The level of ambiguity in describing glycan structure has significantly increased with the upsurge of large-scale glycomics and glycoproteomics experiments. Consequently, an ontology-based model ...appears as an appropriate solution for navigating these data. However, navigation is not sufficient and the model should also enable advanced search and comparison. A new ontology with a tree logical structure is introduced to represent glycan structures irrespective of the precision of molecular details. The model heavily relies on the GlycoCT encoding of glycan structures. Its implementation in the GlySTreeM knowledge base was validated with GlyConnect data and benchmarked with the Glycowork library. GlySTreeM is shown to be fast, consistent, reliable and more flexible than existing solutions for matching parts of or whole glycan structures. The model is also well suited for painless future expansion.
This is GlycoQL Hayes, Catherine; Daponte, Vincenzo; Mariethoz, Julien ...
Bioinformatics,
09/2022, Letnik:
38, Številka:
Supplement_2
Journal Article
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Abstract
Motivation
We have previously designed and implemented a tree-based ontology to represent glycan structures with the aim of searching these structures with a glyco-driven syntax. This ...resulted in creating the GlySTreeM knowledge-base as a linchpin of the structural matching procedure and we now introduce a query language, called GlycoQL, for the actual implementation of a glycan structure search.
Results
The methodology is described and illustrated with a use-case focused on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike protein glycosylation. We show how to enhance site annotation with federated queries involving UniProt and GlyConnect, our glycoprotein database.
Availability and implementation
https://glyconnect.expasy.org/glycoql/.
The CMS High Level Trigger (HLT) is a collection of software algorithms that run using an optimized version of the CMS offline reconstruction software. The HLT uses Python configuration files each ...containing hundreds of "modules", organized in "sequences" and "paths". Each configuration usually uses an average of 2200 different modules and more than 400 independent trigger paths. The complexity of the HLT configurations and their large number require the design of a suitable data management system. The work presented here describes the solution designed to manage the considerable number of configurations developed and to assist the editing of new configurations.
The construction of an ontology of scientific knowledge objects, presented here, is part of the development of an approach oriented towards the visualization of scientific knowledge. It is motivated ...by the fact that the concepts that are used to organize scientific knowledge (theorem, law, experience, proof, etc.) appear in existing ontologies but that none of these ontologies is centered on this topic and presents them in a simple and easily understandable organization. This ontology has been constructed by 1) selecting concepts that appear in high level ontologies or in ontologies of knowledge objects of specific fields and 2) by interviewing scientists in different fields. We have aligned this ontology with some of the sources used, which has allowed us to verify its consistency with respect to them. The validation of the ontology consists in using it to formalize knowledge from various sources, which we have begun to do in the field of physics.
Individuals with metastatic melanoma have a poor prognosis. Many human melanomas are auxotrophic for arginine, and arginine is not an essential amino acid in humans. We hypothesized that this ...auxotrophy may be therapeutically exploited. A novel amino acid-degrading enzyme (arginine deiminase) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) was used to lower plasma arginine in individuals with metastatic melanoma.
Two cohort dose-escalation studies were performed. A phase I study in the United States enrolled 15 patients, and a phase I to II study in Italy enrolled 24 patients. The Italian patients also received two subsequent cycles of treatment, each consisting of four once-weekly injections of 160 U/m2. The goals of these studies were to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and the antitumor activity of ADI-SS PEG 20,000 mw.
PK and PD studies indicated that a dose of 160 U/m2 lowered plasma arginine from a resting level of approximately 130 micromol/L to less than 2 micromol/L for at least 7 days; nitric oxide levels also were lowered. There were no grade 3 or 4 toxicities directly attributable to the drug. Six of 24 phase I to II patients responded to treatment (five partial responses and one complete response; 25% response rate) and also had prolonged survival. CONCLUSION Elimination of all detectable plasma arginine in patients with metastatic melanoma was well tolerated and may be effective in the treatment of this cancer. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with metastatic melanoma is warranted.
•KIs are the only medical therapy available for iodine-refractory DTC.•Only 2 agents, sorafenib and lenvatinib, achieved the phase III evaluation.•Evidence defining whether and when starting KIs ...administration is poor.•Many other KIs showed promising activity, but no placebo-controlled trials are available.•Emerging frontiers include iodine-redifferentiation and highly selective pharmacodynamics.
