tbuckley/cabot-search huggingface dataset:
Preoperative radiochemotherapy is successful also in patients with locally advanced rectal cancer who have intrinsically high apoptotic tumours
Authors: M.J.E.M. Gosens, R.C. Dresen, H.J.T. Rutten, G.A.P. Nieuwenhuijzen, J.A.W.M. van der Laak, H. Martijn, I. Tan-Go, I.D. Nagtegaal, A.J.C. van den Brule, J.H.J.M. van Krieken
Journal: Annals of Oncology (2008)
R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer
Authors: Sacha J. Holland, Alison Pan, Christian Franci, Yuanming Hu, Betty Chang, Weiqun Li, Matt Duan, Allan Torneros, Jiaxin Yu, Thilo J. Heckrodt, Jing Zhang, Pingyu Ding, Ayodele Apatira, Joanne Chua, Ralf Brandt, Polly Pine, Dane Goff, Rajinder Singh, Donald G. Payan, Yasumichi Hitoshi
Journal: Cancer Research (2010)

Abstract Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, &amp;gt;80 days compared with 52 days; P &amp;lt; 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors. Cancer Res; 70(4); 1544–54
Analysis of risk factors for acute cutaneous graft-versus-host disease after allogeneic stem cell transplantation
Authors: E. Vargas-Di'ez, J. Ferna'ndez-Herrera, A. Marin, R. Ca'mara, A. Garci'a-Di'ez
Journal: British Journal of Dermatology (2003)

Although skin is typically the first site of involvement of acute graft-versus-host disease (GVHD), most standard recommended staging and grading criteria allow enrolment of patients with involvement of GVHD target organs other than the skin in studies analysing risk factors for acute GVHD after stem cell transplantation (SCT).To determine the risk factors for developing histologically confirmed acute cutaneous GVHD in patients who underwent allogeneic SCT for different haematological disorders.This retrospective study was based on review of clinical files and databases from 300 consecutive patients with several haematological disorders who received allogeneic SCT between 1 January 1984 and 31 December 1999 at Hospital Universitario de la Princesa, Madrid, Spain. Variables evaluated included diagnosis of haematological disorder, age and gender (donor and recipient), HLA matching, female donor to male recipient, donor and recipient viral serology (cytomegalovirus), conditioning regimen, GVHD prophylaxis, blood counts at day of engraftment, mortality, cause of death, and survival at 100 days, 5 years and 10 years following SCT.In multivariate analysis, risk factors for acute cutaneous GVHD were type of haematological disease (P = 0.006), HLA disparity (P = 0.006), number of transplants per patient (P = 0.017), conditioning regimen (P = 0.001), and GVHD prophylaxis (P = 0.025). Survival rates did not differ significantly for cases and controls.Risk factors for acute cutaneous GVHD were a diagnosis of chronic myeloid leukaemia, HLA disparity, receipt of more than one SCT, conditioning regimens including total body irradiation, and GVHD prophylaxis regimens other than ciclosporin plus methotrexate. Other common risk factors for acute GVHD without specific target organ involvement showed no significant association with the risk for developing acute GVHD affecting the skin as primary target organ.
The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice
Authors: Michelle L. Gumz, Lisa R. Stow, I. Jeanette Lynch, Megan M. Greenlee, Alicia Rudin, Brian D. Cain, David R. Weaver, Charles S. Wingo
Journal: Journal of Clinical Investigation (2009)

The mineralocorticoid aldosterone is a major regulator of sodium transport in target epithelia and contributes to the control of blood pressure and cardiac function. It specifically functions to increase renal absorption of sodium from tubular fluid via regulation of the alpha subunit of the epithelial sodium channel (alphaENaC). We previously used microarray technology to identify the immediate transcriptional targets of aldosterone in a mouse inner medullary collecting duct cell line and found that the transcript induced to the greatest extent was the circadian clock gene Period 1. Here, we investigated the role of Period 1 in mediating the downstream effects of aldosterone in renal cells. Aldosterone treatment stimulated expression of Period 1 (Per1) mRNA in renal collecting duct cell lines and in the rodent kidney. RNA silencing of Period 1 dramatically decreased expression of mRNA encoding alphaENaC in the presence or absence of aldosterone. Furthermore, expression of alphaENaC-encoding mRNA was attenuated in the renal medulla of mice with disruption of the Per1 gene, and these mice exhibited increased urinary sodium excretion. Renal alphaENaC-encoding mRNA was expressed in an apparent circadian pattern, and this pattern was dramatically altered in mice lacking functional Period genes. These results suggest a role for Period 1 in the regulation of the renal epithelial sodium channel and more broadly implicate the circadian clock in control of sodium balance.
Structural Determinants of Protein Evolution Are Context-Sensitive at the Residue Level
Authors: E. A. Franzosa, Y. Xia
Journal: Molecular Biology and Evolution (2009)

Structural properties of a protein residue's microenvironment have long been implicated as agents of selective constraint. Although these properties are inherently quantitative, structure-based studies of protein evolution tend to rely upon coarse distinctions between "surface" and "buried" residues and between "interfacial" and "noninterfacial" residues. Using homology-mapped yeast protein structures, we explore the relationships between residue evolution and continuous structural properties of the residue microenvironment, including solvent accessibility, density and distribution of residue–residue contacts, and burial depth. We confirm the role of solvent exposure as a major structural determinant of residue evolution and also identify a weak secondary effect arising from packing density. The relationship between solvent exposure and evolutionary rate (dN/dS) is found to be strong, positive, and linear. This reinforces the notion that residue burial is a continuous property with quantitative fitness implications. Next, we demonstrate systematic variation in residue-level structure–evolution relationships resulting from changes in global physical and biological contexts. We find that increasing protein-core size yields a more rapid relaxation of selective constraint as solvent exposure increases, although solvent-excluded residues remain similarly constrained. Finally, we analyze the selective constraint in protein–protein interfaces, revealing two fundamentally different yet separable components: continuous structural constraint that scales with total residue burial and a more surprising fixed functional constraint that accompanies any degree of interface involvement. These discoveries serve to elucidate and unite structure–evolution relationships at the residue and whole-protein levels.
The effects of vagotomy on the intestinal handling of water and electrolytes
Authors: G. A. Bunch, R. Shields
Journal: Gut (1973)

A technique of intestinal perfusion has been used to investigate the effects of vagotomy on the intestinal handling of water and electrolytes. The capacity of the vagotomized jejunum to absorb water and electrolytes was found to be unimpaired, even in patients who had severe postvagotomy diarrhoea.
Consensus meeting for the management of gastrointestinal stromal tumors Report of the GIST Consensus Conference of 20–21 March 2004, under the auspices of ESMO
Authors: J-Y Blay, S Bonvalot, P Casali, H Choi, M Debiec-Richter, A P Dei Tos, J-F Emile, A Gronchi, P C W Hogendoorn, H Joensuu, A Le Cesne, J McClure, J Mac Clure, J Maurel, N Nupponen, I Ray-Coquard, P Reichardt, R Sciot, S Stroobants, M van Glabbeke, A van Oosterom, G D Demetri
Journal: Annals of Oncology (2005)
Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer
Authors: C. Aggarwal, N.J. Meropol, C.J. Punt, N. Iannotti, B.H. Saidman, K.D. Sabbath, N.Y. Gabrail, J. Picus, M.A. Morse, E. Mitchell, M.C. Miller, S.J. Cohen
Journal: Annals of Oncology (2012)
Inhibition of WISE Preserves Renal Allograft Function
Authors: Xueming Qian, Xiaodong Yuan, Steven Vonderfecht, Xupeng Ge, Jae Lee, Anke Jurisch, Li Zhang, Andrew You, Vincent D. Fitzpatrick, Alexia Williams, Eliane G. Valente, Jim Pretorius, Jennitte L. Stevens, Barbara Tipton, Aaron G. Winters, Kevin Graham, Lindsey Harriss, Daniel M. Baker, Michael Damore, Hossein Salimi-Moosavi, Yongming Gao, Abdallah Elkhal, Chris Paszty, W. Scott Simonet, William G. Richards, Stefan G. Tullius
Journal: Journal of the American Society of Nephrology (2012)

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68+ macrophages and CD8+ T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.
STAT3-Driven Upregulation of TLR2 Promotes Gastric Tumorigenesis Independent of Tumor Inflammation
Authors: Hazel Tye, Catherine L. Kennedy, Meri Najdovska, Louise McLeod, William McCormack, Norman Hughes, Anouk Dev, William Sievert, Chia Huey Ooi, Tomo-o Ishikawa, Hiroko Oshima, Prithi S. Bhathal, Andrew E. Parker, Masanobu Oshima, Patrick Tan, Brendan J. Jenkins
Journal: Cancer Cell (2012)
Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial
Authors: Guillaume Portier, Dominique Elias, Olivier Bouche, Philippe Rougier, Jean-François Bosset, Jean Saric, Jacques Belghiti, Pascal Piedbois, Rosine Guimbaud, Bernard Nordlinger, Roland Bugat, Franck Lazorthes, Laurent Bedenne
Journal: Journal of Clinical Oncology (2006)

Complete resection of liver metastases of colorectal origin is the only potentially curative treatment. In order to decrease recurrences, the use of adjuvant systemic chemotherapy after liver resection is controversial because no randomized study demonstrated its benefit.In a multicenter trial, we randomly assigned 173 patients with completely resected (R0) hepatic metastases from colorectal cancer to surgery alone and observation (87 patients) or to surgery followed by 6 months of systemic adjuvant chemotherapy with a fluorouracil and folinic acid monthly regimen (86 patients). The main outcome criterion was disease-free survival. Secondary outcome measures were overall survival and treatment-related toxicity.The intention-to-treat analysis was based on 171 patients, after a median follow-up of 87 months (SE = 5.8). The 5-year disease-free survival rate, after adjustment for major prognostic factors, was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio for recurrence or death = 0.66; 95% CI, 0.46 to 0.96; P = .028). With regard to secondary outcome measures, a trend towards increased overall survival was observed but did not reach statistical significance (5-year overall survival: chemotherapy group, 51.1% v control group, 41.1%; odds ratio for death, 0.73; 95% CI, 0.48 to 1.10; P = .13).Despite a suboptimal regimen, which was the standard at the beginning of the study, adjuvant intravenous systemic chemotherapy provided a significant disease-free survival benefit for patients with resected liver metastases from colorectal cancer.
Multiple follicular hamartomas with sweat gland and sebaceous differentiation, vermiculate atrophoderma, milia, hypotrichosis, and late development of multiple basal cell carcinomas
Authors: Ramon M. Pujol, Cristina Nadal, Xavier Matias-Guiu, Jordi Peyrí, Carlos Ferrándiz, J Palou, José M. de Moragas
Journal: Journal of the American Academy of Dermatology (1998)
Identification of an epidermal basement membrane defect in recessive forms of dystrophic epidermolysis bullosa by LH 7:2 monoclonal antibody: use in diagnosis
Authors: A.H.M. HEAGERTY, A.R. KENNEDY, I.M. LEIGH, P. PURKIS, R.A.J. EADY
Journal: British Journal of Dermatology (1986)

LH 7:2 is a monoclonal antibody that was raised against an extract of human epidermal cells and identifies an epitope within the lamina densa of the basement membrane of stratified squamous epithelia. Using indirect immunofluorescence we found intense labelling with LH 7:2 at the epidermal basement membrane (EBM) of normal skin, and in skin samples from patients with simplex, junctional, dominantly inherited dystrophic and acquired forms of epidermolysis bullosa (EB), as well as bullous pemphigoid. Staining was absent or only very faint in generalized recessive dystrophic EB (RDEB), and patchily reduced in the localized form of RDEB. We conclude that LH 7:2 recognizes an EBM antigen which may be important in the pathogenesis of RDEB. Moreover, the antibody provides a useful probe for the rapid diagnosis of RDEB and is of special value in helping to discriminate between localized RDEB and typical dominant dystrophic EB—conditions which closely resemble each other clinically and which cannot be distinguished by means of transmission electron microscopy.
Failure to Censor Forbidden Clones of CD4 T Cells in Autoimmune Diabetes
Authors: Sylvie Lesage, Suzanne B. Hartley, Srinivas Akkaraju, Judith Wilson, Michelle Townsend, Christopher C. Goodnow
Journal: The Journal of Experimental Medicine (2002)

Type 1 diabetes and other organ-specific autoimmune diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immunoregulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet β cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance.
The Role of Overdiagnosis and Reclassification in the Marked Increase of Esophageal Adenocarcinoma Incidence
Authors: H. Pohl, H. G. Welch
Journal: JNCI Journal of the National Cancer Institute (2005)

The incidence of esophageal adenocarcinoma is rising dramatically. This increase may reflect increased disease burden, reclassification of related cancers, or overdiagnosis resulting from increased diagnostic intensity, particularly upper endoscopy for patients with gastroesophageal reflux disease or Barrett esophagus.We used the National Cancer Institute's Surveillance, Epidemiology, and End Results database to extract information on incidence, stage distribution, and disease-specific mortality for esophageal adenocarcinoma as well as information on related cancers.From 1975 to 2001, the incidence of esophageal adenocarcinoma rose approximately sixfold in the United States (from 4 to 23 cases per million), a relative increase greater than that for melanoma, breast, or prostate cancer. Reclassification of squamous cell carcinoma is an unlikely explanation for the rise in incidence, because the anatomic distribution of esophageal cancer in general has changed. The only location with increased incidence is the lower third of the esophagus-the site where adenocarcinoma typically arises. Reclassification of adjacent gastric cancer is also unlikely because its incidence has also increased. Because there has been little change in the proportion of patients found with in situ or localized disease at diagnosis since 1975 (from 25% to 31%) and because esophageal adenocarcinoma mortality has increased more than sevenfold (from 2 to 15 deaths per million), overdiagnosis can be excluded as an explanation for the rise in incidence.The rising incidence of esophageal adenocarcinoma represents a real increase in disease burden.
Proliferation of Bone Marrow-Derived Cells Contributes to Regeneration after Folic Acid-Induced Acute Tubular Injury
Authors: Te-Chao Fang, Malcolm R. Alison, Terence H. Cook, Rosemary Jeffery, Nicholas A. Wright, Richard Poulsom
Journal: Journal of the American Society of Nephrology (2005)

Studies of tissue from recipients of bone marrow transplantation or organ allograft suggest that bone marrow-derived cells (BMDC) may differentiate into a variety of nonhematologic tissues, including renal tubular epithelium. The aims of this study were to examine whether BMDC contribute to recovery after acute renal injury and to assess the effects of cytokine mobilization on regeneration. Female mice (6 wk old) were lethally irradiated and transplanted with male bone marrow (BM) cells and later assigned into control, folic acid-treatment, and folic acid-treatment with granulocyte-colony stimulating factor (G-CSF), and control with G-CSF. Tritiated thymidine was given 1 h before death. Kidney sections were stained for a tubular epithelial marker, Y chromosome (in situ hybridization), periodic acid-Schiff staining, and subjected to autoradiography. Renal tubular epithelial cells in S-phase were scored as female (indigenous) or male (BM-derived). This is the first report to show that BMDC can respond by engrafting the renal tubules and undergo DNA synthesis after acute renal injury. BMDC contributed to the renal tubular epithelial cell population, although most (90%) renal tubular regeneration came from female indigenous cells. Some evidence was found for cell fusion between indigenous renal tubular cells and BMDC, but this was infrequent and the significance and consequences of cell fusion in the kidney are unresolved. G-CSF treatment nearly doubled the frequency of thymidine-labeled BM-derived tubular cells and might facilitate the recovery of renal tubular epithelium.
Mitochondrial Energetics and Therapeutics
Authors: Douglas C. Wallace, Weiwei Fan, Vincent Procaccio
Journal: Annual Review of Pathology Mechanisms of Disease (2010)

Mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and aging. All these clinical manifestations arise from the central role of bioenergetics in cell biology. Although genetic therapies are maturing as the rules of bioenergetic genetics are clarified, metabolic therapies have been ineffectual. This failure results from our limited appreciation of the role of bioenergetics as the interface between the environment and the cell. A systems approach, which, ironically, was first successfully applied over 80 years ago with the introduction of the ketogenic diet, is required. Analysis of the many ways that a shift from carbohydrate glycolytic metabolism to fatty acid and ketone oxidative metabolism may modulate metabolism, signal transduction pathways, and the epigenome gives us an appreciation of the ketogenic diet and the potential for bioenergetic therapeutics.
Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting
Authors: D. Clark Files, Chun Liu, Andrea Pereyra, Zhong-Min Wang, Neil R. Aggarwal, Franco R. D’Alessio, Brian T. Garibaldi, Jason R. Mock, Benjamin D. Singer, Xin Feng, Raghunatha R. Yammani, Tan Zhang, Amy L. Lee, Sydney Philpott, Stephanie Lussier, Lina Purcell, Jeff Chou, Michael Seeds, Landon S. King, Peter E. Morris, Osvaldo Delbono
Journal: Science Translational Medicine (2015)

Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)-mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans.