The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, ...invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.
Objective
To evaluate the Safety and Efficacy of Hydroxychloroquine as add-on therapy in uncontrolled type 2 diabetes patients who were using two oral antidiabetic drugs.
Materials and methods
This ...was a double blind, placebo controlled, parallel group study in 304 inadequately controlled type 2 diabetes (T2DM) subjects with two oral antidiabetic drugs (glimepiride 4 mg and metformin 500 mg) were randomised to hydroxychloroquine (HCQ) 200 mg, 300 mg, 400 mg once daily (OD) or placebo. Dose of hydroxychloroquine was selected as per body weight of the subject. Primary end point was glycated haemoglobin (HbA1c) change at week 12 from baseline. Secondary endpoint was change in fasting plasma glucose (FPG), post prandial plasma glucose (PPG), body weight and any adverse reaction including no of hypoglycemic events, as well as a change in the percentage of subjects with A1C < 7.0% and > 6.5% after 12 weeks of treatment.. In follow-up of 400 mg once daily was once again divided to 200 mg twice daily (BD) to study the effect on tolerability profile for further 12 weeks.
Results
Hydroxychloroquine was associated with significant reduction in HbA1c from baseline (7–8.5%) in 12 weeks −0.78%, −0.91% and 1.2% for hydroxychloroquine 200 mg, 300 mg and 400 mg OD, respectively, versus 0.13% with placebo (
P
< 0.005). FPG and PPG were reduced by −25 to −38 mg/dl and 34–53 mg/dl, respectively. Body weight also reduced in each group of HCQ. Hypoglycemia was reported only with 300 mg (1.2%) and 400 mg (2.1%) group of HCQ. It was observed that patients who complains with mild GI disturbance with HCQ 400 mg glycemic efficacy was maintained with 200 mg BD with significant relief of the symptoms.
Conclusion
Hydroxychloroquine added to sulphonylurea and metformin, improves glycemic control significantly in T2DM patients. Glycemic effect of different dose of hydroxychloroquine is dose dependent. The safety/tolerability profile of hydroxychloroquine was favourable except GI disturbance which is more frequent with 400 mg. This can be avoided with 200 mg BD without compromise on efficacy.
•Fabrication of flexible Graphite/PDMS sensor patches using 3D printed molds.•Casting technique was used to develop the electrodes and substrate of the sensor patches.•Interdigitated electrodes were ...employed for the patches operating on capacitive principle.•The sensor patches were characterized for the change in responses with stress and iterative bending cycles.•The sensor patches were used for low-force sensing applications ranging from 3.5 mN to 17.5 mN.
This paper concerns the design, fabrication and characterization of graphite/PDMS sensors for low-force sensing applications. Exploiting the design flexibility of 3D printing, moulds of specific dimensions were prepared onto which graphite powder and PDMS were cast, to develop sensor patches. The sensor patches were highly flexible with repeatable responses to iterative bending cycles. The patches were tested in terms of stretchability, strain and bending-cycle responses. The sensor patches had interdigitated electrodes operating on capacitive sensing, where the effective capacitance changes with an applied force because of changes in their dimensions. Forces ranging from 3.5 mN to 17.5 mN were applied to determine the capability of these sensor patches for low-force sensing applications. The sensor patches had a quick recovery having a sensitivity and SNR per unit force of 0.2542 pF mN−1 and 10.86 respectively. The patches were capable of differentiating the forces applied on them, when they were attached to different objects in daily use.
The microscopic origins of emergent behaviours in condensed matter systems are encoded in their excitations. In ordinary magnetic materials, single spin-flips give rise to collective dipolar magnetic ...excitations called magnons. Likewise, multiple spin-flips can give rise to multipolar magnetic excitations in magnetic materials with spin S ≥ 1. Unfortunately, since most experimental probes are governed by dipolar selection rules, collective multipolar excitations have generally remained elusive. For instance, only dipolar magnetic excitations have been observed in isotropic S = 1 Haldane spin systems. Here, we unveil a hidden quadrupolar constituent of the spin dynamics in antiferromagnetic S = 1 Haldane chain material Y
BaNiO
using Ni L
-edge resonant inelastic x-ray scattering. Our results demonstrate that pure quadrupolar magnetic excitations can be probed without direct interactions with dipolar excitations or anisotropic perturbations. Originating from on-site double spin-flip processes, the quadrupolar magnetic excitations in Y
BaNiO
show a remarkable dual nature of collective dispersion. While one component propagates as non-interacting entities, the other behaves as a bound quadrupolar magnetic wave. This result highlights the rich and largely unexplored physics of higher-order magnetic excitations.
