tbuckley/cabot-search huggingface dataset:
Molecular studies on two variant repeat types of the common cetacean DNA satellite of the sperm whale, and the relationship between Physeteridae (sperm whales) and Ziphiidae (beaked whales).
Authors: S Grétarsdóttir, U Arnason
Journal: Molecular Biology and Evolution (1993)

In the sperm whale (Physeter macrocephalus) two different repeat types (A and B) of the common cetacean DNA satellite were identified. The evolution of each group of repeats appears to be independent from that of the other. The sequence similarity between the two groups is less than the similarity between group A and repeats of the satellite in related whale species. The systematic relationship within and between the families Physeteridae (sperm whales) and Ziphiidae (beaked whales) was addressed by both sequence analysis of the satellite and comparisons with the families Delphinidae and Phocoenidae. The mysticete blue whale (Balaenoptera musculus) was used as an outgroup in the comparisons. The molecular phylogeny, when maximum-parsimony analysis and the neighbor-joining method were used, grouped together species of each family. At the family level the ziphiids grouped closet to the families Phocoenidae and Delphinidae. The similarities between the common cetacean satellite of the blue whale and the sperm whale were greater than those between the blue whale and the other odontocetes included, suggesting that the evolution of the satellite is slower in the sperm whale than in the other odontocetes.
FAM3A activates PI3K p110α/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis
Authors: Chunjiong Wang, Yujing Chi, Jing Li, Yifei Miao, Sha Li, Wen Su, Shi Jia, Zhenzhen Chen, Shengnan Du, Xiaoyan Zhang, Yunfeng Zhou, Wenhan Wu, Mingyan Zhu, Zhiwei Wang, Huaqian Yang, Guoheng Xu, Shiqiang Wang, Jichun Yang, Youfei Guan
Journal: Hepatology (2013)

FAM3A belongs to a novel cytokine-like gene family, and its physiological role remains largely unknown. In our study, we found a marked reduction of FAM3A expression in the livers of db/db and high-fat diet (HFD)-induced diabetic mice. Hepatic overexpression of FAM3A markedly attenuated hyperglycemia, insulin resistance, and fatty liver with increased Akt (pAkt) signaling and repressed gluconeogenesis and lipogenesis in the livers of those mice. In contrast, small interfering RNA (siRNA)-mediated knockdown of hepatic FAM3A resulted in hyperglycemia with reduced pAkt levels and increased gluconeogenesis and lipogenesis in the livers of C57BL/6 mice. In vitro study revealed that FAM3A was mainly localized in the mitochondria, where it increases adenosine triphosphate (ATP) production and secretion in cultured hepatocytes. FAM3A activated Akt through the p110α catalytic subunit of PI3K in an insulin-independent manner. Blockade of P2 ATP receptors or downstream phospholipase C (PLC) and IP3R and removal of medium calcium all significantly reduced FAM3A-induced increase in cytosolic free Ca2+ levels and attenuated FAM3A-mediated PI3K/Akt activation. Moreover, FAM3A-induced Akt activation was completely abolished by the inhibition of calmodulin (CaM). Conclusion : FAM3A plays crucial roles in the regulation of glucose and lipid metabolism in the liver, where it activates the PI3K-Akt signaling pathway by way of a Ca2+/CaM-dependent mechanism. Up-regulating hepatic FAM3A expression may represent an attractive means for the treatment of insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). (Hepatology 2014;59:1779–1790)
Interleukin-21-Producing CD4+ T Cells Promote Type 2 Immunity to House Dust Mites
Authors: Jonathan M. Coquet, Martijn J. Schuijs, Mark J. Smyth, Kim Deswarte, Rudi Beyaert, Harald Braun, Louis Boon, Gunilla B. Karlsson Hedestam, Steven L. Nutt, Hamida Hammad, Bart N. Lambrecht
Journal: Immunity (2015)
Abstract 585: A Novel LXR Ligand Reduces LDL Cholesterol in Monkey
Authors: Elaine Quinet, Michael D Basso, Anita R Halpern, Robert J Steffan, David W Yates, Elizabeth DiBlasio-Smith, William M Mounts, Edward LaVallie, Jay Wrobel, Ponnal Nambi
Journal: Circulation (2007)

LXRs act as a transcriptional master switch for coordinate regulation of gene expression involved in cellular cholesterol homeostasis encompassing cholesterol transport, catabolism and absorption. ...
Abstract 4074: Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation
Authors: Hyemin Kim, Yejin Kim, Jiwon Choi, Mirim Jang, Jiyea Choi, Young-il Hwang, Jae Seung Kang, Wang Jae Lee
Journal: Cancer Research (2014)

Abstract It is recently reported that CD40-CD40 ligand (CD40L) interaction is important to Th17 development. Also, it is known that transforming growth factor-beta (TGF-β) promotes tumorigenesis as an immunosuppressive cytokine and is crucial for the development of Th17. In this study, we investigated the role of CD40 on breast cancer cells and its role on the immune suppressive function and tumor progression. CD40 stimulation on breast cancer cell line, MDA-MB231, caused up-regulation of TGF-β, and direct CD40-CD40L interaction between breast cancer cells and activated T cells increased TFG-β production. Moreover, direct interaction of CD40-CD40L induced the production of IL-17, which increased the proliferation of MDA-MB231 cells via the activation of STAT3. Therefore, direct CD40-CD40L interaction of breast tumor and activated T cells increases the TGF-β production and the differentiation of Th17 cells, which promote the proliferation of breast cancer cells. Citation Format: Hyemin Kim, Yejin Kim, Jiwon Choi, Mirim Jang, Jiyea Choi, Young-il Hwang, Jae Seung Kang, Wang Jae Lee. Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4074. doi:10.1158/1538-7445.AM2014-4074
Modeling Signaling Networks to Advance New Cancer Therapies
Authors: Julio Saez-Rodriguez, Aidan MacNamara, Simon Cook
Journal: Annual Review of Biomedical Engineering (2015)

Cell signaling pathways control cells' responses to their environment through an intricate network of proteins and small molecules partitioned by intracellular structures, such as the cytoskeleton and nucleus. Our understanding of these pathways has been revised recently with the advent of more advanced experimental techniques; no longer are signaling pathways viewed as linear cascades of information flowing from membrane-bound receptors to the nucleus. Instead, such pathways must be understood in the context of networks, and studying such networks requires an integration of computational and experimental approaches. This understanding is becoming more important in designing novel therapies for diseases such as cancer. Using the MAPK (mitogen-activated protein kinase) and PI3K (class I phosphoinositide-3' kinase) pathways as case studies of cellular signaling, we give an overview of these pathways and their functions. We then describe, using a number of case studies, how computational modeling has aided in understanding these pathways' deregulation in cancer, and how such understanding can be used to optimally tailor current therapies or help design new therapies against cancer.
The hardest word: managers and leaders should say sorry too
Authors: David Oliver
Journal: BMJ (2015)

Thymidine phosphorylase (TPase) is one of the key enzymes involved in the pyrimidine nucleoside salvage pathway. However, TPase also stimulates angiogenesis, and its expression correlates well with microvessel density and metastasis in a variety of human tumors. We have shown recently that 5′-<i>O</i>-trityl-inosine (KIN59) allosterically inhibits TPase enzymatic activity. KIN59 also inhibits TPase-induced angiogenesis in the chick chorioallantoic membrane (CAM) assay. The trityl group was found to be instrumental to preserve both the anti-TPase and antiangiogenic effect. We have now synthesized a variety of novel 5′-<i>O</i>-trityl nucleoside derivatives. Enzyme activity studies showed that the anti-TPase activity is significantly improved by replacement of the hypoxanthine base by thymine [3.5-fold; i.e., 5′-<i>O</i>-tritylthymidine (KIN6)] and the introduction of chloride on the trityl group [7-fold; i.e., 5′-<i>O</i>-(4-chlorotrityl)-inosine (TP136)], whereas removal of 2′-hydroxyl in the ribose did not significantly alter the anti-TPase activity. Enzyme kinetic studies also demonstrated that 1-(5′-<i>O</i>-trityl-β-d-ribofuranosyl)-thymine (TP124), like KIN59, inhibits TPase in a noncompetitive fashion both with respect to phosphate and thymidine. Most KIN59 analogs markedly inhibited TPase-induced angiogenesis in the CAM assay. In vitro studies showed that the antiangiogenic effect of these compounds is not attributed to endothelial cell toxicity. For several compounds, there was no stringent correlation between their anti-TPase and antiangiogenic activity, indicating that these compounds may also act on other angiogenesis mediators. The antiangiogenic 5′-<i>O</i>-trityl nucleoside analogs also caused degradation of pre-existing, immature vessels at the site of drug exposure. Thus, 5′-<i>O</i>-trityl nucleoside derivatives combine antiangiogenic and vascular-targeting activities, which opens perspectives for their potential use as anticancer agents.
Slimming on the Internet
Authors: John Miles, Catherine Petrie, Michael Steel
Journal: Journal of the Royal Society of Medicine (2000)

Summary The first 50 websites identified on searching the Internet for ‘weight loss diets’ were assessed systematically and their content compared with published clinical guidelines for management of obesity. The relevance and quality of the sites varied enormously. Only 3 confined themselves to sound dietary advice. Most promoted dietary supplements or other ‘slimming aids’, often of uncertain composition and based on dubious physiological principles. Potential hazards—for example, those of very low calorie diets—were rarely highlighted and certain regimens on offer were potentially dangerous.
Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin's disease.
Authors: S S Donaldson, M P Link
Journal: Journal of Clinical Oncology (1987)

High doses of radiation administered to children with Hodgkin's disease may be associated with long-term alterations in soft tissue and bone growth. In an attempt to minimize this complication, we initiated a protocol using low doses of radiation in conjunction with six cycles of MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy in newly diagnosed, pathologically staged children with Hodgkin's disease. Of 55 children treated in this fashion, the actuarial survival and freedom from relapse rates are 89% and 90%, respectively, with median follow-up of 7 1/2 years and maximum follow-up of 15 1/2 years. The local control rate is 97%. The previously encountered growth alteration did not occur when lower doses of radiation were used. However, three children developed acute leukemia. This study demonstrates that the vast majority of children with Hodgkin's disease can be cured with combined modality therapy. This experience provides long-term follow-up and thus serves as the basis for new ongoing protocols using low-dose involved field radiation with new drug combinations.
Late recurrence of testicular cancer.
Authors: N Borge, S D Fosså, S Ous, A E Stenwig, H H Lien
Journal: Journal of Clinical Oncology (1988)

The aim of this study is to draw attention to important points concerning the clinical management of late relapses in testicular cancer. From 1972 to 1982 The Norwegian Radium Hospital (NRH) has treated 1,008 patients with testicular cancer. Fifteen (1.5%) of these patients relapsed 36 months or more after their primary treatment. The patients' medical records were reviewed in this retrospective study, and all available histological sections were reevaluated. Six patients had pure seminoma initially and relapsed after an average of 54.5 months. Five of them had subjective symptoms due to recurrent tumor. Four patients relapsing in the supradiaphragmatic lymph nodes only are alive with no evidence of disease after an observation time of 17 to 30 months after treatment. Nine nonseminoma patients relapsed after an average of 85 months (36 to 194 months). Eight of these were aware of subjective signs or symptoms due to recurrent tumor leading to the diagnosis of the relapse. Four of these patients are alive with no evidence of disease after an observation time of 4 to 46 months after treatment. Two of these patients relapsed with pure mature teratoma. Late relapses do occur although they are rare events. Seminoma patients relapsing in the lymph nodes only have a good prognosis, and nonseminoma patients have a slightly poorer prognosis. Active follow-up for relapse detection is not justified. All testicular cancer patients should instead be informed of typical signs and symptoms that can be related to a relapse and encouraged to seek medical help for further investigation.
Abnormal erythroid maturation leads to microcytic anemia in the TSAP6/Steap3 null mouse model
Authors: Lionel Blanc, Julien Papoin, Gargi Debnath, Michel Vidal, Robert Amson, Adam Telerman, Xiuli An, Narla Mohandas
Journal: American Journal of Hematology (2014)

Genetic ablation of the ferrireductase STEAP3, also known as TSAP6, leads to severe microcytic and hypochromic red cells with moderate anemia in the mouse. However, the mechanism leading to anemia is poorly understood. Previous results indicate that TSAP6/Steap3 is a regulator of exosome secretion. Using TSAP6/Steap3 knockout mice, we first undertook a comprehensive hematologic characterization of the red cell compartment, and confirmed a dramatic decrease in the volume and hemoglobin content of these erythrocytes. We observed marked anisocytosis as well as the presence of fragmenting erythrocytes. Consistent with these observations, we found by ektacytometry decreased membrane mechanical stability of knockout red cells. However, we were unable to document significant changes in the expression levels of the major skeletal and transmembrane proteins to account for this decrease in the membrane stability. Furthermore, there were no differences in red cell survival between wild type and knockout animals. However, when we monitored erythropoiesis, we found a decreased number of proerythroblasts in the bone marrow of TSAP6/Steap3(-/-) animals. In addition, progression from the proerythroblastic to the orthochromatic stage was affected, with accumulation of cells at the polychromatic stage. Altogether, our findings demonstrate that abnormal erythroid maturation is the main cause of anemia in these mice.
Adenosquamous cell carcinoma derived from intraductal papillary mucinous neoplasm of the pancreas confirmed by genetic analysis.
Authors: Hidenori Karasaki, Toru Kono, Yusuke Ono, Taku Maejima, Yusuke Mizukami
Journal: Journal of Clinical Oncology (2015)

275 Background: Adenosquamous cell carcinoma (ASC) is an uncommon histologic variant of pancreatic cancer, representing only 1-4 % of all pancreatic neoplasms. Here we reported the extremely rare case of ASC derived from intraductal papillary mucinous neoplasm (IPMN) of the pancreas with intensive pathological and molecular analysis. Methods: A 72-year-old diabetic male with five-year history of non-alcoholic chronic pancreatitis was admitted to our hospital with complaint of epigastric pain. The patient was diagnosed as pancreatic cancer associated with IPMN and pylorus preserving pancreaticoduodenectomy was performed in April 2012. The resected pancreas was fixed in 10% formaldehyde, and the whole specimen was sliced at a thickness of 5-mm for i) pathological analyses using hematoxylin-eosin (H-E) staining and immunostaining with specific antibodies against MUC-1, -2, -5AC, -6, p63 and CD5/6, and ii) deep sequencing of multiplex PCR amplicons of 50 cancer-associated genes utilizing Ion Torrent PGM platform. DNA was obtained from intraepithelial lesions of IPMN, invasive squamous cell carcinoma (SCC) and adenocarcinoma (AC) after enrichment for neoplastic cellularity, using manual microdissection. Results: Pathological findings showed IPMN extended from main pancreatic duct to branch ducts. The invasive tumor was predominantly consisted of poorly-differentiated SCC and small poorly-differentiated AC was also found in the edge of the SCC. All IPMN area analyzed shared combination of the mutations, KRAS G12D and GNAS R201C . The identical mutations in KRAS and GNAS as IPMNs were also found in SCC and AC. Conclusions: It generally difficult to fully discriminate IPMN-derived cancer (invasive IPMN) from concomitantly and independently developed de novo pancreatic ductal adenocarcinoma (PDA) originating from the “field defect”. In the current case, although SCC is a rare histotype of IPMNs, we considered that the invasive carcinoma was derived from IPMN based on their mutational profile.
Tartrate-Resistant Acid Phosphatase 5b is a Useful Serum Marker for Extensive Bone Metastasis in Breast Cancer Patients
Authors: Tsu-Yi Chao, Jyh-Cherng Yu, Chih-Hung Ku, Mary M. Chen, Su-Huei Lee, Anthony J. Janckila, Lung T. Yam
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Previous studies showed that serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity was increased in 70% to 94% of breast cancer (BC) patients with bone metastasis (BM). This study aims to determine whether serum TRACP5b is useful for identifying limited or extensive BM in BC patients. Experimental Design: Serum TRACP5b activity was measured in 168 BC patients, including 81 who were newly diagnosed with early BC, 20 with extraosseous metastasis, 24 with limited BM, and 43 with extensive BM. Serum TRACP5b activity was also measured monthly in 151 patients with early BC until they developed BM. Four hundred and twenty-seven (427) healthy women ages 18 to 90 served as control. One-way ANOVA was used to compare serum TRACP5b among groups. The sensitivity and specificity of serum TRACP5b as a marker for BM were estimated by receiver operator characteristic (ROC) curves. Results: Serum TRACP5b increased with age in healthy women ( P &amp;lt; 0.0001). It was significantly elevated in patients with extensive BM compared with all other groups ( P &amp;lt; 0.0001). ROC analysis established a cutoff value of 4.026 units/L to identify patients with extensive BM with a specificity of 98% and a sensitivity of 93% (area under the curve = 0.9807; 95% CI = 0.9698-0.9915). Among the 151 patients with early BC, 6 developed limited BM and 2 developed extensive BM during the follow-up period. Serum TRACP5b remained below the cutoff value in patients with limited BM, but became significantly increased in those whose BM became extensive. Conclusion: Serum TRACP5b activity is a useful diagnostic marker for extensive BM in patients with BC.
Abstract 1651: Exercise Improves Aging-associated Myocardial Insulin Resistance by Enhancing Mitochondrial Function in an eNOS Dependent Mechanism
Authors: Qiu X Li, Quan J Zhang, Hai F Zhang, Kun R Zhang, Jia Li, Wen Y Guo, Hai C Wang, Xin L Ma, Feng Gao
Journal: Circulation (2007)

Objective . This study sought to determine whether exercise reduces aging-associated myocardial insulin resistance, with a specific focus on the role of eNOS and its relation to mitochondria. Methods . Aging male Sprague-Dawley rats (24 months) were subjected to swim training (60 min/d, 5 d/wk, 9 wk) or assigned as sedentary control. The myocardial contraction, myocardial glucose uptake, mitochondrial function, and eNOS signaling were determined. Results. Aging rats had myocardial insulin resistance as shown by decreased insulin-induced glucose uptake (0.22±0.05 μmol/min/g in aging heart vs.1.29 ± 0.13 μmol/min/g in adult heart, n=8, P &lt;0.01) and attenuated insulin’s positive inotropic role as evidenced by reduced left ventricular developed pressure (90±12 mmHg in aging heart vs. 155±14 mmHg in adult heart, P &lt;0.01). Mitochondrial function was decreased in aging hearts as manifested by the attenuated maximum O 2 consumption by FCCP (1.85±0.39 μmol/min/g in aging hearts vs. 3.72±0.40 μmol/min/g in adult hearts, P &lt;0.01). This was accompanied with the reduced insulin-induced O 2 consumption (1.37±0.31 μmol/min/g in aging heart vs. 2.35±0.31 μmol/min/g in adult heart, P &lt;0.01). In addition, eNOS expression and its phosphorylation by insulin were reduced by 1.2- and 2.3-fold in aging heart, respectively ( P &lt;0.01). Swim training upregulated eNOS expression by 72% ( P &lt;0.01), facilitated eNOS phosphorylation by insulin ( P &lt;0.01), and improved myocardial insulin sensitivity as shown by enhanced glucose uptake by insulin ( P &lt;0.01). Moreover, mitochondrial function was facilitated as manifested by the enhanced O 2 consumption by insulin ( P &lt;0.05), and maximum O 2 consumption ( P &lt;0.01) following swim training. Pretreatment with Cavtratin, an eNOS inhibitor, abolished exercise-improved mitochondrial response to insulin, blocked exercise-improved myocardial insulin sensitivity and the positive inotropic response to insulin in aging heart. Conclusion . These results demonstrate that impaired eNOS signaling and subsequent mitochondrial depression is a major mechanism contributes to aging-associated myocardial insulin resistance, and that exercise improves insulin sensitivity by restoring eNOS signaling and enhancing mitochondrial function.
The Fundamental Difficulty With Evaluating the Accuracy of Biomarkers for Guiding Treatment
Authors: Holly Janes, Margaret S. Pepe, Lisa M. McShane, Daniel J. Sargent, Patrick J. Heagerty
Journal: JNCI Journal of the National Cancer Institute (2015)

Developing biomarkers that can predict whether patients are likely to benefit from an intervention is a pressing objective in many areas of medicine. Recent guidance documents have recommended that the accuracy of predictive biomarkers, ie, sensitivity, specificity, and positive and negative predictive values, should be assessed. We clarify the meanings of these entities for predictive markers and demonstrate that generally they cannot be estimated from data without making strong untestable assumptions. Language suggesting that predictive biomarkers can identify patients who benefit from an intervention is also widespread. We show that in general one cannot estimate the chance that a patient will benefit from treatment. We recommend instead that predictive biomarkers be evaluated with respect to their ability to predict clinical outcomes among patients treated and among patients receiving standard of care, and the population impact of treatment rules based on those predictions. Ideally these entities are estimated from a randomized trial comparing the experimental intervention with standard of care.
Abstract 5479: PPARgamma Agonist Redirects Macrophage Cholesterol from Fecal Excretion to Adipose Tissue Uptake in Mice
Authors: Sue-Anne Toh, Ilia Fuki, John Millar, Snehal Naik, Jeffrey Billheimer, Colin Macphee, Max Walker, Daniel J Rader
Journal: Circulation (2008)

Peroxisome proliferator activated receptor gamma (PPARγ) agonists, used in the treatment of Type 2 diabetes, can raise HDL-C by 15–20%, but their effect on cardiovascular outcomes is controversial....