MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival compared to first-line chemotherapy alone in advanced endometrial cancer, with a much larger effect size in microsatellite-instability high (MSI-H) cases. New biomarkers might help to select patients that may have benefit among those with a microsatellite-stable (MSS) tumor. METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing (NGS) analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases MSI-H, 26 MSS TP53 wild-type (wt), 47 MSS TP53 mutated (mut), and one case with POLE mutation. Four mutated genes were present in more than 30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High TMB (≥10 Muts/Mb) was observed in all MSI-H patients, in four out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on progression-free survival significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction=0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction=0.01; PTEN P interaction=0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.

Impact of surgeon learning curve in minimally invasive radical hysterectomy on early stage cervical cancer patient survival.

Background: Recently, it has been sustained that only surgeons skilled in minimally invasive radical hysterectomy (MI-RH) could provide valuable oncological outcomes in early-stage cervical cancer. Still, literature lacks data correlating surgeon experience with patient survival rate. We aimed to investigate the impact of surgeon training on this rate. Methods: This is a retrospective study of 243 early-stage cervical cancer treated with MI-RH. Multiple regression analyses were undertaken to investigate the impact of the surgeons learning curve, according to the number of MI-RH, on patients prognosis. Results: A steady trend of reduction in disease recurrence risk is associated with increased surgeon experience. The peak of the learning curve was shown at the 19th MI-RH (hazard ratio of disease-free survival: 0.321; 95%CI: 0.140-0.737; p= 0.007). The 3 years disease-free survival that a surgeon could provide to patients is significantly lower at the beginning of his/her learning path comparing to what he/she could guarantee once adequate experience had been achieved (75.4% and 91.6% respectively, p=0.005). Surgeon experience appears to be an independent prognostic factor. Conclusion: The experience that a surgeon can achieve practicing in MI-RH significantly influences oncological outcomes of early-stage cervical cancer patients. Future studies comparing minimally invasive and open surgery should take this into account. It would be advisable that the scientific community precisely establishes the minimum training required in the field of MI-RH for early-stage cervical cancer.

A discrete dynamical system: The poor man's magnetohydrodynamic (PMMHD) equations.

A discrete dynamical system is derived, via a Fourier-Galerkin procedure, from three-dimensional equations describing incompressible plasmas in the magnetohydrodynamic (MHD) framework. The obtained six-dimensional (6D) map, consisting of logistic and nonlinear terms, can provide useful insights into incompressible plasmas dynamics when bifurcation parameters, controlling dissipative and coupling terms, are changed. The map preserves the total energy in the ideal MHD approximation (i.e., by neglecting dissipative terms), manifests a sensitive dependence to the initial conditions as well as at least one Lyapunov exponent is positive (as for chaotic systems), and is characterized by a dissipative nature of its phase space. Moreover, all fixed points of the usual MHD equations are recovered, including the fluid fixed point, the Alfvénic point, and the Taylor force-free solution. Finally, also some interesting properties, as the existence of a kinematic dynamo action, are evidenced, suggesting that discrete dynamical systems deserve consideration for the description of incompressible plasmas.

Development of Multiwell-Plate Methods Using Pure Cultures of Methanogens To Identify New Inhibitors for Suppressing Ruminant Methane Emissions.

Hydrogenotrophic methanogens typically require strictly anaerobic culturing conditions in glass tubes with overpressures of H2 and CO2 that are both time-consuming and costly. To increase the throughput for screening chemical compound libraries, 96-well microtiter plate methods for the growth of a marine (environmental) methanogen Methanococcus maripaludis strain S2 and the rumen methanogen Methanobrevibacter species AbM4 were developed. A number of key parameters (inoculum size, reducing agents for medium preparation, assay duration, inhibitor solvents, and culture volume) were optimized to achieve robust and reproducible growth in a high-throughput microtiter plate format. The method was validated using published methanogen inhibitors and statistically assessed for sensitivity and reproducibility. The Sigma-Aldrich LOPAC library containing 1,280 pharmacologically active compounds and an in-house natural product library (120 compounds) were screened against M. maripaludis as a proof of utility. This screen identified a number of bioactive compounds, and MIC values were confirmed for some of them against M. maripaludis and M. AbM4. The developed method provides a significant increase in throughput for screening compound libraries and can now be used to screen larger compound libraries to discover novel methanogen-specific inhibitors for the mitigation of ruminant methane emissions.IMPORTANCE Methane emissions from ruminants are a significant contributor to global greenhouse gas emissions, and new technologies are required to control emissions in the agriculture technology (agritech) sector. The discovery of small-molecule inhibitors of methanogens using high-throughput phenotypic (growth) screening against compound libraries (synthetic and natural products) is an attractive avenue. However, phenotypic inhibitor screening is currently hindered by our inability to grow methanogens in a high-throughput format. We have developed, optimized, and validated a high-throughput 96-well microtiter plate assay for growing environmental and rumen methanogens. Using this platform, we identified several new inhibitors of methanogen growth, demonstrating the utility of this approach to fast track the development of methanogen-specific inhibitors for controlling ruminant methane emissions.

Explosive Particle Dispersion in Plasma Turbulence.

Particle dynamics are investigated in plasma turbulence, using self-consistent kinetic simulations, in two dimensions. In the steady state, the trajectories of single protons and proton pairs are studied, at different values of plasma ß (ratio between kinetic and magnetic pressure). For single-particle displacements, results are consistent with fluids and magnetic field line dynamics, where particles undergo normal diffusion for very long times, with higher ß's being more diffusive. In an intermediate time range, with separations lying in the inertial range, particles experience an explosive dispersion in time, consistent with the Richardson prediction. These results, obtained for the first time with a self-consistent kinetic model, are relevant for astrophysical and laboratory plasmas, where turbulence is crucial for heating, mixing, and acceleration processes.

Sensitivity of subject-specific models to Hill muscle-tendon model parameters in simulations of gait.

Subject-specific musculoskeletal (MS) models of the lower extremity are essential for applications such as predicting the effects of orthopedic surgery. We performed an extensive sensitivity analysis to assess the effects of potential errors in Hill muscle-tendon (MT) model parameters for each of the 56 MT parts contained in a state-of-the-art MS model. We used two metrics, namely a Local Sensitivity Index (LSI) and an Overall Sensitivity Index (OSI), to distinguish the effect of the perturbation on the predicted force produced by the perturbed MT parts and by all the remaining MT parts, respectively, during a simulated gait cycle. Results indicated that sensitivity of the model depended on the specific role of each MT part during gait, and not merely on its size and length. Tendon slack length was the most sensitive parameter, followed by maximal isometric muscle force and optimal muscle fiber length, while nominal pennation angle showed very low sensitivity. The highest sensitivity values were found for the MT parts that act as prime movers of gait (Soleus: average OSI=5.27%, Rectus Femoris: average OSI=4.47%, Gastrocnemius: average OSI=3.77%, Vastus Lateralis: average OSI=1.36%, Biceps Femoris Caput Longum: average OSI=1.06%) and hip stabilizers (Gluteus Medius: average OSI=3.10%, Obturator Internus: average OSI=1.96%, Gluteus Minimus: average OSI=1.40%, Piriformis: average OSI=0.98%), followed by the Peroneal muscles (average OSI=2.20%) and Tibialis Anterior (average OSI=1.78%) some of which were not included in previous sensitivity studies. Finally, the proposed priority list provides quantitative information to indicate which MT parts and which MT parameters should be estimated most accurately to create detailed and reliable subject-specific MS models.

Spatial interactions in a modified Daisyworld model: Heat diffusivity and greenhouse effects.

In this work we investigate a modified version of the Daisyworld model, originally introduced by Lovelock and Watson to describe in a simple way the interactions between an Earth-like planet, its biosphere, and the incoming solar radiation. Here a spatial dependency on latitude is included, and both a variable heat diffusivity along latitudes and a simple greenhouse effect description are introduced in the model. We show that the spatial interactions between the variables of the system can locally stabilize the coexistence of the two vegetation types. The feedback on albedo is able to generate equilibrium solutions which can efficiently self-regulate the planet climate, even for values of the solar luminosity relatively far from the current Earth conditions.

Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: proof of a concept.

