tbuckley/cabot-search huggingface dataset:
Acceleration of the Healing Process and Myocardial Regeneration May Be Important as a Mechanism of Improvement of Cardiac Function and Remodeling by Postinfarction Granulocyte Colony–Stimulating Factor Treatment
Authors: Shinya Minatoguchi, Genzou Takemura, Xue-Hai Chen, Ningyuan Wang, Yoshihiro Uno, Masahiko Koda, Masazumi Arai, Yu Misao, Chuanjiang Lu, Koji Suzuki, Kazuko Goto, Ai Komada, Tomoyuki Takahashi, Kenichiro Kosai, Takako Fujiwara, Hisayoshi Fujiwara
Journal: Circulation (2004)

We investigated whether the improvement of cardiac function and remodeling after myocardial infarction (MI) by granulocyte colony-stimulating factor (G-CSF) relates to acceleration of the healing process, in addition to myocardial regeneration.In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 microg x kg(-1) x d(-1) of human recombinant G-CSF (G) was injected subcutaneously from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction, and thicker infarct-LV wall were seen in G at 3 months after MI. At 2, 7, and 14 days and 3 months after MI, necrotic tissue areas were 14.2+/-1.5/13.4+/-1.1, 0.4+/-0.1/1.8+/-0.5*, 0/0, and 0/0 mm2 x slice(-1) x kg(-1), granulation areas 0/0, 4.0+/-0.7/8.5+/-1.0*, 3.9+/-0.8/5.7+/-0.7,* and 0/0 mm2 x slice(-1) x kg(-1), and scar areas 0/0, 0/0, 0/0, and 4.2+/-0.5/7.9+/-0.9* mm2 x slice(-1) x kg(-1) in G and S, respectively (*P<0.05, G versus S). Clear increases of macrophages and of matrix metalloproteinases (MMP) 1 and 9 were seen in G at 7 days after MI. This suggests that G accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs. Meanwhile, surviving myocardial tissue areas within the risk areas were significantly increased in G despite there being no difference in LV weight, LV wall area, or cardiomyocyte size between G and S. Confocal microscopy revealed significant increases of cardiomyocytes with positive 3,3,3',3'-tetramethylindocarbocyanine perchlorate and positive troponin I in G, suggesting enhanced myocardial regeneration by G.The acceleration of the healing process and myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.
Life, death, and varices
Authors: D LEBREC
Journal: Gut (2001)

See article on page 682 

In patients with cirrhosis and portal hypertension, gastrointestinal haemorrhage is a major complication and cause of death. Oesophageal varices are present in approximately 50% of patients with cirrhosis; the prevalence is higher in Child-Pugh C patients than in those with Child-Pugh A-B. Among patients with varices, the risk of gastrointestinal haemorrhage ranges from 30% to 50% and half of these patients die within six weeks after bleeding. Thus 10–15% of unselected patients with cirrhosis die from gastrointestinal bleeding. The number of deaths has decreased in the last few decades as a result of modern techniques (see below). The exact mechanisms of variceal rupture have not yet been determined and thus no ideal treatment has been found. However, haemorrhage has been shown to cause different complications such as sepsis or renal failure which may be responsible for death. In patients admitted for variceal haemorrhage, certain prognostic factors for death have been determined such as age, Child-Pugh C, hepatocellular carcinoma, early rebleeding, hepatic encephalopathy, and renal failure.1 

Ideally, patients admitted for acute variceal haemorrhage must be taken to a medical centre with an emergency facility and an intensive care unit …
Prognosis in Women With Myocardial Ischemia in the Absence of Obstructive Coronary Disease
Authors: B. Delia Johnson, Leslee J. Shaw, Steven D. Buchthal, C. Noel Bairey Merz, Hee-Won Kim, Katherine N. Scott, Mark Doyle, Marian B. Olson, Carl J. Pepine, Jan den Hollander, Barry Sharaf, William J. Rogers, Sunil Mankad, John R. Forder, Sheryl F. Kelsey, Gerald M. Pohost
Journal: Circulation (2004)

We previously reported that 20% of women with chest pain but without obstructive coronary artery disease (CAD) had stress-induced reduction in myocardial phosphocreatine-adenosine triphosphate ratio by phosphorus-31 nuclear magnetic resonance spectroscopy (abnormal MRS), consistent with myocardial ischemia. The prognostic implications of these findings are unknown.Women referred for coronary angiography for suspected myocardial ischemia underwent MRS handgrip stress testing and follow-up evaluation. These included (1) n=60 with no CAD/normal MRS, (2) n=14 with no CAD/abnormal MRS, and (3) n=352 a reference group with CAD. Cardiovascular events were death, myocardial infarction, heart failure, stroke, other vascular events, and hospitalization for unstable angina. Cumulative freedom from events at 3 years was 87%, 57%, and 52% for women with no CAD/normal MRS, no CAD/abnormal MRS, and CAD, respectively (P<0.01). After adjusting for CAD and cardiac risk factors, a phosphocreatine-adenosine triphosphate ratio decrease of 1% increased the risk of a cardiovascular event by 4% (P=0.02). The higher event rate in women with no CAD/abnormal MRS was primarily due to hospitalization for unstable angina, which is associated with repeat catheterization and higher healthcare costs.Among women without CAD, abnormal MRS consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catheterization, and greater treatment costs. Further evaluation into the underlying pathophysiology and possible treatment options for women with evidence of myocardial ischemia but without CAD is indicated.
Production of plasminogen activator by human natural killer cells. Large granular lymphocytes.
Authors: R H Goldfarb, T Timonen, R B Herberman
Journal: The Journal of Experimental Medicine (1984)

In this report we have used highly purified populations of natural killer (NK) cells: large granular lymphocytes (LGL). This study demonstrates that freshly isolated and interleukin 2-cultured LGL produce the specific neutral serine protease, plasminogen activator (PA). We have found that the enzyme is expressed in both an extracellular form as well as in a cell-associated form. Upon subcellular distribution the latter form of the enzyme is associated with a cell-surface membrane-enriched fraction. LGL PA exists in multiple molecular weight forms ranging from 100,000 to 26,000. Interferon (IFN), the major positive regulator of NK cytolytic activity, caused a substantial enhancement of cell-associated, but not extracellular, PA. In contrast, LGL isolated from patients with Chediak-Higashi syndrome, who are known to be defective in NK activity, displayed low PA activity, altered morphology, and low NK killing relative to LGL isolated from normal donors. The possible role of LGL PA in the lysis of tumor cells by NK cells, either directly or indirectly, is discussed.
Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats
Authors: W A Dik
Journal: Thorax (2003)

Corticosteroids are routinely used in patients with pulmonary fibrosis. The timing for initiation of treatment is likely to be crucial for corticosteroids to exert an antifibrotic effect. Experimental studies in animals have examined the effect of corticosteroid treatment starting before or at the time of lung injury. However, this is not representative of the human condition as treatment only begins after disease has been established. We examined the effect of a short course corticosteroid treatment starting 3 days after bleomycin induced lung injury on the development of pulmonary fibrosis.Bleomycin (1.5 mg/kg) was instilled intratracheally into rats to induce pulmonary fibrosis. The effect of a 3-day course of dexamethasone (0.5 mg/kg) initiated 3 days after bleomycin induced lung injury on cell proliferation and collagen deposition was examined by analysing bronchoalveolar lavage (BAL) fluid and lung tissue.Treating bleomycin exposed animals after injury with dexamethasone for 3 days inhibited lung collagen deposition compared with animals exposed to bleomycin without dexamethasone treatment (15.2 (2.2) mg collagen/lung v 22.5 (2.1) mg/lung; p<0.05). Dexamethasone treatment reduced pulmonary parenchymal cell proliferation in bleomycin exposed rats but did not influence BAL fluid mitogenic activity for lung fibroblasts or alter the BAL fluid levels of the fibrogenic mediators transforming growth factor-beta(1), platelet derived growth factor-AB, and thrombin.A 3 day course of dexamethasone treatment initiated 3 days after bleomycin induced lung injury reduces lung cell proliferation and collagen deposition by mechanisms other than through reduction of transforming growth factor-beta(1), platelet derived growth factor-AB, and thrombin levels in BAL fluid. We propose that an early short course treatment with dexamethasone may be useful in inhibiting pulmonary fibrosis.
Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial
Authors: R Labianca, A Sobrero, L Isa, E Cortesi, S Barni, D Nicolella, M Aglietta, S Lonardi, D Corsi, D Turci, G D Beretta, G Fornarini, E Dapretto, I Floriani, A Zaniboni
Journal: Annals of Oncology (2010)
Class III β-Tubulin Mediates Sensitivity to Chemotherapeutic Drugs in Non–Small Cell Lung Cancer
Authors: Pei Pei Gan, Eddy Pasquier, Maria Kavallaris
Journal: Cancer Research (2007)

