Inflammatory Breast Cancer (IBC) is a highly aggressive form of cancer characterized by high rates of proliferation, lymphangiogenesis and metastasis, and an overall poor survival. As regular green ...tea consumption has been associated with improved prognosis of breast cancer patients, including decreased risk of recurrence, here the effects of the green tea polyphenol epigallocatechin-3-gallate (EGCG) were tested on two IBC lines: SUM-149 and SUM-190. EGCG decreased expression of genes that promote proliferation, migration, invasion, and survival. Consistently, growth, invasive properties, and survival of IBC cells were reduced by EGCG treatment. EGCG also reduced lymphangiogenesis-promoting genes, in particular VEGF-D. Conditioned media from EGCG-treated IBC cells displayed decreased VEGF-D secretion and reduced ability to promote lymphangiogenesis in vitro as measured by hTERT-HDLEC lymphatic endothelial cell migration and tube formation. Tumorsphere formation by SUM-149 cells was robustly inhibited by EGCG, suggesting effects on self-renewal ability. Stem-like SUM-149 cells with high aldehyde dehydrogenase (ALDH) activity, previously implicated in poor patient prognosis, were isolated. EGCG treatment reduced growth and induced apoptosis of the stem-like SUM-149 cells in culture. In an orthotopic mouse model, EGCG decreased growth of pre-existing tumors derived from ALDH-positive stem-like SUM-149 cells and their expression of VEGF-D, which correlated with a significant decrease in peritumoral lymphatic vessel density. Thus, EGCG inhibits the overall aggressive IBC phenotype. Reduction of the stem-like cell compartment by EGCG may explain the decreased risk of breast cancer recurrence among green tea drinkers. Recent clinical trials demonstrate the efficacy of green tea polyphenol extracts in treatment of prostate cancer and lymphocytic leukemia with low toxicity. Given the poor prognosis of IBC patients, our findings suggest further exploration of EGCG or green tea in combinatorial treatments against active IBC disease or in maintenance regimens to avoid recurrence is warranted.
Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical ...molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1.sup.-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.
Thiostrepton is a potent antibiotic against a broad range of Gram‐positive bacteria, but its medical applications have been limited by its poor aqueous solubility. In this work, the first C(sp2)−H ...amidation of dehydroalanine (Dha) residues was applied to the site selective modification of thiostrepton to prepare a variety of derivatives. Unlike all prior methods for the modification of thiostrepton, the alkene framework of the Dha residue is preserved and with complete selectivity for the Z‐stereoisomer. Additionally, an aldehyde group was introduced by C−H amidation, enabling oxime ligation for the installation of an even greater range of functionality. The thiostrepton derivatives generally maintain antimicrobial activity, and importantly, eight of the derivatives displayed improved aqueous solubility (up to 28‐fold), thereby addressing a key shortcoming of this antibiotic. The exceptional functional group compatibility and site selectivity of CoIII‐catalyzed C(sp2)−H Dha amidation suggests that this approach could be generalized to other natural products and biopolymers containing Dha residues.
Convenient derivatization: CoIII‐catalyzed C−H amidation was used for the site‐selective modification of the antibiotic thiostrepton. A range of amide groups was installed with 1,4,2‐dioxazolone coupling partners. The introduction of an aldehyde group by C−H amidation enabled modular incorporation of additional functionality by oxime formation.
Estimating the spatial scales of electromagnetic ion cyclotron (EMIC) waves is critical for quantifying their overall scattering efficiency and effects on thermal plasma, ring current, and radiation ...belt particles. Using measurements from the dual Van Allen Probes in 2013-2014, we characterize the spatial and temporal extents of regions of EMIC wave activity and how these depend on local time and radial distance within the inner magnetosphere. Observations are categorized into three types: waves observed by only one spacecraft, waves measured by both spacecraft simultaneously, and waves observed by both spacecraft with some time lag. Analysis reveals that dayside (and H+ band) EMIC waves more frequently span larger spatial areas, while nightside (and He+ band) waves are more often localized but can persist many hours. These investigations give insight into the nature of EMIC wave generation and support more accurate quantification of their effects on the ring current and outer radiation belt.