OBJECTIVE: To develop an updated laparoscopy-based model to predict incomplete cytoreduction (RT>0) in advanced epithelial ovarian cancer (AEOC), after the introduction of upper abdominal surgery (UAS). PATIENTS AND METHODS: The presence of omental cake, peritoneal extensive carcinomatosis, diaphragmatic confluent carcinomatosis, bowel infiltration, stomach and/or spleen and/or lesser omentum infiltration, and superficial liver metastases was evaluated by staging laparoscopy (S-LPS) in a consecutive series of 234 women with newly diagnosed AEOC, receiving laparotomic PDS after S-LPS. Parameters showing a specificity≥75%, PPV≥50%, and NPV≥50% received 1 point score, with an additional one point in the presence of an accuracy of ≥60% in predicting incomplete cytoreduction. The overall discriminating performance of the LPS-PI was finally estimated by ROC curve analysis. RESULTS: No-gross residual disease at PDS was achieved in 135 cases (57.5%). Among them, UAS was required in 72 cases (53.3%) for a total of 112 procedures, and around 25% of these patients received bowel resection, excluding recto-sigmoid resection. We observed a very high overall agreement between S-LPS and laparotomic findings, which ranged from 74.7% for omental cake to 94.8% for stomach infiltration. At a LPS-PIV≥10 the chance of achieving complete PDS was 0, and the risk of unnecessary laparotomy was 33.2%. Discriminating performance of LPS-PI was very high (AUC=0.885). CONCLUSIONS: S-LPS is confirmed as an accurate tool in the prediction of complete PDS in women with AEOC. The updated LPS-PI showed improved discriminating performance, with a lower rate of inappropriate laparotomic explorations at the established cut-off value of 10.

TLEM 2.0 - a comprehensive musculoskeletal geometry dataset for subject-specific modeling of lower extremity.

When analyzing complex biomechanical problems such as predicting the effects of orthopedic surgery, subject-specific musculoskeletal models are essential to achieve reliable predictions. The aim of this paper is to present the Twente Lower Extremity Model 2.0, a new comprehensive dataset of the musculoskeletal geometry of the lower extremity, which is based on medical imaging data and dissection performed on the right lower extremity of a fresh male cadaver. Bone, muscle and subcutaneous fat (including skin) volumes were segmented from computed tomography and magnetic resonance images scans. Inertial parameters were estimated from the image-based segmented volumes. A complete cadaver dissection was performed, in which bony landmarks, attachments sites and lines-of-action of 55 muscle actuators and 12 ligaments, bony wrapping surfaces, and joint geometry were measured. The obtained musculoskeletal geometry dataset was finally implemented in the AnyBody Modeling System (AnyBody Technology A/S, Aalborg, Denmark), resulting in a model consisting of 12 segments, 11 joints and 21 degrees of freedom, and including 166 muscle-tendon elements for each leg. The new TLEM 2.0 dataset was purposely built to be easily combined with novel image-based scaling techniques, such as bone surface morphing, muscle volume registration and muscle-tendon path identification, in order to obtain subject-specific musculoskeletal models in a quick and accurate way. The complete dataset, including CT and MRI scans and segmented volume and surfaces, is made available at http://www.utwente.nl/ctw/bw/research/projects/TLEMsafe for the biomechanical community, in order to accelerate the development and adoption of subject-specific models on large scale. TLEM 2.0 is freely shared for non-commercial use only, under acceptance of the TLEMsafe Research License Agreement.

Evaluation of a morphing based method to estimate muscle attachment sites of the lower extremity.

To generate subject-specific musculoskeletal models for clinical use, the location of muscle attachment sites needs to be estimated with accurate, fast and preferably automated tools. For this purpose, an automatic method was used to estimate the muscle attachment sites of the lower extremity, based on the assumption of a relation between the bone geometry and the location of muscle attachment sites. The aim of this study was to evaluate the accuracy of this morphing based method. Two cadaver dissections were performed to measure the contours of 72 muscle attachment sites on the pelvis, femur, tibia and calcaneus. The geometry of the bones including the muscle attachment sites was morphed from one cadaver to the other and vice versa. For 69% of the muscle attachment sites, the mean distance between the measured and morphed muscle attachment sites was smaller than 15 mm. Furthermore, the muscle attachment sites that had relatively large distances had shown low sensitivity to these deviations. Therefore, this morphing based method is a promising tool for estimating subject-specific muscle attachment sites in the lower extremity in a fast and automated manner.

Molecular characterization of the receptor binding structure-activity relationships of influenza B virus hemagglutinin.

