Regulation of bombesin-stimulated cyclooxygenase-2 expression in prostate cancer cells

BACKGROUND: Cyclooxygenase-2 (COX-2) and the bombesin (BBS)-like peptide, gastrin-releasing peptide (GRP), have been implicated in the progression of hormone-refractory prostate cancer; however, a mechanistic link between the bioactive peptide and COX-2 expression in prostate cells has not been made. RESULTS: We report that BBS stimulates COX-2 mRNA and protein expression, and the release of prostaglandin E(2 )from the GRP receptor (GRPR)-positive, androgen-insensitive prostate cancer cell line, PC-3. BBS-stimulated COX-2 expression is mediated, in part, by p38(MAPK )and PI3 kinase (PI3K)/Akt pathways, and blocked by a GRPR antagonist. The PI3K/Akt pathway couples GRPR to the transcription factor, activator protein-1 (AP-1), and enhanced COX-2 promoter activity. Although BBS stimulates nuclear factor-kappaB (NF-κB) in PC-3, NF-κB does not regulate GRPR-mediated COX-2 expression. The p38(MAPK )pathway increases BBS-stimulated COX-2 expression by slowing the degradation of COX-2 mRNA. Expression of recombinant GRPR in the androgen-sensitive cell line LNCaP is sufficient to confer BBS-stimulated COX-2 expression via the p38(MAPK )and PI3K/Akt pathways. CONCLUSIONS: Our study establishes a mechanistic link between GRPR activation and enhanced COX-2 expression in prostate cancer cell lines, and suggests that inhibiting GRPR may, in the future, provide an effective therapeutic alternative to non-steroidal anti-inflammatory drugs for inhibiting COX-2 in patients with recurrent prostate cancer

Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants

Many types of human cancers suppress the expression of argininosuccinate synthase 1 (ASS1), a rate-limiting enzyme for arginine production. Although dependency on exogenous arginine can be harnessed by arginine-deprivation therapies, the impact of ASS1 suppression on the quality of the tumor proteome is unknown. We therefore interrogated proteomes of cancer patients for arginine codon reassignments (substitutants) and surprisingly identified a strong enrichment for cysteine (R&gt;C) in lung tumors specifically. Most R&gt;C events did not coincide with genetically encoded R&gt;C mutations but were likely products of tRNA misalignments. The expression of R&gt;C substitutants was highly associated with oncogenic kelch-like epichlorohydrin (ECH)-associated protein 1 (KEAP1)-pathway mutations and suppressed by intact-KEAP1 in KEAP1-mutated cancer cells. Finally, functional interrogation indicated a key role for R&gt;C substitutants in cell survival to cisplatin, suggesting that regulatory codon reassignments endow cancer cells with more resilience to stress. Thus, we present a mechanism for enriching lung cancer proteomes with cysteines that may affect therapeutic decisions.</p

Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants

Many types of human cancers suppress the expression of argininosuccinate synthase 1 (ASS1), a rate-limiting enzyme for arginine production. Although dependency on exogenous arginine can be harnessed by arginine-deprivation therapies, the impact of ASS1 suppression on the quality of the tumor proteome is unknown. We therefore interrogated proteomes of cancer patients for arginine codon reassignments (substitutants) and surprisingly identified a strong enrichment for cysteine (R&gt;C) in lung tumors specifically. Most R&gt;C events did not coincide with genetically encoded R&gt;C mutations but were likely products of tRNA misalignments. The expression of R&gt;C substitutants was highly associated with oncogenic kelch-like epichlorohydrin (ECH)-associated protein 1 (KEAP1)-pathway mutations and suppressed by intact-KEAP1 in KEAP1-mutated cancer cells. Finally, functional interrogation indicated a key role for R&gt;C substitutants in cell survival to cisplatin, suggesting that regulatory codon reassignments endow cancer cells with more resilience to stress. Thus, we present a mechanism for enriching lung cancer proteomes with cysteines that may affect therapeutic decisions.</p

Influence of high-latitude warming and land-use changes in the early 20th century northern Eurasian CO2 sink

While the global carbon budget (GCB) is relatively well constrained over the last decades of the 20th century [1], observations and reconstructions of atmospheric CO2 growth rate present large discrepancies during the earlier periods [2]. The large uncertainty in GCB has been attributed to the land biosphere, although it is not clear whether the gaps between observations and reconstructions are mainly because land-surface models (LSMs) underestimate inter-annual to decadal variability in natural ecosystems, or due to inaccuracies in land-use change reconstructions. As Eurasia encompasses about 15% of the terrestrial surface, 20% of the global soil organic carbon pool and constitutes a large CO2 sink, we evaluate the potential contribution of natural and human-driven processes to induce large anomalies in the biospheric CO2 fluxes in the early 20th century. We use an LSM specifically developed for high-latitudes, that correctly simulates Eurasian C-stocks and fluxes from observational records [3], in order to evaluate the sensitivity of the Eurasian sink to the strong high-latitude warming occurring between 1930 and 1950. We show that the LSM with improved high-latitude phenology, hydrology and soil processes, contrary to the group of LSMs in [2], is able to represent enhanced vegetation growth linked to boreal spring warming, consistent with tree-ring time-series [4]. By compiling a dataset of annual agricultural area in the Former Soviet Union that better reflects changes in cropland area linked with socio-economic fluctuations during the early 20th century, we show that land-abadonment during periods of crisis and war may result in reduced CO2 emissions from land-use change (44%-78% lower) detectable at decadal time-scales. Our study points to key processes that may need to be improved in LSMs and LUC datasets in order to better represent decadal variability in the land CO2 sink, and to better constrain the GCB during the pre-observational record

Liposome‑delivered baicalein induction of myeloid leukemia K562 cell death via reactive oxygen species generation

Baicalein (BL), a potential cancer chemopreventative flavone, has been reported to inhibit cancer cell growth by inducing apoptosis and causing cell cycle arrest in various human cancer cell models. Delivery of BL via nanoliposomes has been shown to improve its oral bioavailability and long‑circulating property in vivo. However, the role of BL in the inhibition of human chronic myeloid leukemia (CML) K562 cell growth and its underlying mechanisms has yet to be elucidated. In the present study, BL was formulated into liposomes with different sizes to improve its solubility and stability. The cytotoxic and pro‑apoptotic effects of free BL and liposomal BL were also evaluated. The results demonstrated that 100 nm liposomes were the most stable formulation when compared with 200 and 400 nm liposomes. Liposomal BL inhibited K562 cell growth as efficiently as free BL (prepared in DMSO), indicating that the liposome may be a potential vehicle to deliver BL for the treatment of CML. Flow cytometry analysis showed that there was significant (P<0.005) cell cycle arrest in the sub‑G1 phase (compared with vehicle control), indicating cell apoptosis following 20 µM liposomal BL or free BL treatment of K562 cells for 48 h. The induction of cell apoptosis by all BL preparations was further confirmed through the staining of treated cells with Annexin V‑fluorescein isothiocyanate/propidium iodide. A significant increase in reactive oxygen species (ROS) gene­ration was observed in free BL and liposomal BL treated cells, with a higher level of ROS produced from those treated with free BL. This indicated that cell apoptosis induced by BL may be via ROS generation and liposome delivery may further extend the effect through its long‑circulating property

Priming Picture Naming with a Semantic Task: An fMRI Investigation

Prior semantic processing can enhance subsequent picture naming performance, yet the neurocognitive mechanisms underlying this effect and its longevity are unknown. This functional magnetic resonance imaging study examined whether different neurological mechanisms underlie short-term (within minutes) and long-term (within days) facilitation effects from a semantic task in healthy older adults. Both short- and long-term facilitated items were named significantly faster than unfacilitated items, with short-term items significantly faster than long-term items. Region of interest results identified decreased activity for long-term facilitated items compared to unfacilitated and short-term facilitated items in the mid-portion of the middle temporal gyrus, indicating lexical-semantic priming. Additionally, in the whole brain results, increased activity for short-term facilitated items was identified in regions previously linked to episodic memory and object recognition, including the right lingual gyrus (extending to the precuneus region) and the left inferior occipital gyrus (extending to the left fusiform region). These findings suggest that distinct neurocognitive mechanisms underlie short- and long-term facilitation of picture naming by a semantic task, with long-term effects driven by lexical-semantic priming and short-term effects by episodic memory and visual object recognition mechanisms

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV