tbuckley/cabot-search huggingface dataset:
S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial)
Authors: M. Yoshida, M. Ishiguro, K. Ikejiri, I. Mochizuki, Y. Nakamoto, Y. Kinugasa, A. Takagane, T. Endo, H. Shinozaki, Y. Takii, H. Mochizuki, K. Kotake, S. Kameoka, K. Takahashi, T. Watanabe, M. Watanabe, N. Boku, N. Tomita, E. Nakatani, K. Sugihara
Journal: Annals of Oncology (2014)

BackgroundS-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur–uracil plus leucovorin (UFT/LV).Patients and methodsPatients aged 20–80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80–120 mg/day on days 1–28 every 42 days; four courses) or UFT/LV (UFT: 300–600 mg/day and LV: 75 mg/day on days 1–28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years.ResultsA total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70–1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups.ConclusionAdjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer.ClinicalTrials.govNCT00660894.
Measurements of Serum Free Cortisol in Critically Ill Patients
Authors: Amir H. Hamrahian, Tawakalitu S. Oseni, Baha M. Arafah
Journal: New England Journal of Medicine (2004)

Because more than 90 percent of circulating cortisol in human serum is protein-bound, changes in the binding proteins can alter measured serum total cortisol concentrations without influencing free concentrations of this hormone. We investigated the effect of decreased amounts of cortisol-binding proteins on serum total and free cortisol concentrations during critical illness, when glucocorticoid secretion is maximally stimulated.Base-line serum total cortisol, cosyntropin-stimulated serum total cortisol, aldosterone, and free cortisol concentrations were measured in 66 critically ill patients and 33 healthy volunteers in groups that were similar with regard to sex and age. Of the 66 patients, 36 had hypoproteinemia (albumin concentration, 2.5 g per deciliter or less), and 30 had near-normal serum albumin concentrations (above 2.5 g per deciliter).Base-line and cosyntropin-stimulated serum total cortisol concentrations were lower in the patients with hypoproteinemia than in those with near-normal serum albumin concentrations (P<0.001). However, the mean (+/-SD) base-line serum free cortisol concentrations were similar in the two groups of patients (5.1+/-4.1 and 5.2+/-3.5 microg per deciliter [140.7+/-113.1 and 143.5+/-96.6 nmol per liter]) and were several times higher than the values in controls (0.6+/-0.3 microg per deciliter [16.6+/-8.3 nmol per liter], P<0.001 for both comparisons). Cosyntropin-stimulated serum total cortisol concentrations were subnormal (18.5 microg per deciliter [510.4 nmol per liter] or less) in 14 of the patients, all of whom had hypoproteinemia. In all 66 patients, including these 14 who had hypoproteinemia, the base-line and cosyntropin-stimulated serum free cortisol concentrations were high-normal or elevated.During critical illness, glucocorticoid secretion markedly increases, but the increase is not discernible when only the serum total cortisol concentration is measured. In this study, nearly 40 percent of critically ill patients with hypoproteinemia had subnormal serum total cortisol concentrations, even though their adrenal function was normal. Measuring serum free cortisol concentrations in critically ill patients with hypoproteinemia may help prevent the unnecessary use of glucocorticoid therapy.
Small but significant excess mortality compared with the general population for long-term survivors of breast cancer in the Netherlands
Authors: M.L.G. Janssen-Heijnen, L.N. van Steenbergen, A.C. Voogd, V.C.G. Tjan-Heijnen, P.H. Nijhuis, P.M. Poortmans, J.W.W. Coebergh, D.J. van Spronsen
Journal: Annals of Oncology (2013)
Republished research: Non-steroidal anti-inflammatory drugs (NSAIDs)
Authors: Richard O Day, Garry G Graham
Journal: British Journal of Sports Medicine (2013)

A 70 year old obese woman asks if more can be done for her knee and low back pain, due to osteoarthritis. She used to smoke and has type 2 diabetes. Her orthopaedic surgeon does not consider the clinical presentation and radiographic changes in her knees severe enough for surgery. Her height is 160 cm, weight 85 kg, blood pressure 130/80 mm Hg, with normal renal function, plasma cholesterol concentration 5.5 mmol/L, and HDL cholesterol concentration 0.9 mmol/L. Her present drug treatment is paracetamol (4 g daily) and metformin.

NSAIDs act by inhibiting cyclo-oxygenase-1 (COX-1) and COX-2 enzymes, which are involved in prostaglandin synthesis, resulting in their analgesic, anti-inflammatory, and antipyretic effects (figure 1). Although the boundary is blurred, there are two broad groups of NSAIDs—the older, traditional, non-selective NSAIDs that inhibit both COX-1 and COX-2 and the newer, selective COX-2 inhibitors that predominantly inhibit COX-2 (figure 1). The non-selective NSAID aspirin is used primarily for its antiplatelet effect, thus reducing the risk of myocardial re-infarction and stroke.



Figure 1 
Arachidonic acid is metabolised by the cyclo-oxygenase isoenzymes COX-1 and COX-2 to intermediate prostaglandins (PGG2, then PGH2), which are then converted to other prostaglandins that are mediators of pain, inflammation, and fever, and are gastroprotective. Thromboxane A2 causes platelet aggregation, and prostacyclin produces vasodilation. By blocking COX enzymes, NSAIDs inhibit the synthesis and thus the effects of prostaglandins, prostacyclin, and thromboxane A2. The clinical effects of NSAIDs depend largely on their selectivity for these enzymes. Aspirin works by irreversibly inhibiting COX-1 mediated synthesis of thromboxane A2, and is used to inhibit platelet aggregation.



Table 1 shows the indications and effectiveness of the various NSAIDs. There is little difference in their mean efficacy, although a review of individual patient data indicates that patients vary in their responses to different NSAIDs.7 Effectiveness …
TLR-4 Signaling Promotes Tumor Growth and Paclitaxel Chemoresistance in Ovarian Cancer
Authors: Michael G. Kelly, Ayesha B. Alvero, Rui Chen, Dan-Arin Silasi, Vikki M. Abrahams, Serena Chan, Irene Visintin, Thomas Rutherford, Gil Mor
Journal: Cancer Research (2006)

Abstract Evidence suggests that an inflammatory profile of cytokines and chemokines persisting at a particular site would lead to the development of a chronic disease. Recent studies implicate bacterial infection as one possible link between inflammation and carcinogenesis; however, the crucial molecular pathways involved remain unknown. We hypothesized that one possible upstream signaling pathway leading to inflammation in carcinogenesis may be mediated by Toll-like receptors (TLR). We describe for the first time an adaptive mechanism acquired by ovarian cancer cells that allows them to promote a proinflammatory environment and develop chemoresistance. We propose that the TLR-4-MyD88 signaling pathway may be a risk factor for developing cancer and may represent a novel target for the development of biomodulators. Our work explains how bacterial products, such as lipopolysaccharide, can promote, directly from the tumor, the production of proinflammatory cytokines and the enhancement of tumor survival. In addition, we provide new evidence that links TLR-4 signaling, inflammation, and chemoresistance in ovarian cancer cells. (Cancer Res 2006; 66(7): 3859-68)
Human papillomavirus type 58 in Bowen's disease of the elbow
Authors: T. Mitsuishi, M. Kawashima, T. Matsukura, T. Sata
Journal: British Journal of Dermatology (2001)

Human papillomavirus (HPV) can be detected in skin lesions of Bowen's disease, particularly on the fingers, and its genotype is associated with mucosal/genital types of HPV. We report herein an 85-year-old woman who had HPV-associated Bowen's disease on her elbow. HPV-58 DNA was detected in the lesion by polymerase chain reaction with restriction fragment length polymorphism and by Southern blot hybridization. In situ hybridization revealed numerous hybrid cells in the nuclei of the upper epidermis and stratum corneum of Bowen's disease. A high-risk type of mucosal HPV-58 DNA is associated with Bowen's disease in this case, suggesting that HPV-related Bowen's disease is not always restricted to genital or finger lesions.
Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals.
Authors: D Maurer, E Fiebiger, B Reininger, B Wolff-Winiski, M H Jouvin, O Kilgus, J P Kinet, G Stingl
Journal: The Journal of Experimental Medicine (1994)

Suggestive evidence indicates that immunoglobulin E (IgE)-dependent activation of mononuclear phagocytes plays an important pathogenic role in allergic tissue inflammation. Prevailing opinion holds that low affinity IgE receptors are the relevant IgE-binding structures on monocytes/macrophages and that functional events occurring after cross-linking of membrane-bound IgE on these cells are mediated by these receptors. Here we demonstrate that peripheral blood monocytes can bind monomeric IgE via the high affinity IgE receptor (Fc epsilon RI) and that Fc epsilon RI expression on these cells is upregulated in atopic persons. Further, we demonstrate that, upon monocyte adherence to substrate, bridging of monocyte Fc epsilon RI is followed by cell activation. We propose that direct interaction of multivalent allergen with Fc epsilon RI(+)-bound IgE on mononuclear phagocytes results in cell signaling via Fc epsilon RI and that the biological consequences of this event may critically influence the outcome of allergic reactions.
Rituximab in bronchiolitis obliterans after haematopoietic stem cell transplantation
Authors: G. Lorillon, M. Robin, V. Meignin, P. Ribaud, B. Lescoeur, D. Gossot, G. Socié, A. Tazi, A. Bergeron
Journal: European Respiratory Journal (2011)

Rituximab in bronchiolitis obliterans after haematopoietic stem cell transplantationTo the Editors:Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) is recognised as a pulmonary manifestation of chronic graft-versus-host disease (GVHD) [1,2].As lung biopsy is rarely performed in these patients, the diagnosis of BO syndrome (BOS) usually relies on pulmonary function testing (PFT) and computed tomography (CT) lung scans [1,2].Very little retrospective data exist regarding the treatment of BOS, which currently consists of increasing a patient's baseline dose of systemic immunosuppressive therapy; however, this treatment strategy has been shown to have poor efficacy [2,3].The efficacy of new drugs for the treatment of chronic GVHD, including the anti-CD20 monoclonal antibody rituximab, must be specifically evaluated for BOS.Here, we report three cases in which patients received rituximab for BO after allogeneic HSCT.
Gli3 Regulation of Myogenesis Is Necessary for Ischemia-Induced Angiogenesis
Authors: Marie-Ange Renault, Soizic Vandierdonck, Candice Chapouly, Yang Yu, Gangjian Qin, Alexandre Metras, Thierry Couffinhal, Douglas W. Losordo, Qinyu Yao, Annabel Reynaud, Béatrice Jaspard-Vinassa, Isabelle Belloc, Claude Desgranges, Alain-Pierre Gadeau
Journal: Circulation Research (2013)

A better understanding of the mechanism underlying skeletal muscle repair is required to develop therapies that promote tissue regeneration in adults. Hedgehog signaling has been shown previously to be involved in myogenesis and angiogenesis: 2 crucial processes for muscle development and regeneration.The objective of this study was to identify the role of the hedgehog transcription factor Gli3 in the cross-talk between angiogenesis and myogenesis in adults.Using conditional knockout mice, we found that Gli3 deficiency in endothelial cells did not affect ischemic muscle repair, whereas in myocytes, Gli3 deficiency resulted in severely delayed ischemia-induced myogenesis. Moreover, angiogenesis was also significantly impaired in HSA-Cre(ERT2); Gli3(Flox/Flox) mice, demonstrating that impaired myogenesis indirectly affects ischemia-induced angiogenesis. The role of Gli3 in myocytes was then further investigated. We found that Gli3 promotes myoblast differentiation through myogenic factor 5 regulation. In addition, we found that Gli3 regulates several proangiogenic factors, including thymidine phosphorylase and angiopoietin-1 both in vitro and in vivo, which indirectly promote endothelial cell proliferation and arteriole formation. In addition, we found that Gli3 is upregulated in proliferating myoblasts by the cell cycle-associated transcription factor E2F1.This study shows for the first time that Gli3-regulated postnatal myogenesis is necessary for muscle repair-associated angiogenesis. Most importantly, it implies that myogenesis drives angiogenesis in the setting of skeletal muscle repair and identifies Gli3 as a potential target for regenerative medicine.
Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor
Authors: Anna M Nicholson, Trevor A Graham, Ashley Simpson, Adam Humphries, Nicola Burch, Manuel Rodriguez-Justo, Marco Novelli, Rebecca Harrison, Nicholas A Wright, Stuart A C McDonald, Janusz A Jankowski
Journal: Gut (2011)

