tbuckley/cabot-search huggingface dataset:
Tolfenamic Acid and Pancreatic Cancer Growth, Angiogenesis, and Sp Protein Degradation
Authors: Maen Abdelrahim, Cheryl H. Baker, James L. Abbruzzese, Stephen Safe
Journal: JNCI Journal of the National Cancer Institute (2006)

Sp1, Sp3, and Sp4 are transcription factors that regulate cell proliferation and vascular endothelial growth factor (VEGF) expression and are overexpressed in many cancer cell lines. For some cancers, Sp1 overexpression is associated with poor survival. Cyclooxygenase inhibitors decrease Sp1 expression in cancer cells, and therefore different structural classes of nonsteroidal anti-inflammatory drugs (NSAIDs) were screened for their ability to decrease levels of Sp1, Sp3, and Sp4 and to decrease pancreatic tumor growth and metastasis in an in vivo model.Levels of Sp1, Sp3, Sp4, and VEGF proteins in pancreatic cancer cell lines were assessed by immunoblot analysis. mRNA was assessed by reverse transcription-polymerase chain reaction. Panc-1 pancreatic cancer cells transfected with VEGF promoter constructs were used to assess VEGF promoter activation. Pancreatic tumor weight and size and liver metastasis were assessed in an orthotopic mouse model of pancreatic cancer (groups of 10 mice). Protein expression in tumors was assessed immunohistochemically.Tolfenamic acid and structurally related biaryl derivatives induced degradation of Sp1, Sp3, and Sp4 in pancreatic cancer cells. Tolfenamic acid also inhibited VEGF mRNA and protein expression in pancreatic cancer cells; this inhibition was associated with the decreased Sp-dependent activation of the VEGF promoter. In the mouse model for pancreatic cancer, treatment with tolfenamic acid (50 mg/kg of body weight), compared with control treatment, statistically significantly decreased tumor growth and weight (P = .005), liver metastasis (P = .027), and levels of Sp3 and VEGF (P = .009) and Sp1 and Sp4 (P = .006) proteins in tumors. For example, tumors from mice treated with tolfenamic acid (50 mg/kg) had statistically significantly lower VEGF levels (45%, 95% confidence interval = 39% to 51%; P = .009) than tumors from control mice.Tolfenamic acid is a new antipancreatic cancer NSAID that activates degradation of transcription factors Sp1, Sp3, and Sp4; reduces VEGF expression; and decreases tumor growth and metastasis.
Influence of sex and Helicobacter pylori on development and healing of gastroduodenal lesions in non-steroidal anti-inflammatory drug users
Authors: C J Hawkey
Journal: Gut (2002)

<b>Background and aims:</b> Factors predisposing to endoscopic ulcer formation or healing with non-steroidal anti-inflammatory drugs (NSAIDs) have not been well defined. <b>Methods:</b> We used multivariate analysis of data from three large similar trials to identify factors associated with endoscopic lesions and healing. We compared the effectiveness of omeprazole 20 mg and 40 mg daily, misoprostol 200 μg four times daily, and ranitidine 150 mg twice daily in healing ulcers and erosions at different sites and in patients who were <i>Helicobacter pylori</i> positive and negative. <b>Results:</b> Older age, past ulcer history, rheumatoid arthritis, and <i>H pylori</i> infection were significantly associated with ulcers. Duodenal ulcer was significantly more likely than gastric ulcer with a past ulcer history (odds ratio 1.59, 1.16–2.17), <i>H pylori</i> infection (1.4, 1.04–1.92), and male sex (2.35, 1.75–3.16) while female sex, older age (≥60 years: 1.39, 1.03–1.88), and higher NSAID dose (&gt;1 defined daily dose: 1.57, 1.16–2.14) were associated with gastric ulceration. Sex differences were seen in both <i>H pylori</i> positive and negative patients. Gastric and duodenal ulcer healing was significantly faster with omeprazole 20 mg than with misoprostol 200 μg four times daily or ranitidine 150 mg twice daily although misoprostol was more effective at healing erosions. Gastric ulcer healing was slower with large ulcers (0.37, 0.25–0.54 for &gt;10 mm <i>v</i> 5–10 mm) or a past ulcer history (0.51, 0.34–0.76), and faster with <i>H pylori</i> infection (1.55, 1.06–2.29), especially with acid suppression (72% <i>v</i> 37% at four weeks with ranitidine). <b>Conclusions:</b> Among NSAID users, <i>H pylori</i> and male sex independently increase the likelihood of duodenal ulceration. <i>H pylori</i> infection does not affect duodenal ulcer healing and enhances gastric ulcer healing by ranitidine and possibly other acid suppressing treatments.
Leukocyte function in familial mediterranean fever
Authors: Mary C. Territo, Robert S. Peters, Martin J. Cline
Journal: American Journal of Hematology (1976)

Abstract Neutrophilic leukocytes of patients with familial Mediterranean fever and of normal control subjects were studied in vitro. FMF neutrophils were found to be morphologically normal by light and electron microscopy and to have normal quantities of the lysosomal enzyme lysozyme. FMF cells demonstrated a slight decrease in their ability to migrate randomly in capillary tubes, this was primarily seen in Armenian patients and in those experiencing an acute attack. The leukocytes of these patients functioned normally in regard to their chemotactic and Candida‐killing activity.
Contribution of the Na+-K+-2Cl− Cotransporter (NKCC1) to Transepithelial Transport of H+, NH4 +, K+, and Na+ in Rat Outer Medullary Collecting Duct
Authors: Susan M. Wall, Michael P. Fischer
Journal: Journal of the American Society of Nephrology (2002)

In rat kidney, the "secretory" isoform of the Na-K-Cl cotransporter, NKCC1 (BSC-2), localizes to the basolateral membrane of the alpha intercalated cell, the acid secreting cell of the outer medullary collecting duct (OMCD). This laboratory has reported that NKCC1 mediates Cl(-) uptake across the basolateral membrane in series with Cl(-) secretion across the apical membrane in rat OMCD. NKCC1 transports NH(4)(+), K(+), and Na(+) as well as Cl(-); therefore, a role for the cotransporter in the process of HCl, NH(4)Cl, KCl, and NaCl secretion has been suggested. Thus, it was determined if bumetanide, an inhibitor of NKCC1, alters transepithelial cation transport in rat OMCD. OMCD tubules from deoxycorticosterone pivalate (DOCP)-treated rats were perfused in vitro. Hydration of CO(2), rather than NH(4)(+), provides the principle source of H(+) for net acid secretion. In HCO(3)(-)/CO(2)-buffered solutions, no effect of bumetanide on net K(+) flux was detected. Under some conditions, bumetanide addition resulted in a small reduction in secretion of net H(+) equivalents. Transepithelial Na(+) flux, J(Na), was -1.5 +/- 1.7 pmol/mm per min, values not different from zero. However, with the application of bumetanide to the bath, J(Na) was +5.2 +/- 1.3 pmol/mm per min (P < 0.05), which indicates net Na(+) absorption. In conclusion, inhibition of NKCC1 in rat OMCD changes transepithelial movement of Na(+) and Cl(-). The role of NKCC1 in the secretion of net H(+) equivalents is small.
Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications
Authors: M-F Yuen
Journal: Gut (2005)

Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria.To determine risk factors for the development of complications in Asian CHB patients.A total of 3233 Chinese CHB patients (mean follow up 46.8 months) were monitored for liver biochemistry, viral serology, hepatitis B virus (HBV) DNA levels, acute exacerbation, hepatitis B e antigen (HBeAg) seroconversion, and development of cirrhotic complications and hepatocellular carcinoma.Median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years, respectively. Patients with alanine aminotransferase (ALT) levels of 0.5-1 times the upper limit of normal (ULN) and 1-2x ULN had an increased risk for the development of complications compared with patients with ALT levels <0.5x ULN (p<0.0001 for both). HBeAg/antibody to hepatitis B e antigen status, and number of episodes, duration, and peak ALT levels of acute exacerbations were not associated with an increased risk of complications. In patients with complications, 43.6% had HBV DNA levels less than 1.42x10(5) copies/ml. Male sex, stigmata of chronic liver disease, old age, low albumin, and high alpha fetoprotein levels on presentation were independently associated with increased cumulative risk of complications. Male sex, presence of hepatitis symptoms, old age, low albumin level, and presence of complications on presentation were independently associated with shorter survival.Prolonged low level viraemia causing insidious and continual liver damage, as reflected by ALT levels of 0.5-2x ULN, is the most likely pathway for the development of complications in Asian CHB patients.
Safe endoscopic polypectomy of jejunal polyps with a detachable snare during double balloon enteroscopy
Authors: M Matsushita, M Shimatani, K Uchida, K Okazaki
Journal: Gut (2007)

We read with interest the article by Yen et al ( Gut 2007; 56 :12) on a patient with obscure gastrointestinal bleeding in whom a juvenile polyp 1 cm in size, with a shallow ulcerated surface, was found in the jejunum on double balloon enteroscopy (DBE). Because the patient was receiving regular dialysis and because of the hypervascular nature of the polyp, it was resected surgically. In such cases, however, we believe that endoscopic polypectomy can safely be undertaken with the use of a detachable snare.

Major complications of endoscopic polypectomy are bleeding and perforation, which are most commonly associated with the removal of large polyps with thick stalks.1 For safer removal of large polyps, a detachable snare is designed for endoscopic ligation instead of a surgical suture.1 The snare is composed of …
Prognostic role of platinum sensitivity in patients with brain metastases from ovarian cancer: results of a German multicenter study
Authors: J. Sehouli, K. Pietzner, P. Harter, K. Münstedt, S. Mahner, A. Hasenburg, O. Camara, P. Wimberger, D. Boehmer, K.J. Buehling, R. Richter, K. El Khalfaoui, G. Oskay-Ozcelik
Journal: Annals of Oncology (2010)
STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells
Authors: Heng Yang, Takahiro Yamazaki, Federico Pietrocola, Heng Zhou, Laurence Zitvogel, Yuting Ma, Guido Kroemer
Journal: Cancer Research (2015)

STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3(-/-) cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell-dependent and T lymphocyte-mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3(-/-) cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3(Y705F)) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3(-/-) cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3(-/-) and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells.
Two mast cell roads diverge
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Allergen-induced activation of mast cells—which triggers the rapid release of histamine-containing granules and the slower synthesis of inflammatory cytokines—is often thought to be an all-or-none process. Not so, say Klemm and colleagues (page 337), who identify two adaptor proteins that are required for cytokine production by mast cells but are dispensable for degranulation.

The adaptor molecules in question—Malt1 and Bcl10—are required for the activation of the transcription factor NF-κB in T and B cells. But a role for these adaptors in mast cells had never been addressed. Klemm et al. now show that mice lacking either Malt1 or Bcl10 failed to develop late-phase anaphylactic responses, which depend on the production of NF-κB–dependent cytokines. By contrast, acute anaphylaxis—which is driven by mast cell degranulation—was normal in the deficient mice.

Whether physiological situations exist in which mast cells degranulate without producing cytokines is unknown. But the discovery of adaptors that uncouple these signaling pathways might provide a way to block the production of mast cell-derived cytokines, which perpetuate inflammatory diseases such as chronic severe asthma, without hindering degranulation.

Although the advantages of leaving degranulation intact might not be obvious, especially to those who sneeze their way through hay fever season, this process has benefits. One benefit is protection against the damaging side effects of endothelin-1, a potentially harmful vasoactive peptide that is produced by endothelial cells in response to stress and is degraded by mast cell proteases.
Whole-Body Scintigraphy With Radioiodine-131 A Comprehensive List of False-Positives With Some Examples
Authors: I ROSS McDOUGALL
Journal: Clinical Nuclear Medicine (1995)

Whole-body scintigraphy with radiolodine-131 is an important diagnostic test in the management of patients with differentiated thyroid cancer who have undergone surgical treatment. The scan can demonstrate the presence of residual thyroid or functioning metastases in lymph nodes or distant sites. However, there are a number of potential pitfalls in the interpretation of this scan that could lead to a false-positive diagnosis of cancer. The scintiscans are presented for five patients in whom uptake outside of the thyroid was not due to functioning metastases. Some of these abnormalities are physiologic, such as uptake of iodine in the gastrointestinal tract. A comprehensive list of false-positive results are tabulated.
Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout
Authors: Fernando Perez-Ruiz, Lorea Martínez-Indart, Loreto Carmona, Ana Maria Herrero-Beites, Jose Ignacio Pijoan, Eswar Krishnan
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> While several studies have reported a link between the presence of gout and adverse cardiovascular (CV) events in the general population, none has addressed the question of whether the mortality risk of patients with gout is influenced by disease severity. <h3>Methods</h3> We applied survival analysis methodology to prospectively collected data on clinical and radiographic measures of disease severity and mortality in a specialty clinic based cohort of 706 patients with gout (1992–2008). Standardised mortality ratios (SMR) were calculated to assess the magnitude of excess mortality among patients with gout compared with the underlying general population. <h3>Results</h3> Mean follow-up was 47 months. Tophaceous deposition was present in 30.5% of patients; &gt;4 joints were involved in 34.6% of cases. Mean annual flare rate was 3.4. Arterial hypertension (41.2%), hyperlipidaemia (42.2%), diabetes mellitus (20.1%), renal function impairment (26.6%) and a previous CV event (25.3%) were recorded. 64 (9.1%) patients died, death being attributed to vascular causes in 38 (59%) patients. SMR for gout patients was 2.37 (95% CI 1.82 to 3.03), 1.57 (1.18 to 2.05) and 4.50 (2.06 to 8.54) overall, and in men and women, respectively. The presence of tophi and the highest baseline serum urate (SU) levels were independently associated with a higher risk of mortality, in addition to age, loop diuretic use and a history of a previous vascular event. In the multivariable survival regression models, with time varying covariates, the presence of tophi remained a significant mortality risk after adjustment for baseline SU levels (1.98; 1.24 to 3.20). <h3>Conclusions</h3> High baseline SU level and the presence of subcutaneous tophi were both associated with an increased risk of mortality in patients with gout, in most cases attributed to a CV cause. This suggests a plausible pathophysiological link between greater total body urate load and CV disease.
Respiratory mechanics in patients with tense cirrhotic ascites
Authors: R Duranti, G Laffi, G Misuri, D Riccardi, M Gorini, M Foschi, I Iandelli, R Mazzanti, M Mancini, G Scano, P Gentilini
Journal: European Respiratory Journal (1997)

Lung volumes are decreased by tense ascites and increase after large volume paracentesis (LVP). The overall effect of ascites and LVP on the respiratory function is poorly understood. We studied eight cirrhotic patients with tense ascites before and after LVP. Inspiratory muscle force (maximal transdiaphragmatic pressure (Pdi,max), and the lowest pleural pressure (Pp1,min)) was assessed while the patients were seated. Rib cage and abdominal volume displacements, as well as pleural and gastric pressures were measured during quiet breathing while the patients were supine. Pdi,max and Ppl,min were normal and did not change after LVP (from 84.2+/-19.7 to 85.2+/-17.0 cmH2O and from 68.3+/-19.7 to 74+/-15.9 cmH2O, respectively). The abdominal contribution to the generation of tidal volume was greater than that of the rib cage (79 vs 21%), a pattern which did not change after LVP (73 and 27%). Before LVP, tidal swings both of pleural pressure (Ppl,sw) and transdiaphragmatic pressure (Pdi,sw) were large (15.3+/-4.3 and 18.5+/-3.9 cmH2O, respectively) and the load on inspiratory muscles was increased as a consequence of elevated dynamic elastance of the lung (El,dyn) (11.4+/-2.6 cmH2O x L(-1)) and ("intrinsic") positive end-expiratory pressure (PEEPi) (4.3+/-3.5 cmH2O). LVP reduced the load on the inspiratory muscles, as shown by the significant decrease in Ppl,sw (10.6+/-2.0 cmH2O), Pdi,sw (12.8+/-3.0 cmH2O), El,dyn (10.0+/-2.0 cmH2O x L(-1)) and PEEPi (1.1+/-1.3 cmH2O). The amount of fluid removed was closely related to changes in Ppl,sw and PEEPi. We conclude that the strength of the inspiratory muscles is normal or reduced in seated cirrhotic patients. In the supine position, tense ascites results in an increase in lung elastic load and development of positive end-expiratory pressure, with a consequent overload and increased activation of inspiratory muscles. Large volume paracentesis decreases overloading and activation, but does not change the strength of the inspiratory muscles.
Measuring the meaning of disability in rheumatoid arthritis: the Personal Impact Health Assessment Questionnaire (PI HAQ)
Authors: S Hewlett
Journal: Annals of the Rheumatic Diseases (2002)

<h3>Introduction</h3> Endovascular coil embolization has an established role alongside microsurgical clipping in the treatment of aneurysms. We studied previously clipped aneurysms that presented as subarachnoid hemorrhage and were treated by coil embolization. <h3>Methods</h3> A retrospective review was performed of two prospectively maintained databases from two institutions (Cleveland Clinic, Emory University) that spanned 12 years. <h3>Results</h3> Seven patients were identified (mean age 56.9 years) who had previously undergone surgical clipping for aneurysm obliteration; six (86%) were previously ruptured. Patients presented with aneurysm rupture with a mean time of 11.5 years (range 4 months to 20 years) following surgical treatment. Aneurysm location included anterior communicating artery (n=4), posterior communicating artery (n=1), internal carotid artery terminus (n=1) and anterior choroidal (n=1). Three patients presented in Hunt and Hess (HH) grade 1, one in HH2, two in HH3 and one in HH4. Four of the patients underwent unassisted coil embolization while balloon assistance was employed in three. Angiographic results were as follows: complete occlusion (n=3; 42.9%) and residual neck (n=4; 57.1%). There were no intraprocedural complications. <h3>Conclusion</h3> Aneurysm rupture following surgical obliteration is a rare event and may occur remote from the initial treatment. Endovascular embolization with or without balloon assistance can be safely employed in cases of aneurysm recurrence rupture following surgical treatment with satisfactory angiographic treatment.
PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin, and phosphorylated by src kinase.
Authors: L T Duong, P T Lakkakorpi, I Nakamura, M Machwate, R M Nagy, G A Rodan
Journal: Journal of Clinical Investigation (1998)

Osteoclast activation is initiated by adhesion to the bone surface, followed by cytoskeletal rearrangement, the formation of the sealing zone, and a polarized ruffled membrane. This study shows that PYK2/CAKbeta/RAFTK, a cytoplasmic kinase related to the focal adhesion kinase, is highly expressed in rat osteoclasts in vivo. Using murine osteoclast-like cells (OCLs) or their mononuclear precursors (pOCs), generated in a coculture of bone marrow and osteoblastic MB1.8 cells, we show: (a) tyrosine phosphorylation of PYK2 upon ligation of beta3 integrins or adhesion of pOCs to serum, vitronectin, osteopontin, or fibronectin but not to laminin or collagen; (b) coimmunoprecipitation of PYK2 and c-Src from OCLs; (c) PYK2 binding to the SH2 domains of Src; (d) marked reduction in tyrosine phosphorylation and kinase activity of PYK2 in OCLs derived from Src (-/-) mice, which do not form actin rings and do not resorb bone; (e) PYK2 phosphorylation by exogeneous c-Src; (f) translocation of PYK2 to the Triton X-100 insoluble cytoskeletal fraction upon adhesion; (g) localization of PYK2 in podosomes and the ring-like structures in OCLs plated on glass and in the sealing zone in OCLs plated on bone; and (h) activation of PYK2, in the presence of MB1.8 cells, parallels the formation of sealing zones and pit resorption in vitro and is reduced by echistatin or calcitonin and cytochalasin D. Taken together, these findings suggest that Src-dependent tyrosine phosphorylation of PYK2 is involved in the adhesion-induced formation of the sealing zone, required for osteoclastic bone resorption.