Model building and model checking for biochemical processes

A central claim of computational systems biology is that, by drawing on mathematical approaches developed in the context of dynamic systems, kinetic analysis, computational theory and logic, it is possible to create powerful simulation, analysis, and reasoning tools for working biologists to decipher existing data, devise new experiments, and ultimately to understand functional properties of genomes, proteomes, cells, organs, and organisms. In this article, a novel computational tool is described that achieves many of the goals of this new discipline. The novelty of this system involves an automaton-based semantics of the temporal evolution of complex biochemical reactions starting from the representation given as a set of differential equations. The related tools also provide ability to qualitatively reason about the systems using a propositional temporal logic that can express an ordered sequence of events succinctly and unambiguously. The implementation of mathematical and computational models in the Simpathica and XSSYS systems is described briefly. Several example applications of these systems to cellular and biochemical processes are presented: the two most prominent are Leibler et al.'s repressilator (an artificial synthesized oscillatory network), and Curto-Voit-Sorribas-Cascante's purine metabolism reaction model

Breakfast skipping, weight, cardiometabolic risk, and nutrition quality in children and adolescents: A systematic review of randomized controlled and intervention longitudinal trials

Breakfast skipping increases with age, and an association with a high risk of being overweight (OW) and of obesity (OB), cardiometabolic risk, and unhealthy diet regimen has been demonstrated in observational studies with children and adults. Short-term intervention trials in adults reported conflicting results. The purpose of this systematic review was to summarize the association of breakfast skipping with body weight, metabolic features, and nutrition quality in the groups of young people that underwent randomized controlled (RCT) or intervention longitudinal trials lasting more than two months. We searched relevant databases (2000–2021) and identified 584 articles, of which 16 were suitable for inclusion. Overall, 50,066 children and adolescents were in-cluded. No studies analyzed cardiometabolic features. Interventions were efficacious in reducing breakfast skipping prevalence when multi-level approaches were used. Two longitudinal studies reported a high prevalence of OW/OB in breakfast skippers, whereas RCTs had negligible effects. Ten studies reported a lower-quality dietary intake in breakfast skippers. This review provides in-sight into the fact that breakfast skipping is a modifiable marker of the risk of OW/OB and unhealthy nutritional habits in children and adolescents. Further long-term multi-level intervention studies are needed to investigate the relationship between breakfast, nutrition quality, chronotypes, and cardiometabolic risk in youths

Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO

Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status

KRAS and BRAF genotyping of synchronous colorectal carcinomas.

Abstract. v‑Ki‑ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genotyping is required prior to anti‑epidermal growth factor receptor monoclonal antibody therapy administered in cases of metastatic colorectal carcinoma (CRC). Thus, KRAS mutation screening is required for patient management. The present study reported the experience of KRAS/v‑raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational screening on synchronous CRC pairs from 26 patients, which were defined as index lesions (ILs) and concurrent lesions (CLs) on the basis of tumor grade and dimension and their respective lymph node and distant metastases. Overall, KRAS mutations were present in 38.4% of patients, whereas BRAF mutations were present at a frequency of 11.5%. The genotyping of paired synchronous carcinomas indicated that 11 patients (42.3%) exhibited discordant KRAS mutational statuses in terms of the presence of a mutation in only one lesion of the pair or of two different mutations harbored by each lesion. BRAF mutations were present in the synchronous tumors of two cases, whereas in two other cases, only the IL or CL harbored mutant BRAF. Overall, the mutational statuses of distant and lymph node metastases confirm the genetic heterogeneity of synchronous primary tumors. These results highlighted the fact that adequate sampling and comprehensive testing, when feasible, is likely to optimize the decision‑making process for treatment approaches, even in the relatively rare event of multiple synchronous lesions

A general computational method for robustness analysis with applications to synthetic gene networks

Motivation: Robustness is the capacity of a system to maintain a function in the face of perturbations. It is essential for the correct functioning of natural and engineered biological systems. Robustness is generally defined in an ad hoc, problem-dependent manner, thus hampering the fruitful development of a theory of biological robustness, recently advocated by Kitano

Aflibercept Plus FOLFIRI in the Real-life Setting: Safety and Quality of Life Data From the Italian Patient Cohort of the Aflibercept Safety and Quality-of-Life Program Study

