The cyclooxygenase-2 (COX-2) enzyme is frequently overexpressed in epithelial malignancies including those of the breast, prostate, lung, kidney, ovary, and liver and elevated expression is ...associated with worse outcomes. COX-2 catalyzes the metabolism of arachidonic acid to prostaglandins. The COX-2 product prostaglandin E2 (PGE2) binds to four G-protein-coupled EP receptors designated EP1-EP4. EP4 is commonly upregulated in cancer and supports cell proliferation, migration, invasion, and metastasis through activation of multiple signaling pathways including ERK, cAMP/PKA, PI3K/AKT, and NF-κB. EP4 antagonists inhibit metastasis in preclinical models. Cancer stem cells, that underlie therapy resistance and disease relapse, are driven by the expression of EP4. Resistance to several chemotherapies is reversed in the presence of EP4 antagonists. In addition to tumor cell-autonomous roles of EP4, many EP4-positive host cells play a role in tumor behavior. Endothelial cell-EP4 supports tumor angiogenesis and lymphangiogenesis. Natural Killer (NK) cells are critical to the mechanism by which systemically administered EP4 antagonists inhibit metastasis. PGE2 acts on EP4 expressed on the NK cell to inhibit tumor target cell killing, cytokine production, and chemotactic activity. Myeloid-derived suppressor cells (MDSCs), that inhibit the development of cytotoxic T cells, are induced by PGE2 acting on myeloid-expressed EP2 and EP4 receptors. Inhibition of MDSC-EP4 leads to maturation of effector T cells and suppresses the induction of T regulatory cells. A number of EP4 antagonists have proven useful in dissecting these mechanisms. There is growing evidence that EP4 antagonism, particularly in combination with either chemotherapy, endocrine therapy, or immune-based therapies, should be investigated further as a promising novel approach to cancer therapy. Several EP4 antagonists have now progressed to early phase clinical trials and we eagerly await the results of those studies.
The fractional resistance on a fault during slip controls earthquake dynamics. Friction dissipates heat during an earthquake; therefore, the fault temperature after an earthquake provides insight ...into the level of friction. The Japan Trench Fast Drilling Project (Integrated Ocean Drilling Program Expedition 343 and 343T) installed a borehole temperature observatory 16 months after the March 2011 moment magnitude 9.0 Tohoku-Oki earthquake across the fault where slip was ~50 meters near the trench. After 9 months of operation, the complete sensor string was recovered. A 0.31 °C temperature anomaly at the plate boundary fault corresponds to 27 megajoules per square meter of dissipated energy during the earthquake. The resulting apparent friction coefficient of 0.08 is considerably smaller than static values for most rocks.
The Asteroid Terrestrial impact Last Alert System (ATLAS) system consists of two 0.5 m Schmidt telescopes with cameras covering 29 square degrees at plate scale of 1.86 arcsec per pixel. Working in ...tandem, the telescopes routinely survey the whole sky visible from Hawaii (above δ > − 50 ° ) every two nights, exposing four times per night, typically reaching o < 19 magnitude per exposure when the moon is illuminated and c < 19.5 magnitude per exposure in dark skies. Construction is underway of two further units to be sited in Chile and South Africa which will result in an all-sky daily cadence from 2021. Initially designed for detecting potentially hazardous near earth objects, the ATLAS data enable a range of astrophysical time domain science. To extract transients from the data stream requires a computing system to process the data, assimilate detections in time and space and associate them with known astrophysical sources. Here we describe the hardware and software infrastructure to produce a stream of clean, real, astrophysical transients in real time. This involves machine learning and boosted decision tree algorithms to identify extragalactic and Galactic transients. Typically we detect 10-15 supernova candidates per night which we immediately announce publicly. The ATLAS discoveries not only enable rapid follow-up of interesting sources but will provide complete statistical samples within the local volume of 100 Mpc. A simple comparison of the detected supernova rate within 100 Mpc, with no corrections for completeness, is already significantly higher (factor 1.5 to 2) than the current accepted rates.
