tbuckley/cabot-search huggingface dataset:
Reduction of Human Melanoma Tumor Growth in Severe Combined Immunodeficient Mice by Passive Transfer of Antibodies Induced by a High Molecular Weight Melanoma-Associated Antigen Mimotope Vaccine
Authors: Stefan Wagner, Clemens Krepler, Dorothee Allwardt, Julia Latzka, Sabine Strommer, Otto Scheiner, Hubert Pehamberger, Ursula Wiedermann, Christine Hafner, Heimo Breiteneder
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The high molecular weight melanoma-associated antigen (HMW-MAA) is an attractive target for immunotherapy of malignant melanoma. We have recently generated a vaccine based on the HMW-MAA mimotope 225D9.2+ that was able to induce anti-HMW-MAA antibodies with antitumor activity in vitro. Here, we investigated the antitumor activity of these antibodies in a human melanoma xenotransplant severe combined immunodeficient (SCID) mouse model. Experimental Design: Tumors were established by injecting the human melanoma 518A2 cells into C.B.17 SCID/SCID mice. In tumor prevention experiments, 200 μg purified total IgG antibodies were injected intravenously the same day or on day 5 in therapeutic experiments. Antibody administration was repeated every fourth day and tumor volumes were measured. Antibody specificity and tumor infiltration by macrophages were investigated by immunohistochemistry. Results: Within 35 days after cell inoculation, antibody treatment reduced tumor growth up to 40% in the therapeutic and up to 62% in the tumor prevention experiments compared with the control mice. In tumors of all groups, a similar distribution of the HMW-MAA and no differences in infiltration of macrophages were detected by immunohistochemistry. Conclusions: Here, we showed that antibodies induced by the 225D9.2+ mimotope effectively inhibited melanoma tumor growth. Additional mechanisms besides antibody-dependent cell cytotoxicity like disruption of interactions of melanoma cells mediated by extracellular matrix components seem to be involved in tumor growth inhibition. Based on our findings, we suggest that active immunization with this mimotope might be a promising strategy for treatment of melanoma.
Extracellular Signal-Regulated Kinase 8–Mediated c-Jun Phosphorylation Increases Tumorigenesis of Human Colon Cancer
Authors: Yan-Ming Xu, Feng Zhu, Yong-Yeon Cho, Andria Carper, Cong Peng, Duo Zheng, Ke Yao, Andy T.Y. Lau, Tatyana A. Zykova, Hong-Gyum Kim, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2010)

Abstract Extracellular signal-regulated kinase 8 (ERK8), a recently discovered member of the mitogen-activated protein kinase protein family, has been less studied than other family members, leaving its physiologic functions mostly unknown. The biological consequences of overexpression of ERK8 in JB6 Cl41 epidermal skin cells or knockdown of ERK8 in HCT15 colorectal cancer cells was studied. Kinase assays and transient transfection experiments were performed to study the signaling pathway between ERK8 and c-Jun. We found that ERK8 is relatively highly expressed in HCT15 human colorectal cancer cells and plays an important role in the promotion and progression of colorectal cancer. ERK8 promoted neoplastic transformation, and knockdown of ERK8 in HCT15 colorectal cancer cells reduced the tumorigenic properties of these cell lines. Furthermore, a direct interaction between ERK8 and c-Jun was shown. With epidermal growth factor treatment, overexpression of ERK8 in JB6 Cl41 cells caused an increased phosphorylation of c-Jun at Ser63 and Ser73, resulting in increased activator protein-1 transactivation. In contrast, knockdown of ERK8 in HCT15 colorectal cancer cells blocked c-Jun phosphorylation. The interaction between ERK8 and c-Jun seems to increase the tumorigenic properties of HCT15 colorectal cancer cells. Thus, ERK8-regulated signaling might serve as a potential therapeutic target in colorectal cancer. Cancer Res; 70(8); 3218–27. ©2010 AACR.
Fatty acid flux and oxidation are increased by rimonabant in obese women
Authors: Katharine Backhouse, Ivana Sarac, Fariba Shojaee-Moradie, Michael Stolinski, M. Denise Robertson, Gary S. Frost, Jimmy D. Bell, E. Louise Thomas, John Wright, David Russell-Jones, A. Margot Umpleby
Journal: Metabolism (2012)
Performance league tables
Authors: A. Rixom
Journal: BMJ (2002)

Valid performance league tables cannot be formed from indirectly standardised indices.1–5 However, this methodology has been adopted for most of the performance indicators for NHS trusts that relate to outcomes, effectiveness, and access. This includes all the clinical indicators.6 Indirect standardisation is also used to compare general practitioners' prescribing.7

As an illustration, the example in the box includes two study populations with identical category specific rates (these may be for age, ethnicity, or case mix, for example). Despite performing identically, they have two very different indirectly standardised ratios because of their different structures.

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The inappropriate comparison of performance using indirect standardisation arises because of a common misconception about the standard that is being used. For indirect standardisation the study population itself is the standard, as this is the population to which the category specific reference rates are applied. Consequently, a different standard is …

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A Comparative Analysis of Low-Dose Metronomic Cyclophosphamide Reveals Absent or Low-Grade Toxicity on Tissues Highly Sensitive to the Toxic Effects of Maximum Tolerated Dose Regimens
Authors: Urban Emmenegger, Shan Man, Yuval Shaked, Giulio Francia, John W. Wong, Daniel J. Hicklin, Robert S. Kerbel
Journal: Cancer Research (2004)

Abstract The survival benefits of traditional maximum tolerated dose (MTD) cytotoxic therapy have been modest for the treatment of most types of metastatic malignancy and, moreover, often come with increased acute and chronic toxicity. Recent studies have demonstrated that the frequent administration of comparatively low doses of cytotoxic agents, with no extended breaks [low-dose metronomic (LDM) chemotherapy], may not only be at least as efficient as MTD therapy but also less toxic. This coincides with an apparent selectivity for “activated” endothelial cells of the tumor vasculature. However, the impact of LDM chemotherapy on the most sensitive target cell populations normally affected by MTD therapy (i.e., bone marrow progenitors, gut mucosa, and hair follicle cells) has not been analyzed in experimental detail. Therefore, we compared effects of LDM and MTD cyclophosphamide (CTX) on bone marrow and gut mucosa. Furthermore, we studied the potential impact of LDM CTX on angiogenesis in the context of wound healing and evidence of organ toxicity. We show absent or moderate hematologic and intestinal toxicity of LDM as opposed to MTD CTX. Of note was the finding of sustained lymphopenia, which is not unexpected given the use of CTX as immunosuppressive drug. There was no negative impact on wound healing or evidence of organ toxicity. LDM offers clear safety advantages over conventional MTD chemotherapy and therefore would appear to be ideal for long-term combination therapy with targeted antiangiogenic drugs.
STUDIES ON FLUORESCENT ANTIBODY STAINING
Authors: Gerald Goldstein, Irene S. Slizys, Merrill W. Chase
Journal: The Journal of Experimental Medicine (1961)

1. A study has been made of the non-specific fluorescent staining of splenic imprints treated with fluorescent sheep antibody globulins. 2. In tissue imprints made with the spleens of antigen-stimulated animals, no morphological distinction was evident between areas showing non-specific fluorescence and specific fluorescence. 3. Elimination of non-specific fluorescence was not achieved by any one, or any combination of the following: (a) conjugating only gamma globulins with fluorescein isothiocyanate; (b) removal of dialyzable fluorescent products on sephadex, followed by concentration through the use of pressure dialysis; (c) use of crystalline preparations of fluorescein isothiocyanate. 4. Individual preparations of fluorescent antibodies were separated by gradient elution chromatography on diethylaminoethyl (DEAE) cellulose into fractions possessing different numbers of fluorescein radicals per molecule of globulin. 5. The coupling ratio of 50 mg fluorescein isothiocyanate (FITC) per gm of protein, as commonly advocated, can not be recommended for the precise localization of antibody globulin in tissues owing to the capacity of the coupled products to give non-specific fluorescent staining. When crystalline preparations of FITC are used instead of the amorphous product at 50 mg/gm protein, far too high non-specific fluorescence results. 6. A fraction with bright specific fluorescence and no or negligible nonspecific fluorescence was obtained from each fluorescent antibody that was prepared by using 6 to 8 mg of crystalline fluorescein isothiocyanate per gm of globulin and was then subjected to DEAE-cellulose chromatography and gradient elution to eliminate the most highly coupled molecules.
Anti–LFA-1 Blocking Antibodies Prevent Mobilization of Hematopoietic Progenitor Cells Induced by Interleukin-8
Authors: Johannes F.M. Pruijt, Yvette van Kooyk, Carl G. Figdor, Ivan J.D. Lindley, Roel Willemze, Willem E. Fibbe
Journal: Blood (1998)
Echocardiographic Features of the Right Heart in Sleep-Disordered Breathing
Authors: URSULA C. GUIDRY, LISA A. MENDES, JANE C. EVANS, DANIEL LEVY, GEORGE T. O'CONNOR, MARTIN G. LARSON, DANIEL J. GOTTLIEB, EMELIA J. BENJAMIN
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The effect of sleep-disordered breathing (SDB) on right heart structure and function is controversial. Studies of patients referred for evaluation of possible sleep apnea have yielded conflicting results, and the impact of SDB on the right heart has not been investigated in the general population. We examined the echocardiographic features of subjects with SDB at the Framingham Heart Study site of the Sleep Heart Health Study. Of 1,001 polysomnography subjects, 90 with SDB defined as a respiratory disturbance index (RDI) score > 90th percentile (mean RDI = 42) were compared with 90 low-RDI subjects (mean RDI = 5) matched for age, sex, and body mass index. Right heart measurements, made without knowledge of clinical status, were compared between groups. The majority of the subjects were male (74%). After multivariable adjustment, right ventricle (RV) wall thickness was significantly greater (p = 0.005) in subjects with SDB (0.78 ± 0.02 cm) than in the low-RDI subjects (0.68 ± 0.02 cm). Right atrial dimensions, RV dimensions, and RV systolic function were not found to be significantly different between subjects with SDB and the low-RDI subjects. We conclude that in this community-based study of SDB and right heart echocardiographic features, RV wall thickness was increased in subjects with SDB. Whether the RV hypertrophy observed in persons with SDB is associated with increased morbidity and mortality remains unknown.
THE INHIBITION OF PLASMIN, PLASMA KALLIKREIN, PLASMA PERMEABILITY FACTOR, AND THE C'1r SUBCOMPONENT OF THE FIRST COMPONENT OF COMPLEMENT BY SERUM C'1 ESTERASE INHIBITOR
Authors: Oscar D. Ratnoff, Jack Pensky, Derek Ogston, George B. Naff
Journal: The Journal of Experimental Medicine (1969)

The fraction of human serum designated as C'1 esterase inhibitor is known to inhibit the action of C'1 esterase, a plasma kallikrein, and PF/Dil, an enzyme in plasma enhancing cutaneous vascular permeability. In the present study, C'1 esterase inhibitor has been found to block the actions of plasmin and the C'1r subcomponent of the first component of complement, and to retard the generation of PF/Dil. No inhibition of blood clotting or of the generation of plasmin was demonstrable.
Secretory-Defect Distal Renal Tubular Acidosis Is Associated with Transporter Defect in H+-ATPase and Anion Exchanger-1
Authors: Jin Suk Han, Gheun-Ho Kim, Jin Kim, Un Sil Jeon, Kwon Wook Joo, Ki Young Na, Curie Ahn, Suhnggwon Kim, Sang Eun Lee, Jung Sang Lee
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Recent progress in molecular physiology has permitted us to understand pathophysiology of various channelopathies at a molecular level. The secretion of H+ from α-intercalated cells is mediated by apical plasma membrane H+-ATPase and basolateral plasma membrane anion exchanger-1 (AE1). Studies have demonstrated the lack of H+-ATPase immunostaining in the intercalated cells in a few patients with distal renal tubular acidosis (dRTA). Mutations in H+-ATPase and AE1 gene have recently been reported to cause dRTA. This study extends the investigation of the role of transporter defect in dRTA by using immunohistochemical methods. Eleven patients with hyperchloremic metabolic acidosis were diagnosed functionally to have secretory-defect dRTA: urine pH >5.5 during acidemia, normokalemia or hypokalemia, and urine-to-blood pCO2 <25 mmHg during bicarbonaturia. Renal biopsy tissue was obtained from each patient, and immunohistochemistry was carried out using antibodies to H+-ATPase and AE1. For comparison, renal tissues from the patients who had no evidences of distal acidification defect by functional studies were used: four with glomerulopathy or tubulointerstitial nephritis (disease controls) and three from nephrectomized kidneys for renal cell carcinoma (normal controls). The H+-ATPase immunoreactivity in α-intercalated cells was almost absent in all of the 11 patients with secretory-defect dRTA. In addition, 7 of 11 patients with secretory-defect dRTA were accompanied by negative AE1 immunoreactivity. In both disease controls and normal controls, the immunoreactivity of H+-ATPase and AE1 was strong in α-intercalated cells. In conclusion, significant defect in acid-base transporters is the major cause of secretory-defect dRTA.
Pericardial Adipose Tissue, Atherosclerosis, and Cardiovascular Disease Risk Factors: The Jackson Heart Study
Authors: Jiankang Liu, Herman A. Taylor, Caroline S. Fox, J. Jeffery Carr, Jingzhong Ding
Journal: Diabetes Care (2010)

We acknowledge the comment made by Iacobellis and Malavazos (1) and appreciate the opportunity to address it further while clarifying some points. Anatomically, pericardial adipose tissue (PAT) is largely brown adipose tissue and is divided into two layers: epicardial and paracardial fat layers (2,3). In general, PAT is defined as epicardial plus paracardial adipose tissue (2–4). Likewise, using computed tomography or magnetic resonance imaging to provide a detailed anatomic display of the entire pericardium, the volumetric PATs were defined as any adipose tissue located in the pericardial sac (4). Thus, the …
Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension
Authors: F Iannone, M T Riccardi, S Guiducci, R Bizzoca, M Cinelli, M Matucci-Cerinic, G Lapadula
Journal: Annals of the Rheumatic Diseases (2007)

To study the expression of adhesion molecules in patients with systemic sclerosis (SSc) with and without pulmonary arterial hypertension (PAH) and the effects of therapy with the endothelin-1 (ET-1) receptor antagonist, bosentan.In all, 35 patients with SSc and 25 healthy donors (HD) were selected for this study. Of 35 patients, 10 had isolated PAH assessed by Doppler echocardiography and treated with bosentan. Peripheral blood (PB) lymphocytes were isolated by density gradient centrifugation, and the expression of lymphocyte function-associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and L-selectin on CD3 T cells was assessed by double immunofluorescence and flow-cytometry. As endothelial activation markers, serum soluble P-selectin, platelet/endothelial cell adhesion molecule (PECAM)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and von Willebrand factor (vWF) antigen were assessed by ELISA. In patients with SSc-PAH, T cell subsets and soluble endothelial markers were assessed at baseline and after 6 and 12 months of bosentan therapy.In patients with SSc-PAH, serum soluble ICAM-1, VCAM-1, P-selectin and PECAM-1 levels were higher than in HD at baseline and fell to normal values after 12 months of bosentan therapy. CD3-LFA1 T cells were significantly higher in PAH-SSc at baseline than in HD or SSc and significantly decreased after therapy. CD3-L-selectin T cells were significantly lower in SSc-PAH at baseline than in HD or SSc and rose to normal levels after bosentan therapy.This study confirms that endothelial activation occurs in SSc, and suggests that changes in the T cell/endothelium interplay take place in SSc-associated PAH. Bosentan seems to be able to hamper these changes and restore T cell functions in these patients.
Effect of pulmonary vein isolation on atrial fibrillation cycle length
Authors: Mehmet Ozaydin, William Hsu, Hiroshi Tada, Aman Chugh, Christoph Scharf, Radmira Greenstein, Frank Pelosi, Bradley P. Knight, S.Adam Strickbarger, Fred Morady, Hakan Oral
Journal: Journal of the American College of Cardiology (2002)
A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K
Authors: Daniel J. Ma, Evanthia Galanis, S. Keith Anderson, David Schiff, Timothy J. Kaufmann, Patrick J. Peller, Caterina Giannini, Paul D. Brown, Joon H. Uhm, Steven McGraw, Kurt A. Jaeckle, Patrick J. Flynn, Keith L. Ligon, Jan C. Buckner, Jann N. Sarkaria
Journal: Neuro-Oncology (2014)

BackgroundThe mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy.
Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription.
Authors: S R Price, J L Bailey, X Wang, C Jurkovitz, B K England, X Ding, L S Phillips, W E Mitch
Journal: Journal of Clinical Investigation (1996)

In normal subjects and diabetic patients, insulin suppresses whole body proteolysis suggesting that the loss of lean body mass and muscle wasting in insulinopenia is related to increased muscle protein degradation. To document how insulinopenia affects organ weights and to identify the pathway for accelerated proteolysis in muscle, streptozotocin-treated and vehicle-injected, pair-fed control rats were studied. The weights of liver, adipose tissue, and muscle were decreased while muscle protein degradation was increased 75% by insulinopenia. This proteolytic response was not eliminated by blocking lysosomal function and calcium-dependent proteases at 7 or 3 d after streptozotocin. When ATP synthesis in muscle was inhibited, the rates of proteolysis were reduced to the same level in insulinopenic and control rats suggesting that the ATP-dependent, ubiquitin-proteasome pathway is activated. Additional evidence for activation of this pathway in muscle includes: (a) an inhibitor of proteasome activity eliminated the increased protein degradation; (b) mRNAs encoding ubiquitin and proteasome subunits were increased two- to threefold; and (c) there was increased transcription of the ubiquitin gene. We conclude that the mechanism for muscle protein wasting in insulinopenia includes activation of the ubiquitin-proteasome pathway with increased expression of the ubiquitin gene.
Acu-TENS reduces breathlessness during exercise in people with COPD
Authors: Shirley Ngai, Jennifer Alison, Lissa Spencer, Alice Jones
Journal: European Respiratory Journal (2012)

The aim was to evaluate the effect of the application of transcutaneous electrical nerve stimulation of acupoints (Acu-TENS) on breathlessness during exercise.

Methods: Individuals diagnosed with COPD were recruited in this randomized crossover study. Participants performed two incremental shuttle walk tests (ISWT) to determine an appropriate speed for the endurance shuttle walk test (ESWT). After a session for practice of the ESWT, participants attended twice, one week apart, and performed two ESWTs per visit. On each visit, the second ESWT was performed with either Acu-TENS, i.e. application of TENS onto acupoints for breathlessness (EX-B1, Dingchuan) or Sham-TENS, i.e. application of TENS onto non-acupoints on the patella, in random order, for 45 minutes prior to and during the second ESWT. The assessor was blinded to group allocation. The duration of each ESWT and the dyspnoea score (Borg scale, 0-10) at isotime of the two ESWTs on any one visit were recorded for comparison.

Results: Twenty-one participants, mean (±SD) age 71±6 years, FEV1 % pred 51±22%, completed the study. At isotime, Acu-TENS showed a significant between-group reduction in dyspnoea of -0.7 unit (95%CI -1.2 to -0.1), p=0.016. A subgroup analysis of participants with dyspnoea ≥ 4 (n=12) at end of the ISWT showed a significant reduction in dyspnoea with Acu-TENS compared to Sham-TENS of -1 unit (95% CI -1.7 to -0.3), p=0.011, but not in those with dyspnoea <4 (n=9). No significant difference in endurance shuttle walk duration was observed between groups.

Conclusion: Acu-TENS may alleviate dyspnoea during walking in people with COPD, particularly in those who had more severe dyspnoea during exercise.
Constrction of the Neonatal Aorta by Raised Oxygen Tension
Authors: R. G. GILLMAN, A. C. BURTON
Journal: Circulation Research (1966)

A preparation consisting of the great arteries around the heart from neonatal guinea pigs was perfused at constant flow by physiological saline solutions in a bath in which various gases (95% N 2 + 5% CO 2 , air + 5% CO 2 and 95% O 2 + 5% CO 2 ) were bubbled. The pressure drop across the aorta, including the preductal area, was recorded and the changes in resistance in response to these gas tensions were calculated. The well-known closure of the ductus with increased P o 2 occurred, but in addition there was a reversible increase, up to 400%, in the resistance of the aortic segment. This was maximal 1 to 2 days after birth, diminishing with age until after 6 days it was very slight. In very young animals (1 to 2 days), responses to air and oxygen were roughly proportional to the P o 2 . Inspection of injection casts of the vessels showed that the constriction was local in the preductal area, closely resembling that of aortic coarctation. Segments of aorta that did not include the preductal area, and from animals of comparable age, showed very slight constriction to raised P o 2 . The neonatal vessels of pigs, rabbits and cats showed similar O 2 sensitivity of different degrees, and with different peculiarities as to time lag and repeatability. Neither the ductus nor the neonatal aorta of dogs appears to constrict to increased P o 2 , and closure of the ductus in this species must be by a different mechanism. These observations may be interpreted as evidence for the Skodaic theory that infantile aortic coarctation may occur in association and coincident with the closure of the ductus at birth. The administration of high O 2 gases at birth might, in cases of abnormal development, lead to permanent coarctation.
267 DERMATOLOGIC ADVERSE EVENTS WITHIN THE FIRST 60 DAYS OF SORAFENIB TREATMENT ARE ASSOCIATED WITH BETTER OVERALL SURVIVAL (OS) IN PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC)
Authors: M. Reig, C. Rodriguez de Lope, N. Llarch, A. Forner, F. Torres, J. Rios, L. Boix, J. Rimola, A. Darnell, C. Ayuso, J. Bruix
Journal: Journal of Hepatology (2013)