Generic Substitution of Orphan Drugs for the Treatment of Rare Diseases: Exploring the Potential Challenges

Generic drugs are important components of measures introduced by healthcare regulatory authorities to reduce treatment costs. In most patients and conditions the switch from a branded drug to its generic counterpart is performed with no major complications. However, evidence from complex diseases suggests that generic substitution requires careful evaluation in some settings and that current bioequivalence criteria may not always be adequate for establishing the interchangeability of branded and generic products. Rare diseases, also called orphan diseases, are a group of heterogeneous diseases that share important characteristics: in addition to their scarcity, most are severe, chronic, highly debilitating, and often present in early childhood. Finding a treatment for a rare disease is challenging. Thanks to incentives that encourage research and development programs in rare diseases, several orphan drugs are currently available. The elevated cost of orphan drugs is a highly debated issue and a cause of limited access to treatment for many patients. As patent protection and the exclusivity period of several orphan drugs will expire soon, generic versions of orphan drugs should reach the market shortly, with great expectations about their impact on the economic burden of rare diseases. However, consistent with other complex diseases, generic substitution may require thoughtful considerations and may be even contraindicated in some rare conditions. This article provides an overview of rare disease characteristics, reviews reports of problematic generic substitution, and discusses why generic substitution of orphan drugs may be challenging and should be undertaken carefully in rare disease patients

Protein Profiling of Arabidopsis Roots Treated With Humic Substances: Insights Into the Metabolic and Interactome Networks

Background and Aim: Humic substances (HSs) influence the chemical and physical properties of the soil, and are also known to affect plant physiology and nutrient uptake. This study aimed to elucidate plant metabolic pathways and physiological processes influenced by HS activity. Methods: Arabidopsis roots were treated with HS for 8 h. Quantitative mass spectrometry-based proteomics analysis of root proteins was performed using the iTRAQ (Isobaric Tag for Relative and Absolute Quantification) technique. Out of 902 protein families identified and quantified for HS treated vs. untreated roots, 92 proteins had different relative content. Bioinformatic tools such as STRING, KEGG, IIS and Cytoscape were used to interpret the biological function, pathway analysis and visualization of network amongst the identified proteins. Results: From this analysis it was possible to evaluate that all of the identified proteins were functionally classified into several categories, mainly redox homeostasis, response to inorganic substances, energy metabolism, protein synthesis, cell trafficking, and division. Conclusion: In the present study an overview of the metabolic pathways most modified by HS biological activity is provided. Activation of enzymes of the glycolytic pathway and up regulation of ribosomal protein indicated a stimulation in energy metabolism and protein synthesis. Regulation of the enzymes involved in redox homeostasis suggest a pivotal role of reactive oxygen species in the signaling and modulation of HS-induced responses

Progettazione e realizzazione di uno strumento di sviluppo rapido di applicazioni per terminali P.O.S.

Ad oggi, svariato è il numero e la varietà dei dispositivi sui quali è possibile sviluppare una applicazione. Un dispositivo che nell’ultimo decennio ha rivestito un importante ruolo è il terminale POS. Man mano l’oggetto POS è divenuto più performante, più bello, ha acquisito maggiori possibilità consentendo anche la creazione di applicazioni molto più che banali. Però allo stesso tempo non si sono sviluppate le metodologie e gli ambienti di sviluppo a lui collegati. Si utilizzano ancora il linguaggio ANSI C e comuni tecniche di sviluppo, ma la complessità delle applicazioni è notevolmente aumentata insieme alla varietà delle periferiche e delle funzionalità che oggi sono legate ai terminali POS. Non più solo “strisciare la carta”. Allora perché non provare a fornire un nuovo approccio alla programmazione dei terminali POS? Perché non realizzare un ambiente RAD di sviluppo delle applicazioni per questo tipo di dispositivi? Perché non scaricare il programmatore della complessità intrinseca nella programmazione di un terminale POS, cercando di farlo convergere il più possibile verso i problemi che veramente danno valore aggiunto alla sua applicazione? La tesi studia la possibilità e in parte sperimenta una metodologia di realizzazione delle applicazioni composta da • Componenti • Modelli applicativi attraverso la realizzazione di ARTpos, un prototipo di Ambiente di Sviluppo RAD per Terminali POS. ARTpos comprende strumenti grafici per aiutare lo sviluppatore a pensare, documentare e costruire una applicazione per terminali POS, focalizzando maggiormente l’attenzione sull’ideazione e la costruzione dell’interfaccia grafica. Tutto questo utilizzando paradigmi stato dell’arte relativamente al Software Engineering e alla Automatic Code Generation