Abstract First line therapy for non–small cell lung carcinoma (NSCLC) commonly includes combination therapy with a tubulin-binding agent (TBA) and a DNA-damaging agent. TBAs suppress microtubule dynamics by binding to the β-tubulin subunit of α/β-tubulin, inducing mitotic arrest and apoptosis. Up-regulation of class III β-tubulin (βIII-tubulin) has been implicated in clinical resistance in NSCLC, ovarian and breast tumors treated in combination with a TBA and DNA-damaging agent. To investigate the functional significance of βIII-tubulin in resistance to both these classes of agents, small interfering RNA (siRNA) was used to silence the expression of this isotype in two NSCLC cell lines, NCI-H460 and Calu-6. Reverse transcription-PCR and immunoblotting showed that βIII-siRNA potently inhibited the expression of βIII-tubulin, without affecting the expression of other major β-tubulin isotypes. Clonogenic assays showed that βIII-siRNA cells were significantly more sensitive to TBAs, paclitaxel, vincristine, and vinorelbine, and for the first time, DNA-damaging agents, cisplatin, doxorubicin, and etoposide compared with controls. Cell cycle analysis of H460 βIII-siRNA cells showed reduced accumulation at the G2-M boundary and an increase in the sub-G1 population in response to TBA treatment compared with control cells. Importantly, βIII-siRNA cells displayed a significant dose-dependent increase in Annexin V staining when treated with either paclitaxel or cisplatin, compared with controls. These findings have revealed a novel role for βIII-tubulin in mediating response to both TBA and DNA-damaging agent therapy and may have important implications for improving the targeting and treatment of drug-refractory NSCLC. [Cancer Res 2007;67(19):9356–63]
Cross-Species Functional Analysis of Cancer-Associated Fibroblasts Identifies a Critical Role for CLCF1 and IL-6 in Non–Small Cell Lung Cancer <i>In Vivo</i>
Authors: Silvestre Vicent, Leanne C. Sayles, Dedeepya Vaka, Purvesh Khatri, Olivier Gevaert, Ron Chen, Yanyan Zheng, Anna K. Gillespie, Nicole Clarke, Yue Xu, Joseph Shrager, Chuong D. Hoang, Sylvia Plevritis, Atul J. Butte, E. Alejandro Sweet-Cordero
Journal: Cancer Research (2012)

Cancer-associated fibroblasts (CAF) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non-small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLCs, a cross-species functional characterization of mouse and human lung CAFs was conducted. CAFs supported the growth of lung cancer cells in vivo by secretion of soluble factors that directly stimulate the growth of tumor cells. Gene expression analysis comparing normal mouse lung fibroblasts and mouse lung CAFs identified multiple genes that correlate with the CAF phenotype. A gene signature of secreted genes upregulated in CAFs was an independent marker of poor survival in patients with NSCLC. This secreted gene signature was upregulated in normal lung fibroblasts after long-term exposure to tumor cells, showing that lung fibroblasts are "educated" by tumor cells to acquire a CAF-like phenotype. Functional studies identified important roles for CLCF1-CNTFR and interleukin (IL)-6-IL-6R signaling in promoting growth of NSCLCs. This study identifies novel soluble factors contributing to the CAF protumorigenic phenotype in NSCLCs and suggests new avenues for the development of therapeutic strategies.
Integrative Systems Models of Cardiac Excitation–Contraction Coupling
Authors: Joseph L. Greenstein, Raimond L. Winslow
Journal: Circulation Research (2011)

Excitation–contraction coupling in the cardiac myocyte is mediated by a number of highly integrated mechanisms of intracellular Ca 2+ transport. The complexity and integrative nature of heart cell electrophysiology and Ca 2+ cycling has led to an evolution of computational models that have played a crucial role in shaping our understanding of heart function. An important emerging theme in systems biology is that the detailed nature of local signaling events, such as those that occur in the cardiac dyad, have important consequences at higher biological scales. Multiscale modeling techniques have revealed many mechanistic links between microscale events, such as Ca 2+ binding to a channel protein, and macroscale phenomena, such as excitation–contraction coupling gain. Here, we review experimentally based multiscale computational models of excitation–contraction coupling and the insights that have been gained through their application.
Posttraumatic Stress Disorder and Functioning and Quality of Life Outcomes in a Nationally Representative Sample of Male Vietnam Veterans
Authors: Douglas F. Zatzick, Charles R. Marmar, Daniel S. Weiss, Warren S. Browner, Thomas J. Metzler, Jacqueline M. Golding, Anita Stewart, William E. Schlenger, Kenneth B. Wells
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: Although posttraumatic stress disorder (PTSD) is a highly prevalent and often chronic condition, the relationship between PTSD and functioning and quality of life remains incompletely understood. METHOD: The authors undertook an archival analysis of data from the National Vietnam Veterans Readjustment Study. The study subjects consisted of the nationally representative sample of male Vietnam veterans who participated in the National Vietnam Veterans Readjustment Study. The authors estimated PTSD at the time of the interview with the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder. They examined the following outcomes: diminished well-being, physical limitations, bed day in the past 2 weeks, compromised physical health status, currently not working, and perpetration of violence. Logistic models were used to determine the association between PTSD and outcome; adjustment was made for demographic characteristics and comorbid psychiatric and other medical conditions. RESULTS: The risks of poorer outcome were significantly higher in subjects with PTSD than in subjects without PTSD in five of the six domains. For the outcome domains of physical limitations, not working, compromised physical health, and diminished well-being, these significantly higher risks persisted even in the most conservative logistic models that removed the shared effects of comorbid psychiatric and other medical disorders. CONCLUSIONS: The suffering associated with combat related-PTSD extends beyond the signs and symptoms of the disorder to broader areas of functional and social morbidity. The significantly higher risk of impaired functioning and diminished quality of life uniquely attributable to PTSD suggests that PTSD may well be the core problem in this group of difficult to treat and multiply afflicted patients. (Am J Psychiatry 1997; 154:1690–1695)
Quantification of inflammatory bowel disease activity using technetium-99m HMPAO labelled leucocyte single photon emission computerised tomography (SPECT).
Authors: M J Weldon, A M Masoomi, A J Britten, J Gane, C J Finlayson, A E Joseph, J D Maxwell
Journal: Gut (1995)

Technetium-99m HMPAO labelled white cell bowel uptake was quantified in 23 patients with suspected colitis by means of the novel technique of single photon emission computerised tomography (SPECT) using a standard gamma-camera. Uptake in colon segments was quantified on transaxial images and expressed as a fraction of marrow uptake (SPECT score). Segmental histological disease activity was assessed at colonoscopy (20) or at surgery (3). Segmental histology score correlated with SPECT score r = 0.79 (p &lt; 0.001). Overall SPECT score for all affected segments correlated with Crohn9s disease activity index (CDAI) r = 0.66, p = 0.001 and with laboratory activity indices; erythrocyte sedimentation rate r = 0.44, p = 0.03, C reactive protein r = 0.38, p = 0.05, and albumin r = -0.46, p = 0.03. Small bowel SPECT score in 13 patients correlated with CDAI r = 0.65, p &lt; 0.01 but not with erythrocyte sedimentation rate or C reactive protein. Five patients with positive small bowel white cell uptake had normal C reactive protein and erythrocyte sedimentation rate. Overall SPECT score for disease at all sites correlated with both CDAI and with laboratory indices of inflammation. 99mTc HMPAO SPECT provides non-invasive and accurate quantification of inflammatory bowel disease activity in both large and small bowel and may be useful in the objective evaluation of treatment for inflammatory bowel disease.
Albendazole: a Potent Inhibitor of Vascular Endothelial Growth Factor and Malignant Ascites Formation in OVCAR-3 Tumor-Bearing Nude Mice
Authors: Mohammad Hossein Pourgholami, Zhao Yan Cai, Ying Lu, Lisa Wang, David Lawson Morris
Journal: Clinical Cancer Research (2006)

