SIOP PNET5 MB Trial: History and Concept of a Molecularly Stratified Clinical Trial of Risk-Adapted Therapies for Standard-Risk Medulloblastoma

Background. SIOP PNET5 MB was initiated in 2014 as the first European trial using clinical, histological, and molecular parameters to stratify treatments for children and adolescents with standard-risk medulloblastoma. Methods. Stratification by upfront assessment of molecular parameters requires the timely submission of adequate tumour tissue. In the standard-risk phase-III cohort, defined by the absence of high-risk criteria (M0, R0), pathological (non-LCA), and molecular biomarkers (MYCN amplification in SHH–MB or MYC amplification), a randomized intensification by carboplatin concomitant with radiotherapy is investigated. In the LR stratum for localized WNT-activated medulloblastoma and age <16 years, a reduction of craniospinal radiotherapy dose to 18 Gy and a reduced maintenance chemotherapy are investigated. Two additional strata (WNT-HR, SHH-TP53) were implemented during the trial. Results. SIOP PNET5 MB is actively recruiting. The availability of adequate tumour tissue for upfront real-time biological assessments to assess inclusion criteria has proven feasible. Conclusion. SIOP PNET5 MB has demonstrated that implementation of biological parameters for stratification is feasible in a prospective multicentre setting, and may improve risk-adapted treatment. Comprehensive research studies may allow assessment of additional parameters, e.g., novel medulloblastoma subtypes, and identification and validation of biomarkers for the further refinement of risk-adapted treatment in the future.

Neural network analysis of some molecular parameters of the cervical epithelium for cervical cancer diagnostics

Background. A personalized approach is the basis for the specialized care for cancer patients. The relevance of cervical cancer (CC) is still high. The searches for diagnostic criteria of cervical epithelium malignancy are continuing. The application ohm technologies has led to a big number results, the analysis of which is often difficult. The neural network data analysis allows to solve these problems.Objective: to create a technology for diagnosing cervical intraepithelial neoplasia (CIN) and CC, based on a neural network analysis of some molecular parameters.Materials and methods. The research carried out among patients with CIN III (n = 15), patients with CC stages I–IV (n = 49). The control group consisted of female volunteers without cervical pathology (n = 15). Studied molecular parameters: the spectrum of fatty acids was determined in cervical biopsies, proteins OPN, ICAM-1 were studied in blood serum, proteins of the immune cycle sCD25, sCD27 – in the cervical epithelium. Research methods: gas-liquid chromatography, flow cytometry.Results. Significant differences of fatty acids spectrum, local level sCD27 were revealed in among the studied groups. The multilayer perceptron included C18:2ω6, OPN, ICAM-1, sCD25, sCD27. The performed neural network analysis of the molecular data allows to diagnose CIN III (Se = 0.92; Sp = 0.87; AUC = 0.94; p˂0.001) and CC (Se = 1.00; Sp = 1.00; AUC = 1.00; p˂0.001).Conclusion. The created model makes it possible to diagnose CIN III and CC with high accuracy. The configuration of the multilayer perceptron allows confirming the pathophysiological relationships between the studied molecular parameters, to expand the understanding of the mechanisms of cervical carcinogenesis.

Synthesis, Characterization and Computational Study of Discotic Liquid Crystal Compounds

Discotic liquid crystal compounds were synthesized and characterized. Liquid crystalline texture of these compounds was investigated by polarized optical microscopy (POM). The Hartree-Fock approximation (HF) was used to calculate theoretical molecular parameters for synthesized compounds such as optimization, hardness, EHOMO, ELUMO, and energy gap using the Gaussian 09W program.

Molecular Understanding of Calorimetric Protein Unfolding Experiments

Protein unfolding is a dynamic cooperative equilibrium between short lived protein conformations. The Zimm-Bragg theory is an ideal algorithm to handle cooperative processes. Here, we extend the analytical capabilities of the Zimm-Bragg theory in two directions. First, we combine the Zimm-Bragg partition function Z(T) with statistical-mechanical thermodynamics, explaining the thermodynamic system properties enthalpy, entropy and free energy with molecular parameters only. Second, the molecular enthalpy h0 to unfold a single amino acid residue is made temperature-dependent. The addition of a heat capacity term cv allows predicting not only heat denaturation, but also cold denaturation. Moreover, it predicts the heat capacity increase ΔC0p in protein unfolding. The theory is successfully applied to differential scanning calorimetry experiments of proteins of different size and structure, that is, gpW62 (62aa), ubiquitin (74aa), lysozyme (129aa), metmyoglobin (153aa) and mAb monoclonal antibody (1290aa). Particular attention was given to the free energy, which can easily be obtained from the heat capacity Cp(T). The DSC experiments reveal a zero free energy for the native protein with an immediate decrease to negative free energies upon cold and heat denaturation. This trapezoidal shape is precisely reproduced by the Zimm-Bragg theory, whereas the so far applied non-cooperative 2-state model predicts a parabolic shape with a positive free energy maximum of the native protein. We demonstrate that the molecular parameters of the Zimm-Bragg theory have a well-defined physical meaning. In addition to predicting protein stability, independent of protein size, they yield estimates of unfolding kinetics and can be connected to molecular dynamics calculations.

Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial

BackgroundPneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy.MethodsIn order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days.ResultsAmong 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma-derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR).ConclusionsAlthough statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy.

Realism, Physical Meaningfulness, and Molecular Spectroscopy

Although the realism debate has focused on the work of Jean Perrin on Brownian motion, this chapter claims that the best place to look for a resolution of this debate is the period after the late 1920s, when stable theory-mediated measurement of molecular parameters first became possible through the application of quantum mechanics to spectroscopy. The chapter first examines how stable measurement of the molecular parameters of diatomic molecules was achieved in spectroscopy and then gauges what evidence there is that this stable measurement is giving spectroscopists access to the real properties and structure of molecules. It argues that an evaluation of the latter question requires a distinction to be made between physically meaningful representations and those that are not, and a full answer requires the deployment of that distinction in the analysis of scientific research on atoms and molecules in the period after 1950.