In this paper we study a bilinear optimal control problem related to a 2D parabolic-elliptic chemo-repulsion system consider a nonlinear chemical signal production term. We prove the existence of global optimal solutions with bilinear control, and applying a result on the existence of Lagrange multipliers in Banach spaces, we derive an optimality system for a local optimal solution.

Cancer being a multi-factorial disease, a multi-target approach is needed to treat it with minimal side-effects. Therefore, combined use of a proven herbal formula with chemo-therapy could be the better therapeutic. It may maintain homeostasis by synergistically targeting multiple signaling pathways involved in tumorigenesis, thus circumventing recurrence, resistance, and immunosuppression. Here we aim to determine the effectiveness and safety of an FDA-approved herbal formula, SR033 in combination with 5-fluorouracil (5FU) and paclitaxel (PTX). We report chemo-sensitization and chemo-synergy in HeLa and MCF-7 cell lines, immunomodulation of COX-2, PD-L1, VEGF and TGFβ and overall survival in-vitro and in-vivo via oral and topical delivery of SR033. In-vitro, SR033/5FU significantly reverses 5FU and PTX-resistance, lower COX-2, and PD-L1, resulting in TGFβ/ VEGF axis modulation. Furthermore, the study suggests that due to anti-oxidative potential of SR033, oral administration exerts chemo-preventive activity and restores cellular compartment in solid tumor and ascites-bearing mice models. Furthermore, the topical application, SR033L with low-dose 5FU increases survival rate, reduces tumor growth, and completely restores local and peripheral neutrophil-lymphocyte ratio in solid tumor mice model. The study indicates that SR033 could be a strong candidate in combination with low-dose 5FU and PTX for a holistic approach to cancer management.

Temperature dependent entropic force acting between the straight direct current I and the linear system (string with length of L) of N elementary non-interacting magnets/spins μ is reported. The system of elementary magnets is supposed to be in the thermal equilibrium with the infinite thermal bath T. The entropic force at large distance from the current is given by Fmagnen=Nμ02μ2I24π2kBTr3 , where r is the distance between the edge of the string and the current I, and kB is the Boltzmann constant; (r≫L is adopted). The entropic magnetic force is the repulsion force. The entropic magnetic force scales as Fmagnen~1T , which is unusual for entropic forces. The effect of “entropic pressure” is predicted for the situation when the source of the magnetic field is embedded into the continuous media, comprising elementary magnets/spins.

This paper presents one of the approaches to solution of the problem of the repulsion origin in gravity. The approach is based on the property of compactness characteristic for a self-gravitating object in General Relativity. Here we understand compactness as estimation of the upper boundary for mass such an object in a static two--dimensional sphere. Repulsion originates when this boundary is violated. The main hypothesis is formulated in the form of the principle of maximal mass within a two-dimensional static sphere. It is demonstrated that the principle is true for Schwarzschild black holes on absorption of the matter in the process of accretion, both in the classical case and with due regard for quantum-gravitational corrections. The results have been extended to black holes with the Schwarzschild-de Sitter metric in the early Universe. The applicability of the principle suggested is analyzed for the early and for the present Universe.

Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent infiltrating type of pancreatic cancer. The poor prognosis is due to the absence of specific biomarkers, aggressiveness and treatment resistance. PDAC is a deadly malignancy bearing distinct genetic alterations, the most common being those that cause cancer-causing versions of the KRAS gene. Cannabigerol (CBG) is a non-psychomimetic cannabinoid with anti-inflammatory property. Regarding CBG anticancer ef-fect, up to now there are only few evidence in human cancers. We investigated CBG effects on PDAC cell lines, PANC-1 and MIAPaCa-2. It was investigated CBG activity on cell viability, cell death and its effect of EGFR-RAS-associated signalling. Moreover, the potential synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. MTT was applied to investigate CBG effect on PDAC cell lines viability. Annexin-V and Acridine Orange staining followed by cytofluorimetric analysis and Western blot were used to evaluate CBG effect on cell death. Modulation of EGFR-RAS-associated pathways was determined by Western Blot analysis and Milliplex multiplex assay. Moreover, by MTT data and Synergy finder software analysis the effect of the combination of CBG and chemotherapeutic drugs, was determined.

