tbuckley/cabot-search huggingface dataset:
Cryoanalgesia for Intractable Perineal Pain<sup>1</sup>
Authors: P J D Evans, J W Lloyd, T M Jack
Journal: Journal of the Royal Society of Medicine (1981)

Cryoanalgesia, the local application of extreme cold to nerves to produce analgesia, has been used to treat patients with intractable perineal pain. The cryoprobe was inserted percutaneously through the sacral hiatus into the sacral canal to produce anaesthesia of the lower sacral nerve roots. Forty patients received a total of 70 treatments: 31 patients (78%) were helped by the procedure and the median duration of improvement was 30 days. The treatment was more successful in relieving symptoms in patients suffering from pelvic cancer and coccydynia. The best results were obtained in those patients who received numerous freeze applications or prolonged freezing.
Fixation of Deleterious Mutations at Critical Positions in Human Proteins
Authors: S. Subramanian
Journal: Molecular Biology and Evolution (2011)

Deleterious mutations associated with human diseases are predominantly found in conserved positions and positions that are essential for the structure and/or function of proteins. However, these mutations are purged from the human population over time and prevented from being fixed. Contrary to this belief, here I show that high proportions of deleterious amino acid changing mutations are fixed at positions critical for the structure and/or function of proteins. Similarly, a high rate of fixation of deleterious mutations was observed in slow-evolving amino acid positions of human proteins. The fraction of deleterious substitutions was found to be two times higher in relatively conserved amino acid positions than in highly variable positions. This study also found fixation of a much higher proportion of radical amino acid changes in primates compared with rodents and artiodactyls in slow-evolving positions. Previous studies observed a higher proportion of nonsynonymous substitutions in humans compared with other mammals, which was taken as indirect evidence for the fixation of deleterious mutations in humans. However, the results of this investigation provide direct evidence for this prediction by suggesting that the excess nonsynonymous mutations fixed in humans are indeed deleterious in nature. Furthermore, these results suggest that studies on disease-associated mutations should consider that a significant fraction of such deleterious mutations has already been fixed in the human genome, and thus, the effects of new mutations at those amino acid positions may not necessarily be deleterious and might even result in reversion to benign phenotypes.
Adhesion of normal and Plasmodium falciparum ring–infected erythrocytes to endothelial cells and the placenta involves the rhoptry-derived ring surface protein-2
Authors: Jean-Bernard Lekana Douki, Yvon Sterkers, Catherine Lépolard, Boubacar Traoré, Fabio T. M. Costa, Artur Scherf, Jürg Gysin
Journal: Blood (2003)
Master switches of T-cell activation and differentiation
Authors: K. C. Beier, T. Kallinich, E. Hamelmann
Journal: European Respiratory Journal (2007)

T-cells play a central role in allergic airway diseases such as bronchial asthma. The imbalance between allergen-specific pro-inflammatory and pro-allergic T-cell responses on one hand and regulatory or suppressive T-cell responses on the other may best explain the development of unwanted immune responses against environmental allergens, which lead to immunoglobulin E production and airway inflammation. A key role in the fine tuning of any T-cell response is provided by the engagement of so-called co-stimulatory molecules that are required for the full activation of T-cells and the recognition of antigens via the antigen-specific T-cell receptor. Many of these co-stimulatory molecules have been identified only recently, leading to a fundamental change in the overall understanding of T-cell regulation. Due to their pivotal impact on T-cell differentiation and control, co-stimulatory molecules are promising targets for therapeutic intervention in T-cell-regulated or -mediated immune disorders, including allergic diseases and asthma. In the present article, an attempt is made to summarise the current knowledge on the basic concept of co-stimulation, the presently known co-stimulatory molecules and their various functions on T-cell activation or suppression. The mini-series will be completed by two more articles describing the recent experimental studies and preliminary clinical findings regarding the role of co-stimulatory molecules in allergic disorders and bronchial asthma, and a discussion regarding the feasibility of co-stimulatory molecules as potential targets for the treatment of allergic airway disease. Although it is too early for any clinical implication or utilisation at this moment, the authors are convinced that a better understanding of co-stimulation in the context of allergic asthma will finally provide novel and promising approaches for treatment and prevention.
Dr. F. B. Kiernander, FRCP, DMRE, DPhysMed
Authors: H. E. Robson
Journal: British Journal of Sports Medicine (1982)

After many years of ill health, Basil Kiemander died at the end of May this year.He qualified at St. Thomas' Hospital in 1936, having been awarded the Solly Medal, and both the Wainwright and the Toiler prizes.The following year he gained the Membership of the Royal College of Physicians, and was elected Fellow in 1972.He was a pioneer of physical and rehabilitation medicine, being awarded the Diploma of Medical Radiology and Electrolysis in 1938 and was one of the first to obtain the Diploma of Physical Medicine in 1946.His main professional appointment was to the Physical Medicine Department of the Hospital for Sick Children, Great Ormond Street, and his enthusiasm in this field altered the outlook dramatically for many hundreds of children suffering from Still's and other disabling diseases.During the War he was an Honorary Civilian Consultant to the Royal Air Force, and realised early on the immense value that sports participation can have upon the morale and physical well-being of the severely injured.After the War, his interest in the severely maimed continued with the formation of the Cheshire Homes, an interest he was able to expand after retirement from hospital practice in 1978.
Genome-wide profiling of mouse RNA secondary structures reveals key features of the mammalian transcriptome
Authors: Danny Incarnato, Francesco Neri, Francesca Anselmi, Salvatore Oliviero
Journal: Genome biology (2014)

The understanding of RNA structure is a key feature toward the comprehension of RNA functions and mechanisms of action. In particular, non-coding RNAs are thought to exert their functions by specific secondary structures, but an efficient annotation on a large scale of these structures is still missing.By using a novel high-throughput method, named chemical inference of RNA structures, CIRS-seq, that uses dimethyl sulfate, and N-cyclohexyl- N'-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate to modify RNA residues in single-stranded conformation within native deproteinized RNA secondary structures, we investigate the structural features of mouse embryonic stem cell transcripts. Our analysis reveals an unexpected higher structuring of the 5′ and 3′ untranslated regions compared to the coding regions, a reduced structuring at the Kozak sequence and stop codon, and a three-nucleotide periodicity across the coding region of messenger RNAs. We also observe that ncRNAs exhibit a higher degree of structuring with respect to protein coding transcripts. Moreover, we find that the Lin28a binding protein binds selectively to RNA motifs with a strong preference toward a single stranded conformation.This work defines for the first time the complete RNA structurome of mouse embryonic stem cells,revealing an extremely distinct RNA structural landscape. These results demonstrate that CIRS-seq constitutes an important tool for the identification of native deproteinized RNA structures.
Low Hepatic Lipase Activity Is a Novel Risk Factor for Coronary Artery Disease
Authors: Klaus A. Dugi, Karin Brandauer, Nikolaus Schmidt, Barbara Nau, Jochen G. Schneider, Stefani Mentz, Tanja Keiper, Juergen R. Schaefer, Christoph Meissner, Horst Kather, Malte L. Bahner, Walter Fiehn, Joerg Kreuzer
Journal: Circulation (2001)

The crucial function of hepatic lipase (HL) in lipid metabolism has been well established, but the relationship between HL activity and coronary artery disease (CAD) is disputed.We measured HL activity in the postheparin plasma of 200 consecutive men undergoing elective coronary angiography and determined the degree of CAD with the extent score, which has been shown to be better correlated with known risk factors than other measures of CAD extent. We found a significant inverse correlation between HL activity and the extent of CAD (r=-0.19, P<0.01). This association was mainly due to patients with HDL levels >0.96 mmol/L (n=94, r=-0.30, P<0.005). HL activity was lower in 173 patients with CAD than in 40 controls with normal angiograms (286+/-106 versus 338+/-108 nmol. mL(-1). min(-1), P<0.01). To correct for potential confounding factors, we performed multivariate analyses that confirmed the independent association of HL activity with CAD extent. In addition, the presence of the T allele at position -514 in the HL promoter, which leads to a reduced HL promoter activity, was associated with lower HL activity (r=0.30, P<0.001) and higher CAD extent (42.2+/-20.8 versus 35.3+/-23.6 [extent score], P<0.05). In patients with heterozygous familial hypercholesterolemia, calcified lesions in ECG-gated spiral computed tomography were higher in patients with low HL activity (6.3+/-6.8 versus 1.5+/-3.1, P=0.01).Our data show that low HL activity is associated with CAD. Therefore, HL might be useful for CAD risk estimation and might be a target for pharmacological intervention.
A novel model for antigen-dependent activation of normal human T cells. Transmembrane signaling by crosslinkage of the CD3/T cell receptor-alpha/beta complex with the cluster determinant 2 antigen.
Authors: M Suthanthiran
Journal: The Journal of Experimental Medicine (1990)

Transmembrane signaling of normal human T cells was explored with mAbs directed at TCR, CD2, CD4, CD5, or CD8 antigens and highly purified CD4+ T cells and CD8+ T cells. Our experiments explicitly show that: (a) crosslinkage of TCR with the CD2 antigen, and not independent crosslinking of TCR and of CD2 antigen or crosslinking of either protein with the CD4 or CD8 antigen induces significant proliferation independent of co-stimulatory signals (e.g., accessory cells, recombinant lymphokines, or tumor promoter), (b) F(ab')2 fragments of mAb directed at the TCR and F(ab')2 anti-CD2, crosslinked with F(ab')2 fragments of rabbit anti-mouse IgG, promote the proliferation of highly purified T cells, (c) a prompt and sustained increase in intracellular free Ca2+ concentration results from crosslinkage of TCR with the CD2 antigen, (d) T cell proliferation induced by this novel approach is curtailed by EGTA and by direct or competitive inhibitors of PKC, (e) crosslinkage of TCR with the CD2 antigen results in the transcriptional activation and translation of the gene for IL-2 and in the expression of IL-2 receptor alpha (CD25), (f) anti-CD25 mAbs inhibit T cell proliferation initiated by crosslinkage of TCR with the CD2 antigen, and recombinant IL-2 restores the proliferative response. Our first demonstration that crosslinkage of TCR with the CD2 antigen induces proliferation of normal human CD4+ T cells and CD8+ T cells, in addition to revealing a novel activation mechanism utilizable by the two major subsets of T cells, suggest that the CD2 antigen might be targeted for the regulation of antigen-specific T cell immunity (e.g., organ transplantation).
IQGAP1 Protein Specifies Amplifying Cancer Cells in Glioblastoma Multiforme
Authors: Laurent Balenci, Ian D. Clarke, Peter B. Dirks, Nicole Assard, François Ducray, Anne Jouvet, Marie-Françoise Belin, Jerôme Honnorat, Jacques Baudier
Journal: Cancer Research (2006)

The accurate identification and thorough characterization of tumorigenic cells in glioblastomas are essential to enhance our understanding of their malignant behavior and for the design of strategies that target this important cell population. We report here that, in rat brain, the scaffolding protein IQGAP1 is a marker of brain nestin+ amplifying neural progenitor cells. In a rat model of glioma, IQGAP1 also characterizes a subpopulation of nestin+ amplifying tumor cells in glioblastoma-like tumors but not in tumors with oligodendroglioma features. We next confirmed that IQGAP1 represents a new marker that may help to discriminate human glioblastoma from oligodendrogliomas. In human glioblastoma exclusively, IQGAP1 specifies a subpopulation of amplifying nestin+ cancer cells. Neoplastic IQGAP1+ cells from glioblastoma can be expanded in culture and possess all the characteristics of cancer stem-like progenitors. The similarities between amplifying neural progenitors and glioblastoma amplifying cancer cells may have significant implications for understanding the biology of glioblastoma.
Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer
Authors: A. Argiris, M.V. Karamouzis, R. Smith, A. Kotsakis, M.K. Gibson, S.Y. Lai, S. Kim, B.F. Branstetter, Y. Shuai, M. Romkes, L. Wang, J.R. Grandis, R.L. Ferris, J.T. Johnson, D.E. Heron
Journal: Annals of Oncology (2011)
Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Frank L Greenway, Ken Fujioka, Raymond A Plodkowski, Sunder Mudaliar, Maria Guttadauria, Janelle Erickson, Dennis D Kim, Eduardo Dunayevich
Journal: The Lancet (2010)
Small bowel bacterial overgrowth in coeliac disease: a cause of presenting symptoms?
Authors: K. E. Evans, S. Higham, A. Smythe, D. S. Sanders
Journal: Gut (2011)

<h3>Introduction</h3> The relationship between small intestinal bacterial overgrowth (SIBO) and coeliac disease is poorly understood. SIBO is recognised as a cause of persisting symptoms in patients with treated coeliac disease. However, there are very few data on SIBO in untreated coeliac disease. We aimed to assess the prevalence of small bowel bacterial overgrowth in untreated coeliac disease, and to compare with non-coeliac controls. <h3>Methods</h3> Data were collected from consecutive patients with a new diagnosis of coeliac disease, and non-coeliac controls having glucose hydrogen-breath test (GHBT) for gastrointestinal symptoms. All subjects had GHBT performed on a normal, gluten containing diet. A subset of coeliac patients was retested after 6 months on a gluten-free diet (GFD). Concurrent serology (endomysial antibody (EMA) and tissue transglutaminase (tTG)), symptoms, biochemical data (B12, folate, iron, haemoglobin), and duodenal histology were recorded from the coeliac group. None had antibiotics in the 4 weeks prior to testing. A positive result was a rise in hydrogen of at least 20ppm, or methane of 12ppm, over the baseline for each gas. <h3>Results</h3> 43 patients with untreated coeliac disease were identified, 13 male, median age 47 years (range 18–75). They were compared against 43 age and sex matched non-coeliac controls. In the coeliac group 8/43 (18.6%) had a positive result compared with 4/43 (9.3%) controls (p=0.35). Those with coeliac disease had similar baseline values of hydrogen (9.6 ppm ± 8.8) compared with non-coeliacs (11.1 ppm ± 6.7).Peak hydrogen values in coeliacs were significantly lower (12.6 ppm ± 13.6) than in non-coeliacs (28.3 ppm ± 51.6). In the coeliac group, 4/8 with a positive result had a significant rise in methane but not hydrogen. Positive result in the coeliac group was not associated with age, sex, tTG level, presenting complaint, or histological features. 12 patients, including 3 with a positive methane result were retested on GFD. All three were persistently methane positive but the absolute peak methane levels had fallen from a mean of 64 ppm to a mean of 49 ppm. There was no significant difference between the peak level of hydrogen before (7.2 ppm ± 4.2) or after (8.8 ppm ± 5.3) gluten-free diet. Likewise there was no significant change in peak levels of methane before (19.5 ppm ±) or after (16.9 ppm ±) gluten-free diet. <h3>Conclusion</h3> 18.6% of patients presenting with new diagnosis coeliac disease may have SIBO which could contribute significantly to the symptom profile. Clinicians should be mindful of SIBO as a cause of presenting symptoms as well as persisting symptoms in coeliac disease.
Phase I and Imaging Trial of Indium 111-Labeled Anti-Epidermal Growth Factor Receptor Monoclonal Antibody 225 in Patients With Squamous Cell Lung Carcinoma
Authors: C. R. Divgi, S. Welt, M. Kris, F. X. Real, S. D. J. Yeh, R. Gralla, B. Merchant, S. Schweighart, M. Unger, S. M. Larson, J. Mendelsohn
Journal: JNCI Journal of the National Cancer Institute (1991)

Murine monoclonal antibody (MAb) 225 (IgG1) against the epidermal growth factor (EGF) receptor competitively blocks EGF binding and inhibits EGF-induced activation of receptor tyrosine kinase and cell proliferation. The effect of MAb 225 was studied in a phase I trial in patients with inoperable squamous cell carcinoma of the lung, which invariably expresses high levels of EGF receptors. Groups of three patients received total doses of MAb 225 ranging from 1 mg to 300 mg. Except at the lowest dose, each infusion included 4 mg of indium 111 (111In)-labeled MAb 225. No toxicity was observed. Tumors were imaged in all patients who received doses of 20 mg or greater. Presumed metastases greater than or equal to 1 cm in diameter were imaged with doses of 40 mg or greater. Single-photon-emission-computed tomography could be carried out at the 120-mg and 300-mg doses and significantly improved tumor visualization. All patients produced anti-murine antibodies. We conclude that treatment with an MAb that inhibits EGF receptor function is safe at the doses and schedule studied. 111In-labeled MAb images squamous cell lung carcinoma; tumor uptake of the labeled MAb is dose dependent. Further studies are warranted to explore the potential therapeutic efficacy of anti-EGF receptor MAbs and other agents that act in a comparable manner.
Prevention and Management of Hereditary Breast Cancer
Authors: Steven A. Narod, Kenneth Offit
Journal: Journal of Clinical Oncology (2005)

It has been 10 years since the BRCA1 gene was first identified. During this decade, genetic testing for breast cancer susceptibility has been incorporated into the practice of oncology. In this process, the identification of families at the highest hereditary risk for cancer has served as a model to test strategies for prevention or early detection of breast malignancies. An emerging literature has explored primary prevention through risk reducing surgery and chemoprevention, as well as secondary prevention utilizing such approaches as magnetic resonance imaging (MRI) to achieve early detection of breast cancer in women with BRCA1 or BRCA2 mutations. Tailored treatments are being explored for newly diagnosed women with BRCA mutations. Ultimately, individual risk estimates and clinical management plans will be generated for women carrying BRCA mutations, based on consideration of the particular mutation inherited and also on the presence of modifying genetic and environmental factors. Both BRCA1 and BRCA2 are involved in the cellular response to DNA damage and interact with other proteins involved in double-stranded DNA repair. The effects of inherited mutations in these genes are similar, and mutations of both types predispose carriers to female and male breast cancer, and to ovarian cancer. The risk of male breast cancer is higher in BRCA2 carriers; ovarian cancer risk is higher in those carrying BRCA1 mutations. In addition, BRCA2 mutations appear to predispose both men and women to a wide range of other cancer types. The reasons for these tissue-specific differences between the two genes is not clear.
Deregulation of the <i>HOXA10</i> Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition
Authors: Hiroyuki Yoshida, Russell Broaddus, Wenjun Cheng, SuSu Xie, Honami Naora
Journal: Cancer Research (2006)

Homeobox genes encode transcription factors that control cell differentiation and play essential roles in developmental patterning. Increasing evidence indicates that many homeobox genes are aberrantly expressed in cancers, and that their deregulation significantly contributes to tumor progression. The homeobox gene HOXA10 controls uterine organogenesis during embryonic development and functional endometrial differentiation in the adult. We investigated whether HOXA10 expression is deregulated in endometrial carcinomas, and how counteracting this aberrant expression modifies tumor behavior. We found that down-regulation of HOXA10 expression in endometrial carcinomas strongly correlates with increased tumor grade and is associated with methylation of the HOXA10 promoter. Enforced expression of HOXA10 in endometrial carcinoma cells inhibited invasive behavior in vitro and tumor dissemination in nude mice. The inhibitory effect of HOXA10 on invasive behavior was attributable at least in part to the ability of HOXA10 to induce expression of the epithelial cell adhesion molecule E-cadherin by down-regulating expression of Snail, a repressor of E-cadherin gene transcription. These findings reveal a novel role for HOXA10 deregulation in the progression of endometrial carcinoma by promoting epithelial-mesenchymal transition.
CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?
Authors: Cédric Ménard, François Ghiringhelli, Stephan Roux, Nathalie Chaput, Christine Mateus, Ursula Grohmann, Sophie Caillat-Zucman, Laurence Zitvogel, Caroline Robert
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Anti–CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far. Experimental Design: We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti–CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (Treg) functions were evaluated. Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects (obtained in 7 of 10 patients). Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.