Suprofen, A New Peripheral Analgesic1

ABSTRACT Capetola, Rober

Breast Cancer in the Personal Genomics Era

Breast cancer is a heterogeneous disease with a complex etiology that develops from different cellular lineages, progresses along multiple molecular pathways, and demonstrates wide variability in response to treatment. The “standard of care” approach to breast cancer treatment in which all patients receive similar interventions is rapidly being replaced by personalized medicine, based on molecular characteristics of individual patients. Both inherited and somatic genomic variation is providing useful information for customizing treatment regimens for breast cancer to maximize efficacy and minimize adverse side effects. In this article, we review (1) hereditary breast cancer and current use of inherited susceptibility genes in patient management; (2) the potential of newly-identified breast cancer-susceptibility variants for improving risk assessment; (3) advantages and disadvantages of direct-to-consumer testing; (4) molecular characterization of sporadic breast cancer through immunohistochemistry and gene expression profiling and opportunities for personalized prognostics; and (5) pharmacogenomic influences on the effectiveness of current breast cancer treatments. Molecular genomics has the potential to revolutionize clinical practice and improve the lives of women with breast cancer

Imidazolyl Alanes - Synthesis, Structures, and Reactivity Studies – Imidazolyl Alanes - Synthesis, Structures, and Reactivity Studies

Targeting the synthesis of Al/C based ambiphilic molecules, we investigated the dehydrohalogenation of a series of (benz)imidazole alane adducts. Depending on the steric bulk of the heterocycle, different dimeric products with various ring sizes were obtained. Dehydrohalogenation of the adduct of 1‐mesityl imidazole ($^{Mes}$Im) and 0.5 [tBu$_{2}$AlBr]$_{2}$ furnished the dimer 2, featuring a “classical” N‐heterocyclic carbene (NHC) and a mesoionic or “abnormal” NHC (aNHC) subunit within a single molecule. The dimer is bound loosely enough to allow thermally induced isomerization of 2 into the isomers 2$^{NHC}$ (all NHC) and 2$^{aNHC}$ (all aNHC). Dehydrohalogenation of the adduct of 1‐mesityl‐2‐methyl imidazole ($^{Mes}$Im$^{Me}$) and 0.5 [tBu$_{2}$AlBr]$_{2}$ (4) yielded the dimeric compound 5 consisting of two N‐heterocyclic olefin (NHO) subunits. Although these six‐ and eight‐membered heterocycles show no FLP‐type reactivity towards small molecules like H$_{2}$, CO or CO$_{2}$, we observed an ambiphilic behavior of the imidazolyl alanes during our studies. Salt metathesis reactions using $^{Mes}$Im resulted in the formation of 3, which can be viewed as tBu$_{2}$AlBr adduct of an Al/N ambiphile. Utilizing heterocycles such as benzimidazole or spiroindole provided the entry point to C–H (7, 9) and N–H (10) activation products, most likely resulting from a reactivity of intermediate species as Al/C ambiphiles

Global modeling of internal tides within an eddying ocean general circulation model

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91777/1/25-2_arbic_hi.pd

Inferring dynamics from the wavenumber spectra of an eddying global ocean model with embedded tides

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94531/1/jgr_richmanetal_wavenumberspectra_2012.pd

Targeting fatty acid β-oxidation impairs monocyte differentiation and prolongs heart allograft survival

Monocytes play an important role in the regulation of alloimmune responses after heart transplantation (HTx). Recent studies have highlighted the importance of immunometabolism in the differentiation and function of myeloid cells. While the importance of glucose metabolism in monocyte differentiation and function has been reported, a role for fatty acid β-oxidation (FAO) has not been explored. Heterotopic HTx was performed using hearts from BALB/c donor mice implanted into C57BL/6 recipient mice and treated with etomoxir (eto), an irreversible inhibitor of carnitine palmitoyltransferase 1 (Cpt1), a rate-limiting step of FAO, or vehicle control. FAO inhibition prolonged HTx survival, reduced early T cell infiltration/activation, and reduced DC and macrophage infiltration to heart allografts of eto-treated recipients. ELISPOT demonstrated that splenocytes from eto-treated HTx recipients were less reactive to activated donor antigen-presenting cells. FAO inhibition reduced monocyte-to-DC and monocyte-to-macrophage differentiation in vitro and in vivo. FAO inhibition did not alter the survival of heart allografts when transplanted into Ccr2-deficient recipients, suggesting that the effects of FAO inhibition were dependent on monocyte mobilization. Finally, we confirmed the importance of FAO on monocyte differentiation in vivo using conditional deletion of Cpt1a. Our findings demonstrate that targeting FAO attenuates alloimmunity after HTx, in part through impairing monocyte differentiation