We demonstrate high quality (intrinsic Q factor ~2.8×106) racetrack microresonators fabricated on lithium niobate (LN) thin film with a free spectral range (FSR) of ~86.38 pm. By integrating microelectrodes alongside the two straight arms of the racetrack resonator, the resonance wavelength around the 1550 nm can be red shifted by 92 pm when the electric voltage is raised from -100 V to 100 V. The microresonators of the tuning range spanning over a full FSR is fabricated using photolithography assisted chemo-mechanical etching (photolithography assisted chemo-mechanical etching, PLACE).

This is a report on a dynamic autonomous magnetic interaction which does not depend on polarities resulting in short ranged repulsion involving one or more inertial bodies and a new class of bound state based on this interaction. Both effects are new to the literature, found so far. Experimental results are generalized and reported qualitatively. Working principles of these effects are provided within classical mechanics and found consistent with observations and simulations. The effects are based on the interaction of a rigid and finite inertial body (an object having mass and moment of inertia) endowed with a magnetic moment with a cyclic inhomogeneous magnetic field which does not require to have a local minimum. Such a body having some DoF involved in driven harmonic motion by this interaction can experience a net force in the direction of the weak field regardless of its position and orientation or can find stable equilibrium with the field itself autonomously. The former is called polarity free magnetic repulsion and the latter magnetic bound state. Experiments show that a bound state can be obtained between two free bodies having magnetic dipole moment. Various schemes of trapping bodies having magnetic moments by rotating fields are realized as well as rotating bodies trapped by a static dipole field in presence of gravity. Also, a special case of bound state called bipolar bound state between free dipole bodies is investigated.

Gastric cancer, also known as stomach cancer, is a cancer which develops from the lining of the stomach. Accumulated evidences and epidemiological studies have been indicated that natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action did not elucidate yet. Particularly, experimental studies have been showed that natural products displayed a protective effect against gastric cancer via numerous molecular mechanisms such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Although chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy and immunotherapy, but its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. Additionally, intake of naturally occurring phytochemicals could increase the efficacy of gastric chemotherapy and chemotherapeutics resistance. However, natural product structural stability and powerful bioactivity are important to develop novel treatments for gastric cancer that may minimize such adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural products on prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

By combining general relativity and CPT symmetry, the theory of CPT gravity predicts gravitational repulsion between matter and CPT-transformed matter, i.e. antimatter inhabiting an inverted space-time. Such repulsive gravity turned out to be an excellent candidate for explaining the accelerated expansion of the Universe, without the need for dark energy. The recent results of the ALPHA-g experiment, which show gravitational attraction between antihydrogen atoms and the Earth, seem to undermine this success in the cosmological field. Analyzing the above theory, we find two solutions that can be consistent with the experimental results, while preserving the large-scale gravitational repulsion. The first highlights how repulsive gravity can be the result of the interaction with an inverted space-time, but occupied by matter and not antimatter, and therefore the antimatter present in our space-time has no reason to exhibit gravitational repulsion. The second retains the original CPT transformation, resulting in repulsive gravity between matter and antimatter, but with the caveat that antimatter immersed in our space-time cannot exhibit the PT transformation which is the cause of the repulsion. Finally, it is shown that, in a Newtonian approximation of the geodesic equation, time reversal is not a necessary operation for repulsive gravity, therefore opening the possibility of an expanding cosmos with a single time direction.

