A phase Ib/II dose expansion study of subcutaneous sasanlimab in patients with locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma.

BACKGROUND: Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS: Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS: Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS: Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

Molecular-statistical theory of elasticity in nematic liquid crystals composed of polar and nonpolar molecules.

A molecular-statistical theory of the orientational elasticity of nematic liquid crystals has been developed employing the orientational deformation tensor which describes the rotation of the director. An explicit expression for the general elasticity tensor of the nematic phase has been obtained and the Frank elastic constants are expressed in terms of the three independent parameters of this tensor. Explicit expressions for the Frank elastic constants have been derived in the molecular field approximation in terms of the orientational order parameters and the corresponding coefficients of expansion of the intermolecular potential in spherical invariants. Frank elastic constants have been calculated numerically for nematic liquid crystals composed of both polar and nonpolar molecules together with the orientational order parameters using the classical Gay-Berne model interaction potential and the two of its popular modifications. The polarity of the uniaxial molecular shape has been directly introduced into the model potential by modifying the distance of closest approach. The elastic constants are presented as functions of temperature for different values of the molecular elongation, the anisotropy of the potential well and the molecular shape polarity. It has been shown that the elastic constants are much more sensitive to the details of the intermolecular interaction potential in comparison with the orientational order parameters. In particular, a relatively weak polarity of the molecular shape may result in an unusual decrease of the splay constant K_{11} which may vanish at some temperature leading to the instability of the homogeneous nematic phase. This may represent a mechanism of the formation of the splay-bend phase.

Molecular theory of the tilting transition and computer simulations of the tilted lamellar phase of rod-coil diblock copolymers.

Symmetric rod-coil diblock copolymers have been simulated using the method of dissipative particle dynamics in the broad range of the Flory-Huggins parameter. It has been found that the tilted lamellar phase appears to be the most stable one at strong segregation. The rod-coil copolymer tilt angle and orientational order parameters have been determined as functions of the segregation strength. The density functional theory of rod-coil diblock copolymers has been generalized to the case of the tilted lamellar phase and used to study the stability of the orthogonal lamellar phase with respect to tilt. The orthogonal phase indeed appears to be unstable in the broad region of the parameter space in the case of relatively strong segregation. It has also been shown that the transition into the tilted lamellar phase is determined by a strong coupling between two independent tilt order parameters.

Molecular theory of liquid-crystal ordering in rod-coil diblock copolymers.

Molecular-statistical theory of rod-coil diblock copolymers is proposed using the general density functional approach which enables one to consider the cases of both weak and strong segregation. The free energy of the system is expressed as a functional of the phase-space densities of rod and coil monomers, which depend on the orientational and translational order parameters. Temperature-concentration phase diagrams are obtained and the profiles of all order parameters are calculated numerically by minimizing the polymer free energy. The lamellar phase is shown to possess strong orientational order which is partially induced by the phase structural anisotropy. The enhanced stability of the lamellar phase is determined by a combination of the microphase separation effects and the emergence of long-range smectic order.

Phase behavior and orientational ordering in block copolymers doped with anisotropic nanoparticles.

A molecular field theory and coarse-grained computer simulations with dissipative particle dynamics have been used to study the spontaneous orientational ordering of anisotropic nanoparticles in the lamellar and hexagonal phases of diblock copolymers and the effect of nanoparticles on the phase behavior of these systems. Both the molecular theory and computer simulations indicate that strongly anisotropic nanoparticles are ordered orientationally mainly in the boundary region between the domains and the nematic order parameter possesses opposite signs in adjacent domains. The orientational order is induced by the boundary and by the interaction between nanoparticles and the monomer units in different domains. In simulations, sufficiently long and strongly selective nanoparticles are ordered also inside the domains. The nematic order parameter and local concentration profiles of nanoparticles have been calculated numerically using the model of a nanoparticle with two interaction centers and also determined using the results of computer simulations. A number of phase diagrams have been obtained which illustrate the effect of nanoparticle selectivity and molar fraction of the stability ranges of various phases. Different morphologies have been identified by analyzing the static structure factor and a phase diagram has been constructed in coordinates' nanoparticle concentration-copolymer composition. Orientational ordering of even a small fraction of nanoparticles may result in a significant increase of the dielectric anisotropy of a polymer nanocomposite, which is important for various applications.

Ordering of ferromagnetic nanoparticles in nematic liquid crystals.

Dispersions of magnetic nanoparticles in a nematic liquid crystal were investigated as magnetic fields were applied in three different boundary condition geometries: (i) planar substrates and B⊥n, (ii) planar substrates and B‖n, and (iii) homeotropic substrates and B⊥n. Particle chaining is observed when a magnetic field is applied, with a periodicity perpendicular to the chains. Furthermore, linear chains are observed for the magnetic field applied perpendicular to the director, while zigzag chains are formed when the magnetic field direction is parallel to the director field. This is attributed to a change from a dipolar defect configuration around dispersed nanoparticles, to a quadrupolar one, i.e. the change from satellite to Saturn-ring defects. This effect is largely independent of the sample thickness. The dynamic development of the chain length, as well as their two-dimensional order parameter was studied in all cases. Chain lengths increased rapidly until saturation at approximately l = 30 µm after a time of about t = 10 s. Similarly, the chain order parameters increased until saturation between S = 0.8-0.9, independent of sample geometry.

Daily longitudinal self-monitoring of mood variability in bipolar disorder and borderline personality disorder.

BACKGROUND: Traditionally, assessment of psychiatric symptoms has been relying on their retrospective report to a trained interviewer. The emergence of smartphones facilitates passive sensor-based monitoring and active real-time monitoring through time-stamped prompts; however there are few validated self-report measures designed for this purpose. METHODS: We introduce a novel, compact questionnaire, Mood Zoom (MZ), embedded in a customised smart-phone application. MZ asks participants to rate anxiety, elation, sadness, anger, irritability and energy on a 7-point Likert scale. For comparison, we used four standard clinical questionnaires administered to participants weekly to quantify mania (ASRM), depression (QIDS), anxiety (GAD-7), and quality of life (EQ-5D). We monitored 48 Bipolar Disorder (BD), 31 Borderline Personality Disorders (BPD) and 51 Healthy control (HC) participants to study longitudinal (median±iqr: 313±194 days) variation and differences of mood traits by exploring the data using diverse time-series tools. RESULTS: MZ correlated well (|R|>0.5,p<0.0001) with QIDS, GAD-7, and EQ-5D. We found statistically strong (|R|>0.3,p<0.0001) differences in variability in all questionnaires for the three cohorts. Compared to HC, BD and BPD participants exhibit different trends and variability, and on average had higher self-reported scores in mania, depression, and anxiety, and lower quality of life. In particular, analysis of MZ variability can differentiate BD and BPD which was not hitherto possible using the weekly questionnaires. LIMITATIONS: All reported scores rely on self-assessment; there is a lack of ongoing clinical assessment by experts to validate the findings. CONCLUSIONS: MZ could be used for efficient, long-term, effective daily monitoring of mood instability in clinical psychiatric practice.

Effect of polar intermolecular interactions on the elastic constants of bent-core nematics and the origin of the twist-bend phase.

A molecular theory of both elastic constants and the flexoelectric coefficients of bent-core nematic liquid crystals has been developed taking into account dipole-dipole interactions as well as polar interactions determined by the bent molecular shape. It has been shown that if polar interactions are neglected, the elastic constants are increasing monotonically with the decreasing temperature. On the other hand, dipolar interactions between bent-core molecules may result in a dramatic increase of the bend flexocoefficient. As a result, the flexoelectric contribution to the bend elastic constant increases significantly, and the bend elastic constant appears to be very small throughout the nematic range and may vanish at a certain temperature. This temperature may then be identified as a temperature of the elastic instability of the bent-core nematic phase which induces a transition into the modulated phases with bend deformations like recently reported twist-bend phase. The temperature variation of the elastic constants is qualitatively similar to the typical experimental data for bent-core nematics.

