Molecular Landscape and Therapeutic Strategies in Cholangiocarcinoma: An Integrated Translational Approach towards Precision Medicine

Cholangiocarcinomas (CCAs) are heterogeneous biliary tract malignancies with dismal prognosis, mainly due to tumor aggressiveness, late diagnosis, and poor response to current therapeutic options. High-throughput technologies have been used as a fundamental tool in unveiling CCA molecular landscape, and several molecular classifications have been proposed, leading to various targeted therapy trials. In this review, we aim to analyze the critical issues concerning the status of precision medicine in CCA, discussing molecular signatures and clusters, related to both anatomical classification and different etiopathogenesis, and the latest therapeutic strategies. Furthermore, we propose an integrated approach comprising the CCA molecular mechanism, pathobiology, clinical and histological findings, and treatment perspectives for the ultimate purpose of improving the methods of patient allocations in clinical trials and the response to personalized therapies.     

Myositis/Myasthenia after Pembrolizumab in a Bladder Cancer Patient with an Autoimmunity-Associated HLA: Immune–Biological Evaluation and Case Report

Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune–biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.     

Enhancing histograms by tree-like bucket indices

Histograms are used to summarize the contents of relations into a number of buckets for the estimation of query result sizes. Several techniques have been proposed in the past for determining bucket boundaries which provide accurate estimations. However, while search strategies for optimal bucket boundaries are rather sophisticated, no much attention has been paid for estimating queries inside buckets and all of the above techniques adopt naive methods for such an estimation. This paper focuses on the problem of improving the estimation inside a bucket once its boundaries have been fixed. The proposed technique is based on the addition, to each bucket, of a memory-word additional information (organized into a tree-like index), storing approximate cumulative frequencies in a hierarchical fashion. Both theoretical analysis and experimental results show that the proposed approach improves the accuracy of the estimation inside buckets, w.r.t. both classical approaches (like continuous value assumption and uniform spread assumption) and a number of alternative ways to organize the additional information. The index is later added to state-of-the-art histograms obtaining the non-obvious result that despite the spatial overhead which reduces the number of allowed buckets once the storage space has been fixed, the original methods are strongly improved in terms of accuracy. An abridged version of this paper appeared in the Proceedings of the International Conference on Data Engineering (ICDE 2002), IEEE Computer Society 2002, ISBN 0-7695-1531-2 [3].     

Topological properties of reachable sets and the control of quantum bits

We consider the problem of controlling the state of a two-level quantum system (quantum bit) via an externally applied electro-magnetic field. The describing model is a bilinear right-invariant system whose state varies on the Lie group of 2×2 special unitary matrices. We study the topological structure of the reachable sets. If two or more independent controls are used, then every state can be achieved in arbitrary time. However, this is no longer true if only one control is available and, in this case, we give an exact characterization of states reachable in arbitrary time. We prove small time local controllability for any state and the existence of a critical time which is the smallest time after which every transfer of state is possible. We provide upper and lower bounds for such a time. The mathematical development is motivated by the problem of manipulating the state of a quantum bit. Every transfer of state may be interpreted as a quantum logic operation and not every logic operation can be obtained in arbitrary time. The analysis we present provides information about the feasibility of a given operation as well as estimates for the speed of a quantum computer.     

A predictive control strategy for norm‐bounded LPV discrete‐time systems with bounded rates of parameter change

A novel predictive control strategy for input‐saturated norm‐bounded linear parameter varying discrete‐time systems is proposed. The solution is computed by minimizing an upper bound to the ‘worst‐case’ infinite horizon quadratic cost under the constraint of steering the future state evolutions, emanating from the current state, into a feasible and positive invariant set. It will be shown that the ‘size’ of this terminal set depends on the rate of change of the scheduling parameter, which is assumed to be bounded and measurable. Copyright © 2007 John Wiley & Sons, Ltd.     

Robust multiple‐fault detection and isolation: A gradient flow approach

This paper presents a novel solution to the fault detection and isolation observer design problem for linear time‐invariant systems. A gradient flow approach is proposed for synthesizing a residual generator under optimal eigenstructure assignment. This is achieved by minimizing the spectral condition number of the observer eigenvector matrix. The properties of convergence of the gradient flow solution are proved and its efficiency demonstrated via a numerical example. Copyright © 2007 John Wiley & Sons, Ltd.     

Profiling and quantifying quercetin glucosides in onion (Allium cepa L.) varieties using capillary zone electrophoresis and high performance liquid chromatography

There is increasing evidence that flavonols demonstrate beneficial properties for human health. Quercetin is the major flavonol present in onion (Allium cepa cv) and is present predominantly as quercetin 3,4′-diglucoside and quercetin 4′-monoglucoside. These compounds are known to be potent free radical scavengers and antioxidants, and are considered to be protective against cardiovascular disease. Analysis for the presence of these compounds has therefore become more important. Robust capillary zone electrophoresis and high performance liquid chromatography procedures were developed for profiling and quantifying the levels of quercetin 3,4′-diglucoside and quercetin 4′-monoglucoside in 70% methanol/water extracts of six different onion varieties available in Victoria, Australia. Quercetin 3,4′-diglucoside, which is not commercially available as a reference standard, was isolated from freeze-dried onion powder by preparative high performance liquid chromatography and used to quantify the levels in the onion extracts. Significant differences in the levels and ratios of the two compounds were seen between red, brown and white onion varieties (e.g. ‘Redwing’; quercetin 3,4′-diglucoside 191 mg/100 g DW, quercetin 4′-monoglucoside 85 mg/100 g DW; ‘Cream Gold’, quercetin 3,4′-diglucoside 153 mg/100 g DW, quercetin 4′-monoglucoside 58 mg/100 g DW, ‘Spanish white’; quercetin 3,4′-diglucoside <1 mg/100 g DW, quercetin 4′-monoglucoside <1 mg/100 g DW).     

Selection of Streptococcus thermophilus strains able to produce exopolysaccharides in milk

A collection of 139 Streptococcus thermophilus strains was genetically screened by PCR targeting some genes involved in exopolysaccharide (EPS) biosynthesis. Twenty‐nine strains were found to be PCR positive and were grown in skim milk to highlight their ropy character, that is the ability to efficiently thicken the milk cultures and minimise syneresis. Three strains producing a skim milk culture with apparent viscosities of 275 ± 14, 340 ± 21 and 510 ± 42 mPa.s, significantly higher than the average value (135 ± 87.3 mPa.s), were selected. EPS from milk cultures of these three strains was extracted and quantified from 84.4 to 209.2 mg/L.     

Characterisation of lactic acid bacteria isolated from the Georgian,yoghurt‐like Matsoni

Matsoni is a traditional Caucasian fermented milk product, characterised by a lactic acid bacteria (LAB) microbiota. Objectives of the present study were to isolate and identify the LAB of Matsoni samples collected from various Georgian areas and to study their technological characteristics. About 300 LAB from 71 samples of Matsoni were isolated and characterised. The species most representatives were Lactobacillus delbrueckii, Streptococcus thermophilus and Lactobacillus rhamnosus. This study highlighted a high degree of biodiversity and a specific geographical distribution of the dominant LAB present in artisanal Matsoni. Some strains showed technological features useful to design a multistrain starter culture for Matsoni.