To solve a series of major problems, such as the singularity before the Big Bang, the inflation of the early universe and the accelerating expansion of the present universe, this series of studies start with super gravity, dark energy and dark matter, go beyond the surface of a lot of observation data, and systematically reveal the arche-internal mechanism of all things, to establish the arche-unity of physics, and give a natural and reasonable explanation. At present, there are at least three basic pathways that are leading our research field to repulsion against gravitation, quantum repulsion against quantum gravitation and high-dimensional superrepulsion against high-dimensional supergravity, that is, the research on the accelerating expansion mechanism of the current universe, the research on the dynamic mechanism of the early cosmic inflation, and the research on the rebound mechanism near the singularity before the Big Bang. In this series of studies, the arche problem of everything is always placed under the extreme environmental conditions of the initial universe, the starting point of scientific logic is closely combined with the starting point of the universe history, the pseudo vacuum energy considered by the inflationary universe model, the Higgs field predicted by the standard physical model and the dark energy speculated by the observational cosmology are reduced to the positive energy system with strong negative pressure, and they are reduced to the repulsion (all the resistance to gravity) that forms a conjugate relation with gravity. In our opinion, dark energy and dark matter are essentially at the level of quantum gravity and quantum repulsion. Therefore, we not only consider the conventional quantum effect and non commutative quantum effect, but also further consider the arche-conjugate effect and the cluster resonance-at-cofrenquence effect. For noncommutative space-time, we put forth the ultimate supersymmetry, the arche-conjugation and the cluster resonance-at-cofrenquence. A relatively complete natural mechanism forms such an important inference: the closer they get to Planck scale, the stronger the conventional quantum effect, non commutative quantum effect, arche-conjugate effect and co-frequency resonance effect are. In the high-dimensional space-time (the 11 dimensional hyperspace compactly reduced to M 4 × N r ), corresponding to the introduction of supergravity with the supersymmetry between the graviton and the gravitino, we put forth the superrepulsion with the supersymmetry between the repulsion and the repulsitino, and establish the arche-conjugate relationship between the high-dimensional supergravity and the high-dimensional superrepulsion. Therefrom, we propose a basic inference that can be promoted to the principle of hyperholography of high-dimensional universe (or multiuniverse): in a parallel universe formed by mutual coupling and holographic correspondence between the P universe dominated by negative pressure (high-dimensional superrepulsion and quantum repulsion of accumulating positive energy, mainly composed of dark energy) and the N universe dominated by positive pressure (high-dimensional supergravity and quantum gravity of accumulating negative energy, mainly composed of dark matter), there is a correspondence between the small-scale physics (ultraviolet cutoff) of the P universe and the large-scale physics (infrared cutoff) of the N universe, while there is a correspondence between the large-scale physics (ultraviolet cutoff) of the P universe and the small-scale physics (infrared cutoff) of the N universe. In the new research paradigms set in this series, the arche-conjugation between the high-dimensional supergravity and the high-dimensional super repulsion, as well as between the quantum gravity and the quantum repulsion, is higher than the supersymmetry, so it becomes the core concept of the new theory. The arhce-unity of physics is a super unity that transcends the grand unification of four basic interaction, which is formed between high-dimensional supergravity (related to dark matter) and high-dimensional superrepulsion (related to dark energy), between quantum gravity (related to dark matter) and quantum repulsion (related to dark energy). From the basic component point of view, before or after the big bang, the gravitons and repulsons are coupled together, the negative energy contraction dominated by the positive pressure and the positive energy expansion dominated by the negative pressure work alternately, forming the arche-conjugate pulsaton of neither the point particle nor the linear superstring. Under the big unified framework of quantum gravitational field and quantum repulsive field, this series of work comprehensively expands the general relativity and loop quantum ring gravitation theory, sets up the quantum repulsive field equation corresponding to the quantum gravitational field equation, and then establishes the quantum hedge-unified field equation describing the interaction of quantum gravitational field and quantum repulsive field; On this basis, the quantum repulsive universe equation corresponding to the quantum gravitational universe equation is established, thus a set of new equations describing the expansive universe with quantum hedge-unified field are established. On the one hand, scalar disturbance is considered as the exhibition of repulsive effect, on the other hand, tensor disturbance is considered as the exhibition of gravitational effect. In the initial stage of the big ripping, due to the mutual restraint of quantum repulsion and quantum gravity, the scalar and tensor perturbations are not obvious. However, at the end of the big ripping, the scalar and tensor perturbations are very significant, and there is a large power spectral exponential run. Between particle physics and cosmology, we improve and expand the path integral of quantum gravity, create the path integral of quantum hedge-unified field, and set up the basic equation of quantum cosmic-synergetic dynamics, and then establish the basic equation of quantum-cosmic paradigm dynamics. Thus we put up the operator distribution function and its dynamic equation of the quantum arche- pulsaton, and finally use the Wigner-Ville distribution as a non-linear time-frequency distribution to establish the Wigner joint-distribution of quantum-conjuagted pulsation function, so as to analyze the arche of all things with three evolutionary forms: quantum chaotic-pulsaton, quantum quasi-spherical pulsaton and quantum spherical-pulsaton. In this series of work, the mechanism to avoid the singularity of the universe is put forward fundamentally, and the dark energy and dark matter are explained through new mechanisms and effects at the level of quantum gravity. Between particle physics and cosmology, we improve and expand the path integral of quantum gravity, establish the path integral of quantum hedge-unified field, thus establish the basic equation of quantum cosmic-synergy dynamics, and then establish the basic equation of quantum cosmic-paradigm dynamics. Thus the covariant gravitational mass and the covariant inertial mass formed by the ultra-synergy between particles and the universe are presented, and the equivalence hypothesis on the covariant non-inertial system which can be elevated to the basic principle, is presented. Based on this hypothesis, a systematic calculation and analysis of binary stars composed of neutron stars and black holes are made. The master equation, variance and Fokker-Planck equation for the birth-death and migration of a large number of particles are established between binary stars composed of neutron stars and black holes.

The gravitational charge should be the energy instead of mass. This modification will lead to some different results and the experiments to test are also presented. Especially, we propose a scheme to achieve the negative energy and gravitational repulsive force in the lab.

We demonstrate fabrication of single-mode optical waveguides on lithium niobate on insulator (LNOI) by optical patterning combined with chemo-mechanical polishing. The fabricated LNOI waveguides have a nearly symmetric mode profile of a mode field size of ~2.5 µm (full-width at half maximum). We develop a high-precision measurement approach by which the single mode waveguides are characterized to have a propagation loss of ~0.042 dB/cm.

We report fabrication of a multifunctional photonic integrated chip on lithium niobate on insulate (LNOI), which is achieved by femtosecond laser assisted chemo-mechanical polish. We demonstrate a high extinction ratio beam splitter, a 1 × 6 optical switch, and a balanced 3 × 3 interferometer on the fabricated chip by reconfiguring the microelectrode array integrated with the multifunctional photonic circuit.

Application of the Ramsey graph theory to the analysis of physical systems is reported. Physical interactions may be very generally classified as attractive and repulsive. This classification creates the premises for the application of the Ramsey theory to the analysis of physical systems built of electrical charges, electric and magnetic dipoles. The notions of mathematical logic, such as transitivity and intransitivity relations, become crucial for understanding of the behavior of physical systems. The Ramsey theory explains why nature prefers cubic lattices over hexagonal ones for systems built of electric or magnetic dipoles. The Ramsey approach may be applied to the analysis of mechanical systems when actual and virtual paths between the states in the configurational space are considered. Irreversible mechanical and thermodynamic processes are seen within the reported approach as directed graphs. Chains of irreversible processes appear as transitive tournaments. These tournaments are acyclic; the transitive tournaments necessarily contain the Hamiltonian path. The set of states in the phase space of the physical system, between which irreversible processes are possible, is considered. The Hamiltonian path of the tournament emerging from the graph uniting these states is a relativistic invariant. Applications of the Ramsey theory to the general relativity become possible when the discrete changes in the metric tensor are assumed. Reconsideration of the concept of “simultaneity” within the Ramsey approach is reported.