Selectivity of α2,6-linked human-like receptors by B hemagglutinin (HA) is yet to be fully understood. This study integrates binding data with structure-recognition models to examine the impact of regional-specific sequence variations within the receptor-binding pocket on selectivity and structure activity relationships (SAR). The receptor-binding selectivity of influenza B HAs corresponding to either B/Victoria/2/1987 or the B/Yamagata/16/88 lineages was examined using surface plasmon resonance, solid-phase ELISA and gel-capture assays. Our SAR data showed that the presence of asialyl sugar units is the main determinant of receptor preference of α2,6 versus α2,3 receptor binding. Changes to the type of sialyl-glycan linkage present on receptors exhibit only a minor effect upon binding affinity. Homology-based structural models revealed that structural properties within the HA pocket, such as a glyco-conjugate at Asn194 on the 190-helix, sterically interfere with binding to avian receptor analogs by blocking the exit path of the asialyl sugars. Similarly, naturally occurring substitutions in the C-terminal region of the 190-helix and near the N-terminal end of the 140-loop narrows the horizontal borders of the binding pocket, which restricts access of the avian receptor analog LSTa. This study helps bridge the gap between ligand structure and receptor recognition for influenza B HA; and provides a consensus SAR model for the binding of human and avian receptor analogs to influenza B HA.

Scaling properties and intermittency of two-dimensional turbulence in pure electron plasmas.

When the cold nonrelativistic guiding center approximation is valid, the transverse dynamics of highly magnetized electron plasma columns confined in Penning-Malmberg traps is analogous to that of an incompressible, inviscid, two-dimensional (2D) fluid whose vorticity corresponds, up to a constant of proportionality, to the axially averaged electron plasma density. In this work intermittency phenomena in the freely decaying 2D electron plasma turbulence are investigated through scaling properties of the probability density functions and flatness of spatial vorticity increments, computed by analyzing the results of experiments performed in the Penning-Malmberg trap ELTRAP. It is shown that the intermittency properties of the turbulence strongly depends on the initial conditions and the relation of these results to the dynamics of the system is discussed.

Cancellation properties in Hall magnetohydrodynamics with a strong guide magnetic field.

We present a signed measure analysis of compressible Hall magnetohydrodynamic turbulence with an external guide field. Signed measure analysis allows us to characterize the scaling behavior of the sign-oscillating flow structures and their geometrical properties (fractal dimensions of structures). A reduced numerical model, valid when a strong guide magnetic field is present, is used here. In order to discuss the effect of the Hall term, different values for the ion skin depth are considered in the simulations. Results show that as the Hall term is increased, the fractal dimension of the current and vorticity sheets decreases. This observation, together with previous analysis of the same fields, provides a comprehensive description of the effect of the Hall force on the formation of structures. Two main processes are identified, namely, the widening and unraveling of the sheets.

Sensitivity of subject-specific models to errors in musculo-skeletal geometry.

Subject-specific musculo-skeletal models of the lower extremity are an important tool for investigating various biomechanical problems, for instance the results of surgery such as joint replacements and tendon transfers. The aim of this study was to assess the potential effects of errors in musculo-skeletal geometry on subject-specific model results. We performed an extensive sensitivity analysis to quantify the effect of the perturbation of origin, insertion and via points of each of the 56 musculo-tendon parts contained in the model. We used two metrics, namely a Local Sensitivity Index (LSI) and an Overall Sensitivity Index (OSI), to distinguish the effect of the perturbation on the predicted force produced by only the perturbed musculo-tendon parts and by all the remaining musculo-tendon parts, respectively, during a simulated gait cycle. Results indicated that, for each musculo-tendon part, only two points show a significant sensitivity: its origin, or pseudo-origin, point and its insertion, or pseudo-insertion, point. The most sensitive points belong to those musculo-tendon parts that act as prime movers in the walking movement (insertion point of the Achilles Tendon: LSI=15.56%, OSI=7.17%; origin points of the Rectus Femoris: LSI=13.89%, OSI=2.44%) and as hip stabilizers (insertion points of the Gluteus Medius Anterior: LSI=17.92%, OSI=2.79%; insertion point of the Gluteus Minimus: LSI=21.71%, OSI=2.41%). The proposed priority list provides quantitative information to improve the predictive accuracy of subject-specific musculo-skeletal models.

Phase-synchronization, energy cascade, and intermittency in solar-wind turbulence.

The energy cascade in solar wind magnetic turbulence is investigated using MESSENGER data in the inner heliosphere. The decomposition of magnetic field time series in intrinsic functions, each characterized by a typical time scale, reveals phase reorganization. This allows for the identification of structures of all sizes generated by the nonlinear turbulent cascade, covering both the inertial and the dispersive ranges of the turbulent magnetic power spectrum. We find that the correlation (or anticorrelation) of phases occurs between pairs of neighboring time scales, whenever localized peaks of magnetic energy are present at both scales, consistent with the local character of the energy transfer process.

Long-range persistence of temperature records induced by long-term climatic phenomena.

The occurrence of persistence in climatic systems has been investigated by analyzing 1167 surface temperature records, covering 110 years, in the whole United States. Due to the nonlinear and nonstationary character of temperature time series, the seasonal cycle suffers from both phase and amplitude modulations, which are not properly removed by the classical definition of the temperature anomaly. In order to properly filter out the seasonal component and the monotonic trends, we define the temperature anomaly in a different way by using the empirical mode decomposition (EMD). The essence of this method is to empirically identify the intrinsic oscillatory modes from the temperature records according to their characteristic time scale. The original signal is thus decomposed into a collection of a finite small number of intrinsic mode functions (IMFs), having its own time scale and representing oscillations experiencing amplitude and phase modulations, and a residue, describing the mean trend. The sum of all the IMF components as well as the residue reconstructs the original signal. Partial reconstruction can be achieved by selectively choosing IMFs in order to remove trivial trends and noise. The EMD description in terms of time-dependent amplitude and phase functions overcomes one of the major limitation of the Fourier analysis, namely, a correct description of nonlinearities and nonstationarities. By using the EMD definition of temperature anomalies we found persistence of fluctuations with a different degree according to the geographical location, on time scales in the range 3-15 years. The spatial distribution of the detrended fluctuation analysis exponent, used to quantify the degree of memory, indicates that the long-term persistence could be related to to the presence of climatic regions, which are more sensitive to climatic phenomena such as the El Niño southern oscillation.

Sign-singularity of the reduced magnetic helicity in the solar wind plasma.

We investigate the scaling laws of a signed measure derived from the reduced magnetic helicity which has been determined from Cluster data in the solar wind. This quantifies the handedness of the magnetic field; namely, it can be related to the polarization of the magnetic field fluctuations (right or left hand). The measure results to be sign-singular; that is, we do not observe any scale-dependent effect at the ion- and at electron-cyclotron frequencies. Cancellations between right- and left-hand polarizations go on in the dispersive or dissipative range, beyond the electron-cyclotron frequency. This means that the mechanism responsible for the generation of the dispersive or dissipative range is rather insensitive to the polarization of the magnetic field fluctuations.

Amplitude-frequency fluctuations of the seasonal cycle, temperature anomalies, and long-range persistence of climate records.

The presence of long-term persistence of climate records on scales from 2 to 15 yr has been reported in the literature, even if the universality of this result is controversial. In the present paper results from monthly temperature records measured for about 250 yr in Prague and Milan are reported. Because of the nonlinear and nonstationary character of temperature time series the seasonal contribution has been identified through the empirical mode decomposition. We find that the seasonal component of the climate records is characterized by some time scales showing both amplitude and phase fluctuations. By using a more suitable definition of temperature anomalies, and thus excluding persistence effects due to seasonal oscillations and trends, the occurrence of long-term persistence has been investigated through the detrended fluctuation analysis. Our results indicate persistence on scales from 3 to 10 yr with similar values for the detrended fluctuation analysis indices.

Proper orthogonal decomposition analysis of spatio-temporal behavior of renal scintigraphies.

We present a preliminary application of proper orthogonal decomposition (POD) to data sets coming from spatial and temporal evolution of renal scintigraphy. Renal functionalities or pathologies are hardly recognized from the raw scintigraphic images and their identifications could depend on the subjective point of view of the operator. The proposed technique is able to distinguish independent events starting from a more complex phenomenon. The spatio-temporal fields, representing the radiation emitted by the radiopharmaceutical technetium-99m with mercaptoacetiltriglicin (MAG3) within the kidney, have been analyzed for six randomly selected patients. In particular our study was performed on four patients affected by renal pathologies while two scintigraphies refer to healthy patients. First of all POD represents an efficient filtering procedure to cut off noise from the raw images by only selecting the few most energetic modes. When healthy kidneys are analyzed, POD is able to separate the main processes taking place in the organ. When applied to pathological samples, POD underlines the regions of the organ interested by the troubles allowing to analyze them independently. This analysis can be complementary to the identification made by hand by the operator.