[Melatonin enhances antitumor effect of doxorubicin on a model of transplantable Ehrlich tumor in female sHR mice].

A combined antitumor effect of a single injection of doxorubicin and the indole hormone melatonin was investigated in the model of transplantable Ehrlich carcinoma in female SHR mice. Animals received melatonin either subcutaneous 10 mg/ kg in the evening or with water 10 mg/l at night (from 20 pm to 8 am) for 3 weeks. The results of an experiment showed that combined use of doxorubicin and melatonin both subcutaneous and with water leads to statistically significant inhibition of tumor growth compared with control and doxorubicin alone.

[Prospects of use of antidiabetic biguanides for cancer prevention and treatment: results of preclinical studies].

The critical analysis of preclinical testing of anticarcinogenic and antitumor activity of biguanides presented in this paper. Experiments have been conducted using in total more than 20 models of carcinogenesis including models of spontaneous , chemically- , radiation- and virus-induced carcinogenesis, as well as carcinoigenesis induced by special fat diets and by genetic modification in rodents. Cancer preventive effect of buiguanides has been studied in relation to total tumor incidence and to 17 target organs in animals of 3 species, including 25 various strains of mice, 4 strains of rats and 1 strain of hamsters using various routs of administration and doses. In the majority of cases (86%) the exposure to biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed, however there was no any case of stimulation of carcinogenesis by antidiabetic biguanides., Metformin suppressed tumor growth in the majority of in vitro studies conducted in 46 different cell lines originated from malignant tumors of 15 localization as well as in athymic mice with xenografts of 31 tumor lines. It was concluded that there are sufficient experimental evidences of anticarcinogenic and antitumor effects of antidiabetic biguanides revealed in a number of models of induced and spontaneous carcinogenesis.

Effect of nanoparticle chain formation on dielectric anisotropy of nematic composites.

A general theory of the dielectric constant of nematic liquid crystal mixtures is presented including the particular case of nematics doped with polar nanoparticles. The results are used to estimate the contribution of chains of polar nanoparticles to the static dielectric anisotropy and birefringence of the nematic composite taking into account contributions from chains of different lengths. The dependence of the dielectric anisotropy on the dipolar interaction strength is considered in detail and it is shown that formation of polar chains of nanoparticles enables one to explain a significant increase of the dielectric constant of the composite as observed experimentally.

A Catalytic Asymmetric Total Synthesis of (-)-Perophoramidine.

We report a catalytic asymmetric total synthesis of the ascidian natural product perophoramidine. The synthesis employs a molybdenum-catalyzed asymmetric allylic alkylation of an oxindole nucleophile and a monosubstituted allylic electrophile as a key asymmetric step. The enantioenriched oxindole product from this transformation contains vicinal quaternary and tertiary stereocenters, and is obtained in high yield along with high levels of regio-, diastereo-, and enantioselectivity. To install the second quaternary stereocenter in the target, the route utilizes a novel regio- and diastereoselective allylation of a cyclic imino ether to deliver an allylated imino ether product in near quantitative yield and with complete regio- and diastereocontrol. Oxidative cleavage and reductive amination are used as final steps to access the natural product.

[Theoretical and practical aspects of development of biscuits with a modified carbohydrate profile for patients with type 2 diabetes].

