tbuckley/cabot-search huggingface dataset:
Treatment of Lower Extremity Superficial Thrombophlebitis
Authors: Marcello Di Nisio, Saskia Middeldorp
Journal: JAMA (2014)

What treatments for lower extremity superficial thrombophlebitis are associated with lower rates of venous thromboembolic events (VTE), major bleeding, and superficial venous thrombosis extension?Fondaparinux (2.5 mg) subcutaneously once daily for 45 days is associated with fewer symptomatic VTEs and lower rates of superficial venous thrombosis extension and recurrence with no increases in major bleeding compared with placebo. Low-molecular-weight heparin and nonsteroidal anti-inflammatory drugs are associated with lower rates of superficial thrombophlebitis extension or recurrence, but data regarding symptomatic VTEs are inconclusive.
PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1α
Authors: Iris Eke, Ulrike Koch, Stephanie Hehlgans, Veit Sandfort, Fabio Stanchi, Daniel Zips, Michael Baumann, Anna Shevchenko, Christian Pilarsky, Michael Haase, Gustavo B. Baretton, Véronique Calleja, Banafshé Larijani, Reinhard Fässler, Nils Cordes
Journal: Journal of Clinical Investigation (2010)

Tumor cell resistance to ionizing radiation and chemotherapy is a major obstacle in cancer therapy. One factor contributing to this is integrin-mediated adhesion to ECM. The adapter protein particularly interesting new cysteine-histidine-rich 1 (PINCH1) is recruited to integrin adhesion sites and promotes cell survival, but the mechanisms underlying this effect are not well understood. Here we have shown that PINCH1 is expressed at elevated levels in human tumors of diverse origins relative to normal tissue. Furthermore, PINCH1 promoted cell survival upon treatment with ionizing radiation in vitro and in vivo by perpetuating Akt1 phosphorylation and activity. Mechanistically, PINCH1 was found to directly bind to protein phosphatase 1alpha (PP1alpha) - an Akt1-regulating protein - and inhibit PP1alpha activity, resulting in increased Akt1 phosphorylation and enhanced radioresistance. Thus, our data suggest that targeting signaling molecules such as PINCH1 that function downstream of focal adhesions (the complexes that mediate tumor cell adhesion to ECM) may overcome radio- and chemoresistance, providing new therapeutic approaches for cancer.
Small Molecular Weight Variants of p53 Are Expressed in Human Melanoma Cells and Are Induced by the DNA-Damaging Agent Cisplatin
Authors: Kelly A. Avery-Kiejda, Xu Dong Zhang, Luke J. Adams, Rodney J. Scott, Borivoj Vojtesek, David P. Lane, Peter Hersey
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Metastatic melanoma is largely unresponsive to DNA-damaging chemotherapy agents, although WTp53 is frequently detected. Several isoforms of p53 have been discovered, some of which inhibit p53 function. We therefore examined whether p53 isoforms were present in melanoma and whether they may contribute to aberrant p53 function in melanoma. Experimental Design: We studied the expression and subcellular localization of p53 and its isoforms in a panel of human melanoma cell lines using Western blot, two-dimensional electrophoresis, and reverse transcription-PCR. We also characterized the relationship between the expression of p53, p53 isoforms, and p53 target genes following treatment with the DNA-damaging agent cisplatin. Results: We report that p53β and Δ40p53 were expressed in the majority of melanoma cell lines at the mRNA level, but were absent or expressed at low levels in fibroblasts and melanocytes, suggesting that their expression may play a role in melanoma development. Analysis by two-dimensional gel electrophoresis revealed that p53β was expressed at the protein level in melanoma cells. Both p53 and the small molecular weight forms of p53 were aberrantly expressed between the nuclear and cytosolic fractions of melanoma cell lines, compared with normal fibroblasts. Treatment with cisplatin had differential effects on WTp53 and the small molecular weight form of p53 that were cell line dependent. Δ40p53 was shown to inhibit, whereas p53β was shown to enhance, p53-dependent transcription of p21 and PUMA. Conclusions: p53β and Δ40p53 are expressed in melanoma and this may have important implications for understanding resistance of melanoma to DNA-damaging chemotherapy.
Surgery for the treatment of psychiatric illness: the need to test untested theories
Authors: Simon Wessely
Journal: Journal of the Royal Society of Medicine (2009)

I run a clinic for sufferers with chronic fatigue syndrome (CFS), sometimes also called myalgic encephalomyelitis (ME), and known to a previous generation of neurologists as ‘neurasthenia’ or ‘nerve weakness’. It is my practice to record all the previous treatments that any patient has received. Perhaps three or four times a year someone will tell me about their trip to a private clinic where they received ‘colonic lavage’. This was to ‘remove the toxins’ that they have been told are contributing to their fatigue, debility and exhaustion. The fact that they have still come to our clinic suggests that the treatment has not been successful. Despite that, very few express any retrospective scepticism about the procedure, nor regrets for the often considerable money with which they have parted for this and other ‘detoxifications’. The procedure seems logical – numerous media articles remind us that we are ‘overloaded’ with toxins, especially given our modern polluted environment and our poor diets, rich in carbohydrates, awash with food additives and swimming in chemicals. One popular book on ME is called Overload: Beating ME;1 numerous other self-help books, and countless magazine and newspaper articles continue to promote the idea that ME is a very modern illness, linked to the increasing assault on our bodies by a wide range of contaminants and hazards – not just food additives, but also dental amalgam, candida infection, mercury in vaccines, pesticides, electromagnetic radiation and chemicals of almost any description. Those who see patients complaining of multiple chemical sensitivity (MCS) will recognize the above, and more. It all seems very modern, and anyone reading this literature would probably conclude that this is a condition unique to our age, a hubristic response to our despoilation of our planet.

But it is not new. A hundred years ago such theories were espoused by at least some of the most conventional, establishment and orthodox doctors of the period. And while I might regret the fact that my patients seem to have parted with their money for such little benefit, at the beginning of the 20th century many patients paid with their lives as a result of action based on the same theories.
The impact of skin diseases on patients: comparing dermatologists' opinions with research data collected on their patients
Authors: F. Sampogna, A. Picardi, C.F. Melchi, P. Pasquini, D. Abeni
Journal: British Journal of Dermatology (2003)

Research data suggest that the detection of psychiatric disorders by dermatologists is not completely satisfactory, and that patients and dermatologists often assess patients' quality of life differently. Given that expectations influence perception and cognitia, these discrepancies might at least in part descend from conceptual models of skin disease that are prevalent among dermatologists.We explored to what degree dermatologists' opinions about quality of life and prevalence of psychiatric disorders in several dermatological conditions corresponded to the actual data collected on their patients.All dermatologists working in a large institution were asked to express on a five-point scale their opinion about the quality of life and the prevalence of depressive and anxiety disorders in different skin conditions. Physicians' opinions were then compared with the results of a large research project on quality of life and psychological well-being in dermatological out-patients performed in their institution some months before.Forty-six dermatologists (82%) agreed to participate and completed the research questionnaire. We observed a fairly good concordance between dermatologists' opinion about the impact of the various skin conditions on patients' lives and survey data on quality of life impairment. With regard to psychiatric morbidity, we found that dermatologists believe that psychiatric disorders are substantially less frequent than they actually are in many skin conditions.The belief that psychiatric morbidity is rare in patients with certain skin conditions might hamper, at least in part, the recognition of psychiatric disorders in these patients. Dermatologists probably should be more alert to the question of psychiatric morbidity in their patients. Allocating more space to this issue in training programmes for dermatologists might favour a shift in their conceptual models of skin disease.
Immune Enhancement of Skin Carcinogenesis by CD4+ T Cells
Authors: Dylan Daniel, Nicole Meyer-Morse, Emily K. Bergsland, Kerstin Dehne, Lisa M. Coussens, Douglas Hanahan
Journal: The Journal of Experimental Medicine (2003)

In a transgenic model of multi-stage squamous carcinogenesis induced by human papillomavirus (HPV) oncogenes, infiltrating CD4+ T cells can be detected in both premalignant and malignant lesions. The lymph nodes that drain sites of epidermal neoplasia contain activated CD4+ T cells predominantly reactive toward Staphylococcal bacterial antigens. HPV16 mice deficient in CD4+ T cells were found to have delayed neoplastic progression and a lower incidence of tumors. This delay in carcinogenesis is marked by decreased infiltration of neutrophils, and reduced activity of matrix metalloproteinase-9, an important cofactor for tumor progression in this model. The data reveal an unexpected capability of CD4 T cells, whereby, proinflammatory CD4+ T cells, apparently responding to bacterial infection of dysplastic skin lesions, can inadvertently enhance neoplastic progression to invasive cancer.
Selectivity of cyclo-oxygenase inhibitors in human pulmonary epithelial and smooth muscle cells
Authors: S.p Range, L Pang, E Holland, A.j Knox
Journal: European Respiratory Journal (2000)

Cyclo-oxygenase (COX) inhibitors may have a role in reducing inflammation in asthma and other pulmonary diseases. COX inhibitors have different selectivities for the two COX isoenzymes (COX 1 and COX 2) which vary between purified enzyme and intact cell preparations. The relative selectivity of COX inhibitors has not been studied in human airway cells. A number of COX inhibitors in cultured human airway cells were compared which exclusively express either COX 1 (primary degree cultured human airway smooth muscle (HASM) cells) or COX 2 (A549 pulmonary epithelial cell-line) as measured by Western blotting. COX activity was assayed by prostaglandin (PG)E2 production following 30 min incubation with 5 mM arachidonic acid. COX activity in both cell types was similar; HASM cells 92.2+/-12.1 ng PGE2 x mg-1 protein, A549 cells 87.7+/-24.4 ng PGE2 mg-1 protein. In HASM cells the median inhibitory concentration (IC50) was &gt;10-5 M for nimesulide, 3.2 x 10-6 M for N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulphonamide (NS398), 1.8 x 10-8 M for flurbiprofen, 6.7 x 10-9 M for indomethacin and &gt;10-5 M for aspirin. In A549 cells the IC50 was 1.8 x 10-9M for nimesulide, 4.1 x 10-9 M for NS398,6.2 x 10-10 M for flurbiprofen, 1.3 x 10-8 M for indomethacin and &gt;10-5 M for aspirin. Sodium valerate had no effect in either HASM or A549 cells. The COX 2:COX 1 selectivity ratio (COX 2 IC50/COX I IC50) was &lt;0.0001 for nimesulide, 0.001 for NS398, 0.03 for flurbiprofen and 1.9 for indomethacin. In conclusion the present study has shown that cyclo-oxygenase inhibitors have a range of selectivities for cyclo-oxygenase 1 and cyclo-oxygenase 2 in intact human airway cells. The relative cyclo-oxygenase 2 selectivity of N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulphonamide and nimesulide may have implications for the treatment of asthma and other inflammatory pulmonary diseases.
The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection
Authors: S Barrett
Journal: Gut (2001)

The cohort of Irish women infected with hepatitis C virus (HCV) genotype 1b via contaminated anti-D immunoglobulin in 1977 represent a unique homogenous group to investigate the natural course of HCV infection.The clinical status of 87 polymerase chain reaction (PCR) positive and 68 PCR negative women was investigated at diagnosis (1994/95) and after 4-5 years of follow up (21/22 years after inoculation). Other features investigated included: histological status/progression, psychosocial impact of HCV infection, extrahepatic manifestations, and HLA class II associations.The most common symptoms reported were fatigue and arthralgia. Furthermore, 77% of women fell within the clinical range for psychological distress. A history of icteric hepatitis was reported in 20.6% of PCR negative and 3.4% of PCR positive women after inoculation (p=0.002). The mean histological activity index/fibrosis scores of PCR positive and negative women were 4.1 (1.4)/1.1 (1.3) and 2.1 (1.5)/0.15 (0.36) at diagnosis and 4.1 (1.2)/1.0 (1.0) in 44 PCR positive women after five years of follow up. Cirrhosis or hepatocellular carcinoma was not observed. The DRB1*01 allele was present in 28.8% of PCR negative and 8.7% of PCR positive women (p=0.004). The prevalence rates of mixed cryoglobulinaemia, sicca complex, positive thyroid autoantibodies, antinuclear antibody, rheumatoid factor, and antimitochondrial antibody in PCR positive women were 12.7%, 7.6%, 13.9%, 5.1%, 3.8%, and 3.8%.A benign course of HCV infection with lack of disease progression was observed in women with chronic HCV, 22 years after inoculation. Acute icteric hepatitis and the HLA DRB1*01 allele were associated with viral clearance. Despite this favourable outcome, high levels of psychological distress and poor quality of life were present.
Endoscopic ultrasound guided biopsy of mediastinal lesions has a major impact on patient management
Authors: S S Larsen
Journal: Thorax (2002)

A study was undertaken to evaluate the clinical impact of endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) in patients with mediastinal masses suspected of malignancy.From April 1993 to December 1999, 84 patients were referred for EUS-FNA. In all patients CT scanning had shown a lesion of the mediastinum suspected of malignancy located adjacent to the oesophagus. In order to evaluate the clinical impact of EUS-FNA, the history of each patient up to referral for EUS-FNA was reviewed. A board of thoracic specialists was asked to decide the further course of the patient if EUS-FNA had not been available, and this diagnostic strategy was compared with the actual clinical course after EUS-FNA.For the 79 patients in whom sufficient verification was obtained, EUS-FNA had a sensitivity of 92%, specificity of 100%, PPV of 100%, NPV of 80%, and an accuracy of 94% for cancer of the mediastinum. In 18 of 37 patients (49%) a thoracotomy/thoracoscopy was avoided as a result of EUS-FNA, and in 28 of 41 patients (68%) a mediastinoscopy was avoided. The direct result of the cytological diagnosis obtained by EUS-FNA was that a final diagnosis of small cell lung cancer was made in eight patients resulting in referral for chemotherapy, and in another three patients with benign disease specific treatment could be initiated (sarcoidosis, mediastinal abscess, and leiomyoma of the oesophagus).EUS-FNA is a safe and sensitive minimally invasive method for evaluating patients with a solid lesion of the mediastinum suspected by CT scanning. EUS-FNA has a significant impact on patient management and should be considered for diagnosing the spread of cancer to the mediastinum in patients with lung cancer considered for surgery, as well as for the primary diagnosis of solid lesions located in the mediastinum adjacent to the oesophagus.
cAMP activates the sodium pump in cultured cells of the elasmobranch rectal gland.
Authors: S Lear, B J Cohen, P Silva, C Lechene, F H Epstein
Journal: Journal of the American Society of Nephrology (1992)

The inorganic ion content of rectal gland cells cultured from Squalus acanthias was studied by electron probe analysis in order to determine the effect of stimulation by cAMP. Cell sodium was reduced by 30% (P less than 0.01) at 8 min after exposure to dibutyryl cAMP and theophylline and remained low at 25 and 33 min. Chloride content also fell significantly with stimulation. Although cAMP may activate several transport sites, the results are consistent with a direct effect of stimulation to increase the activity of the sodium pump in shark rectal gland.
Nitric oxide in exhaled air
Authors: JO Lundberg, E Weitzberg, JM Lundberg, K Alving
Journal: European Respiratory Journal (1996)

Much interest is now being focused on measurements of nitric oxide (NO) in exhaled air. In healthy subjects exhaled NO seems to originate mainly in the nasal airways, whereas the contribution from the lower respiratory tract is low. In certain inflammatory airway disorders, the excretion of NO into the airways is altered resulting in changes in the levels of NO in exhaled air. New techniques have been developed to measure NO release at different levels of the airways: asthmatics show increased orally-exhaled NO levels, whereas patients with cystic fibrosis or Kartagener's syndrome exhibit a marked reduction in nasal release of NO. It has been suggested that measurements of exhaled NO may be clinically useful in noninvasive diagnosis and monitoring of inflammatory airway diseases. To further evaluate the potential clinical usefulness of measurement of exhaled NO, it is vital to explore how airway NO production is normally regulated and what factors influence airway NO excretion.
The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations
Authors: Donald S Silverberg, Dov Wexler, Miriam Blum, Gad Keren, David Sheps, Eyal Leibovitch, David Brosh, Shlomo Laniado, Doron Schwartz, Tatyana Yachnin, Itzhak Shapira, Dov Gavish, Ron Baruch, Bella Koifman, Carl Kaplan, Shoshana Steinbruch, Adrian Iaina
Journal: Journal of the American College of Cardiology (2000)
Evidence for defective transmembrane signaling in B cells from patients with Wiskott-Aldrich syndrome.
Authors: H U Simon, G B Mills, S Hashimoto, K A Siminovitch
Journal: Journal of Clinical Investigation (1992)

B lymphocytes from patients expressing the X chromosome-linked immune deficiency disorder, Wiskott-Aldrich syndrome (WAS), fail to produce antibodies in response to stimulation with polysaccharides and other type-2 T cell-independent antigens. To investigate whether this abnormality reflects a defect in the signal transduction cascade normally triggered by ligation of surface immunoglobulin (sIg) on B cells, we have examined early signaling events induced by anti-Ig antibody stimulation of EBV B lymphoblastoid cell lines from WAS patients and healthy controls. Despite the expression of comparable levels of sIg and sIgM on WAS and control EBV B cells, WAS cells failed to manifest the increased proliferation in response to anti-Ig treatment observed in the control cell lines. WAS and control EBV B cells also differed in the magnitude of the change in cytosolic free calcium ([Ca2+]i) induced by sIg ligation; WAS cells showed either markedly diminished or no changes in [Ca2+]i levels whereas control EBV B cells consistently showed increases in [Ca2+]i. Anti-Ig-induced changes in inositol phosphate release were also markedly reduced in WAS compared with control cells. As protein tyrosine phosphorylation is thought to represent a proximal event in the activation of B cells, inducing increases in [Ca2+]i by virtue of tyrosine phosphorylation of phospholipase C (PLC)-gamma, profiles of protein tyrosine phosphorylation and expression of tyrosine-phosphorylated PLC-gamma 1 were compared between WAS and normal EBV B cells before and after sIg cross-linking. These studies revealed that in addition to defective mobilization of Ca2+, the WAS cells manifested little or no increase in tyrosine phosphorylation of PLC-gamma 1 or other intracellular proteins after sIg ligation. Together these results indicate the association of WAS with a defect in the coupling of sIg to signal transduction pathways considered prerequisite for B cell activation, likely at the level of tyrosine phosphorylation. The abnormalities observed in these early transmembrane signaling events in WAS EBV B cells may play a role not only in the nonresponsiveness of WAS patient B cells to certain T independent antigens, but also in the genesis of some of the other cellular deficits exhibited by these patients.
Thrombolysis for postoperative pulmonary embolism: limiting the risk of haemorrhage
Authors: H. J. M. Wright, R. Campbell, S. Ellis, M. Batley
Journal: Thorax (2010)

Even with postoperative thromboprophylaxis, 1% of patients will develop venous thromboembolism following elective arthroplasty. Of this number, 5% will suffer a fatal pulmonary embolism (PE).1 Where massive PE occurs causing right ventricular hypokinesis and shock, the mortality may be in excess of 30%.2 British Thoracic Society guidelines recommend thrombolysis for massive PE but, following major surgery, the risk of bleeding is significant and many clinicians would hesitate to expose their patient to this. Here we suggest a novel method …
ADP-Ribosylation Factor 6 Regulates Tumorigenic and Invasive Properties <i>In vivo</i>
Authors: Vandhana Muralidharan-Chari, Holly Hoover, James Clancy, Jill Schweitzer, Mark A. Suckow, Valerie Schroeder, Francis J. Castellino, Jeffrey S. Schorey, Crislyn D'Souza-Schorey
Journal: Cancer Research (2009)

This study shows that the small GTP-binding protein ADP-ribosylation factor 6 (ARF6) is an important regulator of tumor growth and metastasis. Using spontaneous melanoma tumor growth assays and experimental metastasis assays in nude mice, we show that sustained activation of ARF6 reduces tumor mass growth but significantly enhances the invasive capacity of tumor cells. In contrast, mice injected with tumor cells expressing a dominantly inhibitory ARF6 mutant exhibited a lower incidence and degree of invasion and lung metastasis compared with control animals. Effects on tumor growth correlate with reduced cell proliferation capacity and are linked at least in part to alterations in mitotic progression induced by defective ARF6 cycling. Furthermore, phospho-ERK levels in subcultured cells from ARF6(GTP) and ARF6(GDP) tumor explants correlate with invasive capacity. ARF6-induced extracellular signal-regulated kinase (ERK) signaling leads to Rac1 activation to promote invadopodia formation and cell invasion. These findings document an intricate role for ARF6 and the regulation of ERK activation in orchestrating mechanisms underlying melanoma growth, invasion, and metastases.
Evaluation of normalization procedures for oligonucleotide array data based on spiked cRNA controls
Authors: Andrew A Hill, Eugene L Brown, Maryann Z Whitley, Greg Tucker-Kellogg, Craig P Hunter, Donna K Slonim
Journal: Genome biology (2001)

Affymetrix oligonucleotide arrays simultaneously measure the abundances of thousands of mRNAs in biological samples. Comparability of array results is necessary for the creation of large-scale gene expression databases. The standard strategy for normalizing oligonucleotide array readouts has practical drawbacks. We describe alternative normalization procedures for oligonucleotide arrays based on a common pool of known biotin-labeled cRNAs spiked into each hybridization.