The discovery of superconductivity in a d9−δ nickelate has inspired disparate theoretical perspectives regarding the essential physics of this class of materials. A key issue is the magnitude of the ...magnetic superexchange, which relates to whether cuprate-like high-temperature nickelate superconductivity could be realized. We address this question using Ni L-edge and O K-edge spectroscopy of the reduced d9−1/3 trilayer nickelates R4Ni3O8 (where R = La Pr) and associated theoretical modeling. A magnon energy scale of ∼ 80 meV resulting from a nearest-neighbor magnetic exchange of J = 69 (4) meV is observed, proving that d9−δ nickelates can host a large superexchange. This value, along with that of the Ni-O hybridization estimated from our O K -edge data, implies that trilayer nickelates represent an intermediate case between the infinite-layer nickelates and the cuprates. Layered nickelates thus provide a route to testing the relevance of superexchange to nickelate superconductivity.
Investigation of elementary excitations has advanced our understanding of many-body physics governing most physical properties of matter. Recently spin-orbit excitons have drawn much attention, whose ...condensates near phase transitions exhibit Higgs mode oscillations, a long-sought-after physical phenomenon A. Jain, et al., Nat. Phys. 13, 633 (2017)NPAHAX1745-247310.1038/nphys4077. These critical transition points, resulting from competing spin-orbit coupling (SOC), local crystalline symmetry, and exchange interactions, are not obvious in iridium-based materials, where SOC prevails in general. Here, we present results of resonant inelastic x-ray scattering on a spin-orbital liquid Ba_{3}ZnIr_{2}O_{9} and three other 6H-hexagonal perovskite iridates that show magnetism, contrary to the nonmagnetic singlet ground state expected due to strong SOC. Our results show that substantial hopping between closely placed Ir^{5+} ions within Ir_{2}O_{9} dimers in these 6H iridates modifies spin-orbit coupled states and reduces spin-orbit excitation energies. Here, we are forced to use at least a two-site model to match the excitation spectrum going in-line with the strong intradimer hopping. Apart from SOC, low-energy physics of iridates is thus critically dependent on hopping and may not be ignored even for systems having moderate hopping, where the excitation spectra can be explained using an atomic model. SOC, which is generally found to be 0.4-0.5 eV in iridates, is scaled in effect down to ∼0.26 eV for the 6H systems, sustaining the hope of achieving quantum criticality by tuning Ir-Ir separation.
We report on a terrestrial gamma ray flash (TGF) that occurred on 15 August 2014 coincident with an altitude‐triggered lightning at the International Center for Lightning Research and Testing (ICLRT) ...in North Central Florida. The TGF was observed by a ground‐level network of gamma ray, close electric field, distant magnetic field, Lightning Mapping Array (LMA), optical, and radar measurements. Simultaneous gamma ray and LMA data indicate that the upward positive leader of the triggered lightning flash induced relativistic runaway electron avalanches when the leader tip was at about 3.5 km altitude, resulting in the observed TGF. Channel luminosity and electric field data show that there was an initial continuous current (ICC) pulse in the lightning channel to ground during the time of the TGF. Modeling of the observed ICC pulse electric fields measured at close range (100–200 m) indicates that the ICC pulse current had both a slow and fast component (full widths at half maximum of 235 μs and 59 μs) and that the fast component was more or less coincident with the TGF, suggesting a physical association between the relativistic runaway electron avalanches and the ICC pulse observed at ground. Our ICC pulse model reproduces moderately well the measured close electric fields at the ICLRT as well as three independent magnetic field measurements made about 250 km away. Radar and LMA data suggest that there was negative charge near the region in which the TGF was initiated.
Key Points
Best documented TGF observed at ground
Second TGF induced by triggered lightning
An ICC pulse occurred simultaneously (within 20 μs) of the TGF
Terrestrial gamma ray flashes (TGFs) are a class of enigmatic electrical discharges in the Earth's atmosphere. In this study, we analyze an unprecedentedly large dataset comprised of 2188 TGFs whose ...signatures were simultaneously measured using space- and ground-based detectors over a five-year period. The Gamma-ray Burst Monitor (GBM) on board the Fermi spacecraft provided the energetic radiation measurements. Radio frequency (RF) measurements were obtained from the Global Lightning Dataset (GLD360). Here we show the existence of two categories of TGFs - those that were accompanied by quasi-simultaneous electromagnetic pulses (EMPs) detected by the GLD360 and those without such simultaneous EMPs. We examined, for the first time, the dependence of the TGF-associated EMP-peak-amplitude on the horizontal offset distance between the Fermi spacecraft and the TGF source. TGFs detected by the GBM with sources at farther horizontal distances are expected to be intrinsically brighter and were found to be associated with EMPs having larger median peak-amplitudes. This provides independent evidence that the EMPs and TGFs are produced by the same phenomenon, rather than the EMPs being from "regular" lightning in TGF-producing thunderstorms.
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