Long-term durability of the vacuum edge-seal plays a significant part in retrofitting triple vacuum glazing (TVG) to existing buildings in achieving towards zero-energy buildings (ZEB) target. Vacuum pressure decrement with respect to time between panes affect the thermal efficiency of TVG. This study reports a 3D finite element model, with validated mathematical methods and comparison, for the assessment of the influence of vacuum pressure diminution on the thermal transmittance (U value) of TVG. The centre-of-pane and total U values of TVG calculated to be 0.28 Wm⁻²K⁻¹ and 0.94 Wm⁻²K⁻¹ at the cavity vacuum pressure of 0.001 Pa. The results suggests that a rise in cavity pressure from 0.001 Pa to 100 kPa increases the centre-of-pane and total U values from 0.28 Wm⁻²K⁻¹ and 0.94 Wm⁻²K⁻¹ to 2.4 Wm⁻²K⁻¹ and 2.58 Wm⁻²K⁻¹, respectively. The temperature descent on the surfaces of TVG between hot and cold sides’ increases by decreasing the cavity vacuum pressure from 50 kPa to 0.001 Pa. To maintain the cavity vacuum pressure of 0.001 Pa for over 20 years of life span in the cavity of 10 mm wide edge sealed triple vacuum glazing, non-evaporable getters will maintain the cavity vacuum pressure that will enable the long-term durability to TVG.

Based upon Maxwell's equations, it has long been established that oscillating electromagnetic (EM) fields incident upon a metal surface decay exponentially inside the conductor, leading to a virtual EM vacuum at sufficient depths. Magnetic resonance imaging (MRI) utilizes radiofrequency (r.f.) EM fields to produce images. Here we present the first visualization of a virtual EM vacuum inside a bulk metal strip by MRI, amongst several novel findings. We uncover unexpected MRI intensity patterns arising from two orthogonal pairs of faces of a metal strip, and derive formulae for their intensity ratios, revealing differing effective elemental volumes (voxels) underneath these faces. Further, we furnish chemical shift imaging (CSI) results that discriminate different faces (surfaces) of a metal block according to their distinct nuclear magnetic resonance (NMR) chemical shifts, which holds much promise for monitoring surface chemical reactions noninvasively. Bulk metals are ubiquitous, and MRI is a premier noninvasive diagnostic tool. Combining the two, the emerging field of bulk metal MRI can be expected to grow in importance. The fundamental nature of results presented here may impact bulk metal MRI and CSI across many fields.

Background: Extracellular Vesicles are pivotal mediators in intercellular communication, facilitating the exchange of biological information among healthy, pathological and tumor cells. Between the diverse subtypes of extracellular vesicles, exosomes have unique properties, clinical and therapeutical applications, even towards cancer. Breast cancer ranks as one of the most prevalent malignancies across the globe. Both the tumor core and its surrounding microenvironment engage in a complex, orchestrated interaction that facilitates the cancer’s growth and spread. Methods: The most valuable and significant PubMed Literature about extracellular vesicles and adipose–derived stem cells exosomes was selected and analyzed in order to report their biological properties and potential applications, in particular on the Triple–Negative Breast Cancer. Results: Adipose–derived stem cells exosomes represent a potential tool to target the tumor core of the Triple–Negative Breast Cancer, its microenvironment and surrounding tissues including metastasis. The authors are developing a supportive Triple–Adipose–derived stem cells Exosomes [T.A.E.] Technology against breast cancer in order to perform a selective preconditioning of the cancer before or while the traditional oncological treatments are running. Conclusion: The possibility to exploit the impact of Adipose–derived stem cells exosomes within the T.A.E. Technology against the Triple–Negative breast cancer is real, highlighting a new era for supportive measures against breast cancer.Keywords: Extracellular vesicles; Exosomes; Adipose–derived stem cells, Tumor microenvironment, Triple–Negative Breast Cancer, T.A.E. Technology.

This article is the third part of a scientific project under the general title "Geometrized vacuum physics based on the Algebra of Signatures". In the first two papers [1,2], the ideal (i.e., non-curved and immobile) local region of vacuum was studied and the foundations of the Algebra of Signatures were laid. This article considers the possibilities of describing the curved and moving state of the same vacuum region on the basis of the mathematical apparatus of the Algebra of Signatures. The reasons for the multilateral consideration of vacuum and twisting of intra-vacuum processes into spiral bundles are disclosed. The 4-tensor is introduced for two-sided and 16-sided consideration of the curvature of the local vacuum region. On the basis of kinematic models, the following assumptions were made: about the inert properties of vacuum layers; about the possibility of displacement of vacuum layers relative to each other at a speed significantly exceeding the speed of light; about the possibility of "rupture" of the local region of vacuum. The proposed kinematic models of the movement of vacuum layers can be a theoretical basis for the development of "zero" (i.e., vacuum) technologies.

To better understand the shape memory materials and self-healing materials, a new series of liquid-crystalline shape memory polyurethane (LC-SMPU) composites, named SMPU-OOBAm, were successfully prepared by incorporating 4-octyldecyloxybenzoic acid (OOBA) into the PEG-based SMPU. The effect of OOBA on the structure, morphology and properties has been carefully investigated. The results demonstrate that SMPU-OOBAm have liquid crystalline properties, triple-shape memory properties and self-healing properties. The incorporated OOBA promotes the crystallizability of both soft and hard segments of SMPU, and the crystallization rate of the hard segment of SMPU decreases when the OOBA-content increases. Additionally, the SMPU-OOBAm forms a two-phase separated structure (SMPU phase and OOBA phase), and it shows two-step modulus changes upon heating. Therefore, the SMPU-OOBAm shows triple-shape memory behavior, and the shape recovery ratio decreases with an increase in the OOBA content. Finally, SMPU-OOBAm shows self-healing properties. The new mechanism can be ascribed to the heating-induced “bleeding” of OOBA in the liquid crystalline state and the subsequent re-crystallization upon cooling. This successful combination of liquid crystalline properties, triple-shape memory properties and self-healing properties make the SMPU-OOBAm composites with many promise applications in smart optical devices, smart electronic devices and smart sensors.

This article is the fourth part of a scientific project under the general title “Geometrized vacuum physics based on the Algebra of Signatures". In the first three articles [1,2,3], the foundations of the Algebra of Stignatures were laid and the main aspects of the kinematics of vacuum layers were considered. This article continues the development of the mathematical apparatus of the proposed project, in particular, the dynamics of vacuum layers is developed based on the Algebra of Signatures. The development of this direction of research (with simplifications related to Riemann's differential geometry) led to the possibility of a geometrized representation of the electric field strength and magnetic field induction. This geometrized mathematical apparatus allows one to interpret the electromagnetic field as an interweaving of accelerated and rotational flows of the adjacent layers of vacuum. The proposed dynamic models of accelerated movements and rotations of vacuum layers can provide a theoretical basis for the development of “zero” (i.e. vacuum) technologies.

Dark energy and dark matter are described as different manifestations of vacuum energy in a new cyclic universe framework of Extra Dimensional Symmetry (EDS) that doubles large spatial dimensions with microscopic partners. In this testable framework, vacuum energy, constrained by a Planck density constraint, exists in a gravitationally dark state where actual gravitational constant G_o = 0G. While a small repulsive component is constrained by an asymptotically evolving asymmetry to the active state where G_o = 2G, some components in the inert state are enabled to gravitationally attract by neutrino induced gravitational constant with light and shear activated heavy components. Observational and experimental tests are briefly discussed.

Solar radiation is closely related to the energy buildings consume for cooling, heating, and lighting purposes. Glazing is the only material of the building envelope that transmits solar radiation and needs to be appropriately designed to reduce energy cㅈonsumption. Currently, smart glass technology is being actively investigated and developed for effective solar radiation control. Among the various types of smart glass, electrochromic glazing is one of the most promising technologies, as it can adjust transmittance on its own, has a wider transmittance range in both the clear and darkened states, and consumes less electricity. Considering the importance of solar radiation adjustment in electrochromic glazing technology, this study attempted to develop an optimal control method for electrochromic glazing. Toward this goal, the solar radiation incident on vertical surfaces and outdoor temperature conditions were controlled in three regions with different climatic characteristics, and the annual cooling, heating, and lighting loads, discomfort glare, and interior illumination were analyzed. This approach enabled the optimal conditions with respect to visual comfort to be determined. Subsequently, the EDPI (Energy and daylight performance index) was used to optimize control conditions for each region, thereby producing integrated evaluations from results with different units and properties. The proposed control method will be utilized to develop a control algorithm and a control system to reduce building energy consumption.

Ti64 alloy plays a significant role in the biomedical applications such as bioimplants for its excellent biocompatibility. Its usage can be further extended by improving the surface hardness and wear resistance. In this respect, laser surface glazing (LSG), an advanced surface modification technique, is very useful which can produce thin hardened surface layer and strong metallurgical bonding. Investigation of temporal and spatial temperature distributions of laser glazed surface of materials are essential because temperature plays significant role in achieving required surface properties. Therefore, in this study, a 3D Finite element analysis has been developed to perform transient thermal analysis of LSG for Ti64 alloy. The model investigated temperature distribution, depth of modified zone and heating and cooling. The results show that the peak temperature is attained 2095 K for 300 W laser power, 0.2 mm beam width and 0.15 ms residence time. Since this temperature is above the melting point (1933 K) of Ti64 alloy, the melt depth is calculated 22.5 μm. Furthermore, from the simulation results, the average heating and cooling rates are estimated 1.19×10⁷ Ks^-1 and 2.71×10⁶ Ks^-1 respectively which indicate the presence of hard phases in the modified zone.

Today's city needs more than ever methodological devices that ensure a specific urbanism, in keeping with the complexity of relationships that occur in the urban space. Networks or systems of diverse nature must be activated to achieve a certain success of the city, even more so in its fragile central fabrics. The study is focused on the historic neighborhoods of the city of Jaén (Spain), which have a high vulnerability index. The aim is to establish a strategy to revitalize their urban and social capital and improve their articulation with the rest of the urban and territorial structure. A methodological proposal for the analysis of vulnerability factors and an urban and cartographic analysis of the public space is addressed through an interweaving of a triple network: environmental, social, and urban. For this purpose, the configuration of this overlapping network of analysis and formulation of criteria is presented, which considers the urban multiplicity and promotes new dynamics for the integrated urban regeneration of the area and for the activation of public and collective urban spaces.

We discuss the consequences of the unique symmetry of the de Sitter spacetime. This symmetry leads to the specific thermodynamic properties of the de Sitter vacuum, which produces the thermal bath for matter. The de Sitter spacetime is invariant under the modified translations, ${\bf r}\rightarrow {\bf r} -e^{Ht}{\bf a}$, where $H$ is the Hubble parameter. For $H\rightarrow 0$, this symmetry corresponds to the conventional invariance of Minkowski spacetime under translations ${\bf r}\rightarrow {\bf r} -{\bf a}$. Due to this symmetry, all the comoving observers at any point of the de Sitter space perceive the de Sitter environment as the thermal bath with temperature $T=H/\pi$, which is twice larger than the Gibbons-Hawking temperature of the cosmological horizon. This temperature does not violate the de Sitter symmetry, and thus does not require the preferred reference frame, as distinct from thermal state of matter, which violates the de Sitter symmetry. This leads to the heat exchange between gravity and matter, and to instability of de Sitter state towards the creation of matter, its further heating, and finally to the decay of the de Sitter state. The temperature $T=H/\pi$ determines different processes in the de Sitter environment, which are not possible in the Minkowski vacuum, such as the process of ionization of an atom in the de Sitter environment. This temperature also determines the local entropy of the de Sitter vacuum state, and this allows us to calculate the total entropy inside the cosmological horizon. The result reproduces the Gibbons-Hawking area law, which is related to the cosmological horizon, $S_{\rm hor}=4\pi KA$, where $K=1/16\pi G$. This supports the holographic properties of the cosmological event horizon. We extend the consideration of the local thermodynamics of the de Sitter state using the $f({\cal R})$ gravity. In this thermodynamics, the Ricci scalar curvature ${\cal R}$ and the effective gravitational coupling, $K$, are thermodynamically conjugate variables. The holographic connection between the bulk entropy of the Hubble volume, and the surface entropy of the cosmological horizon remains the same, but with the gravitational coupling $K=df/d{\cal R}$. Such connection takes place only in the $3+1$ spacetime, where there is the special symmetry due to which the variables $K$ and ${\cal R}$ have the same dimensionality. We also consider the lessons from the de Sitter symmetry for the thermodynamics of black and white holes.

The Vacuum Energy Parameter (VEP) of standard cosmology denotes the fraction of the critical density attributed to the accelerated expansion of the Universe. Astrophysical evidence sets the numerical range of VEP at 0.692 +, - 0.012, yet the root cause of these values is currently unknown. Drawing from the stochastic interpretation of early-Universe cosmology, we develop here a derivation of the VEP based on classical diffusion theory and the Langevin equation. Predictions are shown to be in reasonable agreement with observations.

In this article various heuristic approaches are discussed to solve the dark matter phenomenon by the concept of vacuum polarization. They are compared with a more fundamental approach, based upon an entropy model of the visible universe. They all make use of some kind of gravitational dipole. These dipoles seem to violate Einstein’s equivalence principle between inertial mass and gravitational mass. It is shown how the paradox can be solved by a quantum mechanical principle.

Phenomenon of vacuum fluctuations of virtual particles in high energy physics has been mathematically modeled by a third order differential equation. Aim of present theory is to unravel underlying mathematical equation capable of explaining microscopic phenomenon of vacuum fluctuations. Solution of such a differential equation after applying appropriate boundary conditions gives an acceptable wave function i.e. . Operation of energy and time operator on this wave function proves that these operators do not hold commutative property. Time energy uncertainty principle has been derived by calculating variance of energy and time for the same wave function.

Triple negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger containing transcription factor), was capable of sensitizing preclinical models of triple negative breast cancer to chemotherapy, in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with inhibition of the P-glycoprotein efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump, in a manner consistent with inhibition of pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in triple negative breast cancer, that has not yet been successfully addressed by clinical efforts.

Scattering of a probe laser pulse by an intense light spring in QED vacuum is considered. This new scattering configuration can be seen as the vacuum equivalent to the process originally associated with scattering of light by a rotating black hole, usually called Penrose superradiance. Here the rotating object is an intense laser beam containing two different components of orbital angular momentum. Due to these two components with slightly different frequencies, the energy profile of the intense laser beam rotates with a frequency that depends on the frequency difference. The nonlinear properties of quantum vacuum are described by first order Euler-Heisenberg Lagrangian. It is shown that, in such a configuration, nonlinear photon-photon coupling leads to scattered radiation, with frequency shift and angular dispersion. These two distinct properties, of frequency and propagation direction, could eventually be favourable for possible experimental observations. In principle, this new scattering configuration can also be reproduced in a nonlinear optical medium.

We present a new perspective of the link between QED and Maxwell's equations. We demonstrate that the interpretation of $\mathbf{D}=\varepsilon_{0} \mathbf{E}$ as vacuum polarization is consistent with QED. A free electromagnetic field polarizes the vacuum, but the polarization and magnetization currents cancel giving zero source current. The speed of light is a universal constant, while the fine structure constant, which couples the electromagnetic field to matter, runs as it should.

This paper seeks to fill in the gaps of modern relativistic Cosmology by utilizing the total symmetry between space and time dimensions and re-interpreting the scale factor of the Universe as a gravitational potential generated by the mass/energy of the entire Universe as a whole. The gradient of this potential is along the cosmological time dimension through which the Universe is falling. This gradient gives us an arrow of time, we find explanations for why the Universe began expanding and why the expansion is accelerating without the need for a Cosmological Constant. In a finite time, the gradient will point in the opposite direction of time turning the expanding Universe into a collapsing one where it is shown that when placing the Schwarzschild metric in the dynamic Cosmological background, gravity becomes repulsive and things like would-be Black Holes become White Holes. The model naturally describes a Universe and an anti-Universe (consisting of antimatter) moving in opposite directions of time that collide at the end of collapse, annihilating and subsequently pair producing two new Universes as the cycle begins again. It is shown that the model's Hubble diagram fits the currently available supernova and quasar data. It is found that Dark Matter can perhaps be understood as ordinary matter that is not connected to us with null geodesics.

The phenomenon of dissipative self-organization is studied on the example of time-crystal networks. Particular attention was given to transient processes, attractor topologies, phase transitions, and asymptotic stability. New concepts were introduced, including topological phases, spinorial states, and bond flavors. Concepts such as ground states, chemical potentials, elastic forces, temperature, and statistical distributions were endowed with a new meaning associated with asymptotic stability. Phenomena usually attributed exclusively to quantum physics have been shown to occur in this essentially classical environment. They coexist with, and in some cases, such as charge quantization, are related to the phenomenon of time dilation. The approach was applied to model vacuum self-organization. We have shown that under the ac-tion of competing forces, such as gravity and antigravity, a cascade of phase transitions can transform an unorganized vacuum into phases in which interactions, fields and waves resemble electromagnetic, weak, and strong, and their elements can be used as building blocks for prototype particles. In addition, some interrelation field parameters and probabilities of particle transmutations were calculated, which are not predicted by the standard model. The results are consistent with the experiment. The presented material and methodology may be of interest for studying self-organization in different environments.

In quantum gravity perturbation theory in Newton's constant $G$ is known to be badly divergent, and as a result not very useful. Nevertheless, some of the most interesting phenomena in physics are often associated with non-analytic behavior in the coupling constant and the existence of nontrivial quantum condensates. It is therefore possible that pathologies encountered in the case of gravity are more likely the result of inadequate analytical treatment, and not necessarily a reflection of some intrinsic insurmountable problem. The nonperturbative treatment of quantum gravity via the Regge-Wheeler lattice path integral formulation reveals the existence of a new phase involving a nontrivial gravitational vacuum condensate, and a new set of scaling exponents characterizing both the running of $G$ and the long-distance behavior of invariant correlation functions. The appearance of such a gravitational condensate is viewed as analogous to the (equally nonperturbative) gluon and chiral condensates known to describe the physical vacuum of QCD. The resulting quantum theory of gravity is highly constrained, and its physical predictions are found to depend only on one adjustable parameter, a genuinely nonperturbative scale $\xi$ in many ways analogous to the scaling violation parameter $\Lambda_{\bar MS} $ of QCD. Recent results point to significant deviations from classical gravity on distance scales approaching the effective infrared cutoff set by the observed cosmological constant. Such subtle quantum effects are expected to be initially small on current cosmological scales, but could become detectable in future high precision satellite experiments.

Triple negative breast cancer (TNBC) has a negative expression of estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptors (HER2). The survival rate for TNBC is generally worse than other breast cancer subtypes. TNBC treatment has made significant advances, but certain limitations remain. Treatment for TNBC can be challenging since the disease has various subtypes. Individualized therapy is recommended rather than generalized therapy, given the genetic variations among these TNBC subtypes. A precise and effective treatment for TNBC requires identifying prognostic markers. Depending on the type and stage of TNBC, patients are treated with various therapeutic interventions. A variety of treatment options are available, such as chemotherapy, immunotherapy, radiotherapy, and surgery. Chemotherapy is the most common of these options. TNBC is generally treated with systemic chemotherapy using drugs such as anthracyclines and taxanes in the neoadjuvant or adjuvant settings. Developing resistance to anticancer drugs and off target toxicity are the primary hindrances to chemotherapeutic solutions for cancer. It is imperative that researchers, clinicians, and pharmaceutical companies work together to develop effective treatment options for TNBC. Several studies have suggested nanotechnology as a potential solution to the problem of suboptimal TNBC treatment.

To further explore the bearing capacity and sustainable construction of vacuum drainage pipe (VDP) piles, field tests were carried out to compare and analyze the ultimate single pile bearing capacity, pile side friction and pile end resistance of ordinary piles and vacuum drainage pipe piles. The effect of the VDP pile on energy conservation and emission reduction in practical projects is discussed. The results shows that the VDP pile basically eliminated the soil squeeze and did not cause excessive relative displacement of pile and soil after vacuum consolidation. The VDP pile enhances pile side friction resistance, resulting in a 17.6% increase in ultimate bearing capacity compared to traditional piles. The VDP pile method can reduce carbon emissions by 31.4% compared to traditional methods. This study provides guidance for the production and design of VDP piles in the future and demonstrates their potential for energy conservation and emission reduction benefits compared to traditional methods.

We present a summary of the main results within the Scale Invariant Vacuum (SIV) paradigm as related to the Weyl Integrable Geometry. After a brief review of the mathematical framework, we will highlight the main results related to inflation within the SIV [9], the growth of the density fluctuations [8], and the application of the SIV to scale-invariant dynamics of Galaxies, MOND, Dark Matter, and the Dwarf Spheroidals [7]. The connection of the weak-field SIV results to the un-proper time parametrization within the reparametrization paradigm is also discussed [14].

In this paper, we present the design, manufacturing and characterization of a soft textile-based clutch (TBC) that switches between locking and unlocking of its linear displacement by exploiting vacuum stimulation. The applied vacuum locks the relative sliding motion between two elaborated textile webbings covered by an elastic silicone rubber bag. Based on different fabrication techniques, such as silicone casting on textile, melt embossing for direct fabrication of miniature patterns on textile and sewing, we developed three groups of TBC samples based on friction and interlocking principles and we compared their performance in blocking configuration. The clutch with interlocking mechanism presented the highest withstanding force (150 N) respect to the one (54 N) recorded for the friction-based clutch. The simple and compact structure of the proposed clutch, together with the intrinsic adaptability of fabric with other clothing and soft materials, make it a proper solution for applications in soft wearable robotics and generally as locking and variable stiffness solution for soft robotic applications.

We review past and present results on the non-local form-factors of the effective action of semiclassical gravity in two and four dimensions computed by means of a covariant expansion of the heat kernel up to the second order in the curvatures. We discuss the importance of these form-factors in the construction of mass-dependent beta functions for the Newton's constant and the other gravitational couplings.

This paper introduces extensions H4,p and X8,p of Horn’s double hypergeometric function H4 and Exton’s triple hypergeometric function X8, taking into account recent extensions of Euler’s beta function, hypergeometric function, and confluent hypergeometric function. Among the numerous extended hypergeometric functions, the primary rationale for choosing H4 and X8 is their comparable extension type. Next, we present various integral representations of Euler and Laplace type, Mellin and inverse Mellin transforms, Laguerre polynomial representation, transformation formulae and a recurrence relation for the extended functions. In particular, we provide a generating function for the X8,p and several bounding inequalities for the H4,p and X8,p.

An explanation of aerodynamic lift still is under controversial discussion as can be seen, for example, in a recent published article in Scientific American [1]. In contrast to an approach via integral conservation laws we here review an approach via the classical Kutta-Condition and its relation to boundary layer theory. Thereby we summarize known results for viscous correction to the lift coefficient for thin aerodynamic profiles and try to remember the work on triple-deck or higher order Boundary Layer theory, its connection to interactive boundary layer theory, viscous/inviscid coupling as implemented to well-known engineering code Xfoil. Finally we compare its findings to simple 2D numerical solution of full Navier Stokes equations (CFD)models. As a conclusion, a clearer definition of terms like understanding and explanation applied to the phenomenon of aerodynamic lift will be given.

