tbuckley/cabot-search huggingface dataset:
TNFα and IL-17 cooperatively stimulate glucose metabolism and growth factor production in human colorectal cancer cells
Authors: Daniel S Straus
Journal: Molecular Cancer (2013)

Inflammation is a well-known etiological factor for colorectal cancer, but mechanisms underlying the linkage between inflammation and cancer are incompletely understood. We hypothesized that two pro-inflammatory cytokines, TNFα and IL-17, might play a role in promoting colorectal carcinogenesis. Aerobic glycolysis is a metabolic adaptation that promotes the survival/proliferation of cancer cells. Paracrine signaling between tumor cells and cancer-associated fibroblasts also plays a role in carcinogenesis.The effect of TNFα and IL-17 on aerobic glycolysis and growth factor production in cultured human colorectal cancer cells was investigated. Glucose utilization and lactate production were quantified by measuring the disappearance of glucose and appearance of lactate in the culture medium. Glucose transporter and glycolytic enzyme expression levels were measured by immunoblotting.TNFα and IL-17 cooperatively stimulated glycolysis in HT-29, T84, Caco-2 and HCT116 colorectal cancer cells. Treatment of HT-29 cells with TNFα plus IL-17 also increased the expression of HIF-1α and c-myc, two factors know to induce the transcription of genes encoding components of the glycolytic pathway. To further investigate mechanisms for cytokine-stimulated glycolysis, the effects of TNFα and IL-17 on expression of six members and one regulator of the glycolytic pathway were investigated. TNFα and IL-17 cooperatively increased the expression of the glucose transporter SLC2A1 and hexokinase-2 but did not regulate expression of glucose transporter SLC2A3, enolase-1, pyruvate kinase M2, lactate dehydrogenase A, or 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Experiments with inhibitors indicated that HIF-1α played a role in induction of SLC2A1 and that the transcription factor NF-κB played a role in induction of hexokinase-2 by TNFα and IL-17. TNFα and IL-17 also synergistically stimulated production by HT-29 cells of a growth factor that simulated proliferation/survival of NIL8 fibroblastic cells. The activity of this factor was not specifically inhibited by the EGFR inhibitor AG1478, indicating that it is not an EGFR ligand.Chronic inflammation is known to promote colorectal tumorigenesis. The pro-inflammatory cytokines TNFα and IL-17 may contribute to this effect by stimulating glycolysis and growth factor production in colorectal cancer cells.
A KCNE2 mutation in a patient with cardiac arrhythmia induced by auditory stimuli and serum electrolyte imbalance
Authors: Earl Gordon, Gianina Panaghie, Liyong Deng, Katharine J. Bee, Torsten K. Roepke, Trine Krogh-Madsen, David J. Christini, Harry Ostrer, Craig T. Basson, Wendy Chung, Geoffrey W. Abbott
Journal: Cardiovascular Research (2007)

AimsAuditory stimulus-induced long QT syndrome (LQTS) is almost exclusively linked to mutations in the hERG potassium channel, which generates the IKr ventricular repolarization current. Here, a young woman with prior episodes of auditory stimulus-induced syncope presented with LQTS and ventricular fibrillation (VF) with hypomagnesaemia and hypocalcaemia after completing a marathon, followed by subsequent VF with hypokalaemia. The patient was found to harbour a KCNE2 gene mutation encoding a T10M amino acid substitution in MiRP1, an ancillary subunit that co-assembles with and functionally modulates hERG. Other family members with the mutation were asymptomatic, and the proband had no mutations in hERG or other LQTS-linked cardiac ion channel genes. The T10M mutation was absent from 578 unrelated, ethnically matched control chromosomes analysed here and was previously described only once—in an LQTS patient—but not functionally characterized.
Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate
Authors: Edward C Keystone, Peter C Taylor, Edit Drescher, Douglas E Schlichting, Scott D Beattie, Pierre-Yves Berclaz, Chin H Lee, Rosanne K Fidelus-Gort, Monica E Luchi, Terence P Rooney, William L Macias, Mark C Genovese
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. <h3>Methods</h3> In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12–24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. <h3>Results</h3> Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p&lt;0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. <h3>Conclusions</h3> Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. <h3>Trial registration number</h3> NCT01185353.
Nuclear Janus-Activated Kinase 2/Nuclear Factor 1-C2 Suppresses Tumorigenesis and Epithelial-to-Mesenchymal Transition by Repressing Forkhead Box F1
Authors: Jeanette Nilsson, Khalil Helou, Anikó Kovács, Pär-Ola Bendahl, Gunnar Bjursell, Mårten Fernö, Peter Carlsson, Marie Kannius-Janson
Journal: Cancer Research (2010)