Effects of grid spacing on high-frequency precipitation variance in coupled high-resolution global ocean–atmosphere models

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Light, C., Arbic, B., Martin, P., Brodeau, L., Farrar, J., Griffies, S., Kirtman, B., Laurindo, L., Menemenlis, D., Molod, A., Nelson, A., Nyadjro, E., O’Rourke, A., Shriver, J., Siqueira, L., Small, R., & Strobach, E. Effects of grid spacing on high-frequency precipitation variance in coupled high-resolution global ocean–atmosphere models. Climate Dynamics, (2022): 1–27, https://doi.org/10.1007/s00382-022-06257-6.High-frequency precipitation variance is calculated in 12 different free-running (non-data-assimilative) coupled high resolution atmosphere–ocean model simulations, an assimilative coupled atmosphere–ocean weather forecast model, and an assimilative reanalysis. The results are compared with results from satellite estimates of precipitation and rain gauge observations. An analysis of irregular sub-daily fluctuations, which was applied by Covey et al. (Geophys Res Lett 45:12514–12522, 2018. https://doi.org/10.1029/2018GL078926) to satellite products and low-resolution climate models, is applied here to rain gauges and higher-resolution models. In contrast to lower-resolution climate simulations, which Covey et al. (2018) found to be lacking with respect to variance in irregular sub-daily fluctuations, the highest-resolution simulations examined here display an irregular sub-daily fluctuation variance that lies closer to that found in satellite products. Most of the simulations used here cannot be analyzed via the Covey et al. (2018) technique, because they do not output precipitation at sub-daily intervals. Thus the remainder of the paper focuses on frequency power spectral density of precipitation and on cumulative distribution functions over time scales (2–100 days) that are still relatively “high-frequency” in the context of climate modeling. Refined atmospheric or oceanic model grid spacing is generally found to increase high-frequency precipitation variance in simulations, approaching the values derived from observations. Mesoscale-eddy-rich ocean simulations significantly increase precipitation variance only when the atmosphere grid spacing is sufficiently fine (< 0.5°). Despite the improvements noted above, all of the simulations examined here suffer from the “drizzle effect”, in which precipitation is not temporally intermittent to the extent found in observations.Support for CXL’s effort on this project was provided by a Research Experiences for Undergraduates (REU) supplement for National Science Foundation (NSF) grant OCE-1851164 to BKA, which also provided partial support for PEM. In addition, BKA acknowledges NSF grant OCE-1351837, which provided partial support for AKO, Office of Naval Research grant N00014-19-1-2712 and NASA grants NNX17AH55G, which also provided partial support for ADN, and 80NSSC20K1135. JTF’s participation, and the SPURS-II buoy data, were funded by NASA grants 80NSSC18K1494 and NNX15AG20G

Chinese hamster ovary cells can produce galactose-α-1,3-galactose antigens on proteins

Chinese hamster ovary (CHO) cells are widely used for the manufacture of biotherapeutics, in part because of their ability to produce proteins with desirable properties, including 'human-like' glycosylation profiles. For biotherapeutics production, control of glycosylation is critical because it has a profound effect on protein function, including half-life and efficacy. Additionally, specific glycan structures may adversely affect their safety profile. For example, the terminal galactose-α-1,3-galactose (α-Gal) antigen can react with circulating anti α-Gal antibodies present in most individuals. It is now understood that murine cell lines, such as SP2 or NSO, typical manufacturing cell lines for biotherapeutics, contain the necessary biosynthetic machinery to produce proteins containing α-Gal epitopes. Furthermore, the majority of adverse clinical events associated with an induced IgE-mediated anaphylaxis response in patients treated with the commercial antibody Erbitux (cetuximab) manufactured in a murine myeloma cell line have been attributed to the presence of the α-Gal moiety. Even so, it is generally accepted that CHO cells lack the biosynthetic machinery to synthesize glycoproteins with α-Gal antigens. Contrary to this assumption, we report here the identification of the CHO ortholog of N-acetyllactosaminide 3-α-galactosyltransferase-1, which is responsible for the synthesis of the α-Gal epitope. We find that the enzyme product of this CHO gene is active and that glycosylated protein products produced in CHO contain the signature α-Gal antigen because of the action of this enzyme. Furthermore, characterizing the commercial therapeutic protein abatacept (Orencia) manufactured in CHO cell lines, we also identified the presence of α-Gal. Finally, we find that the presence of the α-Gal epitope likely arises during clonal selection because different subclonal populations from the same parental cell line differ in their expression of this gene. Although the specific levels of α-Gal required to trigger anaphylaxis reactions are not known and are likely product specific, the fact that humans contain high levels of circulating anti-α-Gal antibodies suggests that minimizing (or at least controlling) the levels of these epitopes during biotherapeutics development may be beneficial to patients. Furthermore, the approaches described here to monitor α-Gal levels may prove useful in industry for the surveillance and control of α-Gal levels during protein manufacture.National Center for Research Resources (U.S.) (Grant P41 RR018501-01

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Experienced stressors and coping strategies among Iranian nursing students

<p>Abstract</p> <p>Background</p> <p>College students are prone to stress due to the transitional nature of college life. High levels of stress are believed to affect students' health and academic functions. If the stress is not dealt with effectively, feelings of loneliness, nervousness, sleeplessness and worrying may result. Effective coping strategies facilitate the return to a balanced state, reducing the negative effects of stress.</p> <p>Methods</p> <p>This descriptive cross-sectional study was performed to determine sources of stress and coping strategies in nursing students studying at the Iran Faculty of Nursing & Midwifery. All undergraduate nursing students enrolled in years 1-4 during academic year 2004-2005 were included in this study, with a total of 366 questionnaires fully completed by the students. The Student Stress Survey and the Adolescent Coping Orientation for Problem Experiences Inventory (ACOPE) were used for data collection.</p> <p>Results</p> <p>Most students reported "finding new friends" (76.2%), "working with people they did not know" (63.4%) as interpersonal sources of stress, "new responsibilities" (72.1%), "started college" (65.8%) as intrapersonal sources of stress more than others. The most frequent academic source of stress was "increased class workload" (66.9%) and the most frequent environmental sources of stress were being "placed in unfamiliar situations" (64.2%) and "waiting in long lines" (60.4%). Interpersonal and environmental sources of stress were reported more frequently than intrapersonal and academic sources. Mean interpersonal (P=0.04) and environmental (P=0.04) sources of stress were significantly greater in first year than in fourth year students. Among coping strategies in 12 areas, the family problem solving strategies, "trying to reason with parents and compromise" (73%) and "going along with family rules" (68%) were used "often or always" by most students. To cope with engaging in demanding activity, students often or always used "trying to figure out how to deal with problems" (66.4%) and "trying to improve themselves" (64.5%). The self-reliance strategy, "trying to make their own decisions" (62%); the social support strategies, "apologizing to people" (59.6%), "trying to help other people solve their problems" (56.3%), and "trying to keep up friendships or make new friends" (54.4%); the spiritual strategy, "praying" (65.8%); the seeking diversions strategy, "listening to music" (57.7%), the relaxing strategy "day dreaming" (52.5%), and the effort to "be close with someone cares about you" (50.5%) were each used "often or always" by a majority of students. Most students reported that the avoiding strategies "smoking" (93.7%) and "drinking beer or wine" (92.9%), the ventilating strategies "saying mean things to people" and "swearing" (85.8%), the professional support strategies "getting professional counseling" (74.6%) and "talking to a teacher or counselor" (67.2%) and the humorous strategy "joking and keeping a sense of humor" (51.9%) were used "seldom or never".</p> <p>Conclusion</p> <p>First year nursing students are exposed to a variety of stressors. Establishing a student support system during the first year and improving it throughout nursing school is necessary to equip nursing students with effective coping skills. Efforts should include counseling helpers and their teachers, strategies that can be called upon in these students' future nursing careers.</p