patient. Furthermore, an increase in the significance of the DRB1 * 15 allele can be seen, which has also been associated with Sjögren's syndrome and multiple sclerosis. Since the data that can be obtained could represent a useful aid to the clinician to predict and monitor the evolution of undifferentiated connective tissue diseases and the onset of other immune  pathologies, it would be desirable to enroll and analyze a greater number of affected pregnant patients. from rheumatic diseases to give statistical weight to the study. It would also be interesting to proceed with the determination of the genomic polymorphism of HLA-G and HLA-E to establish, together with HLA-DRB1, their involvement in autoimmune diseases during pregnancy. It would be advisable to continue with the analysis of the plasma concentration of soluble HLA-G as an indicator of progression or improvement of autoimmune pathology.

Luca De Martinis.
Diseases of the endocrine system
Istituti Clinico Scientifici Maugeri (supervisor: L Chiovato)

As a 4th year student of the specialty course in Endocrinology and Metabolic Diseases I sat the final year 3 examination in December 2017 with top marks presenting a clinical case report of a patient with  Sheehan syndrome and reviewing the latest guidelines on hypopituitarism published in 2016 in the European Journal of Endocrinology. Starting from September 2017, I have carried out clinical activities at the Diabetes clinic of the Maugeri Foundation of Pavia, dealing in particular with new therapeutics for type 2 diabetes mellitus. From January '18 to April '18 I was directly involved in the management of the MAC Endocrinological of our Unit, with particular attention to the execution of endocrine dynamic tests. During this year I also participated in several major national conferences including the annual meeting of the Italian Society of Endocrinology and the Italian Diabetes Society. Finally, I actively contributed to the drafting of several scientific papers in the field of endocrinology and internal medicine that were published in international journals.

Disabling portosystemic encephalopathy in a non-cirrhotic patient: Successful endovascular treatment of a giant inferior mesenteric-caval shunt via the left internal iliac vein.
de Martinis L, Groppelli G, Corti R, Moramarco LP, Quaretti P, De Cata P, Rotondi M, Chiovato L. World J Gastroenterol. 2017 Dec 21;23(47):8426-8431. doi: 10.3748/wjg.v23.i47.8426.

A male patient with acromegaly and breast cancer: treating acromegaly to control tumor progression. Leporati P, Fonte R, de Martinis L, Zambelli A, Magri F, Pavesi L, Rotondi M, Chiovato L. BMC Cancer. 2015 May 12;15:397. doi: 10.1186/s12885-015-1400-0.

The effect of Greek herbal tea consumption on thyroid cancer: a case-control study. Riza E, Linos A, Petralias A, de Martinis L, Duntas L, Linos D. Eur J Public Health. 2015 Dec;25(6):1001-5. doi: 10.1093/eurpub/ckv063. Epub 2015 Apr 4.

Exposure to perfluorinated compounds: in vitro study on thyroid cells. Coperchini F, Pignatti P, Lacerenza S, Negri S, Sideri R, Testoni C, de Martinis L, Cottica D, Magri F, Imbriani M, Rotondi M, Chiovato L. Environ Sci Pollut Res Int. 2015 Feb;22(3):2287-94. doi: 10.1007/s11356-014-3480-9. Epub 2014 Sep 4.

Serum negative autoimmune thyroiditis displays a milder clinical picture compared with classic Hashimoto's thyroiditis. Rotondi M, de Martinis L, Coperchini F, Pignatti P, Pirali B, Ghilotti S, Fonte R, Magri F, Chiovato L. Eur J Endocrinol. 2014 Jul;171(1):31-6. doi: 10.1530/EJE-14-0147. Epub 2014 Apr 17.

Type I and type II interferons inhibit both basal and tumor necrosis factor-α-induced CXCL8 secretion in primary cultures of human thyrocytes. Rotondi M, Coperchini F, Sideri R, Groppelli G, de Martinis L, Villani L, Pignatti P, Magri F, Chiovato L. J Interferon Cytokine Res. 2013 Sep;33(9):508-13. doi: 10.1089/jir.2012.0080. Epub 2013 May 15.

Carla Gualtieri. miRNA and DNA repair in plants
Department of Biology and Biotechnology (supervisor: )

MicroRNAs (miRNAs) are small endogenous non-coding RNAs involved in the regulation of gene expression by complementary binding to mRNA targets, leading to the translational inhibition and/or mRNA degradation. Given their key roles in the regulation of gene expression, these molecules are implicated in all essential physiological processes, including plant growth/development and in stress conditions. Oxidative injury, originating from both cellular metabolism and adverse environmental conditions, causes genotoxic stress and impairs crop productivity. To maintain genome integrity, multiple DNA repair pathways are activated in the context of the highly conserved DNA damage response (DDR). Currently, very little is known about the involvement of miRNAs in this complex network of responses to genome damage in plant as well as in mammals. Medicago truncatula, a model legume, has recently emerged as a relevant system to study DNA damage repair in plants. This background provides a good starting point to investigate the involvement of miRNA in the regulation of DDR gene expression.

Jing Luo.
A High-speed High-resolution Pipeline Analog-to-Digital Converter(ADC) Design
Department of Computer and Industrial Engineering (supervisor: Franco Maloberti)

I am a visiting PhD student of Integrated Microsystem (IMS) research Laboratory in the Department of Electrical Computer and Biomedical Engineering at University of Pavia. During this academic year, I have actively engaged in the project aimed at developing a High-speed High-resolution Pipeline Analog-to-Digital Converter(ADC). I have surveyed the technical literature on pipeline ADC and then established a calculation model of ADC architecture through coding in MATLAB and a behavioural model in Cadence AMS environment. Thereafter, I have been designing transistor-level circuits to replace the ideal devices in our behavioural model. After several attempts, I have designed a high-gain and high-speed operational amplifier and  designed the comparators with threshold offset and switches.

Alberto Martinasso.  Evaluation and treatment of anaemias
ImmunoTransfusional Service, San Matteo Hospital, Pavia (supervisor: Cesare Perotti)

I am a 4th yer specialty student in Clinical Biochemistry and Clinical Pathology and I carry out my training in the therapeutical apheresis unit at the ImmunoTransfusional Service of the San Matteo Hospital. I work on: blood collection from healthy donors, stem cell collection from healthy (related and un-related) donor and non-healthy donors and from blood cord, post-transplant rejection (AGVHD, CGVHD, BOS/CLAD, …), diseases who needs plasma-exchange (TTP, hepatic failure, DIC, polyneuropathy antibodies-related, …) or eritro-exchange (falcemic crisis), blood transfusion, flow cytometry in the hematologic field (to analyze the composition of bone marrow, of stem cell collections before the transplant, …). Since February 2017, I have been in charge of the new outpatient service for the evaluation and treatment of the anemia, as suggested by the Italian Patient Blood Management Plan, in patients who undergo on surgery then in all patient, in collaboration with the Emergency Department and with the Department of Gynaecology and Obstetrics.

Anderson Melchior Hernandez.
Stochastic analysis of evolution equations
Department of Mathematics Mathematics (supervisor: Marco Veneroni)

My PhD project involves the development of mathermatical technicques that aim to quantify the velocity of convergence of some stochastic evolution partial differential equations or their specify large deviations property. I attended a variety of courses in including Bayesian statical theory (A Lijoi), Quantum Markov processes (R Carbone), Variational methods for semi linear elliptic equations (S Secchi), Variational formulations of boundary value problems (G Gilardi), Non linear dispersive equations: theory and applications (D Noja), etc. I have also sat examinations on the following courses: Quantum Markov processes, Variational formulations of boundary value problems and Dirichlet forms, Markov semigroups and gradient flow.

Farshad Piri.  Next-generation 5G communication systems

Department of Industrial and Information Engineering (supervisor: Francesco Svelto)

Since 1980s the Information and Communications Technologies (ICT) has kept growing, providing an increasing amount of end-user oriented applications and benefits. During the past years, both mobile and fixed data traffic has grown exponentially due to the impressive growth of the smartphones, tablets, laptops and etc. The demand for the wireless connectivity will be even larger in the future. As an example, the 4G network enabled a hugely improved multimedia experience as broadband wireless networks started to takeover wired connections. Following this trend next generation networks will require to share an enormous amount of data in a real-time response to wireless users stressing the network capacity. Precise generation of quadrature signals over a wide frequency range is a key function in next-generation 5G communication systems. My research focuses on the design and construction of a wideband quadrature generator based on a single-stage Polyphase Filter (PPF). A phase detector senses the phase error from quadrature signals generated by a single-stage PPF and a feedback circuit continuously tunes the filter center frequency to the input signal frequency by varying the polyphase resistance of a nMOS device in triode. Transformer-based resonant circuits at the input and output of the PPF ensure wide bandwidth and low loss. Prototypes have been realized in a 55nm CMOS technology. Tailored to next-generation 5G systems for cross-network interoperability requirements, the measured quadrature generator shows an IRR>40dB over a bandwidth from 28GHz to 44GHz.  Power consumption is 36mW for the PPF and buffers, and 3mW only for the calibration loop. One key aspect of the proposed solution is its robustness over PVT, one of the weak aspects of alternatives proposed in the literature. This solution compares favorably with state-of-the-art, and shows the largest fractional bandwidth (44%) among the quadrature generators at frequencies greater than 20GHz. The prototype demonstrates state-of-the-art performances over a large fractional bandwidth.

Corrado Regalbuto. Endocrine Diseases.
Department of Internal Medicine and Therapy (supervisor: )

This year I've started the residency in Pediatrics. I've published two articles : " Gynecomastia after euthyroidism restoration in a patient with type 1 diabetes and Graves' disease", a  case report that describes gynecomastia in a male patient with type 1 diabetes and Graves’ disease after thyroid function restoration had been achieved and  "Smoke exposure and cardio-metabolic profile in youth with type 1 diabetes", that evaluates the relationship between smoking and metabolic parameters in patients affected by type 1 diabetes. I've trained for a period of four months in the Allergology and Immunology pediatric department and for a period of four months in the Oncohematology department.

Calcaterra V, Clerici E, Ceolin V, Regalbuto C, Larizza D. Gynecomastia after euthyroidism restoration in a patient with type 1 diabetes and Graves' disease. Clin Case Rep. 2018 Jun 14;6(8):1481-1484. doi: 10.1002/ccr3.1565. eCollection 2018 Aug.

Calcaterra V, Winickoff JP, Klersy C, Schiano LM1, Bazzano R, Montalbano C, Musella V, Regalbuto C, Larizza D, Cena H. Smoke exposure and cardio-metabolic profile in youth with type 1 diabetes. Diabetol Metab Syndr. 2018 Jul 6;10:53. doi: 10.1186/s13098-018-0355-0. eCollection 2018.

Abhijeet Taralkar.  Analog-to-Digital converters (ADCs) in automobile applications.
Department of Industrial and Information Engineering (supervisor: )

Analog-to-Digital converters (ADCs) in automobile applications often require very high absolute accuracy and linearity, and very low offset and noise with low power consumption. ΣΔ (Sigma-Delta) modulation is a relatively simple means of performing data conversion but since ΔΣ modulators oversample the data, the input bandwidth is limited by both the oversampling ratio (OSR) and the maximum sampling frequency. The automobile specifications are not easily satisfied with conventional ADCs, since these do not provide accurate gain control and low offset, and require complex and power-hungry digital filters for high-accuracy performance. In contrast to the conventional ΣΔ ADCs, which converts a waveform operating continuously, incremental data converters (IDC) convert individual input samples. It operates for a predetermined number of clock periods and is then reset. The properties of IDCs are well matched to the requirements of automobile. They provide very precise conversion with accurate gain, high linearity and low offset, and the conversion time can be relatively short. My project involves the design and testing, initial through simulation studies, of IDC converters for automobile application and in 2017/18 academic year I have achieved progress in both these areas.

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