Triple negative breast cancer (TNBC) has a higher mRNA expression of programmed cell death ligand 1 (PD-L1) which is a ligand to programmed cell death protein 1 (PD-1). The binding of the ligand leads to suppressed activity of T-cell-mediated immune response against cancer cells. The approval of anti-PD-L1 drugs including pembrolizumab and atezolizumab in subgroups of TNBC offer potential improvement to the current treatment regimens available for TNBC. We conducted a meta-analysis to review the efficacy of pembrolizumab and atezolizumab for the treatment of TNBC in both adjuvant and neo-adjuvant settings. A systematic strategy was used as per the PRISMA 2020 statement. All statistical analyses were conducted using Review Manager 5.4. Outcome measures included objective response rate, progression free survival, overall survival in adjuvant therapy groups, and pathological complete response rates in neoadjuvant groups. Six clinical trials were included. For adjuvant therapies, the ORR (OR=1.26, P = 0.04) of Atezolizumab/Pembrolizumab plus chemotherapy was higher in intention to treat (ITT) arms than the placebo groups in TNBC. A positive effect size was found for PFS in the ITT arms (Cohen’s d = 1.55, P<0.001). The Atezolizumab plus chemotherapy group had a positive effect size for OS compared to the control groups (Cohen’s d = 0.52, P<0.001). In the neo-adjuvant setting, patients in ITT arms had higher pCR rates as compared to the control groups (OR= 1.61, P = 0.001). Our findings collate evidence of pembrolizumab and atezolizumab as a viable treatment option among patients with TNBC with PDL1+ subgroups deriving benefits.

Marine clay deposits are commonly found worldwide. Considering the cost of dumping and the related environmental concerns, an alternative solution involving the reuse of soils that have poor conditions is crucial. In this research, the authors examined the durability of marine deposited clays and compiled a corresponding database. The use of slag alone as a binder, at any percentage, increased the accumulated mass loss (ALM) up to 2%. However, the use of lime as the third binder seemed to accelerate the chemical reactions associated with the hydration of clay and cementitious material and to enhance the chemical stability, i.e., samples that included both lime and slag experienced the same ALM as samples treated with cement only. Scanning electron microscopy analysis confirmed the durability improvements of these clays. The proposed unconfined compressive strength and accumulated mass loss relationship yielded practical approximation for the fine- and coarse-grained soils blended with up to three binders until 60 days of curing.

The redefined vacuum approach, which is frequently employed in the many-body perturbation theory, proved to be a powerful tool for formula derivation. Here, we elaborate this approach within the bound-state QED perturbation theory. In addition to general formulation, we consider the particular example of a single particle (electron or vacancy) excitation with respect to the redefined vacuum. Starting with simple one-electron QED diagrams, we deduce first- and second-order many-electron contributions: screened self-energy, screened vacuum polarization, one-photon exchange, and two-photon exchange. The redefined vacuum approach provides a straightforward and streamlined derivation and facilitates its application to any electronic configuration. Moreover, based on the gauge invariance of the one-electron diagrams, we can identify various gauge-invariant subsets within derived many-electron QED contributions.

Uchino first initiated the study of generalized Reynolds operators on associative algebras. Recently, related research has become a hot topic. In this paper, we first introduce the notion of generalized Reynolds operators on Hom-Lie triple systems associated to a representation and a 3-cocycle. Then, we develop cohomology of generalized Reynolds operators on Hom-Lie triple systems with coefficients in a suitable representation. As applications, we use the first cohomology group to classify linear deformations and we study the obstruction class of an extendable order $n$ deformation. Finally, we introduce and investigate Hom-NS-Lie triple system as the underlying structure of generalized Reynolds operators on Hom-Lie triple systems.

Triple X syndrome (TXS, also known as trisomy X or 47,XXX) has been associated with impaired overall neurocognitive functioning in children and relatively young adults. However, neurocognitive functioning in adults with TXS is poorly understood. The aim of this study was, therefore, to examine cognitive functioning in adults with TXS. Methods: In this cross-sectional study, data were collected from 34 adult women with TXS (mean age = 32.9; SD = 13.1) and 31 controls (mean age = 34.9; SD = 13.7). General intellectual functioning, semantic/verbal memory, visual/episodic memory, psychomotor speed, and attention and executive functioning were then compared between these two groups. Results: We found that general intellectual functioning was significantly lower in the TXS group compared to the control group. In addition, women with TXS had more attention problems and lower psychomotor speed, particularly motor processing speed. When the analyses were adjusted for IQ, the strength of these associations decreased. The women in the TXS group also scored significantly lower at free recall in the verbal memory test, but not in immediate or delayed recognition. Finally, visual/episodic memory and executive functioning did not differ significantly between groups. Conclusions: Our analysis revealed that women with TXS score lower in general intellectual functioning and have impairments in motor processing speed and attention compared to controls, but do not differ with respect to executive functioning. These results offer new insights for improving the support of adults with TXS both at school and in the workplace.

Objective. To test the hypothesis that a session of unilateral tSMS over the dominant primary motor cortex (M1) in healthy subjects produces a transient decrease in manual dexterity. Methods. A triple-blinded randomized control trial was conducted in 40 healthy participants who were allocated to real- or sham-tSMS group. Each participant underwent one session of tSMS and were assessed before, immediately after, 15 minutes, and 40 minutes after stimulation. Outcome measures were Finger Tapping Test (FTT), 5-seconds FTT, nine Hole Peg Test, and the hand grip assessment. Results: Significant differences were found between groups 15 minutes after stimulation in favor of the tSMS group in the FTT (2.2 ± 0.99; CI= .18-4.22; d= .84p=.034), and 5-second FTT (4.2 ± 1.98; CI= .199-8.2, d= .68; p=.04). In the intragroup analysis, a significantly lower number of taps 15 minutes after stimulation was observed in sham group (3.3 ± 1.01; CI= .47-6.13; d= .42; p=.015), but not in the real stimulation group. Conclusion: A unilateral session of tSMS in the M1 of the dominant hemisphere of healthy individuals does not reduce manual dexterity or grip strength. This technique could have benefits on the motor performance of the arm contralateral to the stimulated motor cortex

In this work, the degassing process of corn seeds was experimentally and numerically analyzed by removing air or other gases from around the seeds, specifically from the seed coating, in a rough vacuum chamber. The two complementary variants are employed to understand and optimize this process to improve the quality and germination rate of the seeds. Several experiments were conducted with well-established durations and masses of corn seeds at different temperatures to observe and record the behavior of the system, facilitating the modeling of the degasification process in the vacuum compartment. Modeling the degasification operation in the vacuum chamber allowed for determining the pressure profiles on the vacuum chamber and its lid. Numerical simulations were either conducted using a simulation program developed in the Visual Basic Applications (VBA) language for Microsoft Excel to model the degassing process in the vacuum chamber, or with the assistance of specialized software (transient structural analysis and simulation program in the ANSYS Workbench environment). Statistical analysis of the correlation between experimental and estimated pressure values revealed that both the proposed mathematical model and the solution method are well-chosen, with differences expressed through the absolute error (EA) being very small. Structural dynamic analysis carried through the Finite Element Method (FEM) highlights that the chosen materials for manufacturing the vacuum chamber vessel (316 stainless steel) or the chamber lid (transparent acrylic plastic) are durable and capable of withstanding the desired pressure and temperature demands in the seed treatment process. Additionally, through structural dynamic analysis, it was possible to study the deformation of system components, providing a detailed perspective on their structural distribution.

Vacuum pump wear is the most prevalent failure mode of the IBA Synthera® automated radiochemistry system. Rebuilding or replacing the pump causes equipment downtime and increases the radiation exposure of the service personnel. We built a dedicated test device to assess new or rebuilt pumps prior to installation, thus reducing downtime and radiation exposure during repairs. The Testbed incorporates a microprocessor that actuates the pump, valves, pressure sensor, and communicates with the user through lights, buttons, and an alphanumeric screen. The Testbed increases productivity and safety in the radiochemistry laboratory.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen receptors (ER), progesterone receptors, and HER-2 receptors. Thus, TNBC tumours do not benefit from the current therapies targeting ER or HER-2. Therefore, there is an urgent need to develop novel treatment for this subtype of breast cancer. Marijuana is a common name given to Cannabis plants, a group of plants in the Cannabis genus of the Cannabaceae family. Cannabis plants are among the oldest cultivated crops, traced back at least 12,000 years and are well known for their multi-purpose usage, including medicinal purposes. The main active compounds extracted from Cannabis plants are 21-carbon-containing terpenophenolics, which are referred to as phytocannabinoids. Of these, the tetrahydrocannabinol (THC) group contains highly potent cannabinoids, including delta-9-tetrahydrocannabinol (∆9-THC) and delta-8-tetrahydrocannabinol (∆8-THC), which are the most abundant THCs and are largely responsible for psychological and physiological effects of marijuana. The use of Cannabis plants for medicinal purposes was first recorded in 2337 BC in China, where Cannabis plants were used to treat pains, rheumatism, and gout. Recently, several cannabinoids have been approved for a number of treatments, one of which is the treatment of nausea and vomiting caused by chemotherapy in cancer patients. Furthermore, increasing evidence shows that cannabinoids not only attenuate side effects due to cancer treatment, but might also potentially possess direct antitumor effects in several cancer types, including breast cancer. However, anti-tumour activity of marijuana has been variable in different studies and even promoted tumour growth in some cases. In addition, the mechanisms of cannabinoid action in cancer remain unclear. This review summarizes evidence about the mixed actions of cannabinoids in cancer in general and triple-negative breast cancer in particular.

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabelled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

This article is the first part of a scientific project under the general title "Geometrized Vacuum Physics". This study is based on two main postulates: 1) independence of the propagation velocity of electromagnetic waves in vacuum from their frequency; 2) the constancy of the averaged zero vacuum balance, associated with the assertion that only mutually opposite formations are born from vacuum, so that on average they completely compensate for each other's manifestations. In this part of the "Geometrized Vacuum Physics" the foundations of the Algebra of Stignatures are laid, which is the mathematical and logical foundation of the entire project. In the next articles of this project it will be shown that the Algebra of Stignatures can be used for the development of "zero" (vacuum) technologies, algebraic genetics, vacuum cosmology, the vacuum standard model of "elementary particles", vacuum gravity and levitation, vacuum energy, ethics and aesthetics and many other branches of knowledge. At the end of this article, one of the many possible applications of the Algebra of Stignatures is given, in particular, the basics of the stignature-spectral analysis are outlined, with the help of which the possibilities of communication channels can be significantly expanded.

This article is the second part of a scientific project under the general name "Geometrized vacuum physics". On the basis of the Algebra of Stignatures presented in the previous article [1], this article develops the main provisions of the Algebra of Signatures. Both of the above algebras are aimed at studying the properties of an ideal vacuum, but at the same time they are universal and can be applied in various branches of knowledge. It is shown that the signature of a quadratic form is related to the topology of the metric space for which the given quadratic form is a metric. Conditions are given under which an additive imposition of metric spaces with different topologies (or signatures) leads to a total Ricci flat space similar to a Calabi-Yau manifold. A spin-tensor representation of metrics with different signatures is considered and a Dirac bundle of quadratic forms is presented. This article does not contain physical applications of the Algebra of Signatures, but the potential power of this mathematical apparatus will be demonstrated in subsequent articles of this project.

We considered a vacuum polarization around a massive object in the eikonal approximation and found two types of vacuum polarization. The first type has the equation of state similar to radiation and can produce a halo that increases the rotation velocity of a test particle with a radial distance. The second type of vacuum polarization has a more complicated equation of state. As a static physical effect, it produces renormalization of the gravitational constant. Besides, we demonstrate that a nonstationary polarization of the second type caused by a swift increase of the galactic nuclei mass results in a gravitational potential looking like a dark matter halo.

We present a cyclic symmetry type II vacuum spacetime admitting closed timelike curves (CTCs) which appear after a certain instant of time, i.e., a time-machine spacetime. The various authors in past have considered the 2D and 4D flat generalization of Misner space, but in the present work, we have considered the curved spacetime generalzations of 4D Misner space, and is asymptotically flat radially

The fact that quantum gravity does not admit a co-variant vacuum state has far-reaching consequences for all physics. It points out that space could not be empty, and we return to the notion of an ether . Such a concept requires a preferred reference frame for, e.g., universe expansion and black holes. Here, we intend to discuss vacuum and quantum gravity from three essential viewpoints: universe expansion, black holes existence, and quantum decoherence.