The negativity of the discrete Wigner functions (DWFs) is a measure of non‐classicality and is often used to quantify the degree of quantum coherence in a system. The study of Wigner negativity and ...its evolution under different quantum channels can provide insight into the stability and robustness of quantum states under their interaction with the environment, which is essential for developing practical quantum computing systems. The variation of DWF negativity of qubit, qutrit, and two‐qubit systems under the action of (non)‐Markovian random telegraph noise (RTN) and amplitude damping (AD) quantum channels is investigated. Different negative quantum states that can be used as a resource for quantum computation and quantum teleportation are constructed. The success of quantum computation and teleportation is estimated for these states under (non)‐Markovian evolutions.
The negative quantum states of qutrit and two‐qubit systems are stated using discrete Wigner Functions. These negative quantum states are benchmarks for success in quantum computation and teleportation using various measures such as Mana, quantum coherence, concurrence, and teleportation fidelity. This is done under (non)‐Markovian unital (random telegraph noise) and non‐unital (amplitude damping) channels.
The quantum speed of evolution for the phase covariant map is investigated. This involves absorption, emission, and dephasing processes. The maps under various combinations of the above processes are ...considered to investigate the effect of phase covariant maps on quantum speed limit time. For absorption‐free phase covariant maps, combinations of dissipative and CP‐(in)divisible (non)‐Markovian dephasing noises are considered. The role of coherence‐mixedness balance on the speed limit time is checked in the presence of both vacuum and finite temperature effects. The rate at which Holevo's information changes and the action quantum speed of evolution for specific cases of the phase covariant map are also investigated.
The phase‐covariant map describes the physical processes involving absorption, emission and pure dephasing. To investigate the effect of phase covariant maps on quantum speed limit time (τQSL)$(\tau_{QSL})$, they consider the maps under various combinations of the above processes and investigate the dependence of τQSL$\tau_{QSL}$ on quantum memory (ζ). For absorption‐free phase covariant maps, both CP‐(in)divisible, (non)‐Markovian dephasing are taken into account. The role of coherence‐mixedness (Mcl)$(M_{cl})$ balance on the speed limit time is checked in the presence of both vacuum and finite temperature effects. For the initial maximal coherent state, they show that the presence of a CP‐indivisible non‐Markovian dephasing map does not always speed up the quantum evolution. They also investigate the rate at which Holevo's information changes and the action quantum speed of evolution for specific cases of the phase covariant map.
Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through ...defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.
We report on 49 fast‐mode forward shocks propagating inside coronal mass ejections (CMEs) as measured by Wind and ACE at 1 AU from 1997 to 2006. Compared to typical CME‐driven shocks, these shocks ...propagate in different upstream conditions, where the median upstream Alfvén speed is 85 km s−1, the proton β = 0.08 and the magnetic field strength is 8 nT. These shocks are fast with a median speed of 590 km s−1 but weak with a median Alfvénic Mach number of 1.9. They typically compress the magnetic field and density by a factor of 2–3. The most extreme upstream conditions found were a fast magnetosonic speed of 230 km s−1, a plasma β of 0.02, upstream solar wind speed of 740 km s−1 and density of 0.5 cm−3. Nineteen of these complex events were associated with an intense geomagnetic storm (peak Dst under −100 nT) within 12 h of the shock detection at Wind, and 15 were associated with a drop of the storm time Dst index of more than 50 nT between 3 and 9 h after shock detection. We also compare them to a sample of 45 shocks propagating in more typical upstream conditions. We show the average property of these shocks through a superposed epoch analysis, and we present some analytical considerations regarding the compression ratios of shocks in low β regimes. As most of these shocks are measured in the back half of a CME, we conclude that about half the shocks may not remain fast‐mode shocks as they propagate through an entire CME due to the large upstream and magnetosonic speeds.
Key Points
Forty‐nine fast forward shocks occurred inside CMEs during SC23
Shocks inside CMEs are fast and weak and propagate through slow and weak CMEs
Shocks inside CMEs can be an important source of intense geomagnetic storms
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