Description: Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 ( 1 ) receptors. Selective 1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity 1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated 1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for 1 sites ( K i 0.46 nM) and 3596-fold selectivity over 2 sites ( K i 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters ( K i 〉100 μ M), and the DAT interaction was weak ( K i 9.0 μ M). In vivo, PD144418 bound to central and peripheral 1 sites in mouse, with an ED 50 of 0.22 μ mol/kg in whole brain. No DAT occupancy by PD144418 (10.0 μ mol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 μ mol/kg) attenuated cocaine-induced hyperactivity in a dose-dependent manner in mice. There was good correlation ( r 2 = 0.88) of hyperactivity reduction with increasing cerebral 1 receptor occupancy. The behavioral ED 50 of 0.79 μ mol/kg corresponded to 80% occupancy. Significant 1 receptor occupancy and the ability to mitigate cocaine’s motor stimulatory effects were observed for 16 hours after a single 10.0 μ mol/kg dose of PD144418.

Description: Background: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. Methods: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided. Results: shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean ≥ 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents. Conclusions: These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.

Description: Background Although p53 is inactivated by point mutations in many tumors, melanomas infrequently harbor mutations in the p53 gene. Here we investigate the biological role of microRNA-18b (miR-18b) in melanoma by targeting the MDM2-p53 pathway. Methods Expression of miR-18b was examined in nevi (n = 48) and melanoma (n = 92) samples and in melanoma cell lines and normal melanocytes. Immunoblotting was performed to determine the expression of various proteins regulated by miR-18b. The effects of miR-18b overexpression in melanoma cell lines were investigated using assays of colony formation, cell viability, migration, invasion, and cell cycle and in a xenograft model (n = 10 mice per group). Chromatin immunoprecipitation and methylation assays were performed to determine the mechanism of microRNA silencing. Results Expression of miR-18b was substantially reduced in melanoma specimens and cell lines by virtue of hypermethylation and was reinduced (by 1.5- to 5.3-fold) in melanoma cell lines after 5-AZA-deoxycytidine treatment. MDM2 was identified as a target of miR-18b action, and overexpression of miR-18b in melanoma cells was accompanied by 75% reduced MDM2 expression and 2.5-fold upregulation of p53, resulting in 70% suppression of melanoma cell colony formation. The effects of miR-18b overexpression on the p53 pathway and on melanoma cell growth were reversed by MDM2 overexpression. Stable overexpression of miR-18b produced potent tumor suppressor activity, as evidenced by suppressed melanoma cell viability, induction of apoptosis, and reduced tumor growth in vivo. miR-18b overexpression suppressed melanoma cell migration and invasiveness and reversed epithelial-to-mesenchymal transition. Conclusions Our results demonstrate a novel role for miR-18b as a tumor suppressor in melanoma, identify the MDM2-p53 pathway as a target of miR-18b action, and suggest miR-18b overexpression as a novel strategy to reactivate the p53 pathway in human tumors.

Description: Antibiotic selection is challenging in patients with severe β-lactam allergy due to declining reliability of alternate antibiotics. Organisms isolated from these patients may exhibit unique resistance phenotypes. The objective of this study was to determine which alternate antibiotics or combinations provide adequate empirical therapy for patients with β-lactam allergy who develop Gram-negative infections at our institution. We further sought to determine the effects of risk factors for drug resistance on empirical adequacy. A retrospective analysis was conducted for adult patients hospitalized from September 2009 to May 2010 who had a severe β-lactam allergy and a urine, blood, or respiratory culture positive for a Gram-negative organism and who met predefined criteria for infection. Patient characteristics, culture and susceptibility data, and predefined risk factors for antibiotic resistance were collected. Adequacies of β-lactam and alternate antibiotics were compared for all infections and selected subsets. The primary outcome was adequacy of each alternate antibiotic or combination for all infections. One hundred sixteen infections (40 pneumonias, 67 urinary tract infections, and 9 bacteremias) were identified. Single alternate agents were adequate less frequently than β-lactams and combination regimens. Only in cases without risk factors for resistance did single-agent regimens demonstrate acceptable adequacy rates; each factor conferred a doubling of risk for resistance. Resistance risk factors should be considered in selecting empirical antibiotics for Gram-negative pathogens in patients unable to take β-lactams due to severe allergy.

Description: The whole-genome duplication 80 million years ago of the common ancestor of salmonids (salmonid-specific fourth vertebrate whole-genome duplication, Ss4R) provides unique opportunities to learn about the evolutionary fate of a duplicated vertebrate genome in 70 extant lineages. Here we present a high-quality genome assembly for Atlantic salmon (Salmo salar), and show that large genomic reorganizations, coinciding with bursts of transposon-mediated repeat expansions, were crucial for the post-Ss4R rediploidization process. Comparisons of duplicate gene expression patterns across a wide range of tissues with orthologous genes from a pre-Ss4R outgroup unexpectedly demonstrate far more instances of neofunctionalization than subfunctionalization. Surprisingly, we find that genes that were retained as duplicates after the teleost-specific whole-genome duplication 320 million years ago were not more likely to be retained after the Ss4R, and that the duplicate retention was not influenced to a great extent by the nature of the predicted protein interactions of the gene products. Finally, we demonstrate that the Atlantic salmon assembly can serve as a reference sequence for the study of other salmonids for a range of purposes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lien, Sigbjorn -- Koop, Ben F -- Sandve, Simen R -- Miller, Jason R -- Kent, Matthew P -- Nome, Torfinn -- Hvidsten, Torgeir R -- Leong, Jong S -- Minkley, David R -- Zimin, Aleksey -- Grammes, Fabian -- Grove, Harald -- Gjuvsland, Arne -- Walenz, Brian -- Hermansen, Russell A -- von Schalburg, Kris -- Rondeau, Eric B -- Di Genova, Alex -- Samy, Jeevan K A -- Olav Vik, Jon -- Vigeland, Magnus D -- Caler, Lis -- Grimholt, Unni -- Jentoft, Sissel -- Inge Vage, Dag -- de Jong, Pieter -- Moen, Thomas -- Baranski, Matthew -- Palti, Yniv -- Smith, Douglas R -- Yorke, James A -- Nederbragt, Alexander J -- Tooming-Klunderud, Ave -- Jakobsen, Kjetill S -- Jiang, Xuanting -- Fan, Dingding -- Hu, Yan -- Liberles, David A -- Vidal, Rodrigo -- Iturra, Patricia -- Jones, Steven J M -- Jonassen, Inge -- Maass, Alejandro -- Omholt, Stig W -- Davidson, William S -- England -- Nature. 2016 Apr 18;533(7602):200-5. doi: 10.1038/nature17164.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, As NO-1432, Norway. ; Department of Biology, University of Victoria, Victoria, British Columbia V8W 3N5, Canada. ; J. Craig Venter Institute, 9704 Medical Center Drive, Rockville, Maryland 20850, USA. ; Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, As NO-1432 Norway. ; Department of Plant Physiology, Umea Plant Science Centre, Umea University, Umea 90187, Sweden. ; Institute for Physical Sciences and Technology, University of Maryland, College Park, Maryland 20742-2431, USA. ; Department of Molecular Biology, University of Wyoming, Laramie, Wyoming 82071, USA. ; Center for Computational Genetics and Genomics, Temple University, Philadelphia, Pennsylvania 19122-6078, USA. ; Department of Biology, Temple University, Philadelphia, Pennsylvania 19122-6078, USA. ; Center for Mathematical Modeling, University of Chile, Santiago 8370456, Chile. ; Center for Genome Regulation, University of Chile, Santiago 8370415, Chile. ; Medical Genetics, Oslo University Hospital and University of Oslo, Oslo NO-0424, Norway. ; Department of Virology, Norwegian Veterinary Institute, Oslo NO-0454, Norway. ; Centre for Ecological and Evolutionary Synthesis (CEES), Department of Biosciences, University of Oslo, Oslo NO-0316, Norway. ; CHORI, Oakland, California 94609, USA. ; AquaGen, Trondheim NO-7462, Norway. ; Nofima, Tromso NO-9291, Norway. ; National Center for Cool and Cold Water Aquaculture, ARS-USDA, Kearneysville, West Virginia 25430, USA. ; Beckman Genomics, Danvers, Massachusetts 01923, USA. ; Courtagen Life Sciences, Woburn, Massachusetts 01801, USA. ; BGI-Shenzhen, Shenzhen 518083, China. ; Laboratory of Molecular Ecology, Genomics, and Evolutionary Studies, Department of Biology, University of Santiago, Santiago 9170022, Chile. ; Faculty of Medicine, University of Chile, Santiago 8380453, Chile. ; Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada. ; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. ; Department of Informatics, University of Bergen, Bergen NO-6020, Norway. ; Centre for Biodiversity Dynamics, Department of Biology, NTNU - Norwegian University of Science and Technology, Trondheim NO-7491, Norway.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27088604" target="_blank"〉PubMed〈/a〉

Description: Objective To examine the influence of solar cycle and geomagnetic effects on the incidence of giant cell arteritis (GCA) and rheumatoid arthritis (RA). Methods We used data from patients with GCA (1950–2004) and RA (1955–2007) obtained from population-based cohorts. Yearly trends in age-adjusted and sex-adjusted incidence were correlated with the F10.7 index (solar radiation at 10.7 cm wavelength, a proxy for the solar extreme ultraviolet radiation) and AL index (a proxy for the westward auroral electrojet and a measure of geomagnetic activity). Fourier analysis was performed on AL, F10.7, and GCA and RA incidence rates. Results The correlation of GCA incidence with AL is highly significant: GCA incidence peaks 0–1 year after the AL reaches its minimum (ie, auroral electrojet reaches a maximum). The correlation of RA incidence with AL is also highly significant. RA incidence rates are lowest 5–7 years after AL reaches maximum. AL, GCA and RA incidence power spectra are similar: they have a main peak (periodicity) at about 10 years and a minor peak at 4–5 years. However, the RA incidence power spectrum main peak is broader (8–11 years), which partly explains the lower correlation between RA onset and AL. The auroral electrojets may be linked to the decline of RA incidence more strongly than the onset of RA. The incidences of RA and GCA are aligned in geomagnetic latitude. Conclusions AL and the incidences of GCA and RA all have a major periodicity of about 10 years and a secondary periodicity at 4–5 years. Geomagnetic activity may explain the temporal and spatial variations, including east-west skewness in geographic coordinates, in GCA and RA incidence, although the mechanism is unknown. The link with solar, geospace and atmospheric parameters need to be investigated. These novel findings warrant examination in other populations and with other autoimmune diseases.

Description: Leukocyte trafficking into the CNS is a prominent feature driving the immunopathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Blocking the recruitment of inflammatory leukocytes into the CNS represents an exploitable therapeutic target; however, the adhesion molecules that specifically regulate the step of leukocyte diapedesis into the CNS remain poorly understood. We report that CD99 is critical for lymphocyte transmigration without affecting adhesion in a human blood–brain barrier model. CD99 blockade in vivo ameliorated experimental autoimmune encephalomyelitis and decreased the accumulation of CNS inflammatory infiltrates, including dendritic cells, B cells, and CD4 + and CD8 + T cells. Anti-CD99 therapy was effective when administered after the onset of disease symptoms and blocked relapse when administered therapeutically after disease symptoms had recurred. These findings underscore an important role for CD99 in the pathogenesis of CNS autoimmunity and suggest that it may serve as a novel therapeutic target for controlling neuroinflammation.

Description: : Gum Hollow Delta is a small microtidal, aggradational to slightly progradational, hyperpycnal, tropical-cyclone-dominated delta in Nueces Bay (Texas). The delta formed over the past 80 years following anthropogenically diverted, high sediment-laden stream runoff through Gum Hollow Creek into Nueces Bay. Gum Hollow Delta formed episodically due to high runoff and increased discharge in Gum Hollow Creek and temporarily elevated sea level during Gulf of Mexico tropical cyclones. The delta is 600 m long, 1000 m wide, and 1.6 m thick. Fifty-one vibracores were taken along four dip transects and two strike transects to delineate the internal sedimentology, architecture, and geochronology of the delta. The delta consists of nine bedsets (tempestites) representing deltaic growth events. Internal stratigraphic correlations were constrained by the identification of significant widespread flooding surfaces and by 137 Cs geochronology. Flooding surfaces formed as storm surges produced short-term base-level rises in Nueces Bay, which were followed by rapid hyperpycnal sedimentation events. Tropical cyclones such as the 1933 Hurricane (Hurricane Eleven), 1945 Hurricane (Hurricane Five), and the 1949 Hurricane (Hurricane Ten) and named hurricanes Alice (1954), Carla (1961), Beulah (1967), Celia (1970), Allen (1980), and Bret (1999) produced significant base-level rises and deltaic depositional events. Distributary-channel avulsions are also associated with the landfall of these tropical cyclones. Comparison of the timing of the deposition of these hyperpycnal tempestites, constrained by 137 Cs geochronology, historical aerial photographs, and the historical record of Gulf of Mexico tropical cyclones indicate that the Gum Hollow Delta preserves an 80-year record of storminess.

Description: Purpose: Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however, current models are limited both in their availability and suitability to characterize these rare cells. Experimental Design: Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient. Patient and PDX samples were analyzed by RNA-seq and Exome-seq. Sphere formation potential and in vivo tumorigenicity was assessed by sorting for Aldefluor (ALDH) activity and CD44-expressing subpopulations. Results: For successive MEC relapses we found a time-dependent increase in CSCs (ALDH + CD44 high ), increasing from 0.2% to 4.5% ( P =0.033), but more importantly we observed an increase in individual CSC sphere formation and tumorigenic potential. A 50% increase in mutational burden was documented in subsequent MEC tumors, and this was associated with increased expression of tumor-promoting genes ( MT1E, LGR5 , and LEF1 ), decreased expression of tumor-suppressor genes ( CDKN2B, SIK1 , and TP53 ), and higher expression of CSC-related proteins such as SOX2, MYC, and ALDH1A1. Finally, genomic analyses identified a novel NFIB – MTFR2 fusion in an ACC tumor and confirmed previously reported fusions ( NTRK3 – ETV6 and MYB – NFIB) . Conclusions: Sequential MEC PDX models preserved key patient features and enabled the identification of genetic events putatively contributing to increases in both CSC proportion and intrinsic tumorigenicity, which mirrored the patient's clinical course. Clin Cancer Res; 24(12); 2935–43. ©2018 AACR .

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, John R -- New York, N.Y. -- Science. 2012 Mar 16;335(6074):1312-3. doi: 10.1126/science.1219134.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉JME, Inc., 23500 Mercantile Road, Beachwood, OH 44122, USA. jmecapacitor@att.net〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22422970" target="_blank"〉PubMed〈/a〉