Dual mTOR1/2 Inhibitor Sapanisertib (FTH-003/TAK-228) in Combination With Weekly Paclitaxel in Patients With Previously Treated Metastatic Urothelial Carcinoma: A Phase II Open-Label Study.

BACKGROUND: The PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib. PATIENTS AND METHODS: This was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8, and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders. RESULTS: 22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (n = 4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI: 1.8-6.1) and median OS was 6.1 months (95% CI: 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders. CONCLUSIONS: Although the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.

Corrigendum: Candidate biomarkers for the prediction and monitoring of partial remission in pediatric type 1 diabetes.

[This corrects the article DOI: 10.3389/fimmu.2022.825426.].

Corrigendum: NK cell subsets changes in partial remission and early stages of pediatric type 1 diabetes.

[This corrects the article DOI: 10.3389/fimmu.2020.611522.].

Personalized medicine in acromegaly: The ACROFAST study.

Medical treatment of acromegaly is currently performed through a trial-error approach using first generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated. METHODS AND SUBJECTS: prospective trial (21 university hospitals) comparing the effectiveness and time-to control of two treatment protocols during 12 months: A) A personalized protocol in which first option were fgSRLs as monotherapy or in combination with pegvisomant or, pegvisomant as monotherapy depending on the short Acute Octreotide Test (sAOT) results, tumor T2 Magnetic Resonance (MRI) signal or immunostaining for E-cadherin and, B) A control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control. RESULTS: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, p < 0.05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI 1.30-4.80). Patients from personalized arm were controlled in a shorter period of time (p = 0.01). CONCLUSION: Personalized medicine is feasible using a relatively simple protocol and allows a higher number of patients achieving control in a shorter period of time.

Ordering dynamics of nonlinear voter models.

We study the ordering dynamics of nonlinear voter models with multiple states, also providing a discussion of the two-state model. The rate with which an individual adopts an opinion scales as the qth power of the number of the individual's neighbors in that state. For q>1 the dynamics favor the opinion held by the most agents. The ordering to consensus is driven by deterministic drift, and noise plays only a minor role. For q<1 the dynamics favors minority opinions, and for multistate models the ordering proceeds through a noise-driven succession of metastable states. Unlike linear multistate systems, the nonlinear model cannot be reduced to an effective two-state model. We find that the average density of active interfaces in the model with multiple opinion states does not show a single exponential decay in time for q<1, again at variance with the linear model. This highlights the special character of the conventional (linear) voter model, in which deterministic drift is absent. As part of our analysis, we develop a pair approximation for the multistate model on graphs, valid for any positive real value of q, improving on previous approximations for nonlinear two-state voter models.

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly.

Introduction: We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) . Methods: A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively. Results: In all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01). Conclusion: The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.

Contrarian Majority Rule Model with External Oscillating Propaganda and Individual Inertias.

We study the Galam majority rule dynamics with contrarian behavior and an oscillating external propaganda in a population of agents that can adopt one of two possible opinions. In an iteration step, a random agent interacts with three other random agents and takes the majority opinion among the agents with probability p(t) (majority behavior) or the opposite opinion with probability 1-p(t) (contrarian behavior). The probability of following the majority rule p(t) varies with the temperature T and is coupled to a time-dependent oscillating field that mimics a mass media propaganda, in a way that agents are more likely to adopt the majority opinion when it is aligned with the sign of the field. We investigate the dynamics of this model on a complete graph and find various regimes as T is varied. A transition temperature Tc separates a bimodal oscillatory regime for TTc in which m oscillates around zero. These regimes are characterized by the distribution of residence times that exhibit a unique peak for a resonance temperature T*, where the response of the system is maximum. An insight into these results is given by a mean-field approach, which also shows that T* and Tc are closely related.

Spatial effects in parasite-induced marine diseases of immobile hosts.