<h3>Background</h3> Little is known about the stem cell organisation of the normal oesophagus or Barrett9s metaplastic oesophagus. Using non-pathogenic mitochondrial DNA mutations as clonal markers, the authors reveal the stem cell organisation of the human squamous oesophagus and of Barrett9s metaplasia and determine the mechanism of clonal expansion of mutations. <h3>Methods</h3> Mutated cells were identified using enzyme histochemistry to detect activity of cytochrome <i>c</i> oxidase (CCO). CCO-deficient cells were laser-captured and mutations confirmed by PCR sequencing. Cell lineages were identified using immunohistochemistry. <h3>Results</h3> The normal squamous oesophagus contained CCO-deficient patches varying in size from around 30 μm up to about 1 mm. These patches were clonal as each area within a CCO-deficient patch contained an identical mitochondrial DNA mutation. In Barrett9s metaplasia partially CCO-deficient glands indicate that glands are maintained by multiple stem cells. Wholly mutated Barrett9s metaplasia glands containing all the expected differentiated cell lineages were seen, demonstrating multilineage differentiation from a clonal population of Barrett9s metaplasia stem cells. Patches of clonally mutated Barrett9s metaplasia glands were observed, indicating glands can divide to form patches. In one patient, both the regenerating squamous epithelium and the underlying glandular tissue shared a clonal mutation, indicating that they are derived from a common progenitor cell. <h3>Conclusion</h3> In normal oesophageal squamous epithelium, a single stem cell clone can populate large areas of epithelium. Barrett9s metaplasia glands are clonal units, contain multiple multipotential stem cells and most likely divide by fission. Furthermore, a single cell of origin can give rise to both squamous and glandular epithelium suggesting oesophageal plasticity.
Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification
Authors: Kozo Morita, Takeshi Miyamoto, Nobuyuki Fujita, Yoshiaki Kubota, Keisuke Ito, Keiyo Takubo, Kana Miyamoto, Ken Ninomiya, Toru Suzuki, Ryotaro Iwasaki, Mitsuru Yagi, Hironari Takaishi, Yoshiaki Toyama, Toshio Suda
Journal: The Journal of Experimental Medicine (2007)

Chondrocyte hypertrophy during endochondral ossification is a well-controlled process in which proliferating chondrocytes stop proliferating and differentiate into hypertrophic chondrocytes, which then undergo apoptosis. Chondrocyte hypertrophy induces angiogenesis and mineralization. This step is crucial for the longitudinal growth and development of long bones, but what triggers the process is unknown. Reactive oxygen species (ROS) have been implicated in cellular damage; however, the physiological role of ROS in chondrogenesis is not well characterized. We demonstrate that increasing ROS levels induce chondrocyte hypertrophy. Elevated ROS levels are detected in hypertrophic chondrocytes. In vivo and in vitro treatment with N-acetyl cysteine, which enhances endogenous antioxidant levels and protects cells from oxidative stress, inhibits chondrocyte hypertrophy. In ataxia telangiectasia mutated (Atm)–deficient (Atm−/−) mice, ROS levels were elevated in chondrocytes of growth plates, accompanied by a proliferation defect and stimulation of chondrocyte hypertrophy. Decreased proliferation and excessive hypertrophy in Atm−/− mice were also rescued by antioxidant treatment. These findings indicate that ROS levels regulate inhibition of proliferation and modulate initiation of the hypertrophic changes in chondrocytes.
Capillary Filtration Coefficient in the Extremities of Man in High Environmental Temperatures
Authors: CHESTER HYMAN, W. H. WONG
Journal: Circulation Research (1968)

The capillary filtration coefficient was measured in human extremities by a simplified technique using the capacitance plethysmograph. The method was validated in terms of consistency of values obtained on the same individual at various times, the correspondence between values obtained on a group of normal persons, and the agreement between values reported here and those of earlier workers made under corresponding environmental conditions and duration of measurement after venous occlusion. The technique was used to evaluate the change in capillary filtration coefficient in the calves of subjects when ambient temperature was increased from 20° to 35°C. Corresponding measurements of total blood flow in this segment and determinations of the clearance of iodide ion from pretibial intradermal depots were made in both environments. Cutaneous blood flow increased by almost 170% and the capillary filtration coefficient by about 40%, whereas the clearance did not change. It is concluded that neither the capillary filtration coefficient nor the clearance of isotopes from tissue depots has been established as a valid measure of capillary surface area. The possibility that during venous occlusion, fluid accumulated primarily in the subcutaneous tissues of the extremity is suggested and discussed.
Dermal elastosis in hairless mice after UV-B and UV-A applied simultaneously, separately or sequentially
Authors: J.T. POULSEN, B. STABERG, H.C. WULF, H. BRODTHAGEN
Journal: British Journal of Dermatology (2006)

The elastosis-inducing capacity of UV-A and UV-B was studied in the skin of hairless mice. After irradiation with UV-B and UV-A applied either simultaneously, separately or sequentially, the degree of elastosis in the dermis was microscopically evaluated. This semi-quantitative method showed no significant elastosis in the UV-A irradiated mice, and moderate elastosis in the UV-B irradiated mice. Heavy elastosis was observed when the mice were exposed sequentially to UV-B and a large dose of UV-A, but if a moderate dose of UV-A was given simultaneously with UV-B, the degree of elastosis was slightly reduced compared with the elastosis induced by UV-B alone.
Evidence of epistasis between interleukin 1 and selenoprotein-S with susceptibility to rheumatoid arthritis
Authors: I Marinou, K Walters, M C Dickson, M H Binks, D E Bax, A G Wilson
Journal: Annals of the Rheumatic Diseases (2008)

Objective: Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1β and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF. Methods: Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel–Haenszel (M–H) test and the linkage disequilibrium (LD)-based statistic. Results: No association of SELS −105 genotype and RA susceptibility was detected. Stratification of SELS −105 genotypes by IL1 −511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS −105 locus) in individuals with the GG/AG genotype at the IL1β −511 locus was significantly lower than that in individuals having the AA genotype at the IL1β −511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M–H test). Significant epistasis was also detected using the LD-based statistic (p = &lt;0.001). No interaction was observed between SELS −105 and IL6 or TNF variants. Conclusion: Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene–gene interactions in the pathogenesis of RA.
A case of steroid responsive pulmonary hyalinising granuloma: complicated by deep venous thrombosis
Authors: K.M.A. O'Reilly, J.A. Boscia, K.L. Kaplan, P.J. Sime
Journal: European Respiratory Journal (2004)

A case of pulmonary hyalinising granuloma (PHG) complicated by deep venous thrombosis (DVT) is presented. The DVT was associated with the presence of a lupus anticoagulant. In the past PHG has been linked to various auto-antibodies, but to the best of the authors' knowledge, this is the first case reporting PHG in association with a lupus anticoagulant and clinically significant venous thrombosis. Historically, PHG has been regarded as poorly corticosteroid responsive. However, the patient in this case study responded dramatically to prednisone. This case study suggests that in selected patients with pulmonary hyalinising granuloma experiencing disabling symptoms and worsening pulmonary function, a trial of corticosteroids may be warranted.
Pneumothorax and malignant mesothelioma in patients over the age of 40.
Authors: J D Sheard, W Taylor, A Soorae, M G Pearson
Journal: Thorax (1991)

Five patients over the age of 40 with malignant mesothelioma of the pleura presented with a spontaneous pneumothorax in the course of five years. The diagnosis of malignant mesothelioma was not suspected at surgery but was made by histological examination of the pleurectomy specimens. During this time 91 pleurectomies for recurrent pneumothorax were performed, 45 in patients over the age of 40; malignant mesothelioma therefore accounted for 11% of spontaneous pneumothorax requiring pleurectomy in this age group. The association of spontaneous pneumothorax and malignant mesothelioma is not emphasised in current publications. These five cases highlight the need for all pleurectomy specimens in cases of spontaneous pneumothorax to be sent for histological examination and for a full occupational history to be taken, especially in older patients.