The Italian subset of the real-life Aflibercept Safety and Quality-of-Life Program study evaluated the safety and health-related quality of life (HRQL) of aflibercept plus FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) in 200 patients with pretreated metastatic colorectal cancer (mCRC). No significant worsening of HRQL occurred, and the safety profile was consistent with the reported data. The combination was well tolerated as second-line treatment for patients with mCRC in a real-life setting. Background: Aflibercept combined with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) as second-line treatment of metastatic colorectal cancer (mCRC) significantly improved survival compared with FOLFIRI alone in the pivotal VELOUR (aflibercept vs. placebo in combination with irinotecan and 5-fluorouracil in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin-based regimen) trial. No quality-of-life assessment was performed in VELOUR; therefore, the ASQoP (Aflibercept Safety and Quality-of-Life Program) trial was designed to capture the safety and health-related quality of life (HRQL). Patients and Methods: ASQoP was an international, open-label, single-arm trial evaluating the safety and HRQL of aflibercept combined with FOLFIRI administered in a real-life setting to 781 patients with mCRC, pretreated with an oxaliplatin-based regimen with or without bevacizumab. The Italian subset of ASQoP enrolled 200 patients from 28 institutions. The primary endpoint was safety; HRQL was a secondary endpoint, assessed by validated questionnaires (European quality of life 5-dimension instrument 3-level; European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30, version 3; and EORTC-CR29) at baseline, during treatment, and at the end of treatment. Results: The median age of the Italian ASQoP population was 63 years; the median number of aflibercept and FOLFIRI cycles was 7. Treatment-emergent adverse events were reported in 97.5% of patients. Hypertension (28.5%), neutropenia (27.5%; from laboratory data), asthenic conditions (20.0%), diarrhea (17.0%), and stomatitis (13.0%) were the most frequent (incidence, ≥ 5%) grade 3/4 toxicities. One toxic death occurred during the study period due to sepsis, without neutropenic complications. No significant worsening of HRQL was shown during treatment. Conclusion: Aflibercept combined with FOLFIRI was well tolerated when administered as second-line treatment for patients with mCRC in a real-life setting. It did not affect HRQL and showed similar rates of treatment-emergent adverse events as those observed in the VELOUR trial. No new safety signals were identified

Intensified ChlVPP/ABVVP chemotherapy regimen and pegfilgrastim support in advanced Hodgkin lymphoma

We present feasibility, toxicity and efficacy results of an intensified six-cycle ChlVPP/ABVVP regimen in advanced Hodgkin lymphoma (HL). From February 2004 to August 2007, 82 consecutive eligible patients were enrolled. According to the Hasenclever index, 64 patients (78%) were considered at low risk, 15 (18%) at intermediate and 3 (4%) at high risk. The most relevant toxicity was haematological: grade 3–4 neutropenia occurred in 32% of patients, grade 3–4 anaemia in 26% of patients. Severe infections and febrile neutropenia were observed in 8% of patients. With a median follow-up of 35 months (range 12–55), the three-year freedom from treatment failure (FFTF) and overall survival (OS) were 75% (95% CI 65%–86%) and 94% (95% CI 87%–99%), respectively. The intensified ChlVPP/ABVVP regimen in advanced HL is effective, does not seem to differ from standard regimens in terms of FFTF and OS and showed a favourable toxicity profile

SiO2nanoparticles modulate the electrical activity of neuroendocrine cells without exerting genomic effects

Engineered silica nanoparticles (NPs) have attracted increasing interest in several applications, and particularly in the field of nanomedicine, thanks to the high biocompatibility of this material. For their optimal and controlled use, the understanding of the mechanisms elicited by their interaction with the biological target is a prerequisite, especially when dealing with cells particularly vulnerable to environmental stimuli like neurons. Here we have combined different electrophysiological approaches (both at the single cell and at the population level) with a genomic screening in order to analyze, in GT1-7 neuroendocrine cells, the impact of SiO2NPs (50\u2009\ub1\u20093\u2009nm in diameter) on electrical activity and gene expression, providing a detailed analysis of the impact of a nanoparticle on neuronal excitability. We find that 20\u2009\ub5g\u2009mL-1NPs induce depolarization of the membrane potential, with a modulation of the firing of action potentials. Recordings of electrical activity with multielectrode arrays provide further evidence that the NPs evoke a temporary increase in firing frequency, without affecting the functional behavior on a time scale of hours. Finally, NPs incubation up to 24\u2009hours does not induce any change in gene expression