Emerging marine infectious diseases pose a substantial threat to marine ecosystems and the conservation of their biodiversity. Compartmental models of epidemic transmission in marine sessile organisms, available only recently, are based on non-spatial descriptions in which space is homogenized and parasite mobility is not explicitly accounted for. However, in realistic scenarios epidemic transmission is conditioned by the spatial distribution of hosts and the parasites' mobility patterns, calling for an explicit description of space. In this work, we develop a spatially explicit individual-based model to study disease transmission by waterborne parasites in sessile marine populations. We investigate the impact of spatial disease transmission through extensive numerical simulations and theoretical analysis. Specifically, the effects of parasite mobility into the epidemic threshold and the temporal progression of the epidemic are assessed. We show that larger values of pathogen mobility imply more severe epidemics, as the number of infections increases, and shorter timescales to extinction. An analytical expression for the basic reproduction number of the spatial model, R ~ 0 , is derived as a function of the non-spatial counterpart, R 0, which characterizes a transition between a disease-free and a propagation phase, in which the disease propagates over a large fraction of the system.

Contrarian Voter Model under the Influence of an Oscillating Propaganda: Consensus, Bimodal Behavior and Stochastic Resonance.

We study the contrarian voter model for opinion formation in a society under the influence of an external oscillating propaganda and stochastic noise. Each agent of the population can hold one of two possible opinions on a given issue­against or in favor­and interacts with its neighbors following either an imitation dynamics (voter behavior) or an anti-alignment dynamics (contrarian behavior): each agent adopts the opinion of a random neighbor with a time-dependent probability p(t), or takes the opposite opinion with probability 1−p(t). The imitation probability p(t) is controlled by the social temperature T, and varies in time according to a periodic field that mimics the influence of an external propaganda, so that a voter is more prone to adopt an opinion aligned with the field. We simulate the model in complete graph and in lattices, and find that the system exhibits a rich variety of behaviors as T is varied: opinion consensus for T=0, a bimodal behavior for TTc, and full disorder for T≫1. The transition temperature Tc vanishes with the population size N as Tc≃2/lnN in complete graph. In addition, the distribution of residence times tr in the bimodal phase decays approximately as tr−3/2. Within the oscillatory regime, we find a stochastic resonance-like phenomenon at a given temperature T*. Furthermore, mean-field analytical results show that the opinion oscillations reach a maximum amplitude at an intermediate temperature, and that exhibit a lag with respect to the field that decreases with T.

Optimal control for a SIR epidemic model with limited quarantine.

Social distance, quarantines and total lock-downs are non-pharmaceutical interventions that policymakers have used to mitigate the spread of the COVID-19 virus. However, these measures could be harmful to societies in terms of social and economic costs, and they can be maintained only for a short period of time. Here we investigate the optimal strategies that minimize the impact of an epidemic, by studying the conditions for an optimal control of a Susceptible-Infected-Recovered model with a limitation on the total duration of the quarantine. The control is done by means of the reproduction number [Formula: see text], i.e., the number of secondary infections produced by a primary infection, which can be arbitrarily varied in time over a quarantine period T to account for external interventions. We also assume that the most strict quarantine (lower bound of [Formula: see text]) cannot last for a period longer than a value [Formula: see text]. The aim is to minimize the cumulative number of ever-infected individuals (recovered) and the socioeconomic cost of interventions in the long term, by finding the optimal way to vary [Formula: see text]. We show that the optimal solution is a single bang-bang, i.e., the strict quarantine is turned on only once, and is turned off after the maximum allowed time [Formula: see text]. Besides, we calculate the optimal time to begin and end the strict quarantine, which depends on T, [Formula: see text] and the initial conditions. We provide rigorous proofs of these results and check that are in perfect agreement with numerical computations.

Modeling and Analysis of Social Phenomena: Challenges and Possible Research Directions.