A causative relationship between chronic inflammation and cancer has been postulated for many years, and clinical observations and laboratory experiments support the hypothesis that inflammation ...contributes to tumor onset and progression. However, the precise mechanisms underlying the relationship are not known. We recently reported that the proinflammatory cytokine, interleukin-1beta, induces the accumulation and retention of myeloid-derived suppressor cells (MDSC), which are commonly found in many patients and experimental animals with cancer and are potent suppressors of adaptive and innate immunity. This finding led us to hypothesize that inflammation leads to cancer through the induction of MDSC, which inhibit immunosurveillance and thereby allow the unchecked persistence and proliferation of premalignant and malignant cells. We now report that host MDSC have receptors for prostaglandin E2 (PGE2) and that E-prostanoid receptor agonists, including PGE2, induce the differentiation of Gr1(+)CD11b(+) MDSC from bone marrow stem cells, whereas receptor antagonists block differentiation. BALB/c EP2 knockout mice inoculated with the spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma have delayed tumor growth and reduced numbers of MDSC relative to wild-type mice, suggesting that PGE2 partially mediates MDSC induction through the EP2 receptor. Treatment of 4T1-tumor-bearing wild-type mice with the cyclooxygenase 2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation, further showing that PGE2 induces MDSC and providing a therapeutic approach for reducing this tumor-promoting cell population.
Earthquakes occur by overcoming fault friction; therefore, quantifying fault resistance is central to earthquake physics. Values for both static and dynamic friction are required, and the latter is ...especially difficult to determine on natural faults. However, large earthquakes provide signals that can determine friction in situ. The Japan Trench Fast Drilling Project (JFAST), an Integrated Ocean Discovery Program expedition, determined stresses by collecting data directly from the fault 1-2 years after the 2011
M
w
9.1 Tohoku earthquake. Geological, rheological, and geophysical data record stress before, during, and after the earthquake. Together, the observations imply that the shear strength during the earthquake was substantially below that predicted by the traditional Byerlee's law. Locally the stress drop appears near total, and stress reversal is plausible. Most solutions to the energy balance require off-fault deformation to account for dissipation during rupture. These observations make extreme coseismic weakening the preferred model for fault behavior.
Determining the friction during an earthquake is required to understand when and where earthquakes occur.
Drilling into the Tohoku fault showed that friction during the earthquake was low.
Dynamic friction during the earthquake was lower than static friction.
Complete stress drop is possible, and stress reversal is plausible.
The rapid emergence of antimicrobial resistance presents serious health challenges to the management of infectious diseases, a problem that is further exacerbated by slowing rates of antimicrobial ...drug discovery in recent years. The phenomenon of collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities to address both these challenges. Here, we present a high-throughput screening platform termed Collateral Sensitivity Profiling (CSP) to map the difference in bioactivity of large chemical libraries across 29 drug-resistant strains of E. coli. CSP screening of 80 commercial antimicrobials demonstrated multiple CS interactions. Further screening of a 6195-member natural product library revealed extensive CS relationships in nature. In particular, we report the isolation of known and new analogues of borrelidin A with potent CS activities against cephalosporin-resistant strains. Co-dosing ceftazidime with borrelidin A slows broader cephalosporin resistance with no recognizable resistance to borrelidin A itself.
Abstract
Supernova (SN) 2021ocs was discovered in the galaxy NGC 7828 (
z
= 0.01911) within the interacting system Arp 144 and subsequently classified as a normal Type Ic SN around peak brightness. ...Very Large Telescope/FORS2 observations in the nebular phase at 148 days reveal that the spectrum is dominated by oxygen and magnesium emission lines of different transitions and ionization states: O
i
, O
i
, O
ii
, O
iii
, Mg
i
, and Mg
ii
. Such a spectrum has no counterpart in the literature, though it bears a few features similar to those of some interacting Type Ibn and Icn SNe. Additionally, SN 2021ocs showed a blue color, (
g
−
r
) ≲ −0.5 mag, after the peak and up to late phases, atypical for a Type Ic SN. Together with the nebular spectrum, this suggests that SN 2021ocs underwent late-time interaction with an H/He-poor circumstellar medium (CSM) resulting from the pre-SN progenitor mass loss during its final ∼1000 days. The strong O and Mg lines and the absence of strong C and He lines suggest that the progenitor star’s O–Mg layer is exposed, which places SN 2021ocs as the most extreme case of a massive progenitor star’s envelope stripping in interacting SNe, followed by Type Icn (stripped C–O layer) and Ibn (stripped He-rich layer) SNe. This is the first time such a case is reported in the literature. The SN 2021ocs emphasizes the importance of late-time spectroscopy of SNe, even for those classified as normal events, to reveal the inner ejecta and progenitor star’s CSM and mass loss.
The Welfare Quality® Assessment protocol for poultry (WQA) provides animal-based measures allowing welfare comparisons across farms and housing systems. It was used to compare Lohmann LSL Classic ...White hens housed in an enriched colony (EC), aviary (AV), and conventional cage system (CC) on a commercial farm over 2 flock cycles. Hens (n = 100/system) were scored on a variety of measures. A baseline measurement was made at placement at 19 wk of age for 1 flock, since AV hens had been reared in an aviary pullet facility (AVP) while EC and CC hens were reared in a conventional pullet facility (CCP). Hens in all systems were then assessed at 52 and 72 wk of age. Necropsies were performed on all mortalities 1 wk before and after the WQA sampling. WQAs were analyzed using Mann–Whitney U and Kruskal–Wallis tests for prevalence and Fisher's exact tests for severity. There was an effect of rearing, with AVP having shorter claws (P = 0.01), dirtier feathers (P = 0.03), and more keel abnormalities (P < 0.0001) than CCP at placement. For the hens, there were several significant housing system effects across flocks and age periods (all P ≤ 0.05). AV and EC hens had more keel abnormalities than CC hens. They also had fewer foot abnormalities than CC hens, although those in AV hens were more severe. AV hens had consistently dirtier feathers than EC and CC hens. While AV hens had the best overall feather cover, feather loss patterns suggested that loss was due to head pecking for AV, whereas in EC and CC it was due to cage abrasion. The necropsy findings and the WQA results were similar, except that the WQA failed to find enteritis at 19 wk, although it was detected in the necropsies during this sampling period. These results show that the WQA is a useful tool for detecting hen condition differences across housing systems.
Abstract
We present the discovery and extensive follow-up of a remarkable fast-evolving optical transient, AT 2022aedm, detected by the Asteroid Terrestrial impact Last Alert Survey (ATLAS). In the ...ATLAS
o
band, AT 2022aedm exhibited a rise time of 9 ± 1 days, reaching a luminous peak with
M
g
≈ −22 mag. It faded by 2 mag in the
g
band during the next 15 days. These timescales are consistent with other rapidly evolving transients, though the luminosity is extreme. Most surprisingly, the host galaxy is a massive elliptical with negligible current star formation. Radio and X-ray observations rule out a relativistic AT 2018cow–like explosion. A spectrum in the first few days after explosion showed short-lived He
ii
emission resembling young core-collapse supernovae, but obvious broad supernova features never developed; later spectra showed only a fast-cooling continuum and narrow, blueshifted absorption lines, possibly arising in a wind with
v
≈ 2700 km s
−1
. We identify two further transients in the literature (Dougie in particular, as well as AT 2020bot) that share similarities in their luminosities, timescales, color evolution, and largely featureless spectra and propose that these may constitute a new class of transients: luminous fast coolers. All three events occurred in passive galaxies at offsets of ∼4–10 kpc from the nucleus, posing a challenge for progenitor models involving massive stars or black holes. The light curves and spectra appear to be consistent with shock breakout emission, though this mechanism is usually associated with core-collapse supernovae. The encounter of a star with a stellar-mass black hole may provide a promising alternative explanation.
Chemokines comprise a superfamily of at least 46 cytokines that were initially described based on their ability to bind to 18 to 22 G protein-coupled receptors to induce the directed migration of ...leukocytes to sites of inflammation or injury. In addition to mediating cellular migration, chemokine/chemokine receptor pairs have been shown to affect many cellular functions, including survival, adhesion, invasion, and proliferation, and to regulate circulating chemokine levels. Most malignancies also express one or more chemokine receptors. Early studies established a role for CXCR4 and CXCR7 in mediating breast cancer metastasis, but other chemokine receptors, including CXCR3, now are implicated in several malignancies as biomarkers of tumor behavior as well as potential therapeutic targets. This review summarizes our current understanding regarding the contribution of CXCR4 and CXCR3 to tumor behavior and how receptor expression is regulated, transduces intracellular signals, and contributes at the molecular level to tumor behavior. It also describes recent therapeutic approaches that target these receptors or their ligands.
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