tbuckley/cabot-search huggingface dataset:
Epithelioma Primarily Affecting the Tonsil
Authors: J. W. Downie
Journal: BMJ (1890)

disappeared, and the boy could count fingers with right eye.J. B. continued steadily to improve, iodid. of potassium having been substituted for the salicin, the optic disc cleared although it re- mained white.When I lastsawthepatient, on Mlay 4th, hecould read 0. 6 of Snellen with the right eye; he was then returning to schiool.The following case seems to demonstrate the importance of prompt treatment in instances of rheumatic papillitis.Miss ---, a robust young woman, who had enjoyed excellent health; she belonged to a rheumatic family; her father, in particular, had suffered much from rheumatism.The patient was seized with persistent pain in the muscles of her neck and left arm, which lasted for some three weeks, and was stated to be of a rheumatic character by her medical attendant.Miss had hardly re- covered from this attack when, about the middle of December, she experienced great pain in her right eye; there was much photo- phobia, and the pain was increased by pressure on, or any move- ment of, the globe of the eye.Notwithstanding these symptoms and great impairment of vision, the patient for ten or twelve days remamined under the treatment of a chemist, who prescribed a lotion.No improvement having taken place, Miss then consulted her medical attendant (on January lst), and he at once pro- nounced the disease from which she was suffering to be neuro- retinitis; he sent the patient on to me.On January 3rd I found that Miss -could hardly distinguish light from darkness with the right eye; the optic papilla was much swollen (about 3 D), and its outlines were completely obscured; the retinal veins were
Threshold Methotrexate Concentration for In Vivo Inhibition of DNA Synthesis in Normal and Tumorous Target Tissues
Authors: Bruce A. Chabner, Robert C. Young
Journal: Journal of Clinical Investigation (1973)

The suppression of DNA synthesis in host and tumor tissues by methotrexate has been monitored in mice by determining the in vivo incorporation of tritium-labeled deoxyuridine ([3H]UdR) into DNA. The duration of inhibition of [3H]UdR incorporation in normal tissues was related to the dose of methotrexate and was a direct function of plasma drug concentration. [3H]UdR incorporation recovered to 50% of pretreatment levels in bone marrow when plasma methotrexate concentration was 10-8 M or less, irrespective of the dose administered, while 50% recovery of DNA synthesis in intestinal epithelium was not observed until plasma methotrexate levels were 5 × 10-9 M or less. Ascitic L1210 leukemia cells did not fully return to pretreatment levels of [3H]UdR incorporation at any time, although a partial recovery of incorporation was noted at methotrexate ascitic fluid concentrations of approximately 10-8 M.
GROWTH HORMONE AS THERAPY FOR OLDER MEN AND WOMEN
Authors: Robert Marcus, Andrew R. Hoffman
Journal: The Annual Review of Pharmacology and Toxicology (1998)

▪ Abstract Progressive deficits in the growth hormone (GH)/insulin-like growth factor I axis may contribute to the acquired biochemical, body composition, and functional changes of normal human aging, but they do not offer a sole, or even a major explanation for these changes. The concept that GH “replacement” would materially benefit the daily function of older men and women finds little support in the results of the controlled clinical trials that have been reported. GH, either as monotherapy or in combination with antiresorptive medication, does not offer a clinically useful improvement in bone mass, and it is difficult to find a rationale for its use in the treatment of osteoporosis. GH may yet prove to be a useful agent for older men and women in the management of other clinical syndromes, such as visceral obesity, but conclusions in this area await compelling evidence. For the time being, potential benefits of GH in older men and women must be viewed with skepticism, and use of this agent outside the context of a clinical trial is not justified.
Myocardial liposome uptake in the early stages of myocardial infarction
Authors: A. W G COLE, R. O KINGABY, M. J LAB, T N. PALMER
Journal: Cardiovascular Research (1982)

Multiply-labelled neutral or positively-charged liposomes were given iv to open-chested dogs or pigs 0.5 h or 5 h after coronary artery occlusion. Myocardial blood flow was measured by labelled microspheres. Animals were killed 3.5 h or 6 h after coronary artery occlusion and the myocardial distribution of liposomal labels was correlated with that of the microspheres. No evidence was found that liposomes are taken up preferentially by ischaemic myocardium. The results suggest that liposomes have limited potential as a means of drug delivery in myocardial infarction.
Lysine Demethylase KDM4A Associates with Translation Machinery and Regulates Protein Synthesis
Authors: Capucine Van Rechem, Joshua C. Black, Myriam Boukhali, Martin J. Aryee, Susanne Gräslund, Wilhelm Haas, Cyril H. Benes, Johnathan R. Whetstine
Journal: Cancer Discovery (2015)

Chromatin-modifying enzymes are predominantly nuclear; however, these factors are also localized to the cytoplasm, and very little is known about their role in this compartment. In this report, we reveal a non-chromatin-linked role for the lysine-specific demethylase KDM4A. We demonstrate that KDM4A interacts with the translation initiation complex and affects the distribution of translation initiation factors within polysome fractions. Furthermore, KDM4A depletion reduced protein synthesis and enhanced the protein synthesis suppression observed with mTOR inhibitors, which paralleled an increased sensitivity to these drugs. Finally, we demonstrate that JIB-04, a JmjC demethylase inhibitor, suppresses translation initiation and enhances mTOR inhibitor sensitivity. These data highlight an unexpected cytoplasmic role for KDM4A in regulating protein synthesis and suggest novel potential therapeutic applications for this class of enzyme.
The significance of the gut barrier in disease
Authors: J. Meddings
Journal: Gut (2007)

In the paper by Wapenaar et al ( see page 10.1136/gut.2007.133132 ) the authors have taken a fascinating approach to identifying shared mechanisms involved in the genesis of either coeliac disease or inflammatory bowel disease (IBD).1 They argue that in these two prototypical inflammatory diseases of the intestinal mucosa there exists reasonable evidence for a defect in barrier function that appears to be required before the development of disease. Furthermore, as both diseases have strong genetic components they speculated that these syndromes might share common genetic defects in the control of intestinal barrier function. They used a genetic association analysis approach and through this identified two adapter protein coding genes that were associated with coeliac disease in patients from both Great Britain and The Netherlands. They went on to demonstrate that one of these genes was also associated with ulcerative colitis in a Dutch patient cohort.

These observations are important not only for the conclusions reached in the paper but also in the broader context. Until recently, it was believed that IBD, such as Crohn’s disease, represented dysregulation of the adaptive immune system. Over the past decade, however, there has been increasing recognition of the importance of both epithelial barrier function and innate immunity in the genesis of intestinal inflammation. In the broadest sense these two factors could be argued to be different aspects of the same basic system. Within the gastrointestinal tract there is significant exposure to foreign compounds that can drive systemic inflammation through a variety of mechanisms. The gut has a tremendous number of defence mechanisms that have evolved to manage this ever-changing threat (fig 1). In general terms these include the ability to manage commensal flora in preference to pathogenic organisms, the secretion of toxic molecules such as defensins, the scavenging and binding of luminal organisms by …
Randomized Phase II Study of Erlotinib in Combination With Placebo or R1507, a Monoclonal Antibody to Insulin-Like Growth Factor-1 Receptor, for Advanced-Stage Non–Small-Cell Lung Cancer
Authors: Suresh S. Ramalingam, David R. Spigel, David Chen, Martin B. Steins, Jeffrey A. Engelman, Claus-Peter Schneider, Silvia Novello, Wilfried E.E. Eberhardt, Lucio Crino, Kai Habben, Lian Liu, Pasi A. Jänne, Carrie M. Brownstein, Martin Reck
Journal: Journal of Clinical Oncology (2011)

R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study.
Assessing Progress in Retinopathy Outcomes in Type 1 Diabetes
Authors: Tamara J. LeCaire, Mari Palta, Ronald Klein, Barbara E.K. Klein, Karen J. Cruickshanks
Journal: Diabetes Care (2012)

The Wisconsin Diabetes Registry Study (WDRS) cohort consisted of patients diagnosed with type 1 diabetes in the same geographic region as, but 8-34 years later than the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) cohort, providing a unique opportunity to assess changes in complications. We estimated the current prevalence and severity of diabetic retinopathy at 20 years of diabetes duration, compared these between eras, and evaluated the influence of diabetes management.Twenty-year examinations, including fundus photographs, were completed on 305 WDRS subjects during 2007-2011. A subgroup of the WESDR cohort participated in one of four study visits during 1980-1996, at similar diabetes duration (n = 583). Adjusted ordinal logistic regression with three retinopathy severity categories was used to estimate odds ratios (ORs) of more severe retinopathy with diagnosis during an earlier era.Mean hemoglobin A(1c) (HbA(1c)) was lower in WDRS than in WESDR (8.0% vs. 9.3% [P < 0.001], and 93.4% vs. 21.3% [P < 0.001]) used ≥3 daily insulin injections or an insulin pump. In WDRS, 18% had vision-threatening levels of retinopathy vs. 43% in WESDR. The adjusted OR of more severe retinopathy in the earlier era (OR 3.0 [95% CI 2.2-4.0]) was reduced by including 20-year HbA(1c) in the model (OR 2.2 [1.6-3.0]).Retinopathy severity at a diabetes duration of 20 years is lower in the more recent era of type 1 diabetes. Updated projections should be used when informing newly diagnosed individuals of prognosis and for health care cost assessments. Current glycemic control explained a limited amount of the difference.
A calcified caecal mass
Authors: A Hokama
Journal: Gut (2004)

The advent of recombinant peptide technology offers the potential to use one or several peptides to treat a variety of gastrointestinal conditions.However, although cell culture and animal models have shown proof of concept, we are still at a relatively early stage in translating their use to standard clinical practice.Similarly, peptide and nonpeptide antagonists of growth factor receptors show great potential as novel antichemotherapy agents.However, their actual place in clinical practice has yet to be established.. . . . .
Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas
Authors: Jane Houldsworth, Adam B. Olshen, Giorgio Cattoretti, Gerard B. Donnelly, Julie Teruya-Feldstein, Jing Qin, Nallasivam Palanisamy, Yingjing Shen, Katerina Dyomina, Marina Petlakh, Qiulu Pan, Andrew D. Zelenetz, Riccardo Dalla-Favera, R. S. K. Chaganti
Journal: Blood (2003)
The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?
Authors: Julien Ablain, Rihab Nasr, Ali Bazarbachi, Hugues de Thé
Journal: Cancer Discovery (2011)

Abstract Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs. Summary: Some cancer therapies may degrade oncoproteins. Loss of the driver oncoprotein is associated with loss of cancer cell self-renewal. Leukemia- or sarcoma-associated fusion proteins are the best candidates for small-molecule screens aimed at initiating oncoprotein degradation. Cancer Discovery; 1(2). 117–27. ©2011 AACR.
Randomized Phase III Multi-Institutional Study of TNFerade Biologic With Fluorouracil and Radiotherapy for Locally Advanced Pancreatic Cancer: Final Results
Authors: Joseph M. Herman, Aaron T. Wild, Hao Wang, Phuoc T. Tran, Kenneth J. Chang, Gretchen E. Taylor, Ross C. Donehower, Timothy M. Pawlik, Mark A. Ziegler, Hongyan Cai, Dionne T. Savage, Marcia I. Canto, Jason Klapman, Tony Reid, Raj J. Shah, Sarah E. Hoffe, Alexander Rosemurgy, Christopher L. Wolfgang, Daniel A. Laheru
Journal: Journal of Clinical Oncology (2013)

TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy.In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity.The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05).SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.
Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm?
Authors: A R L Medford
Journal: Thorax (2006)

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), remains a devastating condition with a high mortality. It is characterised by alveolar injury and increased pulmonary vascular permeability. Vascular endothelial cell growth factor (VEGF) was identified by its properties to increase permeability and act as a cellular growth factor, hence its potential for a key role in the pathogenesis of ALI/ARDS. This review describes the basic biology of VEGF and its receptors as an essential prerequisite to discussing the available and sometimes paradoxical published data, before considering a paradigm for the role of VEGF in the human lung.
Hormone Replacement Therapy, Insulin Sensitivity, and Abdominal Obesity in Postmenopausal Women
Authors: Alice S. Ryan, Barbara J. Nicklas, Dora M. Berman
Journal: Diabetes Care (2002)

OBJECTIVE—The purpose of this study was to determine whether insulin sensitivity differs between postmenopausal women taking estradiol, women on estrogen plus progesterone hormone replacement therapy (HRT), and women not on HRT and whether differences are explained by the differences in total and/or abdominal adiposity and fat deposition in the muscle. RESEARCH DESIGN AND METHODS—We studied 28 obese, sedentary postmenopausal Caucasian women. Women taking oral estrogen (n = 6) were matched for age (57 ± 3 vs. 58 ± 2 years), weight (87.9 ± 6.0 vs. 83.0 ± 3.9 kg), and BMI (33.9 ± 1.7 vs. 33.9 ± 1.9 kg/m2) with women not on HRT (n = 6). Eight women taking oral estrogen plus progesterone were matched with eight different women not on HRT for age (59 ± 2 vs. 60 ± 2 years), weight (82.8 ± 3.7 vs. 83.7 ± 4.1 kg), and BMI (30.7 ± 1.0 vs. 29.9 ± 1.3 kg/m2). RESULTS—Vo2max (maximal aerobic capacity), percentage of fat, total body fat mass, and fat-free mass (FFM) were similar between groups. Visceral fat, subcutaneous abdominal fat, sagittal diameter, and mid-thigh low-density lean tissue (intramuscular fat) did not differ by hormone status. Basal carbohydrate and fat utilization was not different among groups. Fasting plasma glucose and insulin did not differ by hormone use. Glucose utilization (M) was measured during the last 30 min of a 3-h hyperinsulinemic-euglycemic clamp (40 mU · m2 · min−1). Postmenopausal women taking oral estrogen had a 31% lower M than women not on HRT (42.7 ± 4.0 vs. 61.7 ± 4.7 μmol · kgFFM · min−1, P &amp;lt; 0.05). M was 26% lower in women taking estrogen plus progesterone (44.0 ± 3.5 vs. 59.7 ± 6.2 μmol · kgFFM · min−1, P &amp;lt; 0.05) than women not on HRT. M/I, the amount of glucose metabolized per unit of plasma insulin (I), an index of insulin sensitivity, was 36% lower in women taking estrogen compared with matched women not on HRT (P &amp;lt; 0.05) and 28% lower in women taking estrogen plus progesterone compared with matched women not on HRT (P &amp;lt; 0.05). CONCLUSIONS—Postmenopausal women taking oral estrogen or those taking a combination of estrogen and HRT are more insulin-resistant than women not on HRT, even when women are of comparable total and abdominal adiposity.
Granuloma annulare induced by anti-tumour necrosis factor therapy
Authors: P V Voulgari, T E Markatseli, S A Exarchou, A Zioga, A A Drosos
Journal: Annals of the Rheumatic Diseases (2007)

Objective: To describe granuloma annulare (GA) skin lesion development in patients during anti-tumour necrosis factor (TNF) therapy. Methods: 199 patients with rheumatoid arthritis and 127 suffering from spondyloarthropathies treated with anti-TNF antagonists were analysed to identify skin lesions suggesting GA. Results: Nine cases of GA during anti-TNF therapy (123 treated with infliximab, 57 with adalimumab and 17 with etanercept) for rheumatoid arthritis were identified. Two have been treated with infliximab, six with adalimumab and one with etanercept, and here the development of GA was 4.5%. No patient with spondyloarthropathies developed such skin lesions. All patients developed the generalised form of GA. None had or developed diseases, or conditions known to be associated with GA. In seven patients the skin eruptions developed during the first year of anti-TNF treatment, while they developed in two patients during the second year. Two patients had to stop anti-TNF therapy due to the extent of skin lesions. All patients responded well to the local corticosteroid therapy. Conclusions: Our series strongly supports a link between TNF inhibition and the development of GA in some patients. When dealing with patients on these agents physicians should be aware of possible adverse events and the potential development of such complications.
A nonpolymorphic major histocompatibility complex class Ib molecule binds a large array of diverse self-peptides.
Authors: S Joyce, P Tabaczewski, R H Angeletti, S G Nathenson, I Stroynowski
Journal: The Journal of Experimental Medicine (1994)

Unlike the highly polymorphic major histocompatibility complex (MHC) class Ia molecules, which present a wide variety of peptides to T cells, it is generally assumed that the nonpolymorphic MHC class Ib molecules may have evolved to function as highly specialized receptors for the presentation of structurally unique peptides. However, a thorough biochemical analysis of one class Ib molecule, the soluble isoform of Qa-2 antigen (H-2SQ7b), has revealed that it binds a diverse array of structurally similar peptides derived from intracellular proteins in much the same manner as the classical antigen-presenting molecules. Specifically, we find that SQ7b molecules are heterodimers of heavy and light chains complexed with nonameric peptides in a 1:1:1 ratio. These peptides contain a conserved hydrophobic residue at the COOH terminus and a combination of one or more conserved residue(s) at P7 (histidine), P2 (glutamine/leucine), and/or P3 (leucine/asparagine) as anchors for binding SQ7b. 2 of 18 sequenced peptides matched cytosolic proteins (cofilin and L19 ribosomal protein), suggesting an intracellular source of the SQ7b ligands. Minimal estimates of the peptide repertoire revealed that at least 200 different naturally processed self-peptides can bind SQ7b molecules. Since Qa-2 molecules associate with a diverse array of peptides, we suggest that they function as effective presenting molecules of endogenously synthesized proteins like the class Ia molecules.
Serial minimal residual disease (MRD) analysis as a predictor of response duration in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) during imatinib treatment
Authors: U J Scheuring, H Pfeifer, B Wassmann, P Brück, B Gehrke, E K Petershofen, H Gschaidmeier, D Hoelzer, O G Ottmann
Journal: Leukemia (2003)
Relationship between specific adverse events and efficacy of exemestane therapy in early postmenopausal breast cancer patients
Authors: D.B.Y. Fontein, D. Houtsma, E.T.M. Hille, C. Seynaeve, H. Putter, E. Meershoek-Klein Kranenbarg, H.J. Guchelaar, H. Gelderblom, L.Y. Dirix, R. Paridaens, J.M.S. Bartlett, J.W.R. Nortier, C.J.H. van de Velde
Journal: Annals of Oncology (2012)