tbuckley/cabot-search huggingface dataset:
Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini
Authors: D J Kowalewski, S Walz, L Backert, H Schuster, O Kohlbacher, K Weisel, S M Rittig, L Kanz, H R Salih, H-G Rammensee, S Stevanović, J S Stickel
Journal: Blood Cancer Journal (2016)

Abstract Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment.
Does kinship terminology provide evidence for or against universal grammar?
Authors: Christina Behme
Journal: Behavioral and Brain Sciences (2010)

Abstract Jones introduces an intricate machinery of kin classification that overcomes limitations of previous accounts. I question whether such a machinery is plausible. Because individuals never need to learn the entire spectrum of kin terminology, they could rely on data-driven learning. The complexity of Jones's machinery for kin classification casts doubt on the existence of innate structures that cover the complete linguistic domain.
P31 Predictors of fluid responsiveness in patients with acute liver failure
Authors: V. K. Audimoolam, M. Mcphail, C. Willars, W. Bernal, J. A. Wendon, G. Auzinger
Journal: Gut (2011)

<h3>Introduction</h3> Profound haemodynamic changes are invariably seen in ALF and resemble those found in later stages of septic shock. Vasopressor support is frequently required and in discriminatory fluid resuscitation can worsen intracranial hypertension (ICH) and lung injury. Markers of preload dependency have thus far not been studied in this patient group and response to dynamic manoeuvres such as passive leg raising or end expiratory hold cannot be considered safe in this population due to the high incidence of ICH. <h3>Method</h3> Patients admitted to a tertiary referral specialist ICU with ALF. All patients were in vasoplegic shock, requiring multiorgan support including controlled mechanical ventilation. Cardiac output monitoring via transpulmonary thermodilution (TPTD) and pulse contour analysis (PiCCO_, Pulsion Munich) was performed. Markers of fluid responsiveness were compared between responders (CI≥15%) and non-responders to a colloid fluid challenge (5 ml/kg IBW). All patients had a transthoracic echocardiogram (TTE) performed before and after fluid administration. The predictive capacity of stroke volume—pulse pressure variation (SVV, PPV) and respiratory change in peak aortic velocity (DV peak) for preload dependency was analysed. <h3>Results</h3> 26 patients (mean age 40 (13), 15 M: 11 F,) with mixed aetiology ALF were assessed. The mean APACHE II score was 23 (4) and mean SOFA 15 (2). Change in CI and SVI were closely correlated (R=0.726, p&lt;0.001). There was no difference between those defined as responders using a cut-off of CI or SVI of 10%. When using 15%, 7 patients would have been classified differently. Intraclass correlation coefficient (ICC) for CI and SVI change was 0.83 (0.62–0.92), confirmed using Pasing &amp; Blakock regression (A= −0.278, −0.88 to 0.16, B=1.26, 0.88 to 1.72) suggesting haemodynamic changes in both measures are interchangeable. Using a cut-off of a change in CI of 15% only PPV predicted fluid responsiveness (AUROC 0.79, 0.58–0.93, p=0.005, cut-off &gt;9%, sensitivity 75%, specificity 62%). SVV weakly predicted fluid responsiveness in this cohort (AUROC 0.73, 0.52–0.87, p=0.005, cut-off &gt;11%), While there was a trend towards reduction in DV peak (mean difference −3%, p=0.080) this was not different between those defined as fluid responders by CI (Repeated measures ANOVA p=0.124) and AVV prior to fluid bolus did not predict a CI response (AUROC 0.637, 0.413–825, p=0.322). <h3>Conclusion</h3> Baseline PiCCO parameters predict fluid responsiveness but the respiratory variability in DV peak did not predict a CI response to fluid bolus in this cohort of ALF patients. PPV may be a more suitable PiCCO index for assessing fluid requirements in patients with ALF than SVV.
Abstract 1937: Nemo-like kinase expression is altered during prostate cancer progression
Authors: Lisha G. Brown, Tiffany EM Pitts, Xiaotun Zhang, Robert L. Vessella, Eva Corey
Journal: Cancer Research (2011)