Correlated Mott insulators in a strong electric field: The effects of phonon renormalization

We characterize the response of a Mott insulating system to a static electric field in terms of its conducting and spectral properties. Dissipation is included by a coupling to fermionic baths and to either optical or acoustic phonons. This paper extends and completes the analysis made in a previous work by the authors [arXiv:2207.01921]. In the present work phonons are included diagrammatically within the Migdal approximation by also including self-consistency from the electronic feedback. The nonequilibrium steady-state is addressed by means of the dynamical mean-field theory based on the nonequilibrium Green's function approach, while the so-called auxiliary master equation approach is employed as impurity solver. With optical phonons the self-consistency suppresses the steady-state current at the onset of the metallic phase with respect to the nonself-consistent case. This is due to the interaction of phonons with the hot electrons of the lattice which increases their temperature, thus providing a less effective relaxation channel for the current-induced Joule heat. In addition, in the case of optical phonons the results are essentially independent of the temperature of the fermionic baths, as the latter is sensibly smaller than their characteristic frequency. On the other hand, with acoustic phonons the steady-state current is slightly suppressed by the self-consistent treatment only at field strengths close to half of the gap, away from the metallic phase, and especially at very small phonon frequency. Also, in this case the results seem to slightly depend on the temperature of the fermionic baths.Comment: 14 pages, 19 figures, comments are welcom

Sunitinib in metastatic renal cell carcinoma: The pharmacological basis of the alternative 2/1 schedule

No abstract availabl

Lumican is overexpressed in lung adenocarcinoma pleural effusions.

Adenocarcinoma (AdC) is the most common lung cancer subtype and is often associated with pleural effusion (PE). Its poor prognosis is attributable to diagnostic delay and lack of effective treatments and there is a pressing need in discovering new biomarkers for early diagnosis or targeted therapies. To date, little is known about lung AdC proteome. We investigated protein expression of lung AdC in PE using the isobaric Tags for Relative and Absolute Quantification (iTRAQ) approach to identify possible novel diagnostic/prognostic biomarkers. This provided the identification of 109 of lung AdC-related proteins. We further analyzed lumican, one of the overexpressed proteins, in 88 resected lung AdCs and in 23 malignant PE cell-blocks (13 lung AdCs and 10 non-lung cancers) using immunohistochemistry. In AdC surgical samples, lumican expression was low in cancer cells, whereas it was strong and diffuse in the stroma surrounding the tumor. However, lumican expression was not associated with tumor grade, stage, and vascular/pleural invasion. None of the lung cancer cell-blocks showed lumican immunoreaction, whereas those of all the other tumors were strongly positive. Finally, immunoblotting analysis showed lumican expression in both cell lysate and conditioned medium of a fibroblast culture but not in those of A549 lung cancer cell line. PE is a valid source of information for proteomic analysis without many of the restrictions of plasma. The high lumican levels characterizing AdC PEs are probably due to its release by the fibroblasts surrounding the tumor. Despite the role of lumican in lung AdC is still elusive, it could be of diagnostic value

Advances in centerline estimation for autonomous lateral control

The ability of autonomous vehicles to maintain an accurate trajectory within their road lane is crucial for safe operation. This requires detecting the road lines and estimating the car relative pose within its lane. Lateral lines are usually retrieved from camera images. Still, most of the works on line detection are limited to image mask retrieval and do not provide a usable representation in world coordinates. What we propose in this paper is a complete perception pipeline based on monocular vision and able to retrieve all the information required by a vehicle lateral control system: road lines equation, centerline, vehicle heading and lateral displacement. We evaluate our system by acquiring data with accurate geometric ground truth. To act as a benchmark for further research, we make this new dataset publicly available at http://airlab.deib.polimi.it/datasets/.Comment: Presented at 2020 IEEE Intelligent Vehicles Symposium (IV), 8 pages, 8 figure

Precision medicine in lymphoma by innovative instrumental platforms

Since the last years, many efforts have been addressed to the growing field of precision medicine in order to offer individual treatments to every patient on the basis of his/her genetic background. Formerly adopted to achieve new disease classifications as it is still done, innovative platforms, such as microarrays, genome-wide association studies (GWAS) and next generation sequencing (NGS), have made the progress in pharmacogenetics faster and cheaper than previously expected. Several studies in lymphoma patients have demonstrated that these platforms can be used to identify biomarkers predictive of drug efficacy and tolerability, discovering new possible druggable proteins. Indeed, GWAS and NGS allow the investigation of the human genome, finding interesting associations with putative or unexpected targets, which in turns may represent new therapeutic possibilities. Importantly, some objective difficulties have initially hampered the translation of findings in clinical routines, such as the poor quantity/quality of genetic material or the paucity of targets that could be investigated at the same time. At present, some of these technical issues have been partially solved. Furthermore, these analyses are growing in parallel with the development of bioinformatics and its capabilities to manage and analyze big data. Because of pharmacogenetic markers may become important during drug development, regulatory authorities (i.e., EMA, FDA) are preparing ad hoc guidelines and recommendations to include the evaluation of genetic markers in clinical trials. Concerns and difficulties for the adoption of genetic testing in routine are still present, as well as affordability, reliability and the poor confidence of some patients for these tests. However, genetic testing based on predictive markers may offers many advantages to caregivers and patients and their introduction in clinical routine is justified

Evaluation of the subscapularis split created with passive rotation during arthroscopic dynamic anterior stabilization (DAS): A cadaveric study.

Abstract Introduction The purpose of the present study was to analyze the ability to create a subscapularis split by passive rotation of the arm during dynamic anterior stabilization (DAS) and to analyze the new geometry of the long head of the biceps LHB. Hypothesis The hypothesis was that this passive simple technique can create subscapularis split without additional dissection giving rise to new position of LHB with a new stabilization function. Material and methods A technique of subscapularis split using the LHB was used in 12 fresh-frozen human cadaveric shoulders. A subscapularis split was created by passive rotation of the arm after the LHB is shuttled into the joint during DAS. The length of the subscapularis split, post-DAS position and length of the LHB, and the angulation of the LHB relative to bicipital groove were measured after DAS and if this new geometry can give a new dynamic effect on subscapularis muscle. Results The mean length of the subscapular split after maximal rotation was 20.4 ± 6.0 mm (range: 10–32 mm). The mean elongation of the LHB was 0.6 ± 1.4 mm (range: −1 to +3 mm). The final angle of the LHB relative to the bicipital groove was 45 ± 5 degrees (range: 41 to 55 degrees). Discussion There is no need to create a distinct split prior to DAS. Additionally, DAS maintains the length-tension relationship of the LHB. The post-procedure medial angulation of the LHB relative to the bicipital groove may provide a lowering of the subscapularis, helping explain the anterior reinforcement of this technique. Level of evidence Basic science study, cadaver study

Molecular characterization of Prototheca strains isolated from Italian dairy herds.

One hundred sixty-one Prototheca spp. strains isolated from composite milk and barn-surrounding environmental samples (bedding, feces, drinking, or washing water, surface swabs) of 24 Italian dairy herds were characterized by genotype-specific PCR analysis. Overall, 97.2% of strains isolated from composite milk samples were characterized as Prototheca zopfii genotype 2, confirming its role as the main mastitis pathogen, whereas Prototheca blaschkeae was only sporadically isolated (2.8%). Regarding environmental sampling, 84.9% of isolates belonged to P. zopfii genotype 2, 13.2% to P. blaschkeae, and 1.9% to P. zopfii genotype 1. The data herein contradict previous hypotheses about the supposed exclusive role of P. zopfii genotype 2 as the causative agent of protothecal mastitis and, on the contrary, confirm the hypothesis that such pathology could be caused by P. blaschkeae in a few instances