The purpose of this research was to develop formulation and technology of flour confectionery products in the form of biscuits with a modified carbohydrate profile, a study of physico-chemical and structural-mechanical properties. The оbjects of this research were: basic food matrix, are the prototype of the designed product without modification of the carbohydrate profile prepared by the classic recipe and traditional technologies; model samples of cookies with a modified carbohydrate profile; the experimental sample cookie with a modified carbohydrate profile and optimized physic-chemical, structural-mechanical and organoleptic indicators. Determination of physic-chemical and organoleptic characteristics of biscuits was carried out by standard methods. The water activity was determined on the analyzer using a cooled mirror dew point sensor, structural-mechanical properties ­ on texturename with conical and cylindrical nozzles, imitating the processes of breakage and bite, describing the hardness, brittleness, breakage, and other properties of a food product. The modification of the carbohydrate profile of biscuit, consisting in the replacement of wheat flour traditionally used in the recipe of flour confectionery products, by the composition containing oat, barley and buckwheat flour, and in the exclusion of sugar and the introduction of ingredients that do not cause hyperglycemic effect: maltitol as a sweetener and beta-glucans. The technological scheme of production of new kinds of cookies has been developed, the parameters of the production process have been worked out, physical-chemical, structural-mechanical and organoleptic properties of a new type of cookie have been optimized. Analysis of the chemical composition of the cookies showed that 100 g contains 9.3 g of protein, 17.0 g of fat and 44.5 g of carbohydrates, including 42.4 g of starch, and 2.1 g mono- and disaccharides, 2.2 g dietary fiber, 20 g maltitol; caloric value of 420 kcal/1760 kJ. In accordance with the developed technology an experimental batch of cookies with a modified carbohydrate profile has been produced to evaluate its impact on postprandial glycemia in patients with type 2 diabetes.

Molecular theory of proper ferroelectricity in bent-core liquid crystals.

Antiferro- and ferro-electric ordering has been discovered in orthogonal smectic phases composed of nonchiral bent-core molecules. These systems are the only proper fluid ferroelectrics confirmed experimentally so far. We consider a molecular theory of proper ferroelectric ordering in isotropic, nematic and smectic A phases and conclude that the delicate balance between the tendencies for local parallel and antiparallel ordering of molecular electric and steric dipoles is strongly shifted in restricted geometries. This is a reason why dipolar ordering is more likely to occur within a smectic layer. We derive model interaction potentials for polar bent-core molecules and present the results of the mean-field theory of ferroelectric ordering in the orthogonal smectic phase taking into account also the molecular biaxiality. Order parameter profiles have been calculated numerically and phase diagrams are presented which enable one to analyze the relative importance of dipole-dipole interaction and intermolecular attraction modulated by polar bent-core molecular shape.

A review of signals used in sleep analysis.

This article presents a review of signals used for measuring physiology and activity during sleep and techniques for extracting information from these signals. We examine both clinical needs and biomedical signal processing approaches across a range of sensor types. Issues with recording and analysing the signals are discussed, together with their applicability to various clinical disorders. Both univariate and data fusion (exploiting the diverse characteristics of the primary recorded signals) approaches are discussed, together with a comparison of automated methods for analysing sleep.

Biaxial order parameter in the homologous series of orthogonal bent-core smectic liquid crystals.

The fundamental parameter of the uniaxial liquid crystalline state that governs nearly all of its physical properties is the primary orientational order parameter (S) for the long axes of molecules with respect to the director. The biaxial liquid crystals (LCs) possess biaxial order parameters depending on the phase symmetry of the system. In this paper we show that in the first approximation a biaxial orthogonal smectic phase can be described by two primary order parameters: S for the long axes and C for the ordering of the short axes of molecules. The temperature dependencies of S and C are obtained by the Haller's extrapolation technique through measurements of the optical birefringence and biaxiality on a nontilted polar antiferroelectric (Sm-AP(A)) phase of a homologous series of LCs built from the bent-core achiral molecules. For such a biaxial smectic phase both S and C, particularly the temperature dependency of the latter, are being experimentally determined. Results show that S in the orthogonal smectic phase composed of bent cores is higher than in Sm-A calamatic LCs and C is also significantly large.