Vacuum drying can dehydrate materials further than dry heat methods while protecting sensitive materials from thermal degradation. Many industries have shifted to vacuum drying as cost- or time-saving measures. Small-scale vacuum drying, however, has been limited by high costs of specialty scientific tools. To make vacuum drying more accessible, this study provides design and performance information for a small-scale open source vacuum oven, which can be fabricated from off-the-shelf and 3-D printed components. The oven is tested for drying speed and effective-ness on both waste plastic polyethylene terephthalate (PET) and a consortium of bacteria developed for bioprocessing of terephthalate wastes to assist in distributed recycling of PET for both additive manufacturing as well as potential food. Both materials can be damaged when exposed to high temperatures, making vacuum drying a desirable solution. The results showed the open source vacuum oven was effective at drying both plastic and biomaterials, drying at a higher rate than a hot-air dryer for small samples or for low volumes of water. The system can be constructed for less than 20% of commercial vacuum dryer costs for several laboratory-scale applications including dehydration of bio-organisms, drying plastic for distributed recycling and additive manufacturing, and chemical processing.

In this paper, a novel integrated high precision vacuum microelectronic accelerometer is put forward based on the theory of field emission, the accelerometer consists of sensitive structure and interface ASIC. The sensitive structure has a mass of a cathode cone tips array, a folded beam, an emitter electrode and a feedback electrode. The sensor is fabricated on a double side polished (1 0 0) N-type silicon wafer, the tips array of cathode are shaped by wet etching with HNA (HNO3, HF and CH3COOH) and metalized by TiW/Au thin film. The structure of sensor is released by ICP process finally. The interface ASIC was designed and fabricated based on the P-JFET high voltage bipolar process. The accelerometer is tested through static field rollover test, and the test results show the integrated vacuum microelectronic accelerometer has good performances, which sensitivity is 3.081V/g and non-linearity is 0.84% in the measuring range of −1g~1g.

New multilayer 3D nanocomposite wear-resistant ion-plasma hard and superhard coatings Avinit [(TiN-AlN)(Mo-Cr-V-Si)]_n have been developed.The introduction of additional alloying elements (Mo, Cr, V, Si) into the Ti-Al-N coating composition, which have a high affinity for nitrogen and are capable of forming strong nitride nanoparticles in the Ti-N and Al-N layers.This makes it possible to obtain hard and superhard hardening coatings.The metallographic and tribological studies carried out indicate the prospects of the developed multicomponent multilayer nano- and microstructured Avinit coatings for increasing wear resistance and reducing friction coefficients.This paper is devoted to the development and implementation of Avinit vacuum plasma technologies for strengthening cutting and forming tools to improve tool performance.Production tests of cutting tools with Avinit's developed multilayer wear-resistant ion-plasma coatings in production conditions at many large machine-building enterprises have shown their high efficiency.In serial production, the wear resistance of tools increases by 3 to 30 times, stamps by 5 to 100 times, and parts rubbing against abrasive materials by 10 to 100 times.Avinit's vacuum plasma technologies have been successfully implemented in production in the aggregate and engine building, transport engineering, and power engineering industries.Positive experience in applying multicomponent coatings has been gained not only when applying hardening coatings to manufactured cutting tools, but also after regrinding to regrindable carbide cutting tools from domestic and foreign manufacturers.

Large inconsistencies in the outcome of precise measurements of Newtonian gravitational ‘constant’ were identified throughout more than three hundred experiments conducted up to date. This paper illustrates the dependency of the Newtonian gravitational parameter on the curvature of the background and the associated field strength of vacuum energy. Additionally, the derived interaction field equations show that boundary interactions and spin-spin correlations of vacuum and conventional energy densities contribute to the emergence of mass. Experimental conditions are recommended to achieve consistent outcomes of the parameter precision measurements, which can directly falsify or provide confirmations to the presented field equations.

The cyclic universe theory is a model of cosmic evolution according to which the universe undergoes endless cycles of expansion and cooling, each beginning with a big bang and ending in a big crunch. In this paper, the researcher finds a unique property of Space-time, this particular and marvelous nature of space shows us that space can shrink, expand, and stretch. This property of space is caused the size of the Universe changing over time: growing or shrinking. The observed accelerated expansion, which relates the stretching of Shrunk space for the new theory, is derived. This model is based on three underlying notions: First, the Big Bang was not the beginning of Space-time, but rather at the very beginning fraction of a second there was an infinite force of infinite Shrunk space in the cosmic singularity, that force gave rise to the big bang and caused the rapidly growing of space-time, and all other forms of energy are transformed into matter and radiation and a new period of expansion and cooling begins. Second, there was a previous phase leading up to it, with multiple cycles of contraction and expansion that repeat indefinitely. Third, the two principal long-range forces are the gravitational force and the repulsive force generated by shrunk space. They are the two most fundamental quantities in the universe that govern cosmic evolution. They may provide the clockwork mechanism that operates our eternal cyclic universe. The space will not continue to expand forever, no need however, for dark energy and dark matter. This model of Space-time and its unique properties enables us to describe a sequence of events from the Big Bang to the Big Crunch.

A number of experiments suggest that the elementary particles are non-local entities. A dissipative self-organization, that treats particles as open systems may provide a better understanding of the underlying phenomena than conservative models. The proposed toy model is such an attempt. We found that self-gravitation (although accompanied by self-diffusion) may not only be compatible with the quantum phenomena but is perhaps the major reason for the existence of quantum fields. According to the proposed model, fields/particles (resemble those of the Standard Model) emerge from a dynamic self-organized medium (which we associate with vacuum dust) from competition between self-gravitation and self-diffusion. These forces produce turbulence in the form of vortices (which we call vacuum cells) that serve as the building blocks for fields and particles. Field/particle features and symmetries are based on their internal (intracellular) dynamics and vortex synchronization (intercellular dynamics). This model allows for rough estimations of relative field coupling strengths, the quantity of charges and flavors, the probabilities of quark transmutations, the dimensionality and the topologies of phase spaces, and other Standard Model parameters that came not from the theory but rather determined by experiment.

We discuss a possible scale of gravitational origin at around 10 MeV, or 10⁻¹² cm, which arises in the MacDowell-Mansouri formalism of gravity due to the topological Gauss-Bonnet term in the action, as pointed out by Bjorken several years ago.~A length scale of the same size emerges also in the Kodama solution in gravity, which is known to be closely related to the MacDowell-Mansouri formulation. We particularly draw attention to the intriguing incident that existence of six compact extra dimensions originated from TeV-scale quantum gravity as well points to a length scale of 10⁻¹² cm, as the compactification scale. The presence of six such extra dimensions is also in remarkable consistency with the MacDowell-Mansouri formalism; it provides a possible explanation for the factor of ~10¹²⁰ multiplying the Gauss-Bonnet term in the action. We also comment on the relevant implications of such a scale regarding the thermal history of the universe motivated by the fact that it is considerably close to 1–2 MeV below which the weak interactions freeze out, leading to Big Bang Nucleosynthesis.

The study examines malnutrition's triple burden, including anaemia, overweight, and stunting, among children aged 6-59 months. Using data from the National Family Health Survey-5 (2019-21), the study identifies risk factors and assesses the contribution at different levels to existing malnutrition burden. A random intercept multilevel logistic regression model and spatial analysis are employed to identify child, maternal, and household level risk factors for stunting, overweight, and anaemia. The study finds that 34% of children were stunted, 4% overweight, and 66% anaemic. Stunting and anaemia prevalence were higher in central and eastern regions, while overweight was more prevalent in the north-eastern and northern regions. At macro-level, the coexistence of stunting, overweight, and anaemia circumstantiates the triple burden of childhood malnutrition with substantial spatial variation (Moran’s I: stunting-0.53, overweight-0.41 and anaemia-0.53). Multilevel analysis reveals that child, maternal, and household variables play a substantial role in determining malnutrition burden in India. The nutritional health is significantly influenced by a wide range of determinants, necessitating multilevel treatments targeting households to address this diverse group of coexisting factors. Given the intra-country spatial heterogeneity, the treatment also needs to be tailor-made for various disaggregated levels.

Insecticidal toxins from Bacillus thuringiensis (Bt) are valuable tools for pest management worldwide, contributing to the management of human disease insect vectors and phytophagous insect pests of agriculture and forestry. Here, we report the effects of dual and triple Bt toxins expressed in transgenic cotton cultivars on the fitness and demographic performance of Helicoverpa zea (Boddie), a noctuid pest known as cotton bollworm and corn earworm. Life-history traits were determined for individuals of three field populations from a region where H. zea overwintering is likely. Triple-gene Bt cotton cultivars expressing Cry and Vip3Aa toxins killed 100% of the larvae in all populations tested. In contrast, dual-gene Bt cotton expressing Cry1Ac+Cry1F and Cry1Ac+Cry2Ab2 allowed population growth with the intrinsic rate of population growth (rm) 38% lower than on non-Bt cotton. The insects feeding on Bt cotton plants expressing Cry1Ac+Cry2Ab2, Cry1Ac+Cry1F, or Cry1Ab+Cry2Ae exhibited reduced larval weight, survival rate, and increased development time. Additionally, fitness parameters varied significantly among the insect populations, even on non-Bt cotton plants, likely because of their different genetic background and/or previous Bt toxin exposure. This is the first report of the comparative fitness of H. zea field populations on dual-gene Bt cotton after the recent reports of field resistance to certain Bt toxins. These results document the population growth rates of H. zea from an agricultural landscape with 100% Bt cotton cultivars. Our results will help to refine models designed to predict resistance evolution and improve insect resistance management for Bt crops.

We study spherically symmetric spacetimes in Einstein-aether theory in three different coordinate systems, the isotropic, Painlev\`e-Gullstrand, and Schwarzschild coordinates, and present both time-dependent and time-independent exact vacuum solutions. In particular, in the isotropic coordinates we find a class of exact static solutions characterized bya single parameter $c_{14}$ in closed forms, which satisfies all the current observational constraints of the theory, and reduces to the Schwarzschild vacuum black hole solution in the decoupling limit ($c_{14} = 0$). However, as long as $c_{14} \not= 0$, a marginally trapped throat with a finite non-zero radius always exists, and in one side of it the spacetime is asymptotically flat, while in the other side the spacetime becomes singular within a finite proper distance from the throat, although the geometric area is infinitely large at the singularity. Moreover, the singularity is a strong and spacetime curvature singularity, at which both of the Ricci and Kretschmann scalars become infinitely large.

The aim of the article is to develop geometrized physics of a vacuum on the basis of two basic postulates: 1) the constancy of the speed of light (more precisely, the speed of propagation of electromagnetic waves) in the vacuum; 2) the ‘vacuum balance condition’ associated with the statement that only mutually opposite formations are born from the vacuum, so that, on average, they completely compensate of the manifestations of each other. The Algebra of signatures is proposed as a mathematical basis for geometrized physics of a vacuum.

Standard of care for triple negative breast cancer (TNBC) involves the use of microtubule poisons like paclitaxel, which are proposed to work by inducing lethal levels of aneuploidy in tumor cells. While these drugs are initially effective in treating cancer, dose-limiting peripheral neuropathies are common. Unfortunately, patients often relapse with drug resistant tumors. Identifying agents against targets that limit aneuploidy may be a valuable approach for therapeutic development. One potential target is the microtubule depolymerizing kinesin, MCAK, which limits aneuploidy by regulating microtubule dynamics during mitosis. Using publicly available datasets, we found that MCAK is upregulated in triple negative breast cancer and is associated with poorer prognoses. Knockdown of MCAK in tumor-derived cell lines caused a two- to five-fold reduction in the IC50 for paclitaxel, without affecting normal cells. Using FRET and image-based assays, we screened compounds from the ChemBridge 50k library and discovered three putative MCAK inhibitors. These compounds reproduced the aneuploidy-inducing phenotype of MCAK loss, reduced clonogenic survival of TNBC cells regardless of taxane-resistance, and the most potent of the three, C4, sensitized TNBC cells to paclitaxel. Collectively, our work shows promise that MCAK may serve as both a biomarker of prognosis and as a therapeutic target.