Angiogenesis and vessel hyperpermeability are the two factors leading to the formation of ascites. Vascular endothelial growth factor (VEGF) plays a pivotal role in malignant ascites formation. We have recently shown that albendazole inhibits peritoneal growth of human colorectal cancer cells (HT-29). The present study was designed to find out if albendazole can suppress ascites formation in ascites-producing peritoneal carcinomatosis.Female nude mice bearing peritoneal tumors of human ovarian cancer cells (OVCAR-3) were treated with albendazole. Following i.p. inoculation and ascites development, mice were given i.p. albendazole (150 mg/kg) or the vehicle x 3 weekly for 4 weeks.Whereas vehicle-treated mice developed overt ascites requiring repeated aspiration, ascites formation in the albendazole-treated mice was markedly suppressed. As a result of this, 7 of 10 mice from the control group had to be euthanized before the course of treatment was over. Suppressed ascites production and reduced tumor vascularity observed was a result of dramatic reduction in tumor VEGF production as revealed by profoundly lower VEGF ascites fluid and plasma levels. In vitro, incubation of SKOV-3 cells with various concentrations of albendazole led to significant dose-dependent inhibition of VEGF secretion. Examination of floating tumor cells collected from the peritoneal wash revealed profound down-regulation of VEGF mRNA in albendazole-treated mice.These findings suggest for the first time that in nude mice bearing OVCAR-3 peritoneal tumors, by inhibiting VEGF production, albendazole abolishes tumor angiogenesis and ascites formation.
Cardiac differentiation in Xenopus requires the cyclin-dependent kinase inhibitor, p27Xic1
Authors: Mehregan Movassagh, Anna Philpott
Journal: Cardiovascular Research (2008)

Cyclin-dependent kinase inhibitors (CDKIs) play a critical role in negatively regulating the proliferation of cardiomyocytes, although their role in cardiac differentiation remains largely undetermined. We have shown that the most prominent CDKI in Xenopus, p27(Xic1)(Xic1), plays a role in neuronal and myotome differentiation beyond its ability to arrest the cell cycle. Thus, we investigated whether it plays a similar role in cardiomyocyte differentiation.Xenopus laevis embryos were sectioned, and whole-mount antibody staining and immunofluorescence studies were carried out to determine the total number and percentage of differentiated cardiomyocytes in mitosis. Capped RNA and/or translation-blocking Xic1 morpholino antisense oligonucleotides (Xic1Mo) were microinjected into embryos, and their role on cardiac differentiation was assessed by in situ hybridization and/or PCR. We show that cell-cycling post-gastrulation is not essential for cardiac differentiation in Xenopus embryos, and conversely that some cells can express markers of cardiac differentiation even when still in cycle. A targeted knock-down of Xic1 protein by Xic1Mo microinjection decreases the expression of markers of cardiac differentiation, which can be partially rescued by co-injection of full-length Xic1 RNA, demonstrating that Xic1 is essential for heart formation. Furthermore, using deleted and mutant forms of Xic1, we show that neither its abilities to inhibit the cell cycle nor the great majority of CDK kinase activity are essential for Xic1's function in cardiomyocyte differentiation, an activity that resides in the N-terminus of the molecule.Altogether, our results demonstrate that the CDKI Xic1 is required in Xenopus cardiac differentiation, and that this function is localized at its N-terminus, but it is distinct from its ability to arrest the cell cycle and inhibit overall CDK kinase activity. Hence, these results suggest that CDKIs play an important direct role in driving cardiomyocyte differentiation in addition to cell-cycle regulation.
Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma
Authors: Sabina Sangaletti, Claudio Tripodo, Caterina Vitali, Paola Portararo, Carla Guarnotta, Patrizia Casalini, Barbara Cappetti, Silvia Miotti, Patrizia Pinciroli, Fabio Fuligni, Franco Fais, Pier Paolo Piccaluga, Mario P. Colombo
Journal: Cancer Discovery (2013)

Altered expression of matricellular proteins can become pathogenic in the presence of persistent perturbations in tissue homeostasis. Here, we show that autoimmunity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defective collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty delivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5(+) B cells, which underwent malignant transformation due to defective apoptosis under the pressure of neutrophil-derived trophic factors and NF-κB activation. Furthermore, this model of defective stromal remodeling during lymphomagenesis correlates with human lymphomas arising in a SPARC-defective environment, which is prototypical of CD5(+) B-cell chronic lymphocytic leukemia (CLL).