Progression to metastasis is the proximal cause of most cancer-related mortality. Yet much remains to be understood about what determines the spread of tumor cells. This paper describes a novel pathway in breast cancer that regulates epithelial-to-mesenchymal transition (EMT), motility, and invasiveness. We identify two transcription factors, nuclear factor 1-C2 (NF1-C2) and Forkhead box F1 (FoxF1), downstream of prolactin/nuclear Janus-activated kinase 2, with opposite effects on these processes. We show that NF1-C2 is lost during mammary tumor progression and is almost invariably absent from lymph node metastases. NF1-C2 levels in primary tumors correlate with better patient survival. Manipulation of NF1-C2 levels by expression of a stabilized version or using small interfering RNA showed that NF1-C2 counteracts EMT, motility, invasiveness, and tumor growth. FoxF1 was found to be a direct repressed target of NF1-C2. We provide the first evidence for a role of FoxF1 in cancer and in the regulation of EMT in cells of epithelial origin. Overexpression of FoxF1 was associated with a mesenchymal phenotype, increased invasiveness in vitro, and enhanced growth of breast carcinoma xenografts in nude mice. The relevance of these findings is strengthened by the correlation between FoxF1 expression and a mesenchymal phenoype in breast cancer cell isolates, consistent with the interpretation that FoxF1 promotes invasion and metastasis.
Cyclin-Dependent Kinase 5 Is Amplified and Overexpressed in Pancreatic Cancer and Activated by Mutant K-Ras
Authors: John P. Eggers, Paul M. Grandgenett, Eric C. Collisson, Michelle E. Lewallen, Jarrod Tremayne, Pankaj K. Singh, Benjamin J. Swanson, Judy M. Andersen, Thomas C. Caffrey, Robin R. High, Michel Ouellette, Michael A. Hollingsworth
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression. Experimental Design: We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer. Results: Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K-Ras (G12D) that involves mitogen-activated protein/extracellular signal–regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels. Conclusion: These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells. Clin Cancer Res; 17(19); 6140–50. ©2011 AACR.
Beta-blockers in bronchial asthma: effect of propranolol and pindolol on large and small airways.
Authors: D Patakas, V Argiropoulou, G Louridas, V Tsara
Journal: Thorax (1983)

In 11 asthmatic subjects the relative magnitude and the site of airway bronchoconstriction were compared after the oral administration of 40 mg of propranolol and 2.5 mg of pindolol and the magnitude and site of bronchodilation produced by 0.5 mg subcutaneous terbutaline were tested after pretreatment with propranolol and pindolol. Specific airway conductance (sGaw) and peak expiratory flow rate (PEFR), both believed to reflect changes in large airways, and capacity isoflow (Ciso-v) and delta Vmax50, both believed to reflect changes in small airways, were determined before and after administration of placebo, pindolol, and propranolol. Treatments were given double blind and in random order. After the administration of propranolol we noted a significant bronchoconstrictive effect in the large airways (mean values of PEFR and sGaw, expressed as percentages of control values, decreased by 87.4% +/- 13.2% and 43.3% +/- 8.9%) and in the small airways (mean value of Ciso-v increased by 20.6% +/- 4.7% and that of delta Vmax50 decreased by 50% +/- 11.9% of control). By contrast, pindolol produced no significant effect on sGaw or PEFR but the tests of small airway function showed significant bronchoconstriction (mean values of Ciso-v increased by 12.9% +/- 2.6% and those of delta Vmax50 decreased by 47.2% +/- 9.2%). This action makes pindolol potentially dangerous in asthmatic patients. The bronchodilator action of terbutaline on large airways is diminished after the use of both propranolol and pindolol.
THE DETERMINATION OF LUNG VOLUME WITHOUT FORCED BREATHING
Authors: Donald D. Van Slyke, Carl A. L. Binger
Journal: The Journal of Experimental Medicine (1923)

1. A method is described for the determination of lung volumes without forced breathing. 2. The method determined total capacity and its subdivisions coincidently. 3. The values obtained were independent of the length of time during which the subject rebreathed after gas mixture was once established. 4. The maximum error of the method is estimated at +/- 3 per cent of the lung volume determined. Considerably greater variation from the mean may be encountered, however, because of inconstancy in the lung positions assumed by the subject.
Cleavable ErbB4 Isoform in Estrogen Receptor–Regulated Growth of Breast Cancer Cells
Authors: Teemu T. Junttila, Maria Sundvall, Mikael Lundin, Johan Lundin, Minna Tanner, Pirkko Härkönen, Heikki Joensuu, Jorma Isola, Klaus Elenius
Journal: Cancer Research (2005)

Abstract ErbB1 and ErbB2 receptors are well-characterized targets for anticancer drugs, but the clinical relevance of the related ErbB4 receptor is unknown. Here, we have assessed the clinical significance of the proteolytically cleavable ErbB4 isoforms in breast cancer patients and investigated their functions in vitro. The expression of transcripts encoding the cleavable ErbB4 isoforms associated with estrogen receptor-α (ER) expression (P &amp;lt; 0.001) and a high histologic grade of differentiation (P ≤ 0.002) in real-time reverse transcription-PCR analysis of 62 breast cancer samples. Despite high ErbB4 mRNA expression levels in a subset of samples, ErbB4 gene amplification was not observed. High ErbB4 protein expression levels, as assessed by immunohistochemistry, associated with a favorable outcome in ER-positive cases from a series of 458 breast cancer patients (P = 0.01), whereas no association between ErbB4 expression and survival was found among women with ER-negative cancer (P = 0.86). However, nuclear ErbB4 immunoreactivity was associated with poor survival as compared with women whose cancer had membranous ErbB4 staining (P = 0.04). In vitro, overexpression of a cleavable ErbB4 isoform in ER-positive breast cancer cells resulted in translocation of a proteolytically released intracellular ErbB4 receptor fragment into the nucleus, as well as, enhanced proliferation, anchorage-independent growth, and estrogen response element–mediated transcriptional activity. These results suggest that the association of ErbB4 expression with clinical outcome is dependent on the subcellular localization of ErbB4 and that a proteinase-cleavable ErbB4 isoform promotes growth of ER-positive breast cancer and enhances ER-mediated gene transcription.
Acidosis, non-invasive ventilation and mortality in hospitalised COPD exacerbations
Authors: C. M. Roberts, R. A. Stone, R. J. Buckingham, N. A. Pursey, D. Lowe
Journal: Thorax (2010)

<h3>Background</h3> Reports of non-invasive ventilation (NIV) use in clinical practice reveal higher mortality rates than in corresponding randomised clinical trials. <h3>Aim</h3> To explore factors related to chronic obstructive pulmonary disease (COPD) admissions and NIV use that may explain some of the previously reported high mortality rates. <h3>Methods</h3> National UK audit of clinical care of consecutive COPD admissions from March to May 2008. Retrospective case note audit with prospective case ascertainment. Participating units completed a web-based audit proforma of process and outcomes of clinical care. <h3>Results</h3> 232 hospital units collected data on 9716 patients, mean age 73, 50% male. 1678 (20%) of those with gases recorded on admission were acidotic and another 6% became acidotic later. 1077 patients received NIV, 55% had a pH&lt;7.26 and 49% (305/618) had or were still receiving high flow oxygen. 30% (136/453) patients with persisting respiratory acidosis did not receive NIV while 11% (15/131) of acidotic admissions had a pure metabolic acidosis and did. Hospital mortality was 25% (270/1077) for patients receiving NIV but 39% (86/219) for those with late onset acidosis and was higher in all acidotic groups receiving NIV than those treated without. Only 4% of patients receiving NIV who died had invasive mechanical ventilation. <h3>Conclusions</h3> COPD admissions treated with NIV in usual clinical practice were severely ill, many with mixed metabolic acidosis. Some eligible patients failed to receive NIV, others received it inappropriately. NIV appears to be often used as a ceiling of treatment including patient groups in whom efficacy of NIV is uncertain. The audit raises concerns that challenge the respiratory community to lead appropriate clinical improvements across the acute sector.
Distinct roles for Syk and ZAP-70 during early thymocyte development
Authors: Emil H. Palacios, Arthur Weiss
Journal: The Journal of Experimental Medicine (2007)

The spleen tyrosine kinase (Syk) and ζ-associated protein of 70 kD (ZAP-70) tyrosine kinases are both expressed during early thymocyte development, but their unique thymic functions have remained obscure. No specific role for Syk during β-selection has been established, and no role has been described for ZAP-70 before positive selection. We show that Syk and ZAP-70 provide thymocytes with unique and separable fitness advantages during early development. Syk-deficient, but not ZAP-70–deficient, thymocytes are specifically impaired in initial pre-TCR signaling at the double-negative (DN) 3 β selection stage and show reduced cell-cycle entry. Surprisingly, and despite overlapping expression of both kinases, only ZAP-70 appears to promote sustained pre-TCR/TCR signaling during the DN4, immature single-positive, and double-positive stages of development before thymic selection occurs. ZAP-70 promotes survival and cell-cycle progression of developing thymocytes before positive selection, as also shown by in vivo anti-CD3 treatment of recombinase-activating gene 1–deficient mice. Our results establish a temporal separation of Syk family kinase function during early thymocyte development and a novel role for ZAP-70. We propose that pre-TCR signaling continues during DN4 and later stages, with ZAP-70 dynamically replacing Syk for continued pre-TCR signaling.
Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies
Authors: Zhaoyang Li, Kenisha Younger, Ronald Gartenhaus, Ann Mary Joseph, Fang Hu, Maria R. Baer, Patrick Brown, Eduardo Davila
Journal: Journal of Clinical Investigation (2015)