We present a summary of the main results within the Scale Invariant Vacuum (SIV) paradigm based on the Weyl Integrable Geometry (WIG) as an extension to the standard Einstein General Relativity (EGR). After a brief review of the mathematical framework, where we also highlight the connection between the weak-field SIV equations and the notion of un-proper time parametrization within the reparametrization paradigm, we continue with the main results related to early Universe; that is, applications to inflation, Big Bang Nucleosynthesis, and the growth of the density fluctuations within the SIV. In the late time Universe the applications of the SIV paradigm are related to scale-invariant dynamics of galaxies, MOND, dark matter, and the dwarf spheroidals where one can find MOND to be a peculiar case of the SIV theory. Finally, within the recent time epoch, we highlight that some of the change in the length-of-the-day (LOD), about 0.92 cm/yr, can be accounted for by SIV effects in the Earth-Moon system.

The celebrated geodesic congruence equation of Raychaudhuri, together with the resulting singularity theorems of Penrose and Hawking that it enabled, yield a highly general set of conditions under which a spacetime (or, more generically, a pseudo-Riemannian manifold) is expected to become geodesically incomplete. However, the proofs of these theorems traditionally depend upon a collection of assumptions about the continuum spacetime (and, in the physical case, the stress-energy distribution defined over it), including its global structure, its energy conditions, the existence of trapped null surfaces and the various volume/intersection properties of geodesic congruences, that are inherently difficult to translate to the case of discrete spacetime formalisms, such as causal set theory or the Wolfram model. Some, such as the discrete analog of Raychaudhuri's equation for the volumes of geodesic congruences, are subtle to formulate due to intrinsic differences in the behavior of discrete vs. continuous geodesics; for others, such as the definition of a trapped null surface, no appropriate translation is known for the general discrete case due to a lack of a priori coordinate information. It is therefore a non-trivial question to ask whether (and to what extent) there exist equivalently general conditions under which one expects discrete spacetimes to become geodesically incomplete, and how these conditions might differ from those in the continuum. This article builds upon previous work, in which the conformal and covariant Z4 (CCZ4) formulation of the Cauchy problem for the Einstein field equations, with constraint-violation damping, was defined in terms of Wolfram model evolution over discrete (spatial) hypergraphs for the case of vacuum spacetimes, and proceeds to consider a minimal extension to the non-vacuum case by introducing a massive scalar field distribution, defined in either spherical or axial symmetry. Under appropriate assumptions, this scalar field distribution admits a physical interpretation as a collapsing (and, in the axially-symmetric case, uniformly rotating) dust, and we are able to show, through a combination of rigorous mathematical analysis and explicit numerical simulation, that the resulting discrete spacetimes converge asymptotically to either non-rotating Schwarzschild black hole solutions or maximally-rotating (extremal) Kerr black hole solutions, respectively. Although the assumptions used in obtaining these preliminary results are very strong, they nevertheless offer hope that a more general, perhaps ultimately ``Penrose-like'', singularity theorem may be provable in the discrete spacetime case too.

This paper considers a new approach to the modeling of the vacuum infusion process at the manufacturing three-dimensional composite parts of complex shape. The developed approach and numerical methods are focused on the reliable prediction with the needed accuracy and elimination the unrecoverable defect of composite structure such as the dry spots. The paper presents some experimental results, which demonstrate two cases of dry spots formation in large aircraft composite panels, and analyses the reasons of these defects arising. Our numerical technique is based on the vacuum infusion of the liquid resin into porous preform as the two phase flow, which is described by the phase field equation coupled with the Richards equation describing the fluid motion in unsaturated soils with spatially varied pressure dependant porosity and saturation. This problem statement allowed to correctly reconstruct the resin front motion and formation of inner and outer dry spots depending on its movement. For the rapid detection of preform zones that are suspicious for defect formation two indicators calculated during process simulation are proposed and tested at the numerical experiments. The auxiliary program tool has been developed in MATLAB environment to correctly detect the times of formation, localization and dimensions of the arising dry spots by using the results of the finite element model simulation.

Background: Metastatic triple-negative breast cancer (TNBC) is aggressive with a poor median overall survival (OS), ranging from 8 to 13 months. There exists considerable heterogeneity in the survival at the individual patient level. To better understand the survival heterogeneity and improve risk stratification, our study aims to identify the factors influencing survival utilizing a large patient sample in the National Cancer Database (NCDB). Methods: Women diagnosed with metastatic TNBC from 2010 to 2020 in the NCDB were included. Demographic, clinic-pathological, treatment data, and overall survival (OS) outcomes were collected. Kaplan-Meier curves were used to estimate OS. The log-rank test was used to identify OS differences between groups for each variable in the univariate analysis. For the multivariate analysis, the Cox proportional hazard model with backward elimination was used to identify factors affecting OS. Adjusted hazard ratios and 95% confidence intervals are presented. Results: 2,273 women had a median overall survival of 13.6 months. Factors associated with statistically significantly worse OS included older age, higher comorbidity scores, specific histologies, higher number of metastatic sites, presence of liver or other site metastases in those with only one metastatic site (excluding brain metastases), presence of cranial and extra-cranial metastases, lack of chemotherapy, lack of immunotherapy, lack of surgery to distant sites, lack of radiation to distant sites, and receipt of palliative treatment to alleviate symptoms. In the multivariate analysis, comorbidity score, histology, number of metastatic sites, immunotherapy, and chemotherapy had a statistically significant effect on the OS. Conclusions: Through NCDB analysis, we have identified prognostic factors for metastatic TNBC. These findings will help improve prognostication at diagnosis, optimize treatment strategies, and facilitate patient stratification in future clinical trials.

The efficiencies of conventional triple organic Rankine cycle (TORC) configurations are restricted by the low critical temperatures of common working fluids (＜320 °C). This paper proposes a high-temperature TORC system. A near-azeotropic mixture biphenyl/diphenyl oxide (BDO), which has stellar track record in the high-temperature ORC applications, is innovatively adopted as the top and middle ORC fluid simultaneously. The top cycle evaporation temperature is up to 400 °C in view of BDO’s high stability. Five conventional organic fluids are chosen for the bottom ORC. Fundamentals of the TORC system are illustrated, and mathematical models are built. Thermo-economic performance is investigated. The results hint that the optimal thermodynamic property is achieved on the use of benzene as the bottom fluid. The maximum thermal and exergy efficiencies are respectively 40.86% and 74.14%. The largest irreversible loss occurs inside the heat exchanger coupling the middle and bottom ORCs, accounting for above 30% of the total entropy generation. The levelized energy cost (LEC) is 0.0284 $/kWh. Given the same heat source condition, the TORC system can boost efficiency by 1.02% and drive down LEC by 0.0024 $/kWh compared with a BDO mixture-based cascade ORC.

The current study aims to first, isolate H. pylori in cultures from gastric biopsy samples and test their susceptibility. Secondly, we aim to assess the efficacy of the standard triple therapy from patients coming of the western central region of Colombia. Patients with H. pylori positive re-ceived standard triple therapy with PPI [40 mg b.i.d.], clarithromycin [500 mg b.i.d.], amoxicillin [1g b.i.d.] for 14 days. Thereafter, antibiotic susceptibility of the isolates was assessed by E-Test. From 94 patients enrolled, 67 were positive for H. pylori by histology or culture. Resistance to metronidazole, levofloxacin, rifampicin, clarithromycin and amoxicillin was 81, 26.2, 23.9, 19 and 9.5%, respectively. No resistance was found for tetracycline. 54 patients received standard triple therapy, 48 attended follow-ups testing and of them, 30 had resistance test reports. Overall eradication rate was 81.2%, 4 patients underwent second-line management and only one patient remained H. pylori positive by urea breath test during the follow-up [six weeks]. Eradication was significantly higher in patients with clarithromycin susceptible than in resistant strains [95.6% vs. 42.8% p= 0.001]. The updated percentages of resistance to clarithromycin in this geographical area have increased, so this value must be considered when choosing the treatment regimen.

Chorioamnionitis (CA) at term of pregnancy can have infectious and/or inflammatory origin and is associated with adverse outcomes. Triple I (Intrauterine Inflammation, Infection or both, TI) has been proposed to reduce the overdiagnosis of infection and the neonatal overtreatment. The aim of the study is to identify clinical and histological variables predicting adverse outcomes when TI has been suspected and/or confirmed. This retrospective cohort study included 404 pregnancies ≥37 g.a. that were divided into 5 all-inclusive and mutually exclusive groups. TI was defined according to NICHD definition of 2015 and it could be confirmed (TI+) or not (TI-) by histological examination. Signs of infection/inflammation not respecting the definition of TI were classified as “Clinical suspicion”, supported (CS+) or not (CS-) by histology. Histological chorioamnionitis (HCA) without clinical manifestation represented fifth group. Whole Placental Involvement (WPLI), was defined as a histological inflammation involving maternal and fetal side. There were 113 TI+, 30 TI-, 186 CS+, 35 CS- and 40 isolated HCA. WPLI was diagnosed in 133 cases (39.2%). Composite neonatal outcome (CNO) occurred in 114 cases (28.2%) while composite maternal outcome (CMO) occurred in 192 cases (47.5%). TI+ compared to CS+ was more predictive of CNO (p=0.001), CMO (p<0.001) and WPLI (p=0.005). WPLI was related both to CNO (p<0.001) and CMO (p=0.046). TI+ and WPLI showed similar sensitivity but different specificity in predicting CNO. At logistic regression, CNO was independently predicted by TI+ (OR 2.21; p=0.001) and by WPLI (OR 2.23; p=0.001). TI, compared to CS, is a better predictor of CNO and can be useful for the identification of newborns at risk.

Simple Summary: Breast cancer is the most common invasive cancer among women. Triple-negative breast cancer (TNBC) accounts for 15–20% of newly diagnosed breast cancers and has the worst prognosis. However, TNBC patients are not a homogeneous group, and there are differences in the course of the disease as well as in response to treatment. For this reason, differentiation of subtypes of this tumor is important for optimal therapeutic decision and risk prediction. The presented study focuses on the expression of the androgen receptor (AR) and the infiltration of T-lymphocytes in the tumor stroma (TILs) of TNBC patients. Correlation of these tested biomarkers with standard prognostic factors. Defining new prognostic factors for 3-year overall survival (OS). Abstract: Background: Analysis of the practical benefit of testing the expression of AR and the TILs in patients with TNBC and their correlation with standard prognostic factors. Methods: The study group consisted of 86 female patients treated for TNBC. T-lymphocyte infiltration was examined in H+E staining. AR expression, CD8 and CD4 T-lymphocytes were evaluated in immunohistochemistry. Results: Significantly negative correlation was found between AR expression and the CD8 T-lymphocyte infiltration levels. A significant negative correlation was found between the AR expression and G and Ki 67, and a positive correlation between the TILs levels and G and Ki 67. Patients with AR expression and low TILs levels had the highest percentage of diagnosed distant metastases and 3-years OS. Patients with high TILs no distant metastases or deaths were diagnosed. The level of TILs turned out to be a significant independent prognostic factor. Conclusions: Based on the assessment of AR expression and TILs infiltration, the group of highest and lowest risk was determined. The prognostic factor of known parameters such as TNM and a new factor - TILs was confirmed. On the other hand, parameters such as G and Ki 67 and the tested factor - AR had no effect on the prognosis.

A new frontier in solar thermal panel technology can be a high vacuum collector, thick enough to be equipped with solar concentrators based on non-imaging optics, such as the Compound Parabolic Concentrators (CPC). The high vacuum technology guarantees higher operating temperatures thanks to the enhanced thermal insulation, which leads to pay particular attention to the absorber radiative emission. In this paper by means of numerical simulations we compare the efficiency of a flat selective solar absorber under high vacuum to the efficiency of a CPC under high-vacuum collector.

It is shown that, for a de Sitter Universe, the Hartle-Hawking (HH) wave function can be obtained in a simple way starting from the Friedmann- Lemaitre-Robertson-Walker (FLRW) line element of cosmological equations. An oscillator having imaginary time is indeed derived starting from the Hamiltonian obtaining the HH condition. This proposes again some crucial matter on the meaning of complex time in cosmology. In order to overcome such difficulties, we propose an interpretation of the HH framework based on de Sitter Projective Holography.