PD-1/PD-L1 axis is one key therapeutic target against tumor cell immune escape. Structurally essential to the PD-1/PD-L1-linked immune escape is the binding interface of the PD-1/PD-L1 complex structure. Incorporating currently available PD-1/PD-L1-related experimental structures, this article unveils two sets of experimentally observed inter-molecular electrostatic interactions which stabilize the binding interface of the PD-1/PD-L1 complex structure. For the first time, this article proposes an evolutionary structural hypothesis that, as a result of natural selection, PD-1 is able to genetically mutate itself to structurally disrupt the PD-1/PD-L1 axis towards the restoration of T cell-mediated anti-tumor immunity.

Alteration in heparan sulfate (HS) biosynthesis has been described to impact a range of pivotal processes involved in cancer progression. HS 3-O-sulfotransferase 3B1 (HS3ST3B1) catalyzes the reaction of 3-O-sulfation within HS chains. Over the past few years, a growing number of studies has reported a tumor-promoting effect of this HS-modifying enzyme in various cancers. Consistent with these studies, we previously reported that HS3ST3B1 overexpression increased survival and resistance to apoptosis in MDA-MB-231 breast cancer (BrCa) cells. In the present study, we further investigated the biological and clinical significance of HS3ST3B1 expression in BrCa. Interrogation of public databases revealed that high expression levels of HS3STB1 are associated with invasive and mesenchymal-like phenotype in BrCa cells and predict poor clinical outcome in BrCA patients with chemotherapy. In vitro, HS3ST3B1 overexpression increased the invasive properties of MDA-MB-231 cells and enhanced chemo-resistance to conventional anticancer drugs. Mechanistically, we found that the advantage given by HS3ST3B1 was linked to the expression and activation of PDGF-Rβ. Silencing the expression of this receptor reversed the effects driven by HS3ST3B1 overexpression. Altogether, our results suggest that HS3ST3B1 may play an important role in the progression of aggressive BrCa and offer a potentially druggable target for therapeutic application.

De-escalation is currently taking place both in surgical and systemic treatment of breast cancer. The introduction of trastuzumab, the first monoclonal antibody against the HER2 receptor over 20 years ago was a milestone in the treatment of HER2 positive breast cancer and marked the beginning of a new era in targeted tumor therapy. In the sense of de-escalation, omitting non-targeted cytotoxic chemotherapy altogether is often hailed as the ultimate goal of oncological research. Especially in case of small, node-negative, HER2 positive early breast cancer, it remains a challenge for clinicians to establish the safest and most efficient treatment plan while considering the significant potential for toxic side effects associated with chemotherapy and HER2 targeted therapy, and the generally excellent prognosis. In this context, several ongoing studies are currently assessing chemotherapy-free regimens as part of strategies aimed at de-escalating therapy in the field of HER2 positive early breast cancer. Despite promising early results from these studies, combination of anti-HER2 treatment with chemotherapy backbone remains standard of care.

We demonstrate hybrid integration of a lithium niobate microring resonator with a silicon nitride waveguide in the vertical configuration to achieve efficient light coupling. The microring resonator is fabricated on a lithium niobate on insulator (LNOI) substrate using photolithography assisted chemo-mechanical etching (PLACE). A fused silica cladding layer is deposited on the LNOI ring resonator. The silicon nitride waveguide is further produced on the fused silica cladding layer by first fabricating a trench in the fused silica using focused ion beam (FIB) etching for facilitating the evanescent coupling, followed by formation of the silicon nitride waveguide on the bottom of the trench. The FIB etching ensures the required high positioning accuracy between the waveguide and the ring resonator. We achieve Q-factors as high as 1.4*10^7 with the vertically integrated device.

Laboratory experiments and investigations into natural phenomena in this research series have unveiled the presence of a gravitational repulsion force that permeates our environment on both microscopic and macroscopic scales, contingent upon the thermal energy present. This paper presents a study exploring novel properties of gravitational forces among gas molecules, employing principles of thermodynamics. A model has been devised based on the interactions between pairs of gas molecules. While traditional models treat gravitational interaction as a singular force, our experimental approach validates it as the composite of two distinct forces: gravitational repulsion and attraction. By utilizing established experimental data on gas thermodynamics, our model demonstrates robust performance both analytically and experimentally. It verifies the coexistence of gravitational repulsion and attraction forces among gas molecules, showcases their Inverse-Cube relationship with distance, and elucidates the direct proportionality of the repulsion force to absolute temperature. This bridges a crucial gap between energy and fundamental forces. The order of magnitudes of gravitational repulsion and attraction forces are found to be considerably large, contrasting with the low values predicted by classical theory, which results from their amalgamation. Recognizing these forces as substantial in magnitude promises unprecedented outcomes and advancements.

We report fabrication of crystalline microresonators of high quality (Q) factors with a controllable wedge angle on lithium niobate on insulator (LNOI). Our technique relies on femtosecond laser assisted chemo-mechanical polish which allows us to achieve ultrahigh surface smoothness as critically demanded by high Q microresonator applications. We show that by refining the polish parameters, Q factors as high as 4.7 × 10⁷ can be obtained and the wedge angle of the LNOI can be continuously tuned from 9° to 51°.

We develop a technique for realizing lithium niobate on insulator (LNOI) waveguides of a multi-centimeter-length with a propagation loss as low as 0.027 dB/cm. Our technique relies on patterning a chromium (Cr) thin film coated on the top surface of LNOI into a hard mask with a femtosecond laser followed by the chemo-mechanical polishing for structuring the LNOI into the waveguides. The surface roughness on the waveguides is determined to be 0.452 nm with an atomic force microscope (AFM). The approach is compatible with other surface patterning technologies such as optical and electron beam lithographies or laser direct writing, enabling high-throughput manufacturing of large-scale LNOI-based photonic integrated circuits.

Men with non-small cell lung cancer (NSCLC) have a more favorable response to immune-checkpoint inhibitor (ICI) monotherapy, while women especially benefit from ICI-chemotherapy (CHT) combinations. To elucidate such sex differences in clinical practice, we retrospectively analyzed two cohorts treated with either ICI monotherapy (n=228) or ICI-CHT combination treatment (n=80) for advanced NSCLC. Kaplan-Meier analyses were used to calculate progression-free (PFS) and overall survival (OS), influencing variables were evaluated using Cox-regression analyses. No significant sex differences for PFS/OS could be detected in either cohort. Men receiving ICI monotherapy had a statistically significant independent impact on PFS by Eastern Cooperative Oncology Group performance status (ECOG) ≥2 (hazard ratio (HR) 1.90, 95% confidence interval (CI): 1.10-3.29, p=0.021), higher C-reactive protein (CRP; HR 1.06, 95%CI: 1.00-1.11, p=0.037) and negative programmed death-ligand 1 (PD-L1) status (HR 2.04, 95%CI: 1.32-3.15, p=0.001), and on OS by CRP (HR 1.09, 95%CI: 1.03-1.14, p=0.002). In men on ICI-CHT combinations, multivariate analyses (MVA) revealed squamous histology (HR 4.00, 95%CI: 1.41-11.2, p=0.009) significant for PFS; ECOG≥2 (HR 5.58, 95%CI: 1.88-16.5, p=0.002) and CRP (HR 1.19, 95%CI: 1.06-1.32, p=0.002) for OS. Among women undergoing ICI monotherapy, no variable proved significant for PFS, ECOG≥2 had a significant interaction with OS (HR 1.90, 95%CI 1.04-3.46, p=0.037). Women treated with ICI-CHT had significant MVA findings for CRP with both PFS (HR 1.09, 95%CI: 1.02-1.16, p=0.007) and OS (HR 1.11, 95%CI: 1.03-1.19, p=0.004). Although men and women responded similarly to both ICI mono- and ICI-CHT treatment, predictors of response differed by sex.

A major advance of drug discovery and targeted therapy directed to cancer cells may be achieved by exploitation and immunomodulation of their unique biological property. This re-view summarizes our efforts to develop novel chemo-thermo-immuno-therapy (CTI therapy) by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In our approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) generation upon exposure to an alternating magnetic field (AMF). The feasibility of our approach was successfully shown in experimental in vivo and in vitro mouse melanoma models and in preliminary clinical trials to a limited number of advanced melanoma patients.