tbuckley/cabot-search huggingface dataset:
T cell proliferative response induced by DNA topoisomerase I in patients with systemic sclerosis and healthy donors.
Authors: M Kuwana, T A Medsger, T M Wright
Journal: Journal of Clinical Investigation (1995)

The in vitro T cell proliferative response to DNA topoisomerase I (topo I) was examined in 26 systemic sclerosis (SSc) patients with anti-topo I antibody, 10 SSc patients without anti-topo I antibody, and 21 healthy donors. Using recombinant fusion proteins encompassing the entire human topo I amino acid sequence, a topo I-specific proliferative response was detected in PBMC cultures from 25 (96%) anti-topo I-positive SSc patients, 4 (40%) anti-topo I-negative SSc patients, and 13 (62%) healthy donors. Molecular typing at MHC class II loci revealed that all SSc patients and healthy donors having either DRB1*1501,2 (DR15), DRB1*1101,3,4 (DR11), or DRB1*07 (DR7) were responders. Characterization of the topo I-induced T cell proliferative response showed that (a) the responding cells were CD4+ T cells; (b) antigen-presenting cells were necessary for the response; (c) the response was restricted by HLA-DR, and to a lesser extent by HLA-DQ; and (d) the estimated frequency of the responding T cells determined by limiting dilution analysis was 1/9,277-1/24,853. PBMC cultures from anti-topo I-positive SSc patients showed a high T cell proliferative response after only 3 d of culture with topo I. Anti-topo I-negative SSc patients and healthy donors had no proliferative response after 3 d, but did respond after 7 d of culture. T cell proliferative responses to six truncated topo I fragments tested individually showed different patterns of T cell proliferation that were dependent upon the responder's HLA-DR alleles. These results indicate that T cells reactive with topo I are components of the normal T cell repertoire, and that the topo I-specific T cell proliferative response is not associated with the presence or absence of SSc or anti-topo I antibody, but is restricted by MHC class II alleles.
Zoledronic Acid Versus Placebo in the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial—The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group
Authors: Lee S. Rosen, David Gordon, Simon Tchekmedyian, Ronald Yanagihara, Vera Hirsh, M. Krzakowski, M. Pawlicki, Paul de Souza, Ming Zheng, Gladys Urbanowitz, Dirk Reitsma, John J. Seaman
Journal: Journal of Clinical Oncology (2003)

To assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to solid tumors other than breast or prostate cancer.Patients were randomly assigned to receive zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months, with concomitant antineoplastic therapy. The 8-mg dose was reduced to 4 mg (8/4-mg group). The primary efficacy analysis was proportion of patients with at least one skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy to bone, and surgery to bone. Secondary analyses (time to first SRE, skeletal morbidity rate, and multiple event analysis) counted hypercalcemia as an SRE.Among 773 patients with bone metastases from lung cancer or other solid tumors, the proportion with an SRE was reduced in both zoledronic acid groups compared with the placebo group (38% for 4 mg and 35% for 8/4 mg zoledronic acid v 44% for the placebo group; P =.127 and P =.023 for 4-mg and 8/4-mg groups, respectively). Additionally, 4 mg zoledronic acid significantly increased time to first event (median, 230 v 163 days for placebo; P =.023), an important end point in this poor-prognosis population, and significantly reduced the risk of developing skeletal events by multiple event analysis (hazard ratio = 0.732; P =.017). Zoledronic acid was well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and vomiting.Zoledronic acid (4 mg infused over 15 minutes) is the first bisphosphonate to reduce skeletal complications in patients with bone metastases from solid tumors other than breast and prostate cancer.
Histamine inhibits the production of interleukin-12 through interaction with H2 receptors.
Authors: T C van der Pouw Kraan, A Snijders, L C Boeije, E R de Groot, A E Alewijnse, R Leurs, L A Aarden
Journal: Journal of Clinical Investigation (1998)

IL-12 is essential for T helper 1 (Th1) development and inhibits the induction of Th2 responses. Atopic diseases, which are characterized by Th2 responses, are associated with the overproduction of histamine. Here we present evidence that histamine, at physiological concentrations, strongly inhibits human IL-12 p40 and p70 mRNA and protein production by human monocytes. The use of specific histamine receptor antagonists reveals that this inhibition is mediated via the H2 receptor and induction of intracellular cAMP. The inhibition of IL-12 production is independent of IL-10 and IFN-gamma. The observation that histamine strongly reduces the production of the Th1-inducing cytokine IL-12 implies a positive feedback mechanism for the development of Th2 responses in atopic patients.
p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction
Authors: Nhat-Tu Le, Yuichiro Takei, Tetsuro Shishido, Chang-Hoon Woo, Eugene Chang, Kyung-Sun Heo, Hakjoo Lee, Yan Lu, Craig Morrell, Masayoshi Oikawa, Carolyn McClain, Xin Wang, Cathy Tournier, Carlos A. Molina, Jack Taunton, Chen Yan, Keigi Fujiwara, Cam Patterson, Jay Yang, Jun-ichi Abe
Journal: Circulation Research (2012)

Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent upregulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown.
APPARENT RECURRENCES OF SCARLET FEVER
Authors: W. H. Kelleher
Journal: BMJ (1929)

JUNE 19 19 -29 1 1 ~~~~~~~~~E V IlMEDICAL Jouu±w.right base, and breath signs were very faint.The temperature ranged from 970 to 990, the pulse rate was 90, and the respira- tion rate 20.On April 9th pus was aspirated from the right chest and a portion of rib was resected for an empyema.On the 12th and following days the empyema wound drained freely, and on the 15th the temperature was normal.On May ist the tempera- ture was still down, the wound was draining slightly, and the patient's general condition was good.Altogetlher she had 2 draclhms of preparation X subcutaneously and 31 by mouth.Of preparation Y she had approximately 24 miniims daily for seventeen days. CASE V.Tlhe patient, a primipara aged 23, had a normal labour at hler own home on March 4tlh, 1929.She was well until the third day,
Role of Sodium and Calcium Dysregulation in Tachyarrhythmias in Sudden Cardiac Death
Authors: Stefan Wagner, Lars S. Maier, Donald M. Bers
Journal: Circulation Research (2015)

Despite improvements in the therapy of underlying heart disease, sudden cardiac death is a major cause of death worldwide. Disturbed Na and Ca handling is known to be a major predisposing factor for life-threatening tachyarrhythmias. In cardiomyocytes, many ion channels and transporters, including voltage-gated Na and Ca channels, cardiac ryanodine receptors, Na/Ca-exchanger, and SR Ca-ATPase are involved in this regulation. We have learned a lot about the pathophysiological relevance of disturbed ion channel function from monogenetic disorders. Changes in the gating of a single ion channel and the activity of an ion pump suffice to dramatically increase the propensity for arrhythmias even in structurally normal hearts. Nevertheless, patients with heart failure with acquired dysfunction in many ion channels and transporters exhibit profound dysregulation of Na and Ca handling and Ca/calmodulin-dependent protein kinase and are especially prone to arrhythmias. A deeper understanding of the underlying arrhythmic principles is mandatory if we are to improve their outcome. This review addresses basic tachyarrhythmic mechanisms, the underlying ionic mechanisms and the consequences for ion homeostasis, and the situation in complex diseases like heart failure.
Lung Squamous Cell Carcinoma mRNA Expression Subtypes Are Reproducible, Clinically Important, and Correspond to Normal Cell Types
Authors: Matthew D. Wilkerson, Xiaoying Yin, Katherine A. Hoadley, Yufeng Liu, Michele C. Hayward, Christopher R. Cabanski, Kenneth Muldrew, C. Ryan Miller, Scott H. Randell, Mark A. Socinski, Alden M. Parsons, William K. Funkhouser, Carrie B. Lee, Patrick J. Roberts, Leigh Thorne, Philip S. Bernard, Charles M. Perou, D. Neil Hayes
Journal: Clinical Cancer Research (2010)

Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous, and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant.Subtypes were detected by unsupervised consensus clustering in five published discovery cohorts of mRNA microarrays, totaling 382 SCC patients. An independent validation cohort of 56 SCC patients was collected and assayed by microarrays. A nearest-centroid subtype predictor was built using discovery cohorts. Validation cohort subtypes were predicted and evaluated for confirmation. Subtype survival outcome, clinical covariates, and biological processes were compared by statistical and bioinformatic methods.Four lung SCC mRNA expression subtypes, named primitive, classical, secretory, and basal, were detected and independently validated (P < 0.001). The primitive subtype had the worst survival outcome (P < 0.05) and is an independent predictor of survival (P < 0.05). Tumor differentiation and patient sex were associated with subtype. The expression profiles of the subtypes contained distinct biological processes (primitive: proliferation; classical: xenobiotic metabolism; secretory: immune response; basal: cell adhesion) and suggested distinct pharmacologic interventions. Comparison with lung model systems revealed distinct subtype to cell type correspondence.Lung SCC consists of four mRNA expression subtypes that have different survival outcomes, patient populations, and biological processes. The subtypes stratify patients for more precise prognosis and targeted research.
Predictors for longitudinal change in 6-minute walk distance in COPD patients
Authors: Bente Frisk, Birgitte Espehaug, Jon Andrew Hardie, Liv Inger Strand, Rolf Moe-Nilssen, Tomas M. Eagan, Per S. Bakke, Einar Thorsen
Journal: European Respiratory Journal (2012)

INTRODUCTION:  The 6-min walk distance (6MWD) is widely used to evaluate exercise capacity in patients with Chronic Obstructive Pulmonary Disease (COPD), and is predictive of mortality and exacerbations.   AIMS:  To examine the change in 6MWD over 3 yrs in COPD patients and elucidate factors at baseline that may predict the change.   METHODS:  This prospective observational study included 389 patients aged 40-75 yrs, with clinically stable COPD in GOLD stage II-IV. Measurements at baseline and after 1 and 3 yrs included 6MWD, spirometry, body mass index (BMI), and assessment of smoking habits and exacerbations by questionnaires. Adjusted generalized estimating equations (GEE) regression analyses were used to analyze predictors for change in 6MWD.   RESULTS:  There was no significant change in 6MWD from baseline to 1 yr for any GOLD stage, or from baseline to 3 yrs for patients in GOLD II. For GOLD III (β= -36 m, 95 % CI=-55, -17) and IV (β=-86 m, 95 % CI= -138, -33) 6MWD decreased (fig.1). In the multivariate GEE forced expiratory volume in one second (FEV 1 ) (p 1  predicted change over time (p=0.003).   CONCLUSION:  Patients in GOLD stage II maintained 6MWD at 3 yrs, while patients in GOLD III and IV reduced 6MWD significantly. FEV 1  was a strong predictor for longitudinal change in 6MWD.
Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study
Authors: Gunter von Minckwitz, Andreas du Bois, Marcus Schmidt, Nicolai Maass, Tanja Cufer, Felix E. de Jongh, Eduard Maartense, Christoph Zielinski, Manfred Kaufmann, Wolfgang Bauer, Klaus H. Baumann, Michael R. Clemens, Ralph Duerr, Christoph Uleer, Michael Andersson, Robert C. Stein, Valentina Nekljudova, Sibylle Loibl
Journal: Journal of Clinical Oncology (2009)

Purpose Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)–positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. Methods Patients with HER-2–positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m 2 body-surface area on days 1 through 14 [1,250 mg/m 2 semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. Results We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. Conclusion Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2–positive breast cancer who experienced progression during trastuzumab treatment.
Cell Lineage in the Development of Invertebrate Nervous Systems
Authors: Gunther S. Stent, David A. Weisblat
Journal: Annual Review of Neuroscience (1985)

Studies of developmental cell lineage, i.e. of the fate of individual blastomeres that arise in an embryo, were begun in the 1 870s , in the context of the con­ troversy then raging about the biogenetic, or recapitulation, law promul­ gated by Ernst Haeckel . The biogenetic law seemed to imply that the early, pre-gastrula stages of metazoan embryogenesis recapitulate the nondifferen­ tiated condition of a remote colonial ancestor. Hence, prior to gastrulation, all blastomeres should be of equivalent developmental potency. Only after gastrulation would particular domains of the embryo become committed to the differentiated tissues characteristic of more recent metazoan ancestors. This implication was tested by a group of American biologists, led by Charles 0. Whitman ( 1878, 1 887). By observing the cleavage pattern of early leech embryos, Whitman traced the fate of individual blastomeres, from the uncleaved egg to the gastrular germ layer stage and concluded that, contrary to the simplest interpretation of the biogenetic law, even the earliest blastomeres are developmentally distinct and that each identified blastomere, and the clone of its descendant cells, plays a specific role in later development. Whitman set the pattern for all subsequent lineage studies. His disciples, including such future leaders of American cell biology as E . B. Wilson, E. G. Conklin, and F. R. Lillie, studied the embryos of other annelids, ascidians, and molluscs. Comparisons of their data revealed significant cross-phyletic similarities, as well as differences, in developmental cell lineage relations. Hence they concluded that there must be some relation between on�ogeny and
Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1
Authors: LC Verhoog, CTM Brekelmans, C Seynaeve, LMC van den Bosch, G Dahmen, AN van Geel, MMA Tilanus-Linthorst, CCM Bartels, A Wagner, A van den Ouweland, P Devilee, EJ Meijers-Heijboer, JGM Klijn
Journal: The Lancet (1998)
A comparison of video and autofluorescence bronchoscopy in patients at high risk of lung cancer
Authors: P. N. Chhajed, K. Shibuya, H. Hoshino, M. Chiyo, K. Yasufuku, K. Hiroshima, T. Fujisawa
Journal: European Respiratory Journal (2005)

The aim of this study was to compare the diagnostic yield of flexible video bronchoscopy (FVB) and autofluorescence bronchoscopy ( i.e. lung imaging fluorescence endoscopy (LIFE)) in 151 patients at a high risk of lung cancer and with moderate dysplasia or worse on sputum cytology mass screening. Findings from FVB and LIFE were classified as either normal, abnormal or suspicious for cancer. Endobronchial biopsies (EBX) were obtained from abnormal or suspicious areas on FVB and/or LIFE, or randomly when FVB and LIFE were normal. Moderate dysplasia and worse were defined as pathologically positive. Overall, 83 out of 343 (24%) EBX were pathologically positive. The sensitivity of FVB was 72% and LIFE 96%. Relative sensitivity of LIFE over FVB was 1.33. Specificities of FVB and LIFE were 53 and 23%, respectively. The numbers of pathologically positive EBX from sites designated normal, abnormal or suspicious were: from FVB, 23 out of 162 (14%), 37 out of 151 (25%) and 23 out of 30 (77%); from LIFE, three out of 69 (4%), 44 out of 212 (21%) and 36 out of 62 (58%). In normal or abnormal areas at FVB, there was a significant increase in the yield of EBX guided by abnormal and suspicious sites noted at LIFE. In conclusion, endobronchial biopsies of suspicious findings from lung imaging fluorescence endoscopy and flexible video bronchoscopy have a good diagnostic yield. Lung imaging fluorescence endoscopy is more useful when flexible video bronchoscopy is either normal or abnormal.
Alterations in tissue ferritins in iron storage disorders.
Authors: L W Powell, L V McKeering, J W Halliday
Journal: Gut (1975)

Purified tissue ferritins isolated from Bantu subjects with gross haemosiderosis, from a patient with idiopathic haemochromatosis (HC) treated by phlebotomy, and from rats with experimental iron overload were studied in order to determine the significance of the abnormality previously demonstrated in tissue isoferritins in patients with IHC. The isoferrin profile of the tissues from the Bantu subjects and the iron-loaded rats showed a similar abnormality to that previously found in patients with untreated IHC--that is, an abnormally uniform distribution of iron-containing isoferritins with an increase in the more basic isoferritins and an apparent absence of the more acidic ones. In contrast, tissues from the patient with treated IHC, who was iron depleted at the time of death, showed the normal organ-specific isoferritin distribution. These findings strongly suggest that the abnormal distribution of tissue isoferritins in IHC is an acquired phenomenon and unlikely to be related to an underlying genetic defect in ferritin or iron metabolism.
Galectin-1, a gene preferentially expressed at the tumor margin, promotes glioblastoma cell invasion
Authors: L Gerard Toussaint, Allan E Nilson, Jennie M Goble, Karla V Ballman, C David James, Florence Lefranc, Robert Kiss, Joon H Uhm
Journal: Molecular Cancer (2012)

High-grade gliomas, including glioblastomas (GBMs), are recalcitrant to local therapy in part because of their ability to invade the normal brain parenchyma surrounding these tumors. Animal models capable of recapitulating glioblastoma invasion may help identify mediators of this aggressive phenotype. Patient-derived glioblastoma lines have been propagated in our laboratories and orthotopically xenografted into the brains of immunocompromized mice. Invasive cells at the tumor periphery were isolated using laser capture microdissection. The mRNA expression profile of these cells was compared to expression at the tumor core, using normal mouse brain to control for host contamination. Galectin-1, a target identified by screening the resulting data, was stably over-expressed in the U87MG cell line. Sub-clones were assayed for attachment, proliferation, migration, invasion, and in vivo tumor phenotype. Expression microarray data identified galectin-1 as the most potent marker (p-value 4.0 x 10-8) to identify GBM cells between tumor-brain interface as compared to the tumor core. Over-expression of galectin-1 enhanced migration and invasion in vitro. In vivo, tumors expressing high galectin-1 levels showed enhanced invasion and decreased host survival. In conclusion, cells at the margin of glioblastoma, in comparison to tumor core cells, have enhanced expression of mediators of invasion. Galectin-1 is likely one such mediator. Previous studies, along with the current one, have proven galectin-1 to be important in the migration and invasion of glioblastoma cells, in GBM neoangiogenesis, and also, potentially, in GBM immune privilege. Targeting this molecule may offer clinical improvement to the current standard of glioblastoma therapy, i.e. radiation, temozolomide, anti-angiogenic therapy, and vaccinotherapy.
An inducible short-hairpin RNA vector against osteopontin reduces metastatic potential of human esophageal squamous cell carcinoma in vitro and in vivo.
Authors: Tetsuo Ito, Yosuke Hashimoto, Eiji Tanaka, Takatsugu Kan, Shigeru Tsunoda, Fumiaki Sato, Motoshige Higashiyama, Tomoyuki Okumura, Yutaka Shimada
Journal: Clinical Cancer Research (2006)

To elucidate the clinical significance of osteopontin and the effect of conditional down-regulation of osteopontin in esophageal squamous cell carcinoma (ESCC), we investigated osteopontin expression in tumors and tested an inducible osteopontin-short-hairpin RNA (shRNA) expression vector in an ESCC cell line.Osteopontin mRNA expression was extracted from gene expression profiles of 23 tumors determined by cDNA microarray and was analyzed. Paraffin sections of 144 tumors were immunohistochemically investigated. Osteopontin protein expression in 34 cell lines was examined by Western blot. A doxycycline-inducible osteopontin-shRNA vector was stably transfected into HSA/c cells to assess the role of osteopontin in cell motility, invasion in vitro, tumor formation, and lymph node metastasis in nude mice.cDNA microarray revealed that high osteopontin mRNA expression was associated with poor survival of ESCC patients (P = 0.029). In immunohistochemistry, osteopontin protein expression was associated with poor prognosis (P < 0.001), distant lymph node metastasis (P = 0.0004), tumor staging (P = 0.027), and histologic grade (P = 0.024). Multivariate analysis showed that osteopontin overexpression was the strongest independent prognostic factor among nine clinicopathologic variables (P < 0.001). Among cell lines tested, 30 had overexpressed osteopontin protein compared with a normal esophageal epithelial cell line. An inducible shRNA vector against osteopontin successfully down-regulated osteopontin expression by 71% to 88% and repressed cell motility by 69% to 97%, cell invasion by 59% to 71%, tumor formation by 56% to 92%, and lymph node metastasis by 50% to 67% in HSA/c cells.Our findings suggest that osteopontin overexpression may play an important role in progression of ESCC and osteopontin could be a potential target of ESCC therapy.