This opening editorial aims to interest researchers and encourage novel research in the closely related fields of sociophysics and computational social science. We briefly discuss challenges and possible research directions in the study of social phenomena, with a particular focus on opinion dynamics. The aim of this Special Issue is to allow physicists, mathematicians, engineers and social scientists to show their current research interests in social dynamics, as well as to collect recent advances and new techniques in the analysis of social systems.

Random multi-player games.

The study of evolutionary games with pairwise local interactions has been of interest to many different disciplines. Also, local interactions with multiple opponents had been considered, although always for a fixed amount of players. In many situations, however, interactions between different numbers of players in each round could take place, and this case cannot be reduced to pairwise interactions. In this work, we formalize and generalize the definition of evolutionary stable strategy (ESS) to be able to include a scenario in which the game is played by two players with probability p and by three players with the complementary probability 1-p. We show the existence of equilibria in pure and mixed strategies depending on the probability p, on a concrete example of the duel-truel game. We find a range of p values for which the game has a mixed equilibrium and the proportion of players in each strategy depends on the particular value of p. We prove that each of these mixed equilibrium points is ESS. A more realistic way to study this dynamics with high-order interactions is to look at how it evolves in complex networks. We introduce and study an agent-based model on a network with a fixed number of nodes, which evolves as the replicator equation predicts. By studying the dynamics of this model on random networks, we find that the phase transitions between the pure and mixed equilibria depend on probability p and also on the mean degree of the network. We derive mean-field and pair approximation equations that give results in good agreement with simulations on different networks.

ENDOCRINE OBESITY: Pituitary dysfunction in obesity.

Obesity, the growing pandemic of the 21st century, is associated with multiple organ dysfunction, either by a direct increase in fatty organ content or by indirect modifications related to general metabolic changes driven by a specific increase in biologic products. The pituitary gland is not protected against such a situation. Different hypothalamic-pituitary axes experience functional modifications initially oriented to an adaptive situation that, with years of obesity, turn to maladaptive dynamics that contribute to perpetuating obesity and specific symptoms of their hormonal nature. This paper reviews the recent knowledge on obesity-related pituitary dysfunction and its pathogenic mechanisms and discusses potential therapeutic actions aimed at contributing to ameliorating the complex treatment of severe cases of obesity.

Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes.

The partial remission (PR) phase, a period experienced by most patients with type 1 diabetes (T1D) soon after diagnosis, is characterized by low insulin requirements and improved glycemic control. Given the great potential of this phase as a therapeutic window for immunotherapies because of its association with immunoregulatory mechanisms and ß-cell protection, our objective was to find peripheral immunological biomarkers for its better characterization, monitoring, and prediction. The longitudinal follow-up of 17 pediatric patients with new-onset T1D over one year revealed that, during the PR phase, remitter patients show increased percentages of effector memory (EM) T lymphocytes, terminally differentiated EM T lymphocytes, and neutrophils in comparison to non-remitter patients. On the contrary, remitter patients showed lower percentages of naïve T lymphocytes, regulatory T cells (TREG), and dendritic cells (DCs). After a year of follow-up, these patients also presented increased levels of regulatory B cells and transitional T1 B lymphocytes. On the other hand, although none of the analyzed cytokines (IL-2, IL-6, TGF-ß1, IL-17A, and IL-10) could distinguish or predict remission, IL-17A was increased at T1D diagnosis in comparison to control subjects, and remitter patients tended to maintain lower levels of this cytokine than non-remitters. Therefore, these potential monitoring immunological biomarkers of PR support that this stage is governed by both metabolic and immunological factors and suggest immunoregulatory attempts during this phase. Furthermore, since the percentage of TREG, monocytes, and DCs, and the total daily insulin dose at diagnosis were found to be predictors of the PR phase, we next created an index-based predictive model comprising those immune cell percentages that could potentially predict remission at T1D onset. Although our preliminary study needs further validation, these candidate biomarkers could be useful for the immunological characterization of the PR phase, the stratification of patients with better disease prognosis, and a more personalized therapeutic management.

Noisy multistate voter model for flocking in finite dimensions.

We study a model for the collective behavior of self-propelled particles subject to pairwise copying interactions and noise. Particles move at a constant speed v on a two-dimensional space and, in a single step of the dynamics, each particle adopts the direction of motion of a randomly chosen neighboring particle within a distance R=1, with the addition of a perturbation of amplitude η (noise). We investigate how the global level of particles' alignment (order) is affected by their motion and the noise amplitude η. In the static case scenario v=0 where particles are fixed at the sites of a square lattice and interact with their first neighbors, we find that for any noise η>0 the system reaches a steady state of complete disorder in the thermodynamic limit, while for η=0 full order is eventually achieved for a system with any number of particles N. Therefore, the model displays a transition at zero noise when particles are static, and thus there are no ordered steady states for a finite noise (η>0). We show that the finite-size transition noise vanishes with N as η_{c}^{1D}∼N^{-1} and η_{c}^{2D}∼(NlnN)^{-1/2} in one- and two-dimensional lattices, respectively, which is linked to known results on the behavior of a type of noisy voter model for catalytic reactions. When particles are allowed to move in the space at a finite speed v>0, an ordered phase emerges, characterized by a fraction of particles moving in a similar direction. The system exhibits an order-disorder phase transition at a noise amplitude η_{c}>0 that is proportional to v, and that scales approximately as η_{c}∼v(-lnv)^{-1/2} for v≪1. These results show that the motion of particles is able to sustain a state of global order in a system with voter-like interactions.

Novel High-Quality Sonographic Methods to Diagnose Muscle Wasting in Long-Stay Critically Ill Patients: Shear Wave Elastography, Superb Microvascular Imaging and Contrast-Enhanced Ultrasound.

Novel ultrasound (US) methods are required to assess qualitative changes in the quadriceps rectus femoris (QRF) muscle when evaluating mechanically ventilated, long-stay ICU patients with suspected neuromuscular acquired weakness (ICUAW). Our aim was to analyze novel US muscle assessment methods in these patients versus healthy controls by carrying out a prospective observational study. Shear wave elastography (SWE) showed, with a receiver operating characteristic (ROC) curve of 0.972 (95% confidence interval (CI) = 0.916-1.000), that patients increased muscle stiffness associated with muscle fibrosis when diagnosed with ICUAW. We also performed, for the first time, superb microvascular imaging (SMI), which is an innovative US technique designed for imaging microvascularization unseen with color Doppler US, and observed that 53.8% of cases had significantly lower QRF muscle microvascular angiogenic activity than controls (p < 0.001). Finally, we used contrast-enhanced ultrasound (CEUS) to analyze maximum and minimum QRF muscle perfusion and obtained a ROC curve of 0.8, but when used as markers for SMI, their diagnostic capacity increased to 0.988 (CI = 0.965-1) and 0.932 (CI = 0.858-1), respectively. These findings show, for the first time, that these novel sonographic muscle methods should be used for their diagnostic capacity when assessing sarcopenic processes associated with this group of critically ill patients.

Long-term efficacy evaluation of a protocol for the management of symptomatic thyroid cysts with ultrasound-guided percutaneous ethanol injection.

AIM: To evaluate the long-term efficacy of percutaneous ethanol injection treatment (PEIT) as an alternative to thyroid surgery in symptomatic thyroid cysts. PATIENTS AND METHODS: 100 subjects (48±12 years; 58% women) with symptomatic thyroid cysts relapsing after drainage were prospectively included. PEIT was conducted using an established procedure, and the initial cyst volume, symptoms and pain perceived by the patient were assessed. The volume of instilled alcohol was ≤2ml without re-extraction in all cases. Patients were followed-up for more than 3 years and final cyst volume and symptom improvement were assessed. RESULTS: Mean maximum cyst diameter before drainage was 3.1±1.2cm. In 71% of patients ≤2 PEIT sessions were required. Median maximum cyst volume was 12.7 (5.4-21.7)ml before the first drainage and median total volume extracted from the cysts was 13.0 (6.2-37.0)ml. After a mean follow-up period of 52±10 months, 98% of patients reported a complete absence of symptoms. The final median volume for the whole group was 0.8 (0.1-2.0)ml with a median volume reduction of 94 (81-99)%. A final volume reduction greater than 65% was observed in 90% of cases. Reported pain during the procedure was absent or mild in 76.4% of cases. CONCLUSIONS: PEIT is a safe and well-tolerated first-line treatment for symptomatic thyroid cysts with long-term effectiveness.

Species exclusion and coexistence in a noisy voter model with a competition-colonization tradeoff.

We introduce an asymmetric noisy voter model to study the joint effect of immigration and a competition-dispersal tradeoff in the dynamics of two species competing for space in regular lattices. Individuals of one species can invade a nearest-neighbor site in the lattice, while individuals of the other species are able to invade sites at any distance but are less competitive locally, i.e., they establish with a probability g≤1. The model also accounts for immigration, modeled as an external noise that may spontaneously replace an individual at a lattice site by another individual of the other species. This combination of mechanisms gives rise to a rich variety of outcomes for species competition, including exclusion of either species, monostable coexistence of both species at different population proportions, and bistable coexistence with proportions of populations that depend on the initial condition. Remarkably, in the bistable phase, the system undergoes a discontinuous transition as the intensity of immigration overcomes a threshold, leading to a half loop dynamics associated to a cusp catastrophe, which causes the irreversible loss of the species with the shortest dispersal range.

Long-term efficacy evaluation of a protocol for the management of symptomatic thyroid cysts with ultrasound-guided percutaneous ethanol injection.

AIM: To evaluate the long-term efficacy of percutaneous ethanol injection treatment (PEIT) as an alternative to thyroid surgery in symptomatic thyroid cysts. PATIENTS AND METHODS: 100 subjects (48±12 years; 58% women) with symptomatic thyroid cysts relapsing after drainage were prospectively included. PEIT was conducted using an established procedure, and the initial cyst volume, symptoms and pain perceived by the patient were assessed. The volume of instilled alcohol was ≤2ml without re-extraction in all cases. Patients were followed-up for more than 3 years and final cyst volume and symptom improvement were assessed. RESULTS: Mean maximum cyst diameter before drainage was 3.1±1.2cm. In 71% of patients ≤2 PEIT sessions were required. Median maximum cyst volume was 12.7 (5.4-21.7)ml before the first drainage and median total volume extracted from the cysts was 13.0 (6.2-37.0)ml. After a mean follow-up period of 52±10 months, 98% of patients reported a complete absence of symptoms. The final median volume for the whole group was 0.8 (0.1-2.0)ml with a median volume reduction of 94 (81-99)%. A final volume reduction greater than 65% was observed in 90% of cases. Reported pain during the procedure was absent or mild in 76.4% of cases. CONCLUSIONS: PEIT is a safe and well-tolerated first-line treatment for symptomatic thyroid cysts with long-term effectiveness.

Ballistic-Diffusive Model for Heat Transport in Superlattices and the Minimum Effective Heat Conductivity.

There has been much interest in semiconductor superlattices because of their low thermal conductivities. This makes them especially suitable for applications in a variety of devices for the thermoelectric generation of energy, heat control at the nanometric length scale, etc. Recent experiments have confirmed that the effective thermal conductivity of superlattices at room temperature have a minimum for very short periods (in the order of nanometers) as some kinetic calculations had anticipated previously. This work will show advances on a thermodynamic theory of heat transport in nanometric 1D multilayer systems by considering the separation of ballistic and diffusive heat fluxes, which are both described by Guyer-Krumhansl constitutive equations. The dispersion relations, as derived from the ballistic and diffusive heat transport equations, are used to derive an effective heat conductivity of the superlattice and to explain the minimum of the effective thermal conductivity.