The kinase-inhibitors (KIs) sorafenib and lenvatinib demonstrated efficacy in iodine-refractory DTC upon phase III studies. However, evidence allowing a punctual balance of benefits and risks is poor. Furthermore, the lack of a direct comparison hampers to establish the proper sequence of administration. However, some insights may provided: a) indirect comparison between phase III trials showed milder toxicity for sorafenib, which should be preferred in case of cardiovascular comorbidities; b) prospective evidence of efficacy in KIs pre-treated patients is available only for lenvatinib, which should be used as second-line.
Promising activity was found for the majority of other tested KIs, but no placebo-controlled trials are available.
Emerging, but still early, frontiers include the restoration of iodine-sensitivity and the selective activity on pathogenic mutations.
In conclusion, the use of KIs in iodine-refractory DTC is far from a structured therapeutic algorithm.
Drug addiction, or substance use disorder (SUD), is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behaviour persist despite serious negative consequences. Drug abuse ...represents a problem that deserves great attention from a social point of view, and focuses on the importance of genetic studies to help in understanding the genetic basis of addiction and its medical treatment. Despite the complexity of drug addiction disorders, and the high number of environmental variables playing a role in the onset, recurrence, and duration of the symptoms, several studies have highlighted the non-negligible role of genetics, as demonstrated by heritability and genome-wide association studies. A correlation between the relative risk of addiction to specific substances and heritability has been recently observed, suggesting that neurobiological mechanisms may be, at least in part, inherited. All these observations point towards a scenario where the core neurobiological factors of addiction, involving the reward system, impulsivity, compulsivity, stress, and anxiety response, are transmitted, and therefore, genes and mutations underlying their variation might be detected. In the last few years, the development of new and more efficient sequencing technologies has paved the way for large-scale studies in searching for genetic and epigenetic factors affecting drug addiction disorders and their treatments. These studies have been crucial to pinpoint single nucleotide polymorphisms (SNPs) in genes that affect the reaction to medical treatments. This is critically important to identify pharmacogenomic approaches for substance use disorder, such as
SNPs and methadone required doses for maintenance treatment (MMT). Nevertheless, despite the promising results obtained by genome-wide association and pharmacogenomic studies, specific studies related to population genetics diversity are lacking, undermining the overall applicability of the preliminary findings, and thus potentially affecting the portability and the accuracy of the genetic studies. In this review, focusing on cannabis, cocaine and heroin use, we report the state-of-the-art genomics and pharmacogenomics of SUDs, and the possible future perspectives related to medical treatment response in people that ask for assistance in solving drug-related problems.
BACKGROUND: High-dose interferon-alpha 2b (IFN-α 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the ...immunomodulatory mechanism of action for IFN-α 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-β (TGF-β), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-α 2b regimen. METHODS: Patients with melanoma received IFN-α 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-β, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. RESULTS: Twenty-two patients with melanoma received IFN-α 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-β, IL-10, and autoantibodies in patients with melanoma treated with IFN-α 2b. CONCLUSIONS: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-α 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.
Sinonasal carcinomas (SNcs) are rare neoplasms arising from the paranasal sinuses and nasal cavity. Although these tumours have a heterogeneous histology, they are commonly diagnosed as a locally ...advanced disease and are associated with a poor prognosis. The present retrospective study reviewed 30 patients with locally advanced SNc, who were treated with surgery followed by chemoradiotherapy or radiotherapy, or radiotherapy with or without concomitant chemotherapy between January 1999 and January 2013 at the Department of Radiation Therapy, University of Naples 'Federico II' (Naples, Italy). A total of 19 patients were treated with upfront surgery followed by adjuvant radio- or chemoradiotherapy (group A), while the remaining 11 patients received exclusive radiotherapy with or without concomitant chemotherapy (group B). Concurrent cisplatin-based chemotherapy (100 mg/m
, days 1, 22 and 43 for 3 cycles) was administered to 34% of patients in group A and 55% of patients in group B. At a median follow-up of 31 months, 33.3% of patients were alive. Cause-specific survival (CSS) and progression-free survival (PFS) times were 32 and 12 months, respectively. No difference in CSS rate was observed between the two treatment groups. Univariate analysis determined that disease stage was the only factor that significantly affected CSS (P=0.002) and PFS (P=0.0001) rates. Acute and chronic toxicities were mild, with only 23.3% of patients reporting G1-2 side effects and no treatment-related blindness. The present study reported moderate activity and efficacy of surgery followed by adjuvant radio- or chemoradiotherapy, and exclusive radiotherapy with or without chemotherapy in this poor prognosis category of patients.
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