Venoms are a rich source of bioactive compounds, and among them is leberagin-C (Leb-C), a disintegrin-like protein derived from the venom Macrovipera lebetina transmediterrannea snakes. Leb-C has shown promising inhibitory effects on platelet aggregation. Previous studies have demonstrated that this SECD protein specifically targets α5β1, αvβ3 and αvβ6 integrins through a mimic mechanism of RGD disintegrins. In our current study, we focused on exploring the potential effects of Leb-C on metastatic breast cancer. Our findings revealed that Leb-C disrupted the adhesion, migration, and invasion capabilities of MDA-MB-231 breast cancer cells and its highly metastatic D3H2LN sub-population. Additionally, we observed significant suppression of adhesion, migration, and invasion of Human Umbilical Vein Endothelial Cells (HUVECs). Furthermore, Leb-C demonstrated a strong inhibitory effect on fibroblast growth factor 2-induced proliferation of HUVEC. We conducted in vivo experiments using nude mice and found that treatment with 2 µM of Leb-C resulted in a remarkable 73% reduction in D3H2LN xenograft tumor size. Additionally, quantification of intratumor microvessels revealed a 50 % reduction in tumor angiogenesis in xenograft after 21 days of twice-weekly treatment with 2 µM of Leb-C. Collectively, these findings suggest the potential utility of this dinsintegrin-like protein for inhibiting aggressive and resistant metastatic breast cancer.

The triple-negative breast cancer (TNBC) subtype is one of the most aggressive forms of breast cancer that has poor clinical outcome and still remains as an unmet clinical challenge. Accumulating evidence suggests that intratumoral heterogeneity or the presence of phenotypically heterogeneous cell populations within a tumor plays a crucial role in chemoresistance, tumor progression and metastasis. Increased understanding of the molecular regulators of intratumoral heterogeneity will enable the development of effective therapeutic strategies in TNBC. We have identified a molecular mediator involved in intratumoral heterogeneity in breast cancer using an unbiased approach. We isolated two heterogeneous tumor cell populations from the 4T1 TNBC tumor model and phenotypic characterization revealed that the cells are distinct in terms of their morphology, proliferation and self-renewal ability in vitro; as well as primary tumor formation and metastatic potential in vivo. Further, RNA sequencing on both cell populations was performed to identify the molecular mediators underlying this heterogeneity. Bioinformatic analysis performed on the differentially expressed genes along with the Kaplan-Meier survival analysis in TNBC patients identified Metastasis associated colon cancer 1 (Macc1) as the top candidate gene mediating the aggressive phenotype. The role of Macc1 in regulating the proliferative phenotype was validated using siRNA mediated gene knockdown. The role of Macc1 in the aggressive cancer cell phenotypes and disease progression is being studied further using a small molecule transcriptional inhibitor of Macc1 in cell line and animal models, thus increasing our understanding of the molecular underpinnings of intratumoral heterogeneity in breast cancer that is critical to the improvement in the treatment of women currently living with the highly aggressive TNBC subtype.

In this paper, modelling design and analysis of a triple inverted pendulum have been done using Matlab/Script toolbox. Since a triple inverted pendulum is highly nonlinear, strongly unstable without using feedback control system. In this paper an optimal control method means a linear quadratic regulator and pole placement controllers are used to stabilize the triple inverted pendulum upside. The impulse response simulation of the open loop system shows us that the pendulum is unstable. The comparison of the closed loop impulse response simulation of the pendulum with LQR and pole placement controllers results that both controllers have stabilized the system but the pendulum with LQR controllers have a high overshoot with long settling time than the pendulum with pole placement controller. Finally the comparison results prove that the pendulum with pole placement controller improve the stability of the system.

Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio-chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation is delivered concomitantly during the first 3 weeks of chemotherapy, and it is based on a 15 fractions scheme (40.5Gy/2.7Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy is based on Pertuzumab-Trastuzumab-Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. 58 patients were enrolled, 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved &gt;90% loss of invasive carcinoma cell in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype respectively achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies are applied simultaneously: fractionation of RT in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging.

Calcium dihydrogen phosphate monohydrate [Ca(H2PO4)2·H2O] (a fertilizer) was successfully synthesized by the recrystallization process by using a prepared triple superphosphate (TSP) that derived from oyster shell waste as starting material. This bio-green, eco-friendly process to produce an important fertilizer can promote a sustainable society. The shell-waste-derived TSP was dissolved in distilled water and kept at 30, 50, and 80 °C. Non-soluble powder and TSP solution were obtained. The TSP solution fraction were then dried and the recrystallized products (RCP30, RCP50, and RCP80) were obtained and confirmed as Ca(H2PO4)2·H2O. Whereas the non-soluble products (NSP30, NSP50, and NSP80) were observed as calcium hydrogen phosphate dihydrate (CaHPO4·2H2O). The recrystallized yields of RCP30, RCP50, and RCP80 were found to be 51.0%, 49.6%, and 46.3%, whereas the soluble percentages were 98.72%, 99.16%, and 96.63%, respectively. RCP30 shows different morphological plate sizes, while RCP50 and RCP80 present the coagulate crystal plates. X-ray diffractograms confirm the formation of both the NSP and RCP. The infrared adsorption spectra confirmed the vibrational characteristics of HPO42‒, H2PO4‒ and H2O existed in CaHPO4·2H2O and Ca(H2PO4)2·H2O. Three thermal dehydration steps of Ca(H2PO4)2·H2O (physisorbed water, polycondensation, and re-polycondensation) were observed. Ca(H2PO4)2 and CaH2P2O7 are the thermodecomposed products from the first and second steps, whereas the final product is CaP2O6.

Classifications of AAFD/PCFD have evolved with an increased understanding of the pathology involved. A review of classification systems helps identify deficiencies and respective contributions to the evolution in understanding the classification of AAFD. Using multiple electronic database searches (Medline, PubMed) and Google search, original papers classifying AAFD were identified. Nine original articles were identified that met the inclusion criteria. Johnson's original classification and multiple variants provided a significant leap in understanding and communicating the pathology but remained tibialis posterior tendon focussed. Drawbacks of these classifications include the implication of causality, linearity of progression through stages, an over-simplification of stage 2 deformity and a failure to understand multiple tendons react, not just tibialis posterior. Later classifications, such as the PCFD classification, are deformity-centric. Early instability in non-cavus feet and all stages of cavus feet can present pain and instability with minor/no deformity. These may not be captured in deformity-based classifications biased to planus feet.' The authors developed the 'Triple Classification' (TC) understanding that primary pathology is a progressive ligament failure/instability that presents as tendon reactivity, deformity, and painful impingement. There is a variable manifestation dependent on starting foot morphology. This review has identified deficiencies within classification systems used in AAFD/PCFD and, as a result, was used to help develop a more comprehensive 'Triple classification'. Advantages of the TC include representing foot types with no deformity, defining complex secondary instabilities, delinking of foot types, tendon reactivity/ligament instability and deformity to represent these independently in a more comprehensive classification system.

(1) Background: Triple negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting high level of recurrence and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis related R-packages were developed for integrative transcriptome to analyze transcriptome datasets: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), breast tumors with clinical data (TCGA and METABRIC cohorts). Protein level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers up-regulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated to overall survival. Breast tumors presenting high expression of CD274 up-regulated some ferroptosis drivers associated to prognosis: IDO1, IFNG and TNFAIP3. CD274-ferroptosis-driver score computed on breast tumor transcriptome stratified patients on their prognosis: low score was observed in basal subgroup with higher level of recurrent risk scores: oncotypeDx, ggi and gene70 scores. In METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found overexpressed in TNBC subgroup. CD274-ferroptosis-driver score was found associated to overall survival independently of TNM classification and age diagnosis. Tumor expression of CD274, TNFAIP3, IFNG and IDO1 in biopsy of breast ductal carcinoma was confirmed at protein level (4) Conclusion: Ferroptosis inducers up-regulate PD-L1 in TNBC cells, known as effective target of immunotherapy in high risk early TNBC which received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. CD274-ferroptosis driver score is associated to prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested in recurrent TNBC.

We investigate the performance of a novel flat photovoltaic-thermal (PV-T) module under high-vacuum through a 1D numerical model based on steady-state energy balance, with the aims of optimizing the simultaneous production of thermal and electrical energy. In the proposed design, the photovoltaic (PV) cell is positioned directly above the selective solar absorber (SSA), in a multilayer or fully integrated PV-SSA structure, which allows full exploitation of spectral solar radiation. In fact, in this configuration the losses related to non-absorption of low-energy photons and thermalization, typical of a classical single-junction PV cell, are reduced. The present study is conducted as the emittance and energy bandgap of the PV layer varied, thus admitting a wide variety of materials into the analysis. The dependence of the temperature coefficient, β(%/K), on the energy bandgap of the PV cell is also included. In the last part of the work, we discuss the performance of the proposed evacuated PV-T equipped with a SSA layer and thin film solar cells, namely those made of CdTe, CdS and GaAs. Overall, the paper highlights the great advantage of using high vacuum insulation, which suppresses conductive losses, and the versatility of the proposed system, which could be adapted to the user's needs simply by choosing the appropriate material for the photovoltaic layer.

Among solar thermal collectors, the evacuated flat panel is emerging as a reference technology for operation at higher temperatures of up to 200 °C with an increased annual energy production owing to both direct and diffuse light capture. Accurate measurements of the optical properties of the selective absorbers used in such devices are key for a reliable estimation of the overall performance. These optical properties must be measured under high vacuum at high temperatures, conditions under which the panels are meant to operate. In this study, we accurately measured these properties using a calorimetric technique. The measurement procedure is based on a power balance equation for a flat sample suspended in a high-vacuum chamber with minimal thermal losses and is well adapted for this class of devices. Calorimetric measurements obtained under Sun and LED light revealed excellent reproducibility and good agreement with those obtained using traditional optical analysis at low temperatures in air. When extended up to the absorber stagnation temperature, which often exceeds 300 °C, the calorimetric measurements started to deviate from the optical measurements, indicating the importance of measuring under the operating conditions.

The textbook analysis of vacuum energy density (VED) in flat spacetime follows from Pauli’s lectures of 1951, in which quantum vacuum is modeled as a reservoir of free harmonic oscillators. In his lectures, Pauli shows that deriving a nearly vanishing VED is contingent upon fulfilling three corollary conditions called polynomial-in-mass-constraints. The goal of this work is to evaluate Pauli’s constraints against the Standard Model parameters and the Higgs mechanism of spontaneous symmetry breaking.

Information-theoretically provable unique true random numbers, which cannot be correlated or controlled by an attacker, can be generated based on quantum measurement of vacuum state and universal-hashing randomness extraction. Quantum entropy in the measurements decides the quality and security of the random number generator (RNG). At the same time, it directly determines the extraction ratio of true randomness from the raw data, in other words, it obviously affects quantum random bits generating rate. In this work, we commit to enhancing quantum entropy content in the vacuum noise based quantum RNG. We have taken into account main factors in this proposal to establish the theoretical model of quantum entropy content, including the effects of classical noise, the optimum dynamical analog-digital convertor (ADC) range, the local gain and the electronic gain of the homodyne system. We demonstrate that by amplifying the vacuum quantum noise, abundant quantum entropy is extractable in the step of post-processing even classical noise excursion, which may be deliberately induced by an eavesdropper, is large. Based on the discussion and the fact that the bandwidth of quantum vacuum noise is infinite, we propose large dynamical range and moderate TIA gain to pursue higher local oscillator (LO) amplification of vacuum quadrature and broader detection bandwidth in homodyne system. High true randomness extraction ratio together with high sampling rate is attainable. Experimentally, an extraction ratio of true randomness of 85.3% is achieved by finite enhancement of the laser power of the LO when classical noise excursions of the raw data is obvious.

Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that anti-proliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a co-culture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to monoculture. Notably, pseudopterosin proved to block cytokine elevation, representing key players in tumor progression, in the co-culture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy.

Eicheon properties are discussed. It is shown that the eicheon surface allows setting a boundary condition for the vacuum polarization and obtaining a solution describing the dark matter tail in the Milky Way. That is, the dark matter in the Milky Way is explained as the F-type of vacuum polarization, which could be treated as dark radiation. The model presented is spherically symmetric, but a surface density of a baryonic galaxy disk is taken into account approximately by smearing the disk over a sphere. This allows the reproduction of the large distance shape of the Milky Way rotational curve. Andromeda's rotational curves are also discussed.

Dynamical manipulation of plasmon-induced transparency (PIT) in graphene metasurfaces is promising for optoelectronic devices such as optical switching and modulating, however, previous design approaches are limited within one or two bright/dark modes, and the realization of dual PIT windows through triple bright modes in graphene metasurfaces is rare and urgently needed. Here we demonstrate that dual PIT can be realized through a symmetry-engineered graphene metasurface, which consists the graphene central cross (GCC) and graphene rectangular ring (GRR) arrays. The GCC supports a bright mode from electric dipole (ED), the GRR supports two nondegenerate bright modes from ED and electric quadrupole (EQ) due to the C2v symmetry breaking, and the resonant coupling of these three bright modes induces the dual PIT windows. A triple coupled-oscillator model (TCM) is proposed to evaluate the transmission performances of the dual PIT phenomenon, and the results are in good agreement with the finite-difference time-domain (FDTD) method. In addition, the dual PIT windows are robust to the variation of the structural parameters of the graphene metasurface except the y-directioned length of the GRR. By changing the carrier mobility of graphene, the amplitudes of the two PIT windows can be effectively tuned. The alteration of the Fermi level of graphene enables the dynamic modulation of the dual PIT with good performances for both modulation degree (MD) and insertion loss (IL).

Protein-drug interactions are crucial for understanding drug delivery and cell functions. Jacalin is a suitable molecule for such targeting, as it specifically recognizes the tu-mor-associated Thomsen-Friedenreich antigen that is expressed on the glycosylated proteins in cancer cells. The present paper describes the interaction of curcumin and jacalin, a possible carrier molecule for the delivery of antitumor drugs due to its ability to recognize tumor cells. Our results have shown that both steady state fluorescence and fluorescent label-ling of jacalin are two reliable methods to determine jacalin-curcumin interactions. The affinity of jacalin for curcumin is consistently within the micromolar range (using flu-orescence and microscale thermophoresis) showing high-affinity binding of the com-plex. In vitro experiments on the triple negative breast cancer MDA-MB-231 cells indi-cated inhibition of cell growth after treating with the jacalin-curcumin complex for 48 h. The cell survival fraction was significantly reduced to 50% after combined treatment. In this paper, we report for the first time about the jacalin-curcumin interaction. We quantified this unique biomolecular interaction and gathered additional information on the binding event. We observed that the jacalin-curcumin complex inhibits the proliferation of the triple negative breast cancer MDA-MB-231 cells.

The main known function of Nudix hydrolase 2 (Nudt2) is to hydrolyze the secondary messenger diadenosine 5', 5’’’-p1, p4-tetraphosphate (Ap4A). In this study we examined the role of Nudt2 in breast carcinoma through its expression in the human invasion ductal carcinoma tissues, and its functions in human triple negative breast cancer (TNBC) cell lines. A significantly high expression of Nudt2 in the human invasion ductal carcinoma tissues was observed in our study. Knockdown of Nudt2 in TNBC cell lines showed a significant reduction in cellular proliferation via the Ki67 marker, accompanied by G0/G1 phase cell cycle arrest. A significant reduction in the migration and invasion of Nudt2 knockdown TNBC cell lines was also observed. The effect of Nudt2 knockdown in the TNBC cell lines on tumorigenicity and anchorage-independent growth was assessed, where significant reductions in the Nudt2 knockdown TNBC cell lines were found. It can therefore be concluded that Nudt2 plays a significant role in promoting TNBC growth.

High Vacuum Flat Plate Collectors (HVFPCs) are the only type of Flat Plate Thermal Collectors capable of producing thermal energy for middle-temperature applications (until 180 °C). As the trend of research plans to develop new Selective Solar Absorbers to extend the range of HVFPC application until 250 °C, it is necessary to correctly evaluate the collector efficiency up to such temperature to predict the energy production accurately. We propose an efficiency model for these collectors based on the selective absorber optical properties. The proposed efficiency model explicitly includes the radiative heat exchange with the ambient, which is the main source of thermal losses for evacuated collectors at high temperatures. It also decouples the radiative losses that depend on the optical properties of the absorber adopted from the other thermal losses due to HVFPC architecture. The model has been validated by applying it to MT-Power HVFPC manufactured by TVP-Solar, and it has been used to predict the efficiency and energy production of HVFPC equipped with new, optimized selective solar absorbers developed in recent years.

According to the current understanding, the recently observed accelerated expansion of the universe is caused by the dark or the vacuum energy. Attempts to calculate the magnitude of this energy using the standard model of particle physics led to values which are 59 – 120 orders of magnitude larger than the experimentally estimated one. Even though the expanding space has positive internal energy, in a flat universe it is completely balanced by the negative energy of gravitational field making the net energy equal to zero. However, the current physical theories may breakdown for times less than or on the order of Planck time and one cannot assume that the above assertion concerning the balance of two energies is valid also in this time scale. In this note it is assumed that this balance of the two energies during the creation of new space as the universe expands takes place only for times larger than the Planck time. If this assumption is correct, the net energy of the newly created space remains positive for times on the order of Planck time and the positive vacuum energy has to be burrowed from empty space before it is being balanced by gravity. This can happen only within the restrictions of the time-energy uncertainty principle. In this note it is shown that such considerations lead to a vacuum energy density of about 0.3 Nanojoules per cubic meter which has to be compared with the measured value of 0.6 Nanojoules per cubic meter.

Strong evidence indicates that insulin resistance contributes to the development of Alzheimer´s disease by promoting inflammation, oxidative stress, and blood vessel damage. Conversely, neuroinflammation induces insulin resistance by targeting insulin signaling molecules: the insulin receptor substrates 1 and 2 (IRS1/2). In addition, neuroinflammation is strongly linked to reduced levels of brain-derived neurotrophic factor (BDNF) expression. BDNF is a key factor for neuronal survival, and its expression is compromised in neurodegenerative disorders. In this study, we show that, in a triple-transgenic (3xTg) mice model of Alzheimer’s disease, the BDNF and IRS2 but not the IRS1 mRNA expression levels were reduced in the hippocampus, together with higher levels of TNFα, compared with wild-type mice. Subgroups of control and 3xTg mice received short and long treatments of Abscisic Acid (ABA), a phytohormone with anti-inflammatory and insulin-sensitizing capabilities. We found that the short ABA treatment can increase the IRS1 and IRS2 mRNA expression both in wild-type and 3xTg mice, concomitant with reducing pro-inflammatory cytokine TNFα in 3xTg mice. However, earlier, and thus longer treatments are required to rescue the BDNF mRNA levels. Our data strongly confirm that ABA administration is a potential treatment to prevent Alzheimer´s disease, via lowering neuroinflammation, potentially rescuing insulin signaling molecules and BDNF mRNA expression.

The akimotoite--majorite--bridgmanite (Ak--Mj--Bm) triple point in MgSiO3 has been measured in large-volume press (LVP; COMPRES 8/3 assembly) and laser-heated diamond anvil cell (LHDAC). For the LVP data, we calculated pressures from the calibration by Leinenweber (2012). For the LHDAC data, we conducted \textit{in situ} determination of pressure at high temperature using the Pt scale by Dorogokupets and Dewaele (2007) at synchrotron. The measured temperatures of the triple point are in good agreement between LVP and LHDAC at 1990-2000 K. However, the pressure for the triple point determined from the LVP is 3.9+/-0.6~GPa lower than that from the LHDAC dataset. The triple point determined through these experiments will provide an important reference point in the pressure-temperature space for future high-pressure experiments and allow mineral physicists to compare the pressure--temperature conditions measured in these two different experimental methods.

Large amounts of gas hydrate are present in marine sediments offshore Taitao Peninsula, near the Chile Triple Junction. Here, marine sediments on the forearc contain carbon that is converted to methane in a zone of very high heat flow and intense rock deformation above the downgoing oceanic spreading ridge separating the Nazca and Antarctic plates. This regime enables vigorous fluid migration. Here we present an analysis of the spatial distribution, concentration, estimate of gas phases (gas hydrate and free gas) and geothermal gradients in the accretionary prism and forearc sediments offshore Taitao (45.5° - 47° S). Velocity analysis of Seismic Profile RC2901-751 indicates gas hydrate concentration values <10% of the total rock volume, and extremely high geothermal gradients (<190 °Ckm^-1). Gas hydrates are located in shallow sediments (90-280 meters below the seafloor). The large amount of hydrate and free gas estimated (7.21x10¹¹ m³ and 4.1x10¹⁰ m³, respectively), the high seismicity, the mechanically unstable nature of the sediments, and the anomalous geothermal conditions, set the stage for potential massive releases of methane to the ocean mainly through hydrate dissociation and/or migration directly to the seabed through faults. We conclude that the Chile Triple Junction is an important methane seepage area and should be the focus of novel geological and ecological research.

Background: Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with poor outcomes. The molecular basis of TNBC remains poorly understood. The objective of this study was to explore the relationship between obesity and TNBC in premenopausal and postmenopausal Caucasian women using whole genome transcription profiling. Methods: We compared gene expression levels of tumor samples drawn from normal weight, overweight and obese in pre and postmenopausal women diagnosed with TNBC. We performed hierarchical clustering to assess similarity in patterns of gene expression profiles, and conducted network and pathway analysis to identify molecular networks and biological pathways. Results: We discovered gene signatures distinguishing normal weight from obese, normal weight from overweight and overweight from obese individuals in both premenopausal and postmenopausal women. The analysis revealed molecular networks and biological pathways dysregulated in response to obesity. Among the discovered pathways included the unfolded protein response, endoplasmatic reticulum stress, B cell receptor and the autophagy signaling pathways in obese premenopausal women and the integrin, axonal guidance, ERK/MAPK and Glutathione biosynthesis signaling pathways obese postmenopausal women. Conclusions: The results suggest that both overweight and obesity are associated with TNBC, highlighting the need for conformation of these results in independent studies.

We work within a Winterberg framework where space, i.e., the vacuum, consists of a two component superfluid/super-solid made up of a vast assembly (sea) of positive and negative mass Planck particles, called planckions. These material particles interact indirectly, and have very strong restoring forces keeping them a finite distance apart from each other within their respective species. Because of their mass compensating effect, the vacuum appears massless, charge-less, without pressure, net energy density or entropy. In addition, we consider two variable models, where, , is Newton’s constant, and, , increases with an increase in cosmological time. We argue that there are at least two competing models for the quantum vacuum within such a framework. The first follows a strict extension of Winterberg’s model. This leads to nonsensible results, if increases, going back in cosmological time, as the length scale inherent in such a model will not scale properly. The second model introduces a different length scale, which does scale properly, but keeps the mass of the Planck particle as, the Planck mass. Moreover we establish a connection between ordinary matter, dark matter, and dark energy, where all three mass densities within the Friedman equation must be interpreted as residual vacuum energies, which only surface, once aggregate matter has formed, at relatively low temperatures. The symmetry of the vacuum will be shown to be broken, because of the different scaling laws, beginning with the formation of elementary particles. Much like waves on an ocean where positive and negative planckion mass densities effectively cancel each other out and form a zero vacuum energy density/ zero vacuum pressure surface, these positive mass densities are very small perturbations (anomalies) about the mean. This greatly alleviates, i.e., minimizes the cosmological constant problem, a long standing problem associated with the vacuum.

This work deals with the performance evaluation of novel flat photovoltaic-thermal (PV-T) modules under vacuum. Through a 1D (dimensional) steady-state-energy-balance numerical model developed in MATLAB, two different layouts are studied: the first consisting of a photovoltaic (PV) cell installed just below the glass encapsulating the flat panel, and the second where the PV cell is placed on the selective solar absorber (SSA). In both cases the thermal and electrical efficiencies have been evaluated at different SSA operating temperatures, in the range of 323 K to 423 K. The analysis has been conducted at different energy bandgap (E_bg) of the PV cell and assuming a variable transmittance or emittance of the PV cell, depending on the design. The two systems efficiency comparison has been carried out at the same operating temperature. Overall, this work highlights the importance of high vacuum insulation, which guarantees the reduction of convective thermal losses, and shows that the maximum energy is produced for PV cells with E_bg ≈1.5-1.7 eV, depending on layout and operating temperature, by including the thermal output in the PV-T optimization. The energy and exergy efficiencies obtainable using the proposed PV-T systems are considerably improved compared to the results previously reported in the literature.

Obesity is one of the most prevalent chronic diseases and has become a global epidemic. Obesity leads to a greater risk of breast cancer (BC), metastases, recurrence, and decreased survival. For sustained weight loss, bariatric surgery is effective as a long-term solution. Bariatric surgery is associated with improved outcomes of several cancers including BC, although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Indeed, patients with greater expression of the bile acid receptor FXR displayed improved survival in specific BC subtypes. Patients with tumors that are estrogen receptor negative (ER-) displayed significantly elevated survival with higher FXR (NR1H4) expression compared to lower expression. FXR is a nuclear hormone receptor activated by bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would display anticancer effects. Indeed, FXR agonism by the bile acid mimetic known commercially as OCALIVA (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor (GPBAR1, TGR5) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. Findings suggest that FXR is a tumor suppressor gene with high potential for personalized therapeutic strategies for individuals with BC.

The main functions of the automated systems rely on the advanced sensors for detection and perception of the environment around the vehicle. Radars and cameras are commonly utilized to detect the potential obstacles and vehicles ahead on the road. Nevertheless, cameras can generate spurious detections in the extreme weather conditions such as fog, rain, dust, snow, dark, and heavy sunlight in the sky. Due to limitations in vertical field view of the radars, single radars are not reliable to detect the height of the targets precisely. In this paper, a triple radar arrangement (long-range, medium-range, and short-range radars) based on sensor fusion technique is proposed to detect objects with different size in level 2 Advanced Driver-Assistance (ADAS) system. The typical objects including truck, pedestrians, and animals are detected in different scenarios. The developed model considered ISO 26262 and ISO/PAS 21448 to reasonably address insufficient robustness and inability of the sensors. The models of sensor and level 2 ADAS systems are developed using MATLAB toolbox and Simulink. Sensor detection performance is determined by running simulations with triple radar setup. Obtained results demonstrate that the proposed approach generates accurate detections of targets in all tested scenarios.

Following the first triple-drug MDA for lymphatic filariasis in Samoa in 2018, unexpected persistence of Mf-positivity in 18 (15%) of 121 antigen-positive persons was observed in a nationwide household survey 1-2 months later, raising concerns about MDA efficacy. In 2019, a monitored treatment study was done before and 7 days after directly observed weight-based treatment. Mf presence and density were evaluated using 1 mL membrane filtered venous blood, and 60uL thick blood films on slides prepared from venous or fingerprick blood. All 14 participants were still Mf positive on filters from venous blood pre-treatment samples, but two were negative by slide made from the same samples. Mf were cleared completely by day 7 in 12 of 13 participants followed up, and by day 30 in the remaining participant. Filtered blood using EDTA samples (to reduce clumping of Mf) is preferred over slides alone for improving the likelihood of detecting Mf and estimating their density. The triple-drug MDA strategy was effective at clearing Mf by day 30 when given and taken at the correct dose.

Rheumatoid arthritis (RA) is a chronic autoimmune disease, causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients, compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and this is associated with cancer metastasis to the bone and poor prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression that may be linked to the pathogenic behavior of fibroblast-like synoviocytes, cartilage destruction, and bone erosion.

Over the last few decades there has been an exponential growth in IT, motivating IT professionals and scientists to explore new dimensions resulting in the advancement of artificial intelligence and its subcategories like computer vision, deep learning and augmented reality. AR is comparatively a new area which was initially explored for gaming but recently a lot of work has been done in education using AR. Most of this focuses on improving students understanding and motivation. Like any other project, the performance of an AR based project is determined by the customer satisfaction which is usually affected by the theory of triple constraints; cost, time and scope. many studies have shown that most of the projects are under development because they are unable to overcome these constraints and meet project objectives. We were unable to find any notable work done regarding project management for augmented reality systems and application. Therefore, in this paper, we propose a system for management of AR applications which mainly focuses on catering triple constraints to meet desired objectives. Each variable is further divided into subprocesses and by following these processes successful completion of the project can be achieved.

Organosilicate glass (OSG) films are a vital component in modern electronic devices, with their electrical properties playing a crucial role in device performance. This comprehensive review systematically examines the influence of chemical composition, vacuum ultraviolet (VUV) irradiation, and plasma treatment on the electrical properties of OSG films. Through an extensive survey of literature and experimental findings, we elucidate the intricate interplay between these factors and the resultant alterations in electrical conductivity, dielectric constant, and breakdown strength of OSG films. Key focus areas include the impact of diverse organic moieties incorporated into the silica matrix, the effects of VUV irradiation on film properties, and the modifications induced by various plasma treatment techniques. Furthermore, we discuss the underlying mechanisms governing these phenomena, shedding light on the intricate molecular interactions and structural rearrangements occurring within OSG films under different environmental conditions. This review not only consolidates existing knowledge but also identifies gaps in understanding and suggests avenues for future research, thereby advancing our comprehension of OSG film behavior and paving the way for enhanced performance in next-generation electronic and photonic devices.

This paper addresses the cosmological constant problem, a significant discrepancy highlighted by \cite{Weinberg:1988cp} that underlines a fundamental inconsistency between quantum field theory (QFT) and general relativity (GR). QFT examines matter dynamics within Lorentzian spacetime under standard model symmetry, while GR uses Riemannian geometry but adapts it to ensure local Lorentzian behavior in small regions. Despite the experimental successes of both theories, a major challenge exists in theoretical understanding. This letter seeks to clarify this critical misunderstanding. As the universe cools from its hot beginning, the \(SU(3) \times SU(2) \times U(1)\) standard model gauge symmetry evolves. This symmetry breaks to \(SU(3) \times U(1)\) upon cooling at the electroweak scale and ultimately to \(SU(3)\) alone as temperatures approach near-absolute zero kelvin, facilitated by the experimental Meissner effect. This suggests that \(SU(3)\) symmetry forms the foundational "atoms" of vacuum energy. Calculating the number of \(SU(3)\) vacuum atoms across the universe results in a value that perfectly aligns the theoretical predictions with the observed vacuum energy densities, thereby resolving the cosmological constant problem. Since \(SU(3)\) atoms account for the cosmological constant, they must be unbreakable. The third law of thermodynamics, which states that it is impossible to reach absolute zero Kelvin, provides the protection that prevents SU(3) atoms from breaking at zero Kelvin. This reveals the connection between the third law of thermodynamics and the quark confinement. This leads to the \(SU(3)\) atom creating a mass gap within the universe. This solution serves as a symmetric evidence of gauge-gravity duality as well as gravity-superconductor duality.

Multilayer absorbers based on Cr2O3 and Cr, designed to improve the Solar-to-thermal conversion efficiency at mid temperatures in high vacuum flat thermal panel, are fabricated via sputtering deposition on bulk copper substrates and characterized by thermal and optical analysis. The refractive index of the single layers has been measured and used to estimate absorber thermal efficiency at the operating temperatures. Multilayers have been produced via sputtering deposition on bulk copper substrates. The absorber multilayers can be 10% more efficient than the commercial alternative at 250 °C operating temperatures, reaching 380 °C stagnation temperature without Sun concentration. The thermal stability has been checked at temperature of 400 °C in vacuum for four hours. High vacuum flat thermal collectors, equipped with the produced selective solar absorbers can obtain unprecedented performances and can give important contribution to the energy transition from fossil fuels to renewable energy for efficient heat production.

Triple-negative breast cancer (TNBC), lacking specific receptors found in other breast cancer subtypes, poses significant treatment challenges due to limited therapeutic options. Therefore, it is necessary to develop novel treatment approaches for TNBC. In the last few decades, many attempts have been reported for alternative tools for TNBC treatment: immunotherapy, radiotherapy, targeted therapy, combination therapy, and nanotechnology-based therapy. Among them, combination therapy and nanotechnology-based therapy show the most promise for TNBC treatment. This review outlines recent advancements in these areas, highlighting the efficacy of combination therapy (immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy) in both preclinical and clinical stages and nanotechnology-based therapies utilizing various nanoparticles loaded with anticancer agents, nucleic acids, immunotherapeutics, or CRISPRs in preclinical stages for TNBC treatment.

Intrinsic subtype of triple-negative breast cancer (TNBC) is based on genomic evaluation. In this study, we report the survival and pathological complete response (pCR) rates of TNBC patients subtyped by IHC and treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 187 TNBC patients who received NACT between 2008 and 2017 was used, and IHC subtyping was performed on biopsy specimens before chemotherapy. The subtyping revealed predominant basal-like tumors (IHC-BL, 61%), followed by basal-like immune-suppressed (IHC-BLIS, 31%), mesenchymal tumors (12.5%), luminal androgen receptor tumors (IHC-LAR, 12%) and basal-like immune-activated (IHC-BLIA, 10.9%). The pathological complete response (pCR) rate varied among subtypes, with IHC-BLIA showing the highest (30.0%) and IHC-LAR showing the lowest (4.5%). IHC-BLIS led in recurrence sites. Overall and disease-free survival analyses did not show significant differences among subtypes. Although, IHC-BLIA demonstrated a trend toward better survival and IHC-mesenchymal worse. Patients who achieved pCR exhibited significantly better disease-free survival and overall survival than non-responders. This study underscores the potential of IHC-based subtyping in TNBC management, highlighting distinct response patterns to neoadjuvant chemotherapy and potential implications for treatment strategies. Further research is warranted to validate these findings and explore tailored therapeutic approaches for specific TNBC subtypes.

Chemotherapy is a standard therapeutic option for triple-negative breast cancer (TNBC); however, its effectiveness is often compromised by drug-related toxicity and resistance development. Herein, we aimed to evaluate whether an improved antineoplastic effect could be achieved in vitro and in vivo in TNBC by combining dovitinib, a multi-kinase inhibitor, with calcitriol, a natural anti-cancer hormone. In vitro, cell proliferation and cell-cycle distribution were studied by sulforhodamine B-assays and flow cytometry. In vivo, dovitinib/calcitriol effects on tumor growth, angiogenesis and endothelium activation were evaluated in xenografted mice by caliper measures, Itgb3-immunohistochemistry and 99mTc-RGD2-tumor uptake. The drug combination elicited a synergistically improved antiproliferative effect in TNBC-derived cells, which allowed a 7-fold dovitinib dose-reduction. Mechanistically, the co-treatment induced cell death and accumulation in S and G2/M phases, while inhibited tumor growth to a greater extent than each compound alone. Tumor uptake of 99mTc-RGD2 was reduced by dovitinib, suggesting angiogenesis inhibition, which was corroborated by decreased endothelial cell growth and tumor vessel density. In summary, calcitriol synergized dovitinib anticancer effects in vitro and in vivo, allowing for a significant dose-reduction of dovitinib, while maintaining its antiproliferative potency. Our results suggest the beneficial convergence of independent antitumor mechanisms of dovitinib and calcitriol to inhibit TNBC-tumor growth.

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs has a strong prognostic role in triple negative breast cancer (TNBC). Little is known about his interaction with Androgen receptor (AR) and Forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), Breast Cancer Type 1 susceptibility protein (BRCA1), Poly [ADP-Ribose] Polymerase 1 (PARP1) and Na+/H+ Exchanger Regulatory Factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS) (p=0.045). A Kaplan-Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p=0.037), and the phenotypes TILs-/AR+ and TILs-/FOXA1- had a worse DFS (p=0.032, p=0.001 respectively). AR was associated with FOXA1 expression (p=0.007), and the tumors FOXA1+ presented low levels of TILs (p=0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p=0.0117). Low TILs score was associated with poor patients’ survival, and TILs level in combination with AR or FOXA1 expression affected patient’s clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments.