tbuckley/cabot-search huggingface dataset:
Na/K-ATPase as a target for anticancer drugs: studies with perillyl alcohol
Authors: Diogo Gomes Garcia, Hugo Caire de Castro-Faria-Neto, Camila Ignácio da Silva, Kauê Francisco Correa de Souza e Souza, Cassiano Felippe Gonçalves-de-Albuquerque, Adriana Ribeiro Silva, Lidia Maria da Fonte de Amorim, Aline Soares Freire, Ricardo Erthal Santelli, Luan Pereira Diniz, Flávia Carvalho Alcantara Gomes, Mauro Velho de Castro Faria, Patrícia Burth
Journal: Molecular Cancer (2015)

Na/K-ATPase (NKA) is inhibited by perillyl alcohol (POH), a monoterpene used in the treatment of tumors, including brain tumors. The NKA α1 subunit is known to be superexpressed in glioblastoma cells (GBM). This isoform is embedded in caveolar structures and is probably responsible for the signaling properties of NKA during apoptosis. In this work, we showed that POH acts in signaling cascades associated with NKA that control cell proliferation and/or cellular death.NKA activity was measured by the amount of non-radioactive Rb(+) incorporation into cultured GBM cell lines (U87 and U251) and non-tumor cells (mouse astrocytes and VERO cells). Cell viability was measured by lactate dehydrogenase levels in the supernatants of POH-treated cells. Activated c-Jun N-terminal Kinase (JNK) and p38 were assessed by western blotting. Apoptosis was detected by flow cytometry and immunocytochemistry, and the release of interleukins was measured by ELISA.All four cell types tested showed a similar sensitivity for POH. Perillic acid (PA), the main metabolite of POH, did not show any effect on these cells. Though the cell viability decreased in a dose-dependent manner when cells were treated with POH, the maximum cytotoxic effect of PA obtained was 30% at 4 mM. 1.5 mM POH activated p38 in U87 cells and JNK in both U87 and U251 cells as well as mouse astrocytes. Dasatinib (an inhibitor of the Src kinase family) and methyl β-cyclodextrin (which promotes cholesterol depletion in cell membranes) reduced the POH-induced activation of JNK1/2 in U87 cells, indicating that the NKA-Src complex participates in this mechanism. Inhibition of JNK1/2 by the JNK inhibitor V reduced the apoptosis of GBM cells that resulted from POH administration, indicating the involvement of JNK1/2 in programmed cell death. 1.5 mM POH increased the production of interleukin IL-8 in the U251 cell supernatant, which may indicate a possible strategy by which cells avoid the cytotoxic effects of POH.A signaling mechanism mediated by NKA may have an important role in the anti-tumor action of POH in GBM cells.
Predictive Gene Signature in MAGE-A3 Antigen-Specific Cancer Immunotherapy
Authors: Fernando Ulloa-Montoya, Jamila Louahed, Benjamin Dizier, Olivier Gruselle, Bart Spiessens, Frédéric F. Lehmann, Stefan Suciu, Wim H.J. Kruit, Alexander M.M. Eggermont, Johan Vansteenkiste, Vincent G. Brichard
Journal: Journal of Clinical Oncology (2013)

Purpose To detect a pretreatment gene expression signature (GS) predictive of response to MAGE-A3 immunotherapeutic in patients with metastatic melanoma and to investigate its applicability in a different cancer setting (adjuvant therapy of resected early-stage non–small-cell lung cancer [NSCLC]). Patients and Methods Patients were participants in two phase II studies of the recombinant MAGE-A3 antigen combined with an immunostimulant (AS15 or AS02 B ). mRNA from melanoma biopsies was analyzed by microarray analysis and quantitative polymerase chain reaction. These results were used to identify and cross-validate the GS, which was then applied to the NSCLC data. Results In the patients with melanoma, 84 genes were identified whose expression was potentially associated with clinical benefit. This effect was strongest when the immunostimulant AS15 was included in the immunotherapy (hazard ratio [HR] for overall survival, 0.37; 95% CI, 0.13 to 1.05; P = .06) and was less strong with the other immunostimulant AS02 B (HR, 0.84; 95% CI, 0.36 to 1.97; P = .70). The same GS was then used to predict the outcome for patients with resected NSCLC treated with MAGE-A3 plus AS02 B ; actively treated GS-positive patients showed a favorable disease-free interval compared with placebo-treated GS-positive patients (HR, 0.42; 95% CI, 0.17 to 1.03; P = .06), whereas among GS-negative patients, no such difference was found (HR, 1.17; 95% CI, 0.59 to 2.31; P = .65). The genes identified were mainly immune related, involving interferon gamma pathways and specific chemokines, suggesting that their pretreatment expression influences the tumor's immune microenvironment and the patient's clinical response. Conclusion An 84-gene GS associated with clinical response for MAGE-A3 immunotherapeutic was identified in metastatic melanoma and confirmed in resected NSCLC.
First time lateral patella dislocations: characterizing their readiness for return to activity
Authors: E Arendt, J Agel, A Moore
Journal: British Journal of Sports Medicine (2011)

Background There are no accepted objective criteria for return to activity after a first time lateral patella dislocation. Objective To define the characteristics of first time lateral patallofemoral dislocation (PFD) patients and their timeline for return to activity. Design Prospective observational. Setting University and private clinic. Patients 31 patients were identified between Sept 2008 and 2010; confirmed by MRI (87%) or requiring reduction maneouver (13%). 23 agreed to non-operative treatment and structured physical therapy. Activity level was recorded. Intervention The independent variable was redislocation. Results There were 15 males and 16 females. Average age was 20. The majority of injuries occurred playing sports and were non-contact (70%). The 23 patients all returned to full activity with no time off to nine months. 12 had no re-dislocations at 1 year. One re-dislocation occurred in a 15 year old male at 18 months. 10 patients had formal clearance for a full return to activity. Seven patients completed physical therapy. KOOS data demonstrated minimal change between time of injury and month 3, and no change between 6 and 12 months. Conclusion All patients were on a structured physical therapy program with clearly defined functional parameters for return to activity. Most patients choose not to complete therapy and used self defined parameters for return to activities. Follow up indicates that most returned to previous level of function without known adverse sequelae. This high rate of non-compliance with physical therapy and lack of physician clearance prior to return to activity is disconcerting. There is a disparity between the clinician's and patient's perceived seriousness and need for time off and rehabilitation. KOOS outcome tool may not be capturing the disability associated with lateral PFD. More attention is warranted to optimise management of this injury, to better understand the degree of impairment and timing of safe return.
JUVENILE DERMATITIS HERPETIFORMIS IN THE LIGHT OF IMMUNOFLUORESCENCE STUDIES
Authors: S. JABLONSKA, T. CHORZELSKI, E. H. BEUTNER, M. BLASZCZYK
Journal: British Journal of Dermatology (2006)

Summary.— Eight cases of juvenile dermatitis herpetiformis (JDH) were investigated by direct and indirect IF methods with anti-IgG and anti-IgA conjugates. In 3 cases the results were completely negative. In 3 cases there were in vivo fixed IgG in the basement membrane, and in 1 case also circulating antibodies as in bullous pemphigoid in adults. In 2 cases there were in vivo bound IgA deposits in the papillae of the apparently unchanged skin surrounding the lesions, as in dermatitis herpetiformis in adults. The results of the IF studies suggest that JDH is not a nosological entity, and that cases occur with the immunological features of either bullous pemphigoid or dermatitis herpetiformis in adults. There remains the group of immunologically negative cases, the nature of which, moreover, requires further investigation.
Deficiency in CD22, a B Cell–specific Inhibitory Receptor, Is Sufficient to Predispose to Development of High Affinity Autoantibodies
Authors: Theresa L. O'Keefe, Gareth T. Williams, Facundo D. Batista, Michael S. Neuberger
Journal: The Journal of Experimental Medicine (1999)

CD22 is a B cell-specific transmembrane glycoprotein that acts to dampen signals generated through the B cell antigen receptor (BCR): B cells from CD22-deficient mice give increased Ca2+ fluxes on BCR ligation. Here we show that this B cell hyperresponsiveness correlates with the development of autoantibodies. After the age of eight months, CD22-deficient mice developed high titers of serum IgG directed against double-stranded DNA; these antibodies were of multiclonal origin, somatically mutated, and high affinity. Increased titers of antibodies to cardiolipin and myeloperoxidase were also noted. The results demonstrate that a single gene defect exclusive to B lymphocytes is, without additional contrivance, sufficient to trigger autoantibody development in a large proportion of aging animals. Thus, CD22 might have evolved specifically to regulate B cell triggering thresholds for the avoidance of autoimmunity.
Management of bronchiectasis in adults
Authors: James D. Chalmers, Stefano Aliberti, Francesco Blasi
Journal: European Respiratory Journal (2015)

Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis. The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life. Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence-based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation. This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials.
AN <i>IN VITRO</i> ASSAY OF LEUKOCYTE MIGRATION INHIBITORY ACTIVITY FROM HUMAN LYMPHOCYTES STIMULATED WITH CONCANAVALIN A
Authors: K. BENDTZEN, V. ANDERSEN, G. BENDIXEN
Journal: Allergy (1975)

Human venous blood lymphocytes, incubated for 22 h in serum-free culture medium with the plant mitogen concanavalin A (Con-A), elaborated products, which inhibited the migration of human buffy coat cells under agarose. Con-A was removed by applying the supernatants on small Sephadex G-100 columns. The leukocyte migration inhibitory activity (LMIA) was tested in a semi-quantitative modification of the indirect leukocyte migration agarose technique, which is described. Lymphokine activity, demonstrable as early as 9 h after activation of lymphocytes, was most pronounced after 22 h. Significant LMIA was demonstrated in 12 of 17 normal individuals at standard dilution of culture supernatants I/3. In 9 of the 12 experiments, assays of LMIA were carried out on stepwise diluted supernatants with detection of the greatest dilution with significant LMIA. In four experiments LMIA could only be detected after 3- to 12-fold concentrations of supernatants. Considerable individual variation was found, the amounts of LMIA varying by a factor of about 300. The reproducibility appeared to be quite high, but the factor stability of supernatants stored at -20 degrees C was surprisingly low.
EXPERIMENTS ON HISTAMINE AS THE CHEMICAL MEDIATOR FOR CUTANEOUS PAIN
Authors: Sol Roy Rosenthal, David Minard
Journal: The Journal of Experimental Medicine (1939)

Experimental evidence shows that histamine is liberated when the upper layers of the skin are stimulated in the threshold range although no gross or microscopic evidence of tissue damage is demonstrable. A histamine-like substance is recoverable from the anterior chamber of the rabbit's eye on electrical stimulation of the cornea. This substance is liberated in direct proportion to the intensity of the stimulus. Histamine when injected intradermally or applied to the denuded skin (less epidermis and some cutis) or cornea causes pain. That the substance liberated is most likely histamine was shown by its action on the intestinal strip of the guinea pig, which action was not effaced by adding atropine to the bath; by its heat stability, its neutralization by histaminase and its dialysability through cellophane membranes, and by the fact that thymoxyethyldiethylamine, which appears to be a specific antagonist to histamine, neutralizes the action of the diffusates of stimulated skin and when injected subcutaneously or rectally abolishes generally the pain responses to pinching, pricking and cutting, and lowers the electrical threshold of the skin markedly without affecting the somatic sensory nerve trunks.
Natural history of primary sclerosing cholangitis. A longterm follow-up study of 394 european primary sclerosing cholangitis patients
Authors: K.M. Boberg, S. Mitchell, U. Broomé, A. Parés, F. Rosina, A. Bergquist, R. Chapman, O. Fausa, G. Rocca, E. Schrumpf
Journal: Journal of Hepatology (2000)
Competing Risk Analysis of Men Aged 55 to 74 Years at Diagnosis Managed Conservatively for Clinically Localized Prostate Cancer
Authors: P C Albertsen, J A Hanley, D F Gleason, M J Barry
Journal: JAMA (1998)

The appropriate therapy for men with localized prostate cancer is uncertain. Until results of clinical trials are available, men and their physicians need guidance.To estimate survival based on a competing risk analysis stratified by age at diagnosis and histologic findings for men diagnosed as having clinically localized prostate cancer and who were managed conservatively.Retrospective cohort study.Connecticut Tumor Registry.A total of 767 men with localized prostate cancer diagnosed between 1971 and 1984, aged 55 to 74 years at diagnosis, either not treated or treated with immediate or delayed hormonal therapy, and followed up for 10 to 20 years after diagnosis.Estimates of the probability of dying from prostate cancer or other competing hazards.Men with tumors that have Gleason scores of 2 to 4, 5, 6, 7, and 8 to 10 face a 4% to 7%, 6% to 11%, 18% to 30%, 42% to 70%, and 60% to 87% chance, respectively, of dying from prostate cancer within 15 years of diagnosis depending on their age at diagnosis.Men whose prostate biopsy specimens show Gleason score 2 to 4 disease face a minimal risk of death from prostate cancer within 15 years of diagnosis. Conversely, men whose biopsy specimens show Gleason score 7 to 10 disease face a high risk of death from prostate cancer when treated conservatively, even when cancer is diagnosed as late as age 74 years. Men with Gleason score 5 or 6 tumors face a modest risk of death from prostate cancer that increases slowly over at least 15 years of follow-up.
<i>Deleted in Colorectal Cancer</i> Is a Putative Conditional Tumor-Suppressor Gene Inactivated by Promoter Hypermethylation in Head and Neck Squamous Cell Carcinoma
Authors: André Lopes Carvalho, Alice Chuang, Wei-Wen Jiang, Juna Lee, Shahnaz Begum, Luana Poeta, Ming Zhao, Carmen Jerónimo, Rui Henrique, Chetan S. Nayak, Hannah L. Park, Mariana R.O. Brait, Chunyan Liu, Shaoyu Zhou, Wayne Koch, Vito Michele Fazio, Edward Ratovitski, Barry Trink, William Westra, David Sidransky, Chul-so Moon, Joseph A. Califano
Journal: Cancer Research (2006)

Abstract Deleted in colorectal cancer (DCC) is a candidate tumor-suppressor gene located at chromosome 18q21. However, DCC gene was found to have few somatic mutations and the heterozygous mice (DCC+/−) showed a similar frequency of tumor formation compared with the wild-type mice (DCC+/+). Recently, DCC came back to the spotlight as a better understating of its function and relationship with its ligand (netrin-1) had shown that DCC may act as a conditional tumor-suppressor gene. We evaluated hypermethylation as a mechanism for DCC inactivation in head and neck squamous cell carcinoma (HNSCC). DCC promoter region hypermethylation was found in 75% of primary HNSCC. There was a significant correlation between DCC promoter region hypermethylation and DCC expression (assessed by immunohistochemistry; P = 0.021). DCC nonexpressing HNSCC cell lines JHU-O12 and JHU-O19 with baseline hypermethylation of the DCC promoter were treated with 5-aza-2′-deoxycytidine (a demethylating agent) and reexpression of DCC was noted. Transfection of DCC into DCC-negative HNSCC cell lines resulted in complete abrogation of growth in all cell lines, whereas additional cotransfection of netrin-1 resulted in rescue of DCC-mediated growth inhibition. These results suggest that DCC is a putative conditional tumor-suppressor gene that is epigenetically inactivated by promoter hypermethylation in a majority of HNSCC. (Cancer Res 2006; 66(19): 9401-07)
Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi
Authors: Junichi Shoda, Koji Oda, Hiroshi Suzuki, Yuichi Sugiyama, Kosei Ito, David E. Cohen, Li Feng, Junichi Kamiya, Yuji Nimura, Hiroshi Miyazaki, Masahito Kano, Yasushi Matsuzaki, Naomi Tanaka
Journal: Hepatology (2001)

Intrahepatic calculi, highly prevalent in the Far East, including Japan, are characterized clinically by chronic proliferative cholangitis with frequent stone recurrences. Intrahepatic calculi consist of 2 groups, i.e., brown pigment stones, including a high cholesterol content, and cholesterol stones, with the former predominating. To gain insights into the pathogenesis of intrahepatic calculi, cholesterol and bile acid biosynthesis, as well as alterations in intracellular transport and/or canalicular secretion of phospholipid and bile acid were investigated in liver of patients with intrahepatic calculi. Enzyme activities of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase were increased (12.8 +/- 1.9 pmol/min/mg protein, mean +/- SEM vs. 5.5 +/- 0.4 in controls; P < .01) and cholesterol 7 alpha-hydroxylase activities were decreased (1.3 +/- 0.4 vs. 4.9 +/- 0.6; P < .01) in liver specimens of patients with brown pigment stones. In addition, messenger RNA (mRNA) levels of multidrug resistance P-glycoprotein 3 (MDR3 Pgp) and phosphatidylcholine transfer protein (PCTP) were markedly low in the liver specimens compared with the levels in specimens of control subjects, gallbladder stone patients, and patients with obstructive cholestasis. The protein levels and the immunohistochemical staining were decreased for MDR3 Pgp and PCTP in the liver. Consistently, the concentrations of phospholipid were markedly reduced in the hepatic bile from both affected and unaffected hepatic segments. In patients with intrahepatic calculi, biliary cholesterol supersaturation and the formation of cholesterol-rich brown pigment as well as cholesterol stones may be attributed to decreased hepatic transport and biliary secretion of phospholipids, in the setting of increased cholesterogenesis and decreased bile acid synthesis.
A technique for complete replacement of the ascending aorta
Authors: H. Bentall, A. De Bono
Journal: Thorax (1968)

A technique for complete replacement of the aortic valve and ascending aorta in cases of aneurysm of the ascending aorta with aortic valve ectasia is described. The proximal aortic root was too attenuated to afford anchorage to the aortic prosthesis, so this was sutured to the ring of a Starr valve and the prostheses were inserted <i>en bloc.</i> The ostia of the coronary arteries were anastomosed to the side of the aortic prosthesis.
On the mechanism of unidirectional killing in mixtures of two cytotoxic T lymphocytes. Unidirectional polarization of cytoplasmic organelles and the membrane-associated cytoskeleton in the effector cell.
Authors: A Kupfer, S J Singer, G Dennert
Journal: The Journal of Experimental Medicine (1986)

In mixtures of two CTL of the type a anti-b and b anti-c, only the latter is lysed; i.e., killing is unidirectional. Here, we show that two profound types of changes occur in the effector CTL but not in the target CTL upon formation of couples between them. One is that the microtubule organizing center (and presumably the Golgi apparatus that is invariably colocalized with it) is reoriented inside the effector CTL to face the bound target CTL. This unidirectional reorientation, it is proposed, serves to direct putative cytotoxic secretory components derived from the Golgi apparatus of the effector cell to the site of cell-cell binding. The second unidirectional change is in the membrane-associated cytoskeleton of the effector CTL in the area of target cell binding. The cytoskeletal protein talin, but not any of four other such proteins assayed, is highly concentrated at the contacting membrane of the effector CTL, while it is uniformly distributed over the entire membrane of the bound target CTL. This localized, massive cytoskeletal reorganization may reflect a mechanism to protect the membrane of the effector CTL from the effects of putative cytotoxic components secreted by the effector cell into the intercellular space between it and the target cell.
A Cell-Molecular Approach Predicts Vertebrate Evolution
Authors: J. S. Torday, V. K. Rehan
Journal: Molecular Biology and Evolution (2011)

In contrast to the conventional use of genes to determine the evolution of phenotypes, we have functionally integrated epithelial–mesenchymal interactions that have facilitated lung phylogeny and ontogeny in response to major geologic epochs. As such, this model reveals the underlying principles of lung physiology based on the evolutionary interactions between internal and external selection pressures, providing a novel understanding of lung biology. As a result, it predicts how cell–molecular changes in this process can cause disease and offers counterintuitive insights to diagnosis and treatment based on evolutionary principles.
Detection, identification and in vivo treatment responsiveness of bone morphogenetic protein (BMP)-activated cell populations in the synovium of patients with rheumatoid arthritis
Authors: P C P M Verschueren, R J U Lories, M Daans, I Théate, P Durez, R Westhovens, F P Luyten
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To characterise the bone morphogenetic protein (BMP) target cells positive for phosphorylated (P)-SMAD1/5, in rheumatoid arthritis (RA) synovium. <h3>Methods:</h3> Synovial biopsies were obtained by needle arthroscopy. Anti-P-SMAD1/5 antibodies were used for Western blot (WB) on protein extracts from RA and normal synovium and for immunostaining of synovial biopsy sections. Positive cells were further identified by double staining for CD3, CD20, CD68, CD138, CD90, α smooth muscle actin (SMA), endoglin (CD105) and von Willebrand factor (VWF). In sections from early patients with RA taken before and under antirheumatic treatment, the degree of inflammation and activation of the BMP pathway were quantified. <h3>Results:</h3> P-SMAD1/5 protein was detected by WB in RA and to a lesser extent in normal synovium. Different P-SMAD1/5 positive cell populations were identified in RA synovium, mainly in perivascular and sublining cells. P-SMAD1/5 positive perivascular cells were αSMA positive and located around VWF positive endothelial cells. Some CD90 positive synovial fibroblasts were P-SMAD1/5 positive, as was part of the CD68 positive synovial cells but other cells of the haematopoietic lineage showed no SMAD1/5 phosphorylation. Treatment resulted in an absolute but not relative decrease in BMP activation in the synovium. <h3>Conclusion:</h3> BMP-activated cells belong to distinct stromal compartments in RA synovium and some of them express markers associated with the mesenchymal progenitor cell lineage. Antirheumatic treatment effectively downregulates synovial inflammation, but BMP activation in the synovium does persist albeit reduced.