Unified molecular field theory of nematic, smectic-A, and smectic-C phases.

A unified mean-field molecular theory of nematic (N(U)), smectic A (SmA), and smectic C (SmC) liquid crystal phases, composed of uniaxial nonpolar molecules, is developed taking into account the variation of all orientational and translational order parameters in these phases. Numerical results, obtained by direct global minimization of the free energy, are presented in the form of three typical phase diagrams of different topology. Temperature variation of the relevant order parameters in different sequences of phases is analyzed for various cross sections of the phase diagrams. The present model enables one to reproduce all possible sequences of phase transitions between the given phases including isotropic (Iso)-N(U)-SmA-SmC, Iso-N(U)-SmC, Iso-SmA-SmC, and Iso-SmC. The properties of the NAC point, where the N(U), SmA, and SmC structures coexist, are considered in detail and the shape of the phase diagram in the vicinity of the NAC point is compared with existing experimental data.

[Markers of effectiveness of preoperative taxane-based chemotherapy for locally advanced breast cancer].

The absolute sensitivity signs of breast cancer to the drug have not yet been developed. Data from clinical trials on the study of experimental laboratory predictive markers of chemosensitivity: TOP2alpha (topoisomerase 2-alpha), beta-tubulin (subunit of dimeric protein tubulin), and BRCA1 (breast cancer 1) are contradictory and not numerous. Analysis of the results by the end of the clinical trial will allow examining the correlation between the effectiveness of preoperative taxane-chemotherapy and the level of experimental and standard molecular markets that is important for development of algorithm of treatment tactics for patients with locally advanced breast cancer.

Orientational order parameters of a de Vries-type ferroelectric liquid crystal obtained by polarized Raman spectroscopy and x-ray diffraction.

The orientational order parameters (P{2}) and (P{4}) of the ferroelectric, de Vries-type liquid crystal 9HL have been determined in the SmA and SmC phases by means of polarized Raman spectroscopy, and in the SmA phase using x-ray diffraction. Quantum density functional theory predicts Raman spectra for 9HL that are in good agreement with the observations and indicates that the strong Raman band probed in the experiment corresponds to the uniaxial, coupled vibration of the three phenyl rings along the molecular long axis. The magnitudes of the orientational order parameters obtained in the Raman and x-ray experiments differ dramatically from each other, a discrepancy that is resolved by considering that the two techniques probe the orientational distributions of different molecular axes. We have developed a systematic procedure in which we calculate the angle between these axes and rescale the orientational order parameters obtained from x-ray scattering with results that are then in good agreement with the Raman data. At least in the case of 9HL, the results obtained by both techniques support a "sugar loaf" orientational distribution in the SmA phase with no qualitative difference to conventional smectics A. The role of individual molecular fragments in promoting de Vries-type behavior is considered.

Molecular theory of smectic ordering in liquid crystals with nanoscale segregation of different molecular fragments.

A molecular statistical theory of the smectic A phase is developed taking into account specific interactions between different molecular fragments which enables one to describe different microscopic scenario of the transition into the smectic phase. The effects of nanoscale segregation are described using molecular models with different combinations of attractive and repulsive sites. These models have been used to calculate numerically coefficients in the mean filed potential as functions of molecular model parameters and the period of the smectic structure. The same coefficients are calculated also for a conventional smectic with standard Gay-Berne interaction potential which does not promote the segregation. The free energy is minimized numerically to calculate the order parameters of the smectic A phases and to study the nature of the smectic transition in both systems. It has been found that in conventional materials the smectic order can be stabilized only when the orientational order is sufficiently high, In contrast, in materials with nanosegregation the smectic order develops mainly in the form of the orientational-translational wave while the nematic order parameter remains relatively small. Microscopic mechanisms of smectic ordering in both systems are discussed in detail, and the results for smectic order parameters are compared with experimental data for materials of various molecular structure.