Signaling via the MyD88/IRAK pathway in T cells is indispensable for cell survival; however, it is not known whether this pathway functions in the progression of T acute lymphoblastic leukemia (T-ALL). Here, we determined that compared with thymic and peripheral T cells, T-ALL cells from patients have elevated levels of IRAK1 and IRAK4 mRNA as well as increased total and phosphorylated protein. Targeted inhibition of IRAK1 and IRAK4, either with shRNA or with a pharmacological IRAK1/4 inhibitor, dramatically impeded proliferation of T-ALL cells isolated from patients and T-ALL cells in a murine leukemia model; however, IRAK1/4 inhibition had little effect on cell death. We screened several hundred FDA-approved compounds and identified a set of drugs that had enhanced cytotoxic activity when combined with IRAK inhibition. Administration of an IRAK1/4 inhibitor or IRAK knockdown in combination with either ABT-737 or vincristine markedly reduced leukemia burden in mice and prolonged survival. IRAK1/4 signaling activated the E3 ubiquitin ligase TRAF6, increasing K63-linked ubiquitination and enhancing stability of the antiapoptotic protein MCL1; therefore, IRAK inhibition reduced MCL1 stability and sensitized T-ALL to combination therapy. These studies demonstrate that IRAK1/4 signaling promotes T-ALL progression through stabilization of MCL1 and suggest that impeding this pathway has potential as a therapeutic strategy to enhance chemotherapeutic efficacy.
Culture of mononuclear phagocytes on a teflon surface to prevent adherence.
Authors: J W van der Meer, D Bulterman, T L van Zwet, I Elzenga-Claasen, R van Furth
Journal: The Journal of Experimental Medicine (1978)

A method is described for the culture of mononuclear phagocytes in suspension by incubation on a Teflon film to which the cells do not adhere. The characteristics of peritoneal macrophages, bone marrow mononuclear phagocytes, macrophage cell lines, and fibroblasts cultured in this way are similar to those observed after culture on glass or plastic surfaces. Culture of mononuclear phagocytes in Teflon film dishes has three important advantages: the cells can be easily harvested without damage, recovery is almost complete, and the cells are not functionally impaired. Thus, this method makes it possible to use cultured mononuclear phagocytes for many studied that could previously only be done in freshly collected cells.
Prostaglandin E1 prevents increased lung microvascular permeability during intravascular complement activation in sheep.
Authors: M H Gee, M V Tahamont, J T Flynn, J W Cox, R H Pullen, N A Andreadis
Journal: Circulation Research (1987)

Prostaglandin E1 (PGE1) inhibits a variety of functions of activated neutrophils including respiratory burst, release of leukotriene B4, and adherence to endothelial cells. To determine if PGE, alters the pathophysiology of complement-induced lung vascular injury, experiments were conducted in anesthetized sheep with lung lymph fistulas given a 1-hour infusion of zymosan-activated plasma. PGE1 (30 ng/min/kg) or its saline vehicle was infused intravenously for 90 minutes beginning 30 minutes before the infusion of activated plasma. PGE1 had no effect on leukocyte count, the initial hypoxemia and thromboxane A2 release, or the development of acute pulmonary hypertension. However, PGE1 prevented steady-state increases in lung lymph flow that in vehicle-treated sheep signaled an increase in lung microvascular permeability. Furthermore, extraction of PGE1 by pulmonary endothelial cells was unaffected by the infusion of activated plasma. We propose that PGE1 prevented the increase in lung vascular permeability by inhibiting adherence of activated neutrophils to endothelial cells.
Immunosuppression Studies in Foreign Body Tumorigenesis: No Evidence for Tumor-Specific Antigenicity2
Authors: Virginia J. Michelich, Lance C. Buoen, K. Gerhard Brand
Journal: JNCI Journal of the National Cancer Institute (1977)

Sarcomas were induced in CBA/H mice by sc implantation of 15 X 22 X 0.2-mm polyvinyl chloride vinyl acetate copolymer films. The animals were immunosuppressed with azathoprine, antilymphocyte globulin, or thymectomy. Sarcoma development was not accelerated in comparison to nonimmunosuppressed demonstrated in sarcomas of immunosuppressed mice. It was concluded that foreign body tumorigenesis in mice in neither associated with nor dependent on the emergence of tumor-specific transplantation antigens.