Abstract MAPKs have been implicated in cancer progression. We have previously shown that Nemo-like kinase (NLK) inhibits androgen receptor signaling and induces apoptosis in prostate cancer cell in vitro. The objective of this study was to investigate NLK expression in clinical samples of primary prostate cancer and in prostate cancer xenografts using immunohistochemistry. TMAs containing primary prostate cancer samples and prostate cancer xenograft tissues were used. Our data show that NLK immunoreactivity is 0.34 higher in primary prostate cancer vs. normal prostate epithelium (p=0.01) but our analysis did not reveal any significant correlations of NLK immunoreactivity with PSA, Gleason score or recurrence of the disease. When we examined NLK immunoreactivity in prostate cancer xenografts our results show that there are signficant differences in cellular localization of NLK between xenografts that respond well to castration vs. those that do not. Xenografts that respond well to castration exhibit lower levels of NLK in nucleoplasm and higher leves of NLK in nucleoli vs. xenografts that do not respons well to castration (t=−4.211, p&amp;lt;.0001, and z=3.994, p&amp;lt;.0001 respectively). Our in vitro studies show that DHT increases localization of NLK in nucleoli of LNCaP. NLK levels in nucleoli negatively correlate with levels of nucleophosmin, a protein involved in regulation of proliferation, in the xenografts and in LNCaP cells in vitro. Interestingly we have also shown that in vitro NLK stimulates wnt signaling in LNCaP cells and this effecst in dependent on expresison of androgen receptor. In summary our data show that NLK expression is altered during prostate cancer progression and that NLK alters androgen receptor and wnt signaling pathways. Further studies to investigate mechanisms of NLK effects and NLK involvement in response to androgen ablation in prostate cancer are ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1937. doi:10.1158/1538-7445.AM2011-1937
Role of phosphoserine phosphatase-like in breast disease in African American women.
Authors: LA Field, B Love, J Kane, B Deyarmin, JA Hooke, RE Ellsworth, CD Shriver
Journal: Cancer Research (2009)

Abstract Abstract #2095 Background: Although breast cancer incidence is higher among Caucasian women (CW), mortality is higher in African American women (AAW). AAW also tend to be diagnosed at a younger age and with larger and more aggressive tumors. Previously, we have found that gene expression patterns in AAW and CW differ in both breast tissues from women without breast disease as well as those from women with invasive breast cancer. Characterization of these differentially expressed genes is critical to understanding breast pathogenesis in AAW.&amp;#x2028; Methods: Total RNA was isolated from breast tissue from 29 AAW and 26 CW without evidence of breast disease using the RNeasy Lipid Tissue Midi kit (Qiagen) and from laser microdissected primary breast tumors from 23 AAW and 24 CW using the RNAqueous Micro kit (Ambion). Based on earlier microarray results, genes were selected for validation by quantitative real-time PCR using TaqMan Gene Expression Assays (Applied Biosystems). All TaqMan assays were performed on duplicate samples using the iCycler Real-Time Detection System (Bio-Rad). Relative expression levels were determined using the Comparative Ct Method. A Wilcoxon test was used to determine significance.&amp;#x2028; Results: Among those genes that were confirmed to be differentially expressed in breast tissues from AAW and CW was phosphoserine phosphatase-like, or PSPHL. PSPHL showed significantly higher expression in both disease-free samples as well as primary tumors from AAW when compared to the same sample type from CW. In tissues from disease-free women, the relative level of PSPHL expression was significantly higher in AAW (median = 17.15) compared to CW (median = 0; P&amp;lt;0.000001). Similarly, primary tumors from AAW also had higher levels of PSPHL expression (median = 42.22) compared to those from CW (median = 0; P&amp;lt;0.0005).&amp;#x2028; Discussion: The current study has confirmed that expression of PSPHL is significantly higher in both disease-free and invasive breast tissues from AAW than those from CW. Recently, PSPHL has also been shown to have higher expression in prostate tumors from African American men than those from Caucasian men. The function of PSPHL is unknown; however, its increased expression has been associated with aberrant cellular proliferation and cell cycle progression in Fanconi anemia. Higher expression of PSPHL in both normal and diseased breast tissues may, therefore, increase cellular proliferation, contributing to the initial development and/or aggressiveness of breast tumors in AAW. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2095.
1086 TUMOR-INFILTRATING IL-10 PRODUCING CELLS ARE POTENT SUPPRESSORS OF THE LOCAL ANTI-TUMOR IMMUNITY IN PATIENTS WITH LIVER CANCER
Authors: A. Pedroza-Gonzalez, J. Kwekkeboom, E. Vargas-Mendez, C. Verhoef, J. de Jonge, K. Biermann, J.N.M. Ijzermans, H.L.A. Janssen, D. Sprengers
Journal: Journal of Hepatology (2013)
Compartmentalization of the adenosine pool of dog and rat hearts.
Authors: R A Olsson, D Saito, C R Steinhart
Journal: Circulation Research (1982)

Studies in rat and dog hearts examined the hypothesis that the cardiac adenosine pool contains an intracellular compartment.Enzymatically dispersed rat cardiocytes contain 70 pmol adenosine/mg protein which is resistant to 10 LJ/ml adenosine deaminase (ADA).Incubating dog heart homogenates for 1 minute at 37°C with 10 U ADA/mL did not change adenosine levels perceptibly from the average control value of 1.28 nmol/g.Studies employing [ 3 H]hypoxanthine arabinoside as an adenosine surrogate showed that this nucleoside penetrates into pericardia!superfusates, attaining concentrations equal to those in blood plasma by 30 minutes.Since blood, cardiac interstitium, and pericardial superfusate are three compartments in series, this validates the use of pericardial superfusates equilibrated for >30 min as probes of cardiac interstitial composition.In eight dogs, pericardial superfusate adenosine concentration averaged 0.24 JUM.Cardiac muscle adenosine content averaged 0.87 nmol/g, indicating that the interstitial compartment accounts for only 6% of the cardiac pool.Dog cardiac muscle contains a [ 3 H]adenosine binding protein whose size, affinity for adenosine analogs, and ability to synthesize S-adenosylhomocysteine (AdoHcy) suggest it is S-adenosylhomocysteine hydrolase (SAH).Studies employing a dog erythrocyte model show that adenosine is bound to a protein in this cell; treatment with L-homocysteine greatly reduces the amount of adenosine recovered.The half-time for the dissociation of [ 3 H]adenosine from SAH at 37°C is 2.5 hours, and in the presence of ADA is >6 hours.Thus, although adenosine bound to SAH can serve as a substrate for AdoHcy synthesis, this experiment does not support the idea that the dissociation of adenosine occurs to a physiologically significant extent.Thus, we are uncertain of the functional role of the intracellular adenosine compartment.
Direct Cell-To-Cell Interactions Between Osteocytes and Multiple Myeloma (MM) Cells Upregulate Sost and Downregulate OPG Expression In Osteocytes: Evidence For Osteocytic Contributions To MM-Induced Bone Disease
Authors: Jesus Delgado Calle, Teresita Bellido, G. David David Roodman
Journal: Blood (2013)
PRELIMINARY REPORTS
Authors: HARBHAJAN SINGH, RICHARD M. FREE
Journal: American Journal of Psychiatry (1960)

The combination of a very potent tranquilizer and an energizer was tried on 25 chronic regressed, withdrawn, patients with various diagnoses. Eight of the patients had to be dropped from the study because of complications. The results of the present pilot study are promising; however, the above-mentioned combination of drugs requires further trials and research before more definitive conclusions can be reached.
SAT0133 Delayed Progression of Carotid Intima Media Thickness in Patients with Rheumatoid Arthritis: 1-Year Results of the FRANCIS Study
Authors: D. Van Breukelen, M. Castro Cabezas, B. Klop, M.A. de Vries, N. van der Meulen, J. van der Arend, G.-J.M. van de Geijn, H.W. Janssen, C. van Casteren-Messidoro, E. Birnie, M.J. Hazes, J. van Zeben
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Rheumatoid arthritis (RA) is recognized as an independent cardiovascular risk factor. Guidelines for cardiovascular risk (CVR) management, advise aggressive treatment in RA. Tight treatment for CVR factors in RA is not standard care and there are no prospective data. <h3>Objectives</h3> To investigate the efficacy of CVR intervention in RA patients participating in the FRANCIS study. FRANCIS is a prospective, randomized, single centre study in RA, initiated before the guidelines advocating CVR treatment in RA patients became available. <h3>Methods</h3> RA patients ≤70 years old with a CVR score &lt;20% and without the presence of clinical cardiovascular disease or diabetes mellitus were included. Patients were randomized to a treat-to-target (TTT) or standard care. TTT consisted of dietary and lifestyle advice and a targeted intervention for blood pressure, lipids and glucose. Patients in the standard care group were referred to their general practitioner with a letter containing treatment advice. Patients underwent a standard physical examination, measurement of carotid intima media thickness (cIMT) and determination of the rheumatoid arthritis activity score (DAS28). Standard laboratory measurements including a complete lipid profile were measured. Both groups visited the outpatient clinic every six months. <h3>Results</h3> In total 318 patients were included of whom 219 patients (69%) had a completed baseline and 1-year follow up data set. 106 patients received standard care and 113 treat-to-target. At baseline there was no difference between usual care and tight control in systolic BP, LDL-C, HDL-C, apoB, triglycerides, glucose cIMT and DAS28. After 1-year of follow up, the LDL-C, apoB levels and systolic BP were lower in both groups. The decrease in LDL-C after one year was significantly greater in the treat-to-target group compared to standard care (-0.7±0.8mmol/L vs.-0.2±1.0mmol/L; P&lt;0.001). The change in systolic BP was not significantly different (-4.7±15,2 mmHg vs. -4.1±18.3mmHg; P=0.79). cIMT increased significantly in the standard care group (+0.019±0.013mm; P=0.01), but not in the treat-to-target group (+0.010±0.059mm; P=0.09). <h3>Conclusions</h3> This is the first prospective study in RA showing that a structured cardiovascular intervention program leads to lower LDL-C levels, and delayed progression of cIMT after 12 months. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1631
Abstract 3868: Long-term inhibition of cells at metaphase with intact mitotic spindles results in unscheduled chromatid separation and catastrophic arrest in mitosis
Authors: John R. Daum, Sushama Sivakumar, Jeremy J. Daniel, Jennifer N. McAvoy, Tamara A. Potapova, Gary J. Gorbsky
Journal: Cancer Research (2010)

Abstract In the presence of unaligned chromosomes or other spindle abnormalities, the mitotic spindle checkpoint blocks both chromatid separation at anaphase and exit from mitosis. The spindle checkpoint is sustained by signaling from kinetochores that are not properly attached to microtubules of the mitotic spindle. Normally, when chromosomes align at the spindle equator at metaphase, microtubule-kinetochore interactions act to extinguish checkpoint signaling. The cessation of the checkpoint signal activates the Anaphase-Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase. The APC/C ubiquitylates the mitotic effectors, securin and cyclin B, which are then degraded by the proteasome. Securin and cyclin B degradation initiates chromatid separation at anaphase and triggers mitotic exit. We have found that long-term arrest of Hela cells with their chromosomes aligned at the metaphase plate results in chromatid separation without mitotic exit. Recently, we and others have characterized C13orf3/Ska3, a newly discovered component of the Ska (Spindle and kinetochore-associated) protein complex. We found that in mitosis Ska3 protein accumulates at kinetochores reaching maximal levels at metaphase. Upon anaphase onset, kinetochore-associated Ska3 levels decline and are eventually lost at telophase. We demonstrated that cells depleted of Ska3 by RNAi achieve metaphase alignment but fail to silence the spindle checkpoint. During this mitotic arrest with chromosomes aligned at the metaphase plate, kinetochores retain robust microtubule attachments. Kinetochores within these Ska3-depleted cells accumulate abnormally high levels of the mitotic spindle checkpoint protein, Bub1, presumably accounting for the inability to silence the checkpoint. Under extended metaphase arrest, the chromatids of individual chromosomes eventually separate, but cells remain arrested in mitosis. To test if other means of inducing metaphase arrest would also lead to chromatid separation, we treated cells in mitosis with the proteasome inhibitor, MG132. Again, after several hours at metaphase, chromatids separated. We speculate that for cells arrested at metaphase, continual pulling forces of the kinetochores on the mitotic spindle eventually overcomes the cohesin complex that holds chromatids together. This “cohesin slippage” results in abnormal chromatid separation for cells still in mid-mitosis. This response reflects a novel terminal phenotype for cells arrested in mitosis with an intact mitotic spindle. (Supported by the NIGMS and the McCasland Foundation.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3868.
775 VIROLOGICAL RESPONSE DOES NOT LOWER LIVER DISEASE PROGRESSION AMONG CHRONIC HEPATITIS B CIRRHOTIC PATIENTS TREATED WITH LONG-TERM NUCLEOS(T)IDE-ANALOGUE
Authors: P.S. Tan, Y.Y. Dan, Y.M. Lee, K. Lim, G.H. Lee, H.C. Low, M.A. Thwin, S.G. Lim
Journal: Journal of Hepatology (2013)
Abstract 5280: Exchange protein activated by cAMP (Epac) accelerates melanoma cell migration through Ca 2+-dependent actin assembly
Authors: Erdene Baljinnyam, Martha Nowycky, Kousaku Iwatsubo
Journal: Cancer Research (2010)

Abstract Background: We previously reported that Epac, a guanine nucleotide exchange factor directly activated by cAMP, increases melanoma cell migration through Ca2+ elevation. Both Epac-induced cell migration and Ca2+ elevation were reduced by pharmacological inhibition of phospholipase C (PLC) and inositol triphosphate (IP3) receptor. Accordingly, we studied the involvement of PLC/IP3 receptor in Epac-induced Ca2+ elevation by knockdown of these molecules. However, the mechanism how Epac-induced Ca2+ elevation mediates melanoma cell migration is unknown. Here, we investigate the effect of Epac induced-Ca2+ elevation on actin assembly, which plays a major role in cell migration. Methods: SK-Mel-2, a cell line from human metastatic melanoma, was used in this study. Intracellular Ca2+ was measured with Fura-2AM fluorescent dye. Cell migration was examined with the Boyden chambers. IP3 production was examined by IP3 radioimmunoassay. Actin assembly was examined by immunocytochemistry. In some experiments, ablation of a target protein with lentivirus-based shRNA induction system was performed. Results: 8-pMeOPT-2′-O-Me-cAMP (8-pMeOPT), an Epac-specific agonist, increased Ca2+ and cell migration in SK-Mel-2. Such Ca2+ elevation and cell migration was negated by ablation of PLCε or IP3 receptor 1. In addition, Epac-induced IP3 production was inhibited by U73122, a PLC inhibitor, and ablation of PLCε. These data suggest that Epac increases Ca2+, and thus cell migration, via the PLCε/IP3 receptor 1 signaling pathway. Cytochalasin D, an actin assembly inhibitor, reduced 8-pMeOPT-induced cell migration. In addition, immunocytochemistry showed that 8-pMeOPT increases actin assembly. When U73122 or Xestopongin C, an IP3 receptor inhibitor, was used, Epac-induced actin assembly was decreased. These data suggest that Epac-induced Ca2+ elevation mediates actin assembly. Further, immunoprecipitation showed that 8-pMeOPT increased physical interaction of myosin heavy chain IIA (MHCIIA), which enhances actin assembly, with S100A4, a Ca2+-binding protein which activates MHCIIA. These data suggest that Epac-induced Ca2+ elevation mediates actin assembly via the S100A4/MHCIIA signaling pathway. Conclusion: Epac increases Ca2+ via the PLCε/IP3 receptor 1 pathway. Also, Epac-induced Ca2+ elevation mediates melanoma cell migration via actin assembly. These data suggested that Epac could